ESR1 gene fusions and uses thereof

Abstract

Provided herein are ESR1 fusion nucleic acid molecules and polypeptides, methods related to detecting ESR1 fusion nucleic acid molecules and polypeptides in cancer, as well as methods of treatment and uses related thereto. Detection of an ESR1 fusion nucleic acid molecule or polypeptide can be used to identify individuals that may benefit from treatment with an anti-cancer therapy other than a SERM or an aromatase inhibitor.

Description

ESRI GENE FUSIONS AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the priority benefit of U.S. Provisional Application No. 63 / 606,010, filed on December 4, 2023, the contents of which are incorporated herein by reference in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (197102017240seqlist.xml; Size: 9,649 bytes; and Date of Creation: November 25, 2024) are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0003] Provided herein are estrogen receptor 1 (ESRE) fusion nucleic acid molecules and polypeptides, methods related to detecting such ESRI fusion nucleic acid molecules and polypeptides, as well as methods of diagnosis / treatment and uses related thereto.BACKGROUND

[0004] Endocrine therapy (ET) has been highly successful in targeted treatment for cancers such as estrogen receptor-positive (ER+) breast cancer, including selective ER modulators or degraders that inhibit estradiol-ER binding and aromatase inhibitors that reduce estradiol production. However, ESRI mutations (ESR 1 mut) are an established biomarker of ET resistance in patients (pts) with hormone receptor positive (HR+) MBC. Moreover, ES' / ? / mut acquired in response to standard-of-care ET now confer access to novel ET recently approved by health authorities. ESRI mutations and fusions have been described in breast cancer and associated with resistance to ET (see, e.g., Hartmaier, R.J. et al. (2018) Ann Oncol.29(4):872-880; Nagy, Z. and Jeselsohn, R. (2023) Front Oncol. 12:1037531; and Jeselsohn, R .et al. (2014) Clin Cancer Res. 20(7): 1757-1767). Although ESRI gene fusions have been observed less frequently than ESRI point mutations, they are thought to be enriched in ET- resistant cancers (Nagy, Z. and Jeselsohn, R. (2023) Front Oncol. 12:1037531).

[0005] Thus, there is a need in the art for characterizing the cancer landscape of ESRI fusions, and for developing methods, compositions, and assays for evaluating and treating patients with such fusions.

[0006] All references cited herein, including patents, patent applications and publications, are hereby incorporated by reference in their entirety. To the extent that any reference incorporated by reference conflicts with the instant disclosure, the instant disclosure shall control.SUMMARY OF THE INVENTION

[0007] In some aspects, provided herein is a method of selecting a therapy for an individual having breast cancer or for identifying an individual having breast cancer who may benefit from a treatment comprising an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor, the method comprising detecting in a sample from the individual an estrogen receptor 1 (ESRI) fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; wherein detection of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample identifies the individual as one who may benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor.

[0008] In some aspects, provided herein is a method of identifying one or more treatment options for an individual having breast cancer, the method comprising detecting or acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP9I, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and generating a report comprising one or more treatment options identified for the individual based, at least in part, on detection or on acquiring knowledge of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample, wherein the one or more treatment options comprise an anti-cancer agent other than a SERM or an aromatase inhibitor.

[0009] In some aspects, provided herein is a method of selecting a treatment for an individual having breast cancer, comprising acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule,in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOCI00422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; wherein responsive to the acquisition of said knowledge: (i) the individual is classified as a candidate to receive a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor; and / or (ii) the individual is identified as likely to respond to a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

[0010] In some aspects, provided herein is a method of predicting survival of an individual having breast cancer, or an individual having breast cancer treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, the method comprising acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP9I, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof; wherein responsive to the acquisition of said knowledge, the individual is predicted to have longer survival when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor.

[0011] In some aspects, provided herein is a method of treating or delaying progression of breast cancer, comprising acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from an individual having breast cancer, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and responsive to said knowledge, administering to the individual an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

[0012] In some aspects, provided herein is a method of treating or delaying progression of breast cancer, comprising administering to an individual having breast cancer an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor, wherein the anti-cancer agent is administered responsive to acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encodedby the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof.

[0013] In some aspects, provided herein is a method of treating or delaying progression of breast cancer, comprising detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from an individual having breast cancer, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof; and administering to the individual an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

[0014] In some aspects, provided herein is a method of monitoring, evaluating or screening an individual having breast cancer, comprising acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; wherein responsive to the acquisition of said knowledge, the individual is predicted to benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor and / or to have longer survival when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, as compared to an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor.

[0015] In some aspects, provided herein is a method of assessing an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide, in breast cancer in an individual, the method comprising detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and providing an assessment of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample.

[0016] In some aspects, provided herein is a method of detecting an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide in breast cancer, the method comprising detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from an individual having breast cancer, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP9I, ZBTB2. IYD, IMPG1, STAG2. TNRC6B. or C6orfl5, or a portion thereof.

[0017] In some aspects, provided herein is a method of detecting the presence or absence of breast cancer in an individual, the method comprising detecting the presence or absence of breast cancer in a sample from the individual; and detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOCI 00422737, SNAP9I, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof. In some embodiments, the method further comprises detecting the presence of breast cancer in a sample from the individual; and / or detecting the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual.

[0018] In some aspects, provided herein is a method of monitoring progression or recurrence of breast cancer in an individual, the method comprising detecting, in a first sample obtained from the individual at a first time point, the presence or absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; detecting, in a second sample obtained from the individual at a second time point after the first time point, the presence or absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; and providing an assessment of breast cancer progression or breast cancer recurrence in the individual based, at least in part, on the presence or absence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the first sample and / or in the second sample; wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof. In some embodiments, the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the first sample and / or in the second sample identifies the individualas having decreased risk of breast cancer progression or breast cancer recurrence when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, the method further comprises selecting a treatment, administering a treatment, adjusting a treatment, adjusting a dose of a treatment, or applying a treatment to the individual based, at least in part, on detecting the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the first sample and / or in the second sample, wherein the treatment comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

[0019] In some aspects, provided herein is a method of monitoring resistance to endocrine therapy in an individual with breast cancer, the method comprising detecting, in a sample obtained from the individual during or after treatment with an endocrine therapy, an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; and providing an assessment of resistance to endocrine therapy in the individual based, at least in part, on the detection of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample; wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2. TNRC6B. or C6orfl5, or a portion thereof. In some embodiments, the method further comprises after providing the assessment of resistance to endocrine therapy, administering to the individual an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor; wherein optionally the method further comprises halting administration of an endocrine therapy to the individual based, at least in part, on the detection of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample.

[0020] In some aspects, provided herein is a method of monitoring sensitivity to endocrine therapy in an individual with breast cancer, the method comprising detecting, in a sample obtained from the individual before, during, or after treatment with an endocrine therapy, absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; and providing an assessment of sensitivity to endocrine therapy in the individual based, at least in part, on the detection of the absence of an ESRI fusion nucleic acid molecule, or ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample; wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genesCCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPGI, STAG2, TNRC6B, or C6orfl5, or a portion thereof. In some embodiments, the method further comprises after providing the assessment of sensitivity to endocrine therapy, administering to the individual an effective amount of an endocrine therapy.

[0021] In some embodiments according to any of the embodiments described herein, the method further comprises, prior to the detection or acquisition of knowledge, administering to the individual an effective amount of an endocrine therapy. In some embodiments, the individual has previously been treated with an endocrine therapy. In some embodiments, the endocrine therapy comprises treatment with a SERM or an aromatase inhibitor.

[0022] In some aspects, provided herein is a method of detecting an ESRI fusion nucleic acid molecule, the method comprising providing a plurality of nucleic acid molecules obtained from a sample from an individual having breast cancer, wherein the plurality of nucleic acid molecules comprises nucleic acid molecules corresponding to an ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOCI 00422737, SNAP9I, ZBTB2, IYD, IMPGI, STAG2, TNRC6B, or C6orfl5, or a portion thereof; optionally, ligating one or more adapters onto one or more nucleic acid molecules from the plurality of nucleic acid molecules; optionally, amplifying the one or more ligated nucleic acid molecules from the plurality of nucleic acid molecules; optionally, capturing amplified nucleic acid molecules from the amplified nucleic acid molecules; sequencing, by a sequencer, the captured nucleic acid molecules to obtain a plurality of sequence reads that represent the captured nucleic acid molecules, wherein one or more of the plurality of sequence reads correspond to the ESRI fusion nucleic acid molecule; analyzing the plurality of sequence reads for the presence or absence of the ESRI fusion nucleic acid molecule; and based on the analyzing step, detecting the presence or absence of the ESRI fusion nucleic acid molecule in the sample. In some embodiments, the sequencer comprises a nextgeneration sequencer.

[0023] In some aspects, provided herein is a method of detecting an ESRI fusion nucleic acid molecule, the method comprising providing a sample from an individual having breast cancer, wherein the sample comprises a plurality of nucleic acid molecules; preparing a nucleic acid sequencing library from the plurality of nucleic acid molecules in the sample; amplifying said library; selectively enriching for one or more nucleic acid molecules comprising nucleotide sequences corresponding to an ESRI fusion nucleic acid molecule in said library to produce an enriched sample, wherein the an ESRI fusion nucleic acid moleculecomprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; sequencing the enriched sample, thereby producing a plurality of sequence reads; analyzing the plurality of sequence reads for the presence or absence of the ESRI fusion nucleic acid molecule; and detecting, based on the analyzing step, the presence or absence of the ESRI fusion nucleic acid molecule in the sample from the individual.

[0024] In some embodiments according to any of the embodiments described herein, the one or more adapters comprise amplification primers, flow cell adapter sequences, substrate adapter sequences, sample index sequences, or unique molecular identifier (UMI) sequences. In some embodiments, the selectively enriching comprises: (a) combining one or more bait molecules with the library, thereby hybridizing the one or more bait molecules to one or more nucleic acid molecules comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule, and producing nucleic acid hybrids; and (b) isolating the nucleic acid hybrids to produce the enriched sample. In some embodiments, the amplified nucleic acid molecules are captured by hybridization with one or more bait molecules. In some embodiments, the amplifying comprises performing a polymerase chain reaction (PCR) amplification technique, a non-PCR amplification technique, or an isothermal amplification technique.

[0025] In some embodiments according to any of the embodiments described herein, the methods further comprise selectively enriching for one or more nucleic acid molecules in the sample comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule; wherein the selectively enriching produces an enriched sample. In some embodiments, the selectively enriching comprises: (a) combining one or more bait molecules with the sample, thereby hybridizing the one or more bait molecules to one or more nucleic acid molecules in the sample comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule and producing nucleic acid hybrids; and (b) isolating the nucleic acid hybrids to produce the enriched sample. In some embodiments, the one or more bait molecules comprise a capture nucleic acid molecule configured to hybridize to a nucleotide sequence corresponding to the ESRI fusion nucleic acid molecule. In some embodiments, the capture nucleic acid molecule comprises between about 10 and about 30 nucleotides, between about 50 and about 1000 nucleotides, between about 100 and about 500 nucleotides, between about 100 and about 300 nucleotides, or between about 100 and about 200 nucleotides. In some embodiments, the one or more bait molecules are conjugated to anaffinity reagent or to a detection reagent. In some embodiments, the affinity reagent is an antibody, an antibody fragment, or biotin, or wherein the detection reagent is a fluorescent marker. In some embodiments, the capture nucleic acid molecule comprises a DNA, RNA, or mixed DNA / RNA molecule. In some embodiments, the selectively enriching comprises amplifying the one or more nucleic acid molecules comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule using a polymerase chain reaction (PCR) to produce an enriched sample. In some embodiments, the methods further comprise sequencing the enriched sample. In some embodiments, the plurality of nucleic acid molecules comprises a mixture of cancer nucleic acid molecules and non-cancer nucleic acid molecules. In some embodiments, the cancer nucleic acid molecules are derived from a tumor portion of a heterogeneous tissue biopsy sample, and the non-cancer nucleic acid molecules are derived from a normal portion of the heterogeneous tissue biopsy sample. In some embodiments, the sample comprises a liquid biopsy sample, and wherein the cancer nucleic acid molecules are derived from a circulating tumor DNA (ctDNA) fraction of the liquid biopsy sample, and the non-cancer nucleic acid molecules are derived from a nontumor fraction of the liquid biopsy sample. In some embodiments, the ctDNA fraction of the liquid biopsy sample comprises at least 1% of nucleic acid molecules in the liquid biopsy sample. In some embodiments, the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; optionally wherein the sequencing comprises a massively parallel sequencing technique, and the massively parallel sequencing technique comprises next- generation sequencing (NGS).

[0026] In some aspects, provided herein is a method of identifying a candidate treatment for breast cancer in an individual in need thereof, comprising: performing DNA sequencing on a sample obtained from the individual to determine a sequencing mutation profile, wherein the sequencing mutation profile identifies presence of an ESRI fusion nucleic acid molecule in the sample, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; wherein the treatment comprises an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, the presence of the ESRI fusion nucleic acid molecule in the sample identifies the individual as one who may benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor; and / or predicts the individual to have longer survival when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule when treated with a treatment comprising a SERM or an aromatase inhibitor. In some embodiments, the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; optionally wherein the sequencing comprises a massively parallel sequencing technique, and the massively parallel sequencing technique comprises next generation sequencing (NGS). In some embodiments, the sequencing mutation profile identifies a fragment of the ESRI fusion nucleic acid molecule comprising a breakpoint or fusion junction.

[0027] In some embodiments according to any of the embodiments described herein, the methods further comprise generating a report, wherein the report: (a) indicates the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample from the individual; and / or (b) indicates a treatment or one or more treatment options identified or selected for the individual based, at least in part, on the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample from the individual, wherein the treatment or the one or more treatment options comprise an anticancer agent other than a SERM or an aromatase inhibitor. In some embodiments, the methods further comprise generating a molecular profile for the individual, based, at least in part, on detecting or acquiring knowledge of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample from the individual. In some embodiments, the molecular profile for the individual further comprises results from a comprehensive genomic profiling (CGP) test, a gene expression profiling test, a cancer hotspot panel test, a DNA methylation test, a DNA fragmentation test, an RNA fragmentation test, or any combination thereof. In some embodiments, the molecular profile for the individual further comprises results from a nucleic acid sequencingbased test. In some embodiments, the methods further comprise selecting a treatment, administering a treatment, or applying a treatment to the individual based on the generated molecular profile, wherein the treatment comprises an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, the methods further comprise generating a report, wherein the report comprises the molecular profile for the individual. In some embodiments, the report further comprises information on a treatment or one or more treatment options identified or selected for the individual based, at least in part, on themolecular profile for the individual, wherein the treatment or one or more treatment options comprise an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, the methods further comprise providing the report to the individual, a caregiver, a healthcare provider, a physician, an oncologist, an electronic medical record system, a hospital, a clinic, a third-party payer, an insurance company, or a government office.

[0028] In some embodiments according to any of the embodiments described herein, the individual is a human. In some embodiments, the methods further comprise obtaining the sample from the individual. In some embodiments, the sample is obtained or derived from the breast cancer. In some embodiments, the sample comprises a tissue biopsy sample, a liquid biopsy sample, or a normal control. In some embodiments, the sample is from a tumor biopsy, tumor specimen, or circulating tumor cell. In some embodiments, the sample is a liquid biopsy sample comprising blood, plasma, cerebrospinal fluid, sputum, stool, urine, or saliva. In some embodiments, the sample comprises cells and / or nucleic acids from the breast cancer. In some embodiments, the sample comprises mRNA, DNA, circulating tumor DNA (ctDNA), cell-free DNA, or cell-free RNA from the breast cancer. In some embodiments, the sample is a liquid biopsy sample comprising circulating tumor cells (CTCs). In some embodiments, the sample is a liquid biopsy sample comprising cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), or any combination thereof. In some embodiments, the acquiring knowledge of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, comprises detecting the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample. In some embodiments, detecting the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample comprises detecting a fragment of the ESRI fusion nucleic acid molecule, or of the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, comprising a breakpoint or fusion junction. In some embodiments, the ESRI fusion nucleic acid molecule is detected in the sample by one or more of: a nucleic acid hybridization assay, an amplification-based assay, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, real-time PCR, a screening analysis, fluorescence in situ hybridization (FISH), spectral karyotyping, multicolor FISH (mFISH), comparative genomic hybridization, in situ hybridization, sequence-specific priming (SSP) PCR, high-performance liquid chromatography (HPEC), mass-spectrometric genotyping, or sequencing. In some embodiments, the sequencing comprises a massively parallelsequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; optionally wherein the massively parallel sequencing (MPS) technique comprises next-generation sequencing (NGS). In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule is detected in the sample by one or more of: immunoblotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry, or mass spectrometry. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule is oncogenic; optionally wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof.

[0029] In some embodiments according to any of the embodiments described herein, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule confers resistance to an endocrine therapy. In some embodiments, the anti-cancer agent comprises one or more of a small molecule inhibitor, an antibody, a cellular therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a PROteolysis-TArgeting Chimera (PROTAC), a treatment for cancer comprising an ESRI gene fusion or rearrangement, an anti-cancer agent being tested in a clinical trial, a treatment for cancer comprising an ESRI gene fusion or rearrangement being tested in a clinical trial, or any combination thereof. In some embodiments, the anticancer agent comprises a selective estrogen receptor covalent antagonist (SERCA). In some embodiments, the anti-cancer agent is H3B-5942 or H3B-6545. In some embodiments, the anti-cancer agent comprises a selective estrogen receptor degrader (SERD). In some embodiments, the anti-cancer agent is fulvestrant, elacestrant, amcenestrant, camizestrant, giredestrant, rintodestrant, imlunestrant, ZB-716, Zn-c5, LSZ102, LY3484356, or D-0502, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-cancer agent comprises a PROTAC. In some embodiments, the PROTAC is ARV-471. In some embodiments, the anti-cancer agent comprises a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, abemaciclib, ribociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-cancer agent comprises treatment with a SERD and a CDK4 / 6 inhibitor. In some embodiments, the anti-cancer agent comprises a PI3K inhibitor. In some embodiments, the PI3K inhibitor is GSK2636771, buparlisib, AZD8186, copanlisib, LY294002, PX-866, TGX115, TGX126, BEZ235, SF1126, idelalisib, pictilisib, GDC0032, IPI145, INK1117, SAR260301, KIN-193, duvelisib, GS-9820, GSK2636771, GDC-0980, AMG319, paxalisib, or alpelisib, or a pharmaceutically acceptable salt thereof.In some embodiments, the anti-cancer agent comprises an mTOR inhibitor. In some embodiments, the mTOR inhibitor is temsirolimus, everolimus, ridaforolimus, dactolisib, GSK2126458, XL765, AZD8055, AZD2014, MLN128, PP242, NVP-BEZ235, LY3023414, PQR309, PKI587, or OSI027, or a pharmaceutically acceptable salt thereof. In some embodiments, the nucleic acid inhibits the expression of an ESRI nucleic acid molecule, or an ESRI polypeptide encoded by the ESRI nucleic acid molecule. In some embodiments, the nucleic acid is a double-stranded RNA (dsRNA), a small interfering RNA (siRNA), or a small hairpin RNA (shRNA). In some embodiments, the cellular therapy is an adoptive therapy, a T cell-based therapy, a natural killer (NK) cell-based therapy, a chimeric antigen receptor (CAR)-T cell therapy, a recombinant T cell receptor (TCR) T cell therapy, a macrophage-based therapy, an induced pluripotent stem cell-based therapy, a B cell-based therapy, or a dendritic cell (DC)-based therapy. In some embodiments, the treatment or the one or more treatment options further comprise an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy comprises one or more of a small molecule inhibitor, a chemotherapeutic agent, a cancer immunotherapy, an antibody, a cellular therapy, a nucleic acid, a surgery, a radiotherapy, an anti- angiogenic therapy, an anti-DNA repair therapy, an anti-inflammatory therapy, an anti-neoplastic agent, a growth inhibitory agent, a cytotoxic agent, a vaccine, a small molecule agonist, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a PROteolysis-TArgeting Chimera (PROTAC), or any combination thereof. In some embodiments, the anti-cancer agent comprises a SERD, and the additional anti-cancer therapy comprises a CDK4 / 6 inhibitor.

[0030] In some embodiments according to any of the embodiments described herein, the SERM is tamoxifen, raloxifene, EM652, GW7604, keoxifene, toremifene, bazedoxifene, broparestrol, clomifene, cyclofenil, lasofoxifene, ormeloxifene, or ospemifene. In some embodiments, the aromatase inhibitor is aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxy androstenedione, 1,4,6- androstatrien-3, 17-dione (ATD), 4- Androstene-3, 6, 17-trione (“6-OXO”), or a pharmaceutically acceptable salt thereof. In some embodiments, an endocrine therapy comprises a SERM or an aromatase inhibitor.

[0031] In some embodiments according to any of the embodiments described herein, the breast cancer is advanced or metastatic. In some embodiments, the breast cancer is hormone receptor positive (HR+) breast cancer. In some embodiments, the cancer is endometrial cancer.

[0032] In some embodiments according to any of the embodiments described herein, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, encoding an ESRI DNA binding domain, or a portion thereof, to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI DNA binding domain, or a portion thereof, fused to a polypeptide encoded by any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a CCDC170 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a CCDC170 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the CCDC170 gene, or a portion thereof, fused to exon 2 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the CCDC170 gene, or a portion thereof, fused to exons 1-2 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a CCDC170 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a CCDC170 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a SMAD4 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a SMAD4 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SMAD4 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SMAD4 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a SMAD4 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a SMAD4 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a EOC 100422737 gene, or a portion thereof, and wherein the ESRI fusion nucleic acidmolecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a EOC100422737 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the EOC100422737 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the EOC100422737 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a EOC 100422737 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a EOC100422737 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a SNAP91 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a SNAP91 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SNAP91 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SNAP91 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a SNAP91 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a SNAP91 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a ZBTB2 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a ZBTB2 gene, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a ZBTB2 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a ZBTB2 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to an IYD gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to an IYD gene, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by theESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to an IYD polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to an IYD polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to an IMPG1 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to an IMPG1 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the IMPG1 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the IMPG1 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to an IMPG1 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to an IMPG1 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a STAG2 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a STAG2 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the STAG2 gene, or a portion thereof, fused to exon 5 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the STAG2 gene, or a portion thereof, fused to exons 1-5 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a STAG2 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a STAG2 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a TNRC6B gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a TNRC6B gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the TNRC6B gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the TNRC6B gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, theESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a TNRC6B polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C- terminus direction, an ESRI polypeptide, or a portion thereof, fused to a TNRC6B polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a C6orfl5 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a C6orfl5 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the C6orfl5 gene, or a portion thereof, fused to exon 5 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the C6orfl5 gene, or a portion thereof, fused to exons 1-5 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a C6orfl5 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a C6orfl5 polypeptide, or a portion thereof.

[0033] In some aspects, provided herein is a system for detecting an ESRI fusion nucleic acid molecule, e.g., according to any one of the embodiments disclosed herein. In some embodiments, the system comprises a memory configured to store one or more program instructions; and one or more processors configured to execute the one or more program instructions, the one or more program instructions when executed by the one or more processors are configured to perform the method according to any one of the embodiments disclosed herein. In some embodiments, the system comprises a memory configured to store one or more program instructions; and one or more processors configured to execute the one or more program instructions, the one or more program instructions when executed by the one or more processors are configured to obtain a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from an individual having breast cancer; analyze the plurality of sequence reads for presence of an ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and detect, based on the analyzing, the ESRI fusion nucleic acid molecule in the sample.

[0034] In some embodiments, the one or more program instructions when executed by the one or more processors are further configured to generate, based at least in part on the detecting, a genomic profile for the sample.

[0035] In some aspects, provided herein is a non-transitory computer readable storage medium comprising one or more programs executable by one or more computer processors for detecting an ESRI fusion nucleic acid molecule, e.g., according to any one of the embodiments disclosed herein. In some embodiments, the method comprises obtaining, using the one or more processors, a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from an individual having breast cancer; analyzing, using the one or more processors, the plurality of sequence reads for presence of an ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and detecting, using the one or more processors and based on the analyzing, the ESRI fusion nucleic acid molecule in the sample.

[0036] In some embodiments, the method further comprises generating, using the one or more processors, a genomic profile for the sample.

[0037] In some embodiments according to any of the embodiments described herein, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule confers resistance to an endocrine therapy. In some embodiments, the plurality of sequence reads is obtained by sequencing; optionally wherein the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; and optionally wherein the massively parallel sequencing technique comprises next generation sequencing (NGS). In some embodiments, the individual is administered a treatment based at least in part on the genomic profile; optionally wherein the treatment comprises an anticancer agent other than a SERM or an aromatase inhibitor. In some embodiments, the genomic profile further comprises results from a comprehensive genomic profiling (CGP) test, a gene expression profiling test, a cancer hotspot panel test, a DNA methylation test, a DNA fragmentation test, an RNA fragmentation test, or any combination thereof. In some embodiments, the genomic profile further comprises results from a nucleic acid sequencingbased test.

[0038] In some embodiments according to any of the embodiments described herein, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, encoding an ESRI DNA binding domain, or a portion thereof, to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI DNA binding domain, or a portion thereof, fused to a polypeptide encoded by any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a CCDC170 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a CCDC170 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the CCDC170 gene, or a portion thereof, fused to exon 2 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the CCDC170 gene, or a portion thereof, fused to exons 1-2 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a CCDC170 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a CCDC170 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a SMAD4 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a SMAD4 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SMAD4 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SMAD4 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a SMAD4 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a SMAD4 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a EOC 100422737 gene, or a portion thereof, and wherein the ESRI fusion nucleic acidmolecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a EOC100422737 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the EOC100422737 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the EOC100422737 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a EOC 100422737 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a EOC100422737 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a SNAP91 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a SNAP91 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SNAP91 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SNAP91 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a SNAP91 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a SNAP91 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a ZBTB2 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a ZBTB2 gene, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a ZBTB2 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a ZBTB2 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to an IYD gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to an IYD gene, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by theESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to an IYD polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to an IYD polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to an IMPG1 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to an IMPG1 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the IMPG1 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the IMPG1 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to an IMPG1 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to an IMPG1 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a STAG2 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a STAG2 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the STAG2 gene, or a portion thereof, fused to exon 5 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the STAG2 gene, or a portion thereof, fused to exons 1-5 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a STAG2 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a STAG2 polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a TNRC6B gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a TNRC6B gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the TNRC6B gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the TNRC6B gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, theESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a TNRC6B polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C- terminus direction, an ESRI polypeptide, or a portion thereof, fused to a TNRC6B polypeptide, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a C6orfl5 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a C6orfl5 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the C6orfl5 gene, or a portion thereof, fused to exon 5 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the C6orfl5 gene, or a portion thereof, fused to exons 1-5 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a C6orfl5 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a C6orfl5 polypeptide, or a portion thereof.

[0039] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art. These and other embodiments of the invention are further described by the detailed description that follows.BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIGS. 1 & 2 show the ESRI mutational landscape observed in liquid and tissue biopsies from patients with metastatic breast cancer (MBC). Shown are ESRI fusions (arrow) detected in liquid and tissue biopsies (as indicated) relative to other ESRI mutations (FIG. 1) or relative to rare ESRI mutations (FIG. 2). Graphs show raw count (n) observed for each mutation or fusion, as indicated.

[0041] FIG. 3A shows variant allele frequency of ESRI fusions (x) in liquid biopsies with highly polyclonal ESRI resistance. Shown are percent tumor fraction and variant allele frequency for 77 liquid biopsies with 4 or more ESRI mutations or fusions. Data for ESRI fusions are circled.

[0042] FIG. 3B shows fusion junctions of ESRI fusions observed in tissue or liquid biopsies.

[0043] FIG. 4 shows ESRI co-occurring mutations in liquid biopsies. ESRI fusions indicated with arrows.

[0044] FIG. 5 shows ESRI co-occurring mutations in tissue biopsies. ESRI fusions indicated with arrows.

[0045] FIG. 6 depicts an exemplary device, in accordance with some embodiments.

[0046] FIG. 7 depicts an exemplary system, in accordance with some embodiments.

[0047] FIG. 8 depicts a block diagram of an exemplary process for detecting an ESRI fusion nucleic acid molecule of the present disclosure, in accordance with some embodiments.DETAILED DESCRIPTION

[0048] The present disclosure relates generally to detecting ESRI gene fusions in cancer, as well as methods of treatment, and uses related thereto. The present disclosure describes the results of comprehensive genomic profiling (CGP) of tissue and liquid biopsies from patients with metastatic breast cancer (MBC), which identified 28 fusions of the ESRI DNA binding domain to 13 unique gene partners. Without wishing to be bound by theory, it is thought that the presence of an ESRI gene fusion (e.g., as described herein) from an individual with breast cancer may identify patients who are more likely to respond to an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor (to which an ESRI gene fusion may confer resistance).I. General Techniques

[0049] The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Eaboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I.Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Celland Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).II. Definitions

[0050] As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[0051] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

[0052] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.

[0053] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers.

[0054] The term “tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” and “tumor” are not mutually exclusive as referred to herein.

[0055] As used herein, the term "ESRl" refers to a gene encoding an estrogen receptor 1 polypeptide. The human ESRI gene is located on chromosome 6q25.1-q25.2. ESRI is alsoknown as ER, ESR, Era, ESRA, ESTRR, and NR3AL In some embodiments, an ESRI gene is a human ESRI gene. An exemplary ESRI amino acid sequence is provided below. In some embodiments, references to a specific ESRI mutation by amino acid position refer to amino acid numbering according to SEQ ID NO:1. In some embodiments, the DNA-binding domain of ESRI is made up of amino acids 180-261 according to SEQ ID NO:1.MTMTLHTKASGMALLHQIQGNELEPLNRPQLKIPLERPLGEVYLDSSKPAVYNYPEGAAYEF NAAAAANA QVYGQTGLPYGPGSEAAAFGSNGLGGFPPLNSVSPSPLMLLHPPPQLSPFLQPHGQQVPYYL ENEPSGYTVREAGPPAFYRPNSDNRRQGGRERLASTNDKGSMAMESAKETRYCAVCNDYASGYHYGVWSC EGCKAFFK RSIQGHNDYMCPATNQCTIDKNRRKSCQACRLRKCYEVGMMKGGIRKDRRGGRMLKHKRQRD DGEGRGEV GSAGDMRAANLWPSPLMIKRSKKNSLALSLTADQMVSALLDAEPPILYSEYDPTRPFSEASM MGLLTNLADRELVHMINWAKRVPGFVDLTLHDQVHLLECAWLEILMIGLVWRSMEHPGKLLFAPNLLLDR NQGKCVEG MVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYTFLSSTLKSLEEKDHIHRVLDKI TDTLIHLMAKAGLTLQQQHQRLAQLLLILSHIRHMSNKGMEHLYSMKCKNWPLYDLLLEMLDAHRLHAP TSRGGASVEETDQSHLATAGSTSSHSLQKYYITGEAEGFPATV ( SEQ ID NO : 1 )

[0056] “Polynucleotide,” “nucleic acid,” or “nucleic acid molecule” as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase, or by a synthetic reaction. Thus, for instance, polynucleotides as defined herein include, without limitation, single- and double- stranded DNA, DNA including single- and double- stranded regions, single- and double- stranded RNA, and RNA including single- and double- stranded regions, hybrid molecules comprising DNA and RNA that may be single- stranded or, more typically, double-stranded or include single- and double- stranded regions. In addition, the term “polynucleotide” as used herein refers to triple- stranded regions comprising RNA or DNA or both RNA and DNA. The strands in such regions may be from the same molecule or from different molecules. The regions may include all of one or more of the molecules, but more typically involve only a region of some of the molecules. One of the molecules of a triple-helical region often is an oligonucleotide. The term “polynucleotide” specifically includes cDNAs.

[0057] A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by nonnucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include, for example, “caps,” substitution of one or more of the naturally-occurring nucleotides with an analog, intemucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, and the like) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, and the like), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, and the like), those with intercalators (e.g., acridine, psoralen, and the like), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, and the like), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid or semi-solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2'-0-methyl-, 2'-0-allyl-, 2'-fluoro-, or 2'- azido-ribose, carbocyclic sugar analogs, a-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(0)S ("thioate"), P(S)S ("dithioate"), "(0)NR2("amidate"), P(0)R, P(0)OR', CO orCH2("formacetal"), in which each R or R' is independently H or substituted or unsubstituted alkyl (1 -20 C) optionally containing an ether (-0-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. A polynucleotide can contain one or more different types of modifications as described herein and / or multiple modifications of the same type. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

[0058] “Oligonucleotide,” as used herein, generally refers to short, single stranded, polynucleotides that are, but not necessarily, less than about 250 nucleotides in length. Oligonucleotides may be synthetic. The terms “oligonucleotide” and “polynucleotide” are not mutually exclusive. The description above for polynucleotides is equally and fully applicable to oligonucleotides.

[0059] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

[0060] “Antibody fragments” comprise a portion of an intact antibody comprising the antigen-binding region thereof. In some embodiments, the antibody fragment described herein is an antigen-binding fragment. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0061] The term “detection” includes any means of detecting, including direct and indirect detection. The term “biomarker” as used herein refers to an indicator, e.g., predictive, diagnostic, and / or prognostic, which can be detected in a sample. The biomarker may serve as an indicator of a particular subtype of a disease or disorder (e.g., cancer) characterized by certain, molecular, pathological, histological, and / or clinical features (e.g., responsiveness to therapy including an immunotherapy, such as a checkpoint inhibitor). In some embodiments, a biomarker is a collection of genes and / or a collective number of mutations / alterations (e.g., somatic mutations) in a collection of genes, for example, a biomarker may comprise an ESRI gene fusion, fusion nucleic acid molecule, or fusion polypeptide. Biomarkers include, but are not limited to, polynucleotides (e.g., DNA and / or RNA), polynucleotide alterations (e.g., polynucleotide copy number alterations, e.g., DNA copy number alterations), polypeptides, polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrates, and / or glycolipid-based molecular markers.

[0062] “Amplification,” as used herein generally refers to the process of producing multiple copies of a desired sequence. “Multiple copies” mean at least two copies. A “copy” does not necessarily mean perfect sequence complementarity or identity to the template sequence. For example, copies can include nucleotide analogs such as deoxyinosine, intentional sequence alterations (such as sequence alterations introduced through a primer comprising a sequence that is hybridizable, but not complementary, to the template), and / or sequence errors that occur during amplification. 1

[0063] The technique of “polymerase chain reaction” or “PCR” as used herein generally refers to a procedure wherein minute amounts of a specific piece of nucleic acid, RNA and / or DNA, are amplified as described, for example, in U.S. Pat. No. 4,683,195. Generally, sequence information from the ends of the region of interest or beyond needs to be available, such that oligonucleotide primers can be designed; these primers will be identical or similar in sequence to opposite strands of the template to be amplified. The 5' terminal nucleotides of the two primers may coincide with the ends of the amplified material. PCR can be used to amplify specific RNA sequences, specific DNA sequences from total genomic DNA, and cDNA transcribed from total cellular RNA, bacteriophage, or plasmid sequences, etc. See generally Mullis et al., Cold Spring Harbor Symp. Quant. Biol. 51:263 (1987) and Erlich, ed., PCR Technology (Stockton Press, NY, 1989). As used herein, PCR is considered to be one, but not the only, example of a nucleic acid polymerase reaction method for amplifying a nucleic acid test sample, comprising the use of a known nucleic acid (DNA or RNA) as a primer and utilizes a nucleic acid polymerase to amplify or generate a specific piece of nucleic acid or to amplify or generate a specific piece of nucleic acid which is complementary to a particular nucleic acid.

[0064] The term “diagnosis” is used herein to refer to the identification or classification of a molecular or pathological state, disease or condition (e.g., cancer). For example, “diagnosis” may refer to identification of a particular type of cancer. “Diagnosis” may also refer to the classification of a particular subtype of cancer, for instance, by histopathological criteria, or by molecular features (e.g., a subtype characterized by expression of one or a combination of biomarkers (e.g., particular genes or proteins encoded by said genes)).

[0065] The term “aiding diagnosis” is used herein to refer to methods that assist in making a clinical determination regarding the presence, or nature, of a particular type of symptom or condition of a disease or disorder (e.g., cancer). For example, a method of aiding diagnosis of a disease or condition (e.g., cancer) can comprise measuring certain somatic mutations in a biological sample from an individual.

[0066] The term “sample,” as used herein, refers to a composition that is obtained or derived from a subject and / or individual of interest that contains a cellular and / or other molecular entity that is to be characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological characteristics. For example, the phrase “disease sample” and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and / or molecular entity that is to be characterized. Samples include, but are not limited to, tissue samples, primary or culturedcells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, plasma, serum, blood-derived cells, urine, cerebro- spinal fluid, saliva, sputum, tears, perspiration, mucus, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, tumor tissue, cellular extracts, and combinations thereof. In some instances, the sample is a whole blood sample, a plasma sample, a serum sample, or a combination thereof. In some embodiments, the sample is from a tumor (e.g., a “tumor sample”), such as from a biopsy. In some embodiments, the sample is a formalin-fixed paraffin-embedded (FFPE) sample.

[0067] A “tumor cell” as used herein, refers to any tumor cell present in a tumor or a sample thereof. Tumor cells may be distinguished from other cells that may be present in a tumor sample, for example, stromal cells and tumor-infiltrating immune cells, using methods known in the art and / or described herein.

[0068] The term “segmentation” (or “sequence segmentation”), as used herein, refers to a process for partitioning of sequence read data into a number of non-overlapping segments that cover all sequence read data points, such that each segment of a plurality of segments is as homogeneous as possible and all sequence reads associated with a given segment have the same copy number. In some instances, segmentation may be performed by processing aligned sequence read data (or other sequencing-related data, e.g., coverage data, allele frequency data, etc., derived from the sequence read data) using any of a variety of methods known to those of skill in the art (see., e.g., Braun and Miller (1998), “Statistical methods for DNA sequence segmentation”, Statistical Science 13(2): 142-162). Examples of segmentation methods include, but are not limited to, circular binary segmentation (CBS) methods, maximum likelihood methods, hidden Markov chain methods, walking Markov methods, Bayesian methods, long-range correlation methods, change point methods, or any combination thereof.

[0069] A “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue,” as used herein, refer to a sample, cell, tissue, standard, or level that is used for comparison purposes.

[0070] By ‘ ‘correlate” or “correlating” is meant comparing, in any way, the performance and / or results of a first analysis or protocol with the performance and / or results of a second analysis or protocol. For example, one may use the results of a first analysis or protocol in carrying out a second protocol and / or one may use the results of a first analysis or protocol to determine whether a second analysis or protocol should be performed. With respect to theembodiment of polypeptide analysis or protocol, one may use the results of the polypeptide expression analysis or protocol to determine whether a specific therapeutic regimen should be performed. With respect to the embodiment of polynucleotide analysis or protocol, one may use the results of the polynucleotide expression analysis or protocol to determine whether a specific therapeutic regimen should be performed.

[0071] ‘ ‘Individual response” or “response” can be assessed using any endpoint indicating a benefit to the individual, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., cancer progression), including slowing down or complete arrest; (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing down, or complete stopping) of cancer cell infiltration into adjacent peripheral organs and / or tissues; (4) inhibition (i.e. reduction, slowing down, or complete stopping) of metastasis; (5) relief, to some extent, of one or more symptoms associated with the disease or disorder (e.g., cancer); (6) increase or extension in the length of survival, including overall survival and progression free survival; and / or (7) decreased mortality at a given point of time following treatment.

[0072] An “effective response” of a patient or a patient's “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for, or suffering from, a disease or disorder, such as cancer. In one embodiment, such benefit includes any one or more of: extending survival (including overall survival and / or progression-free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.

[0073] An “effective amount” refers to an amount of a therapeutic agent to treat or prevent a disease or disorder in a mammal. In the case of cancers, the therapeutically effective amount of the therapeutic agent may reduce the number of cancer cells; reduce the primary tumor size; inhibit (i.e., slow to some extent, and in some embodiments stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent, and in some embodiments stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the disorder. To the extent the drug may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy in vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), response rates (e.g., CR and PR), duration of response, and / or quality of life.

[0074] The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective,and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0075] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0076] As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”, and the like) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0077] As used herein, the terms “individual,” “patient,” or “subject” are used interchangeably and refer to any single animal, e.g., a mammal (including such non-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non- human primates) for which treatment is desired. In particular embodiments, the patient, individual or subject herein is a human.

[0078] As used herein, “administering” (and grammatical variations thereof such as “administration” or “administer”, and the like) refers to a method of giving a dosage of an agent or a pharmaceutical composition (e.g., a pharmaceutical composition including the agent) to a subject (e.g., a patient). Administering can be by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include, for example, intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g., by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules, including, but not limited to, single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.

[0079] The terms “concurrently” or “in combination” are used herein to refer to administration of two or more therapeutic agents, where at least part of the administration overlaps in time. Accordingly, concurrent administration includes a dosing regimen whereinthe administration of one or more agent(s) continues after discontinuing the administration of one or more other agent(s).

[0080] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings concerning the use of such therapeutic products.

[0081] An “article of manufacture” is any manufacture (e.g., a package or container) or kit comprising at least one reagent, e.g., a medicament for treatment of a disease or disorder (e.g., cancer), or a reagent for specifically detecting a biomarker described herein. In certain embodiments, the manufacture or kit is promoted, distributed, or sold as a unit for performing the methods described herein.

[0082] The phrase “based on” when used herein means that the information about one or more biomarkers is used to inform a treatment decision, information provided on a package insert, or marketing / promotional guidance, etc.III. Methods, Systems, and Devices

[0083] In some aspects, provided herein are methods for selecting a therapy for an individual having cancer. In some aspects, provided herein are methods for identifying an individual having cancer who may benefit from a treatment comprising an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor. In some aspects, provided herein are methods for identifying one or more treatment options for an individual having cancer. In some aspects, provided herein are methods for selecting a treatment for an individual having cancer. In some aspects, provided herein are methods for predicting survival of an individual having cancer. In some aspects, provided herein are methods for treating or delaying progression of cancer. In some aspects, provided herein are methods for monitoring, evaluating or screening an individual having cancer. In some aspects, provided herein are methods for assessing an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide, in cancer in an individual. In some aspects, provided herein are methods for detecting an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide in cancer, or in a sample obtained from a cancer or from an individual diagnosed with, suspected to have, or being screen for cancer. In some aspects, provided herein are methods for detecting the presence or absence of cancer in an individual. In some aspects, provided herein are methods for monitoring progression or recurrence of breast cancer in an individual. In some aspects, provided herein are methods for monitoring resistance to endocrine therapy in an individualwith cancer. In some aspects, provided herein are methods for monitoring sensitivity or responsiveness to endocrine therapy in an individual with cancer.

[0084] In some embodiments of any of the methods provided herein, the methods comprise detecting e.g., in a sample from the individual) an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof. In some embodiments, the methods provided herein comprise detecting in a sample from an individual, e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer, an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule.

[0085] In some embodiments, detection of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide, in the sample identifies the individual as one who may benefit from a treatment comprising an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor. In some embodiments, the methods comprise selecting an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor as a treatment for an individual having cancer, e.g., responsive to detection of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual, e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer. In some embodiments, the methods comprise generating a report comprising one or more treatment options identified for an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) based at least in part on detection of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from the individual. In some embodiments, detection of the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide, in the sample identifies the individual as one who may benefit from a treatment comprising an endocrine therapy. In some embodiments, the methods comprise selecting an endocrine therapy as a treatment for an individual having cancer, e.g., responsive to detection of the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual, e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer. In some embodiments, the methods comprise generating areport comprising one or more treatment options identified for an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) based at least in part on detection of the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from the individual. In some embodiments, the one or more treatment options comprise an endocrine therapy. In some embodiments, the methods comprise administering to an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) an effective amount of a treatment that comprises an anti-cancer therapy, such as an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor, responsive to detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from the individual. In some embodiments, the methods comprise administering to an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) an effective amount of a treatment that comprises an endocrine therapy, responsive to detecting the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from the individual. In some embodiments, responsive to detection of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer), the individual is predicted to have longer survival when treated with a treatment comprising an anti-cancer therapy, such as an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor. In some embodiments, the methods comprise providing an assessment of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, e.g., responsive to detecting the presence or absence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide, in a sample. In some embodiments, responsive to detection of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer), the individual is predicted to be resistant to an endocrine therapy. In some embodiments, responsive to detection of the absence of an ESRI fusionnucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer), the individual is predicted to be sensitive to an endocrine therapy. In some embodiments, the methods comprise detecting or acquiring knowledge of the presence or absence of a cancer in a sample from the individual. In some embodiments, the methods comprise detecting, in a first sample obtained from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) at a first time point, the presence or absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule; detecting, in a second sample obtained from the individual at a second time point after the first time point, the presence or absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule; and providing an assessment of cancer progression or cancer recurrence in the individual based, at least in part, on the presence or absence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the first sample and / or in the second sample. In some embodiments, the methods comprise detecting, in a first sample obtained from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) at a first time point, the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule; detecting, in a second sample obtained from the individual at a second time point after the first time point, the presence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule; and providing an assessment of resistance to endocrine therapy in the individual based, at least in part, on the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the second sample. In some embodiments, the methods comprise detecting, in a first sample obtained from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) at a first time point, the presence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule; detecting, in a second sample obtained from the individual at a second time point after the first time point, the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule; and providing an assessment of sensitivity or responsiveness to endocrine therapy in the individual based, at least in part, on the absence of the ESRI fusion nucleic acid molecule, orthe ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the second sample. In some embodiments, the methods comprise performing DNA sequencing on a sample obtained from an individual to determine a sequencing mutation profile, wherein the sequencing mutation profile identifies the presence or absence of an ESRI fusion nucleic acid molecule. In some embodiments, the methods comprise identifying a candidate treatment based, at least in part, on the sequencing mutation profile. In some embodiments, the candidate treatment comprises an anti-cancer therapy described herein, such as an anticancer agent other than a SERM or an aromatase inhibitor or an endocrine therapy. In some embodiments, the candidate treatment is an anti-cancer agent other than a SERM or an aromatase inhibitor and identified based, at least in part, on the presence of an ESRI fusion nucleic acid molecule as identified in the sequencing mutation profile. In some embodiments, the candidate treatment is an endocrine therapy and identified based, at least in part, on the absence of an ESRI fusion nucleic acid molecule as identified in the sequencing mutation profile. In some embodiments, the methods comprise detecting, in a sample obtained from the individual during or after treatment with an endocrine therapy, an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; and providing an assessment of resistance to endocrine therapy in the individual based, at least in part, on the detection of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample. In some embodiments, the methods comprise detecting, in a sample obtained from the individual before, during, or after treatment with an endocrine therapy, absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; and providing an assessment of sensitivity or responsiveness to endocrine therapy in the individual based, at least in part, on the detection of the absence of an ESRI fusion nucleic acid molecule, or ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample.

[0086] In some embodiments, the methods provided herein comprise acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual, e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer. In some embodiments, knowledge of the presence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) identifies the individual as one who may benefitfrom a treatment comprising an anti-cancer therapy, such as an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, the methods comprise selecting an anti-cancer therapy, such as an anti-cancer agent other than a SERM or an aromatase inhibitor, as a treatment for an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer), e.g., responsive to knowledge of the presence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from the individual. In some embodiments, the methods comprise generating a report comprising one or more treatment options identified for an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) based at least in part on knowledge of the presence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule in sample from the individual. In some embodiments, the one or more treatment options comprise an anti-cancer therapy described herein, such as an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, the methods comprise generating a report comprising one or more treatment options identified for an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer) based at least in part on knowledge of the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule in sample from the individual. In some embodiments, the one or more treatment options comprise an endocrine therapy. In some embodiments, responsive to acquisition of knowledge of the presence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer), the individual is classified as a candidate to receive a treatment comprising an anti-cancer therapy, e.g., such as an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, responsive to acquisition of knowledge of the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer), the individual is classified as a candidate to receive a treatment comprising an endocrine therapy.

[0087] In some embodiments, responsive to acquisition of knowledge of the presence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual (e.g., an individual havingcancer, suspected of having cancer, being treated for cancer, or being tested for cancer), the individual is identified as likely to respond to a treatment that comprises an anti-cancer therapy, such as an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, responsive to acquisition of knowledge of the absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual (e.g., an individual having cancer, suspected of having cancer, being treated for cancer, or being tested for cancer), the individual is identified as likely to respond to a treatment that comprises an endocrine therapy. In some embodiments, responsive to acquisition of knowledge of the presence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule, in a sample from an individual, the individual is predicted to have longer survival when treated with a treatment comprising an an anti-cancer agent other than a SERM or an aromatase inhibitor, e.g., as compared to survival an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor.

[0088] In other aspects, provided herein are systems and non-transitory computer readable storage media. In some embodiments, the systems and non-transitory computer readable storage media provided herein are for (e.g., are configured for) performing a method according to any one of the embodiments disclosed herein. In some embodiments, the systems and non-transitory computer readable storage media provided herein are for (e.g., are configured for) detecting (e.g., in a sample from the individual) an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof.

[0089] In some embodiments of any of the methods, systems, or non-transitory computer readable storage media provided herein, the cancer is breast cancer (e.g., HR+ breast cancer). In some embodiments, the cancer is endometrial cancer. In some embodiments, the individual is a human. In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof.ESRI Gene Fusions

[0090] Certain aspects of the present disclosure relate to genomic rearrangements involving an ESRI gene. An ESRI rearrangement of the present disclosure may relate to any chromosomal translocation, fusion, or rearrangement involving the locus of an ESRI gene. In some embodiments, the rearrangements of the disclosure result in an ESRI fusion nucleic acid molecule that comprises at least a portion of an ESRI gene fused to at least a portion of another gene, e.g., CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5. Accordingly, certain aspects of the present disclosure relate to ESRI fusion nucleic acid molecules, as well as to ESRI fusion polypeptides encoded by such ESRI fusion nucleic acid molecules.

[0091] As used herein '^ESRl" refers to a gene encoding an ESRI mRNA or ESRI polypeptide. ESRI is also known as ER, ESR, Era, ESRA, ESTRR, and NR3A1. In some embodiments, an ESRI gene is a human ESRI gene. An exemplary ESRI gene is represented by NCBI Gene ID No. 2099. In some embodiments, an ESRI gene is located at chromosomal coordinates chr6:151, 656, 691-152, 129, 619 forward strand. The ESRI gene encodes 22 exons; additional information about the structure of ESRI and its exons and splice variants can be found under Ensembl Gene Accession ENSG00000091831. An exemplary ESRI mRNA sequence is represented by NCBI Ref. Seq. NM_000125.4, provided below as SEQ ID NO: 2:AGCTGGCGGAGGGCGTTCGTCCTGGGACTGCACTTGCTCCCGTCGGGTCGCCCGGCTTCACC GGACCCGC AGGCTCCCGGGGCAGGGCCGGGGCCAGAGCTCGCGTGTCGGCGGGACATGCGCTGCGTCGCC TCTAACCT CGGGCTGTGCTCTTTTTCCAGGTGGCCCGCCGGTTTCTGAGCCTTCTGCCCTGCGGGGACAC GGTCTGCA CCCTGCCCGCGGCCACGGACCATGACCATGACCCTCCACACCAAAGCATCTGGGATGGCCCT ACTGCATC AGATCCAAGGGAACGAGCTGGAGCCCCTGAACCGTCCGCAGCTCAAGATCCCCCTGGAGCGG CCCCTGGG CGAGGTGTACCTGGACAGCAGCAAGCCCGCCGTGTACAACTACCCCGAGGGCGCCGCCTACG AGTTCAAC GCCGCGGCCGCCGCCAACGCGCAGGTCTACGGTCAGACCGGCCTCCCCTACGGCCCCGGGTC TGAGGCTG CGGCGTTCGGCTCCAACGGCCTGGGGGGTTTCCCCCCACTCAACAGCGTGTCTCCGAGCCCG CTGATGCT ACTGCACCCGCCGCCGCAGCTGTCGCCTTTCCTGCAGCCCCACGGCCAGCAGGTGCCCTACT ACCTGGAG AACGAGCCCAGCGGCTACACGGTGCGCGAGGCCGGCCCGCCGGCATTCTACAGGCCAAATTC AGATAATCGACGCCAGGGTGGCAGAGAAAGATTGGCCAGTACCAATGACAAGGGAAGTATGGCTATGGAA TCTGCCAAGGAGACTCGCTACTGTGCAGTGTGCAATGACTATGCTTCAGGCTACCATTATGGAGTCTGGTCCTGTGAGGGCTGCAAGGCCTTCTTCAAGAGAAGTATTCAAGGACATAACGACTATATGTGTCCAGCCACCAACCAGTGCACCATTGATAAAAACAGGAGGAAGAGCTGCCAGGCCTGCCGGCTCCGTAAATGCTACGAAGTGGGAATGATGAAAGGTGGGATACGAAAAGACCGAAGAGGAGGGAGAATGTTGAAACACAAGCGCCAGA GAG AT GATGGGGAGGGCAGGGGTGAAGTGGGGTCTGCTGGAGACATGAGAGCTGCCAACCTTTGGCCAAGCCCGCTCATGATCAAACGCTCTAAGAAGAACAGCCTGGCCTTGTCCCTGACGGCCGACCAGATGGTCAGTGCCTTGTTGGATGCTGAGCCCCCGATACTCTATTCCGAGTATGATCCTACCAGACCCTTCAGTGAAGCTT C GAT GAT GGGCTTACTGACCAACCTGGCAGACAGGGAGCTGGTTCACATGATCAACTGGGCGAAGAGGGTGCCAGGCTTTGTGGATTTGACCCTCCATGATCAGGTCCACCTTCTAGAATGTGCCTGGCTAGAGATCCTGATGATTGGTCTCGTCTGGCGCTCCATGGAGCACCCAGGGAAGCTACTGTTTGCTCCTAACTTGCTCTTGGACAGGAACCAGGGAAAATGTGTAGAGGGCATGGTGGAGATCTTCGACATGCTGCTGGCTACATCATCTCGGTTCCGCATGATGAATCTGCAGGGAGAGGAGTTTGTGTGCCTCAAATCTATTATTTTGCTTAATTCTGGA GTGTACACATTTCTGTCCAGCACCCTGAAGTCTCTGGAAGAGAAGGACCATATCCACCGAGTCCTGGACA AG AT C AC AGACACTTTGATCCACCTGATGGCCAAGGCAGGCCTGACCCTGCAGCAGCAGCACCAGCGGCTGGCCCAGCTCCTCCTCATCCTCTCCCACATCAGGCACATGAGTAACAAAGGCATGGAGCATCTGTACAGCATGAAGTGCAAGAACGTGGTGCCCCTCTATGACCTGCTGCTGGAGATGCTGGACGCCCACCGCCTACATGCGCCCACTAGCCGTGGAGGGGCATCCGTGGAGGAGACGGACCAAAGCCACTTGGCCACTGCGGGCTCTACTTCATCGCATTCCTTGCAAAAGTATTACATCACGGGGGAGGCAGAGGGTTTCCCTGCCACGGTCTGAGAGCTCCCTGGCTCCCACACGGTTCAGATAATCCCTGCTGCATTTTACCCTCATCATGCACCACTTTAGCCAAATTCTGTCTCCTGCATACACTCCGGCATGCATCCAACACCAATGGCTTTCTAGATGAGTGGCCATTCATTTGCTTGCTCAGTTCTTAGTGGCACATCTTCTGTCTTCTGTTGGGAACAGCCAAAGGGATTCCAAGGCTAAATCTTTGTAACAGCTCTCTTTCCCCCTTGCTATGTTACTAAGCGTGAGGATTCCCGTAGCTCTTCACAGCTGAACTCAGTCTATGGGTTGGGGCTCAGATAACTCTGTGCATTTAAGCTACTTGTAGAGACCCAGGCCTGGAGAGTAGACATTTTGCCTCTGATAAGCACTTTTTAAATGGCTCTAAGAATAAGCCACAGCAAAGAATTT AAAGTGGCTCCTTTAATTGGTGACTTGGAGAAAGCTAGGTCAAGGGTTTATTATAGCACCCTCTTGTATT CCTATGGCAATGCATCCTTTTATGAAAGTGGTACACCTTAAAGCTTTTATATGACTGTAGCAGAGTATCTGGTGATTGTCAATTCATTCCCCCTATAGGAATACAAGGGGCACACAGGGAAGGCAGATCCCCTAGTTGGCAAGACTATTTTAACTTGATACACTGCAGATTCAGATGTGCTGAAAGCTCTGCCTCTGGCTTTCCGGTCATGGGTTCCAGTTAATTCATGCCTCCCATGGACCTATGGAGAGCAGCAAGTTGATCTTAGTTAAGTCTCCCTATATGAGGGATAAGTTCCTGATTTTTGTTTTTATTTTTGTGTTACAAAAGAAAGCCCTCCCTCCCTGAAC TTGCAGTAAGGTCAGCTTCAGGACCTGTTCCAGTGGGCACTGTACTTGGATCTTCCCGGCGTGTGTGTGCCTTACACAGGGGTGAACTGTTCACTGTGGTGATGCATGATGAGGGTAAATGGTAGTTGAAAGGAGCAGGGGCCCTGGTGTTGCATTTAGCCCTGGGGCATGGAGCTGAACAGTACTTGTGCAGGATTGTTGTGGCTACTAGAGAACAAGAGGGAAAGTAGGGCAGAAACTGGATACAGTTCTGAGGCACAGCCAGACTTGCTCAGGGTGGCCCTGCCACAGGCTGCAGCTACCTAGGAACATTCCTTGCAGACCCCGCATTGCCCTTTGGGGGTGCCCTGGGATCCCTGGGGTAGTCCAGCTCTTCTTCATTTCCCAGCGTGGCCCTGGTTGGAAGAAGCAGCTGTCACAGCTGCTGTAGACAGCTGTGTTCCTACAATTGGCCCAGCACCCTGGGGCACGGGAGAAGGGTGGGGACCGTTGCTGTCACTACTCAGGCTGACTGGGGCCTGGTCAGATTACGTATGCCCTTGGTGGTTTAGAGATAATCCAAAATCAGGGTTTGGTTTGGGGAAGAAAATCCTCCCCCTTCCTCCCCCGCCCCGTTCCCTACCGCCTCCACTCCTGCCAGCTCATTTCCTTCAATTTCCTTTGACCTATAGGCTAAAAAAGAAAGGCTCATTCCAGCCACAGGGCAGCCTTCCCTGGGCCTTTGCTTCTCTAGCACAATTATGGGTTACTTCCTTTTTCTTAACAAAAAAGAATGTTTGATTTCCTCTGGGTGACCTTATTGTCTGTAATTGAAACCCTATTGAGAGGTGATGTCTGTGTTAGCCAATGACCCAGGTGAGCTGCTCGGGCTTCTCTTGGTATGTCTTGTTTGGAAAAGTGGATTTCATTCATTTCTGATTGTCCAGTTAAGTGATCACCAAAGGACTGAGAATCTGGGAGGGCAAAAAAAAAAAAAAAGTTTTTATGTGCACTTAAATTTGGGGACAATTTTATGTATCTGTGTTAAGGATATGTTTAAGAACATAATTCTTTTGTTGCTGTTTGTTTAAGAAGCACCTTAGTTTGTTTAAGAAGCACCTTATATAGTATAATATATATTTTTTTGAAATTACATTGCTTGTTTATCAGACAATTGAATGTAGTAATTCTGTTCTGGATTTAATTTGACTGGGTTAACATGCAAAAACCAAGGAAAAATATTTAGTTTTTTTTTTTTTTTTTGTATACTTTTCAAGCTACCTTGTCATGTATACAGTCATTTATGCCTAAAGCCTGGTGATTATTCATTTAAATGAAGATCACATTTCATATCAACTTTTGTATCCACAGTAGACAAAATAGCACTAATCCAGATGCCTATTGTTGGATACTGAATGACA GACAATCTTATGTAGCAAAGATTATGCCTGAAAAGGAAAATTATTCAGGGCAGCTAATTTTGCTTTTACCAAAATATCAGTAGTAATATTTTTGGACAGTAGCTAATGGGTCAGTGGGTTCTTTTTAATGTTTATACTTAGATTTTCTT T T AAAAAAAT T AAAAT AAAAC AAAAAAAAAT TTCTAGGACTAGACGATGTAATACCAGCTA AAGCCAAACAATTATACAGTGGAAGGTTTTACATTATTCATCCAATGTGTTTCTATTCATGTTAAGATAC TACT AC ATTTGAAGTGGGCAGAGAACATCAGATGATTGAAATGTTCGCCCAGGGGTCTCCAGCAACTTTGGAAATCTCTTTGTATTTTTACTTGAAGTGCCACTAATGGACAGCAGATATTTTCTGGCTGATGTTGGTATTGGGTGTAGGAACATGATTTAAAAAAAAACTCTTGCCTCTGCTTTCCCCCACTCTGAGGCAAGTTAAAATGTAAAAGATGTGATTTATCTGGGGGGCTCAGGTATGGTGGGGAAGTGGATTCAGGAATCTGGGGAATGGCAAATATATTAAGAAGAGTATTGAAAGTATTTGGAGGAAAATGGTTAATTCTGGGTGTGCACCAGGGTTCAGTAGAGTCCACTTCTGCCCTGGAGACCACAAATCAACTAGCTCCATTTACAGCCATTTCTAAAATGGCAGCTTCAGTTCTAGAGAAGAAAGAACAACATCAGCAGTAAAGTCCATGGAATAGCTAGTGGTCTGTGTTTCTTTTCGCCATTGCCTAGCTTGCCGTAATGATTCTATAATGCCATCATGCAGCAATTATGAGAGGCTAGGTCATCCAAAGAGAAGACCCTATCAATGTAGGTTGCAAAATCTAACCCCTAAGGAAGTGCAGTCTTTGATTTGATTTCCCTAGTAACCTTGCAGATATGTTTAACCAAGCCATAGCCCATGCCTTTTGAGGGCTGAACAAATAAGGGACTTAC T G AT AAT T T AC T T T T G AT C AC AT T AAG G T G T T C T C AC C T T G AAAT C T T AT AC AC T G AAAT GGCCATTGATTTAGGCCACTGGCTTAGAGTACTCCTTCCCCTGCATGACACTGATTACAAATACTTTCCT ATT CAT ACTTTCCAATTATGAGATGGACTGTGGGTACTGGGAGTGATCACTAACACCATAGTAATGTCTA AT AT TC ACAGGCAGATCTGCTTGGGGAAGCTAGTTATGTGAAAGGCAAATAGAGTCATACAGTAGCTCAAAAGGCAACCATAATTCTCTTTGGTGCAGGTCTTGGGAGCGTGATCTAGATTACACTGCACCATTCCCAAGTTAATCCCCTGAAAACTTACTCTCAACTGGAGCAAATGAACTTTGGTCCCAAATATCCATCTTTTCAGTAGCGTTAATTATGCTCTGTTTCCAACTGCATTTCCTTTCCAATTGAATTAAAGTGTGGCCTCGTTTTTAGT CAT TT AAAATTGTTTTCTAAGTAATTGCTGCCTCTATTATGGCACTTCAATTTTGCACTGTCTTTTGAGATTCAAGAAAAATTTCTATTCTTTTTTTTGCATCCAATTGTGCCTGAACTTTTAAAATATGTAAATGCTGCCATGTTCCAAACCCATCGTCAGTGTGTGTGTTTAGAGCTGTGCACCCTAGAAACAACATATTGTCCCATGAGCAGGTGCCTGAGACACAGACCCCTTTGCATTCACAGAGAGGTCATTGGTTATAGAGACTTGAATTAAT AAGTGACA TTATGCCAGTTTCTGTTCTCTCACAGGTGATAAACAATGCTTTTTGTGCACTACATACTCTT CAGTGTAG AGCTCTTGTTTTATGGGAAAAGGCTCAAATGCCAAATTGTGTTTGATGGATTAATATGCCCT TTTGCCGA TGCATACTATTACTGATGTGACTCGGTTTTGTCGCAGCTTTGCTTTGTTTAATGAAACACAC TTGTAAAC CTCTTTTGCACTTTGAAAAAGAATCCAGCGGGATGCTCGAGCACCTGTAAACAATTTTCTCA ACCTATTTG AT G T T C AAAT AAAG AAT T AAAC T AAA ( SEQ ID NO : 2 )

[0092] An exemplary ESRI amino acid sequence is provided below. In some embodiments, references to a specific ESRI mutation, rearrangement, or gene fusion by amino acid position refer to amino acid numbering according to SEQ ID NO:1. In some embodiments, the DNA- binding domain of ESRI is made up of amino acids 180-261 according to SEQ ID NO:1.MTMTLHTKASGMALLHQIQGNELEPLNRPQLKIPLERPLGEVYLDSSKPAVYNYPEGAAYEF NAAAAANA QVYGQTGLPYGPGSEAAAFGSNGLGGFPPLNSVSPSPLMLLHPPPQLSPFLQPHGQQVPYYL ENEPSGYT VREAGPPAFYRPNSDNRRQGGRERLASTNDKGSMAMESAKETRYCAVCNDYASGYHYGVWSC EGCKAFFK RSIQGHNDYMCPATNQCTIDKNRRKSCQACRLRKCYEVGMMKGGIRKDRRGGRMLKHKRQRD DGEGRGEV GSAGDMRAANLWPSPLMIKRSKKNSLALSLTADQMVSALLDAEPPILYSEYDPTRPFSEASM MGLLTNLA DRELVHMINWAKRVPGFVDLTLHDQVHLLECAWLEILMIGLVWRSMEHPGKLLFAPNLLLDR NQGKCVEG MVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYTFLSSTLKSLEEKDHIHRVLDKI TDTLIHLM AKAGLTLQQQHQRLAQLLLILSHIRHMSNKGMEHLYSMKCKNWPLYDLLLEMLDAHRLHAP TSRGGASV EETDQSHLATAGSTSSHSLQKYYITGEAEGFPATV ( SEQ ID NO : 1 )

[0093] In someembodiments, an ESRI rearrangement results in a gene fusion, resulting in a fusion nucleic acid molecule comprising at least a portion of an ESRI gene, and at least a portion of another gene. Accordingly, in some aspects, provided herein are ESRI fusion nucleic acid molecules comprising at least a portion of an ESRI gene and at least a portion of another gene.

[0094] In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure comprises at least a portion of an ESRI gene and at least a portion of a CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5 gene. In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure comprises at least aportion of an ESRI gene and at least a portion of a fusion partner gene as provided in Table A or FIG. 3B herein.

[0095] As used herein “CCDC170” refers to a gene encoding a CCDC170 mRNA or polypeptide. The CCDC170 gene encodes the coiled-coil domain containing 170 polypeptide. CCDC170 is also known as C6orf97 or bA282Pl l.l. In some embodiments, a CCDC170 gene according to the present disclosure is a human CCDC170 gene. An exemplary CCDC170 gene is represented by NCBI Gene ID No. 80129.

[0096] s used herein “SMAD4” refers to a gene encoding a SMAD4 mRNA or polypeptide. The SMAD4 gene encodes the Smad family 4 (SMAD4) polypeptide. SMAD4 is also known as JIP, DPC4, MADH4, or MYHRS. In some embodiments, a SMAD4 gene according to the present disclosure is a human SMAD4 gene. An exemplary SMAD4 gene is represented by NCBI Gene ID No. 4089.

[0097] As used herein "LOO 00422737'' refers to a gene encoding a LOC100422737 RNA or polypeptide. The LOC100422737 gene encodes the long intergenic non-protein coding RNA 2532. In some embodiments, a LOC100422737 gene according to the present disclosure is a human LOC100422737 gene. An exemplary LOC100422737 gene is represented by NCBI Gene ID No. 100422737.

[0098] As used herein “SNAP91” refers to a gene encoding a SNAP91 mRNA or polypeptide. The SNAP91 gene encodes the synaptosome associated protein 91. SNAP91 is also known as CALM or API 80. In some embodiments, a SNAP91 gene according to the present disclosure is a human SNAP91 gene. An exemplary SNAP91 gene is represented by NCBI Gene ID No. 9892.

[0099] As used herein '^ZBTB2" refers to a gene encoding a ZBTB2 mRNA or polypeptide. The ZBTB2 gene encodes the zinc finger and BTB domain containing 2 protein (ZBTB2). ZBTB2 is also known as ZNF437. In some embodiments, a ZBTB2 gene according to the present disclosure is a human ZBTB2 gene. An exemplary ZBTB2 gene is represented by NCBI Gene ID No. 57621.

[0100] As used herein “IYD” refers to a gene encoding an IYD mRNA or polypeptide. The IYD gene encodes the iodotyrosine deiodinase. IYD is also known as TDH4, IYD-1, DEHAL1, or C6orf71. In some embodiments, an IYD gene according to the present disclosure is a human IYD gene. An exemplary IYD gene is represented by NCBI Gene ID No. 389434.

[0101] As used herein “IMPG1” refers to a gene encoding an 1MPG1 mRNA or polypeptide. The 1MPG1 gene encodes the interphotoreceptor matrix proteoglycan 1. 1MPG1 is also known as RP91, VMD4, GP147, SPACR, or IPM150. In some embodiments, an IMPG1 gene according to the present disclosure is a human 1MPG1 gene. An exemplary 1MPG1 gene is represented by NCBI Gene ID No. 3617.

[0102] As used herein “S7AG2” refers to a gene encoding a STAG2 mRNA or polypeptide. The STAG2 gene encodes the STAG2 cohesin complex component. STAG2 is also known as SA2, MKMS, SA-2, HPE13, SCC3B, NEDXCF, or bA51701.1. In some embodiments, a STAG2 gene according to the present disclosure is a human STAG2 gene. An exemplary STAG2 gene is represented by NCBI Gene ID No. 10735.

[0103] used herein “TNRC6B” refers to a gene encoding a TNRC6B mRNA or polypeptide. The TNRC6B gene encodes the trinucleotide repeat containing adaptor 6B protein. TNRC6B is also known as GDSBA. In some embodiments, a TNRC6B gene according to the present disclosure is a human TNRC6B gene. An exemplary TNRC6B gene is represented by NCBI Gene ID No. 23112.

[0104] As used herein “C6orfl5” refers to a gene encoding a C6orfl5 mRNA or polypeptide. The C6orfl5 gene encodes the chromosome 6 open reading frame 15. C6orfl5 is also known as STG. In some embodiments, a C6orfl5 gene according to the present disclosure is a human C6orfl5 gene. An exemplary C6orfl5 gene is represented by NCBI Gene ID No. 29113.

[0105] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, encoding an ESRI DNA binding domain, or a portion thereof, to any one of genes CCDC170, SMAD4, LOCI 00422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI DNA binding domain, or a portion thereof, fused to a polypeptide encoded by any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof.

[0106] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a CCDC170 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a CCDC170 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the CCDC170 gene, or aportion thereof, fused to exon 2 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the CCDC170 gene, or a portion thereof, fused to exons 1-2 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a CCDC170 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a CCDC170 polypeptide, or a portion thereof.

[0107] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a SMAD4 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a SMAD4 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SMAD4 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SMAD4 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a SMAD4 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a SMAD4 polypeptide, or a portion thereof.

[0108] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a EOC 100422737 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a EOC 100422737 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the EOC100422737 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the EOC100422737 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a EOC 100422737 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C- terminus direction, an ESRI polypeptide, or a portion thereof, fused to a EOC 100422737 polypeptide, or a portion thereof.

[0109] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a SNAP91 gene, or a portion thereof,and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a SNAP91 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SNAP91 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the SNAP91 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a SNAP91 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a SNAP91 polypeptide, or a portion thereof.

[0110] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a ZBTB2 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a ZBTB2 gene, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a ZBTB2 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a ZBTB2 polypeptide, or a portion thereof.

[0111] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to an IYD gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to an IYD gene, or a portion thereof. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to an IYD polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to an IYD polypeptide, or a portion thereof.

[0112] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to an IMPG1 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to an IMPG1 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the IMPG1 gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusionnucleic acid molecule comprises the 1MPG1 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to an 1MPG1 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to an 1MPG1 polypeptide, or a portion thereof.

[0113] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a STAG2 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a STAG2 gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the STAG2 gene, or a portion thereof, fused to exon 5 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the STAG2 gene, or a portion thereof, fused to exons 1-5 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a STAG2 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a STAG2 polypeptide, or a portion thereof.

[0114] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a TNRC6B gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a TNRC6B gene, or a portion thereof. In some embodiments, the ESRI fusion nucleic acid molecule comprises the TNRC6B gene, or a portion thereof, fused to exon 4 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the TNRC6B gene, or a portion thereof, fused to exons 1-4 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a TNRC6B polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a TNRC6B polypeptide, or a portion thereof.

[0115] In some embodiments, the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a C6orfl5 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a C6orfl 5 gene, or a portion thereof. In someembodiments, the ESRI fusion nucleic acid molecule comprises the C6orfl5 gene, or a portion thereof, fused to exon 5 of the ESRI gene. In some embodiments, the ESRI fusion nucleic acid molecule comprises the C6orfl5 gene, or a portion thereof, fused to exons 1-5 of the ESRI gene. In some embodiments, the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a C6orfl5 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a C6orfl5 polypeptide, or a portion thereof.

[0116] I11certain aspects, provided herein are ESRI fusion polypeptides which comprise at least a portion of an ESRI polypeptide and at least a portion of a polypeptide encoded by another gene. In some embodiments, an ESRI fusion polypeptide of the disclosure is a fusion polypeptide encoded by any of the ESRI fusion nucleic acid molecules provided herein, or a portion thereof, e.g., as described above.

[0117] Certain aspects of the present disclosure relate to methods for selecting a therapy for an individual having breast cancer or for identifying an individual having breast cancer who may benefit from a treatment comprising an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor; identifying one or more treatment options for an individual having breast cancer; selecting a treatment for an individual having breast cancer; predicting survival of an individual having breast cancer; treating or delaying progression of breast cancer; monitoring, evaluating or screening an individual having breast cancer; monitoring progression or recurrence of breast cancer in an individual; and / or monitoring resistance to endocrine therapy in an individual with breast cancer. In some embodiments, detection or acquisition of knowledge of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, (e.g., in a sample) identifies the individual as one who may benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, or as one who may be resistant to a treatment comprising an endocrine therapy.

[0118] Certain aspects of the present disclosure relate to methods for selecting a therapy for an individual having breast cancer or for identifying an individual having breast cancer who may benefit from a treatment comprising an endocrine therapy; and / or monitoring sensitivity or responsiveness to endocrine therapy. In some embodiments, detection or acquisition of knowledge of absence of an ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, (e.g., in a sample) identifiesthe individual as one who may benefit from a treatment comprising an endocrine therapy, or as one who may be sensitive to a treatment comprising an endocrine therapy.

[0119] In some embodiments, of any of the methods provided herein, the methods comprise acquiring knowledge of or detecting in a sample from an individual having a cancer an ESRI fusion nucleic acid molecule of the disclosure, e.g., any of the ESRI fusion nucleic acid molecules described above and / or in the Examples herein. In other embodiments, the methods comprise acquiring knowledge of or detecting in a sample from an individual having a cancer an ESRI fusion polypeptide of the disclosure, e.g., any of the ESRI fusion polypeptides described above and / or in the Examples herein.

[0120] In some embodiments, the methods comprise performing DNA sequencing on a sample obtained from the individual to determine a sequencing mutation profile on a group of genes, wherein the sequencing mutation profile identifies the presence or absence of an ESRI fusion nucleic acid molecule of the disclosure. In some embodiments, the methods further comprise identifying a candidate treatment for a cancer in an individual, based at least in part on the sequencing mutation profile. In some embodiments, the candidate treatment comprises an anti-cancer agent other than a SERM or an aromatase inhibitor (e.g., when the sequencing mutation profile identifies the presence of an ESRI fusion nucleic acid molecule of the disclosure). In some embodiments, the candidate treatment comprises an endocrine therapy (e.g., when the sequencing mutation profile identifies the absence of an ESRI fusion nucleic acid molecule of the disclosure). In some embodiments, the sequencing mutation profile identifies the presence or absence of a fragment of the ESRI fusion nucleic acid molecule comprising a breakpoint or fusion junction, e.g., one or more of the corresponding breakpoints described herein.

[0121] In some embodiments of any of the methods provided herein, the methods further comprise generating a report comprising one or more treatment options identified for an individual (e.g., an individual having cancer) based at least in part on detection of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from the individual. In some embodiments, the treatment options comprise an anti-cancer agent other than a SERM or an aromatase inhibitor (e.g., when the report identifies the presence of an ESRI fusion nucleic acid molecule of the disclosure). In some embodiments, the treatment options comprise an endocrine therapy (e.g., when the report identifies the absence of an ESRI fusion nucleic acid molecule of the disclosure).

[0122] In some embodiments of any of the methods provided herein, responsive to acquisition of knowledge of an ESRI fusion nucleic acid molecule or an ESRI fusionpolypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer): (i) the individual is classified as a candidate to receive a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor; and / or (ii) the individual is identified as likely to respond to a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, responsive to acquisition of knowledge of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the individual is predicted to have longer survival when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor. In some embodiments, responsive to acquisition of knowledge of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the methods comprise administering to the individual an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, responsive to acquisition of knowledge of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the individual is predicted to benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor and / or to have longer survival when treated with a treatment comprising an anticancer agent other than a SERM or an aromatase inhibitor, as compared to an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor. In some embodiments, responsive to acquisition of knowledge of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), an individual is predicted to be resistant to a treatment comprising an endocrine therapy.

[0123] In some embodiments of any of the methods provided herein, responsive to detection of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer): (i) the individual is classified as a candidate to receive a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor; and / or (ii) the individual is identified as likely to respond to a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.In some embodiments, responsive to detection of an ESRI fusion nucleic acid molecule or anESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the individual is predicted to have longer survival when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor. In some embodiments, responsive to detection of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the methods comprise administering to the individual an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor. In some embodiments, responsive to detection of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the individual is predicted to benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor and / or to have longer survival when treated with a treatment comprising an anticancer agent other than a SERM or an aromatase inhibitor, as compared to an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor. In some embodiments, responsive to detection of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), an individual is predicted to be resistant to a treatment comprising an endocrine therapy.

[0124] In some embodiments of any of the methods provided herein, responsive to acquisition of knowledge of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer): (i) the individual is classified as a candidate to receive a treatment comprising an endocrine therapy; and / or (ii) the individual is identified as likely to respond to a treatment that comprises an endocrine therapy. In some embodiments, responsive to acquisition of knowledge of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the individual is predicted to have longer survival when treated with a treatment comprising an endocrine therapy, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising an endocrine therapy. In some embodiments, responsive to acquisition of knowledge of the absence of an ESRI fusion nucleic acid molecule or anESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the methods comprise administering to the individual an effective amount of a treatment that comprises an endocrine therapy. In some embodiments, responsive to acquisition of knowledge of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the individual is predicted to benefit from a treatment comprising an endocrine therapy and / or to have longer survival when treated with a treatment comprising an endocrine therapy, as compared to an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising an endocrine therapy. In some embodiments, responsive to acquisition of knowledge of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), an individual is predicted to be sensitive to a treatment comprising an endocrine therapy.

[0125] In some embodiments of any of the methods provided herein, responsive to detection of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer): (i) the individual is classified as a candidate to receive a treatment comprising an an endocrine therapy; and / or (ii) the individual is identified as likely to respond to a treatment that comprises an endocrine therapy. In some embodiments, responsive to detection of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the individual is predicted to have longer survival when treated with a treatment comprising an endocrine therapy, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising an endocrine therapy. In some embodiments, responsive to detection of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the methods comprise administering to the individual an effective amount of a treatment that comprises an endocrine therapy. In some embodiments, responsive to detection of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), the individual is predicted to benefit from a treatment comprising an endocrine therapy and / or to have longer survival when treated with a treatment comprising an endocrine therapy, as compared to an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusionpolypeptide when treated with a treatment comprising an endocrine therapy. In some embodiments, responsive to detection of the absence of an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide of the disclosure in a sample from an individual (e.g., an individual having cancer), an individual is predicted to be sensitive to a treatment comprising an endocrine therapy.

[0126] Certain aspects of the present disclosure relate to treatment with an endocrine therapy. In some embodiments, the endocrine therapy comprises a SERM or an aromatase inhibitor. Examples of SERMs include, without limitation, tamoxifen (NOLVADEX®, SOLTAMOX®, GENOX), raloxifene (EVISTA®, OPTRUMA), EM652, GW7604, keoxifene, toremifene (FARESTON®), bazedoxifene, broparestrol, clomifene, cyclofenil, lasofoxifene, ormeloxifene, ospemifene, or pharmaceutically acceptable salts thereof. Examples of aromatase inhibitors include, without limitation, aminoglutethimide, testolactone (TESLAC®), anastrozole (ARIMIDEX®), letrozole (FEMARA®), exemestane (AROMASIN®), vorozole (RIVIZOR), formestane (LENT ARON®), fadrozole (AFEMA), 4-hydroxyandrostenedione, 1, 4, 6-androstatrien-3, 17-dione (ATD), 4-Androstene-3, 6, 17- trione (“6-OXO”), or pharmaceutically acceptable salts thereof.

[0127] Certain aspects of the present disclosure relate to treatment with an anti-cancer agent other than a SERM or aromatase inhibitor. In some embodiments, the anti-cancer agent is approved or tested for use in E.S7? / mut cancer. In some embodiments, the anti-cancer agent comprises one or more of a small molecule inhibitor, an antibody, a cellular therapy, a nucleic acid, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a PROteolysis-TArgeting Chimera (PROTAC), a treatment for cancer comprising an ESRI mutation, an anti-cancer agent being tested in a clinical trial, a treatment for cancer comprising an ESRI mutation being tested in a clinical trial, or any combination thereof. In some embodiments, the anti-cancer agent comprises a selective estrogen receptor covalent antagonist (SERCA), including without limitation H3B-5942, H3B-6545, or a pharmaceutically acceptable salt thereof (see, e.g., Wang, Y. et al. (2023) Acta Pharmaceutica Sinica B 13( 12):4963-4982). In some embodiments, the anti-cancer agent comprises a selective estrogen receptor degrader (SERD), including without limitation fulvestrant (FASLODEX®), elacestrant (ORSERDU™), amcenestrant, camizestrant, giredestrant, rintodestrant, imlunestrant, ZB-716, Zn-c5, LSZ102, LY3484356, or D-0502, or a pharmaceutically acceptable salt thereof see, e.g., Patel, R. et al. (2023) NPJ Breast Cancer 9(l):20). In some embodiments, the anti-cancer agent comprises a PROTAC, including without limitation ARV-471. In some embodiments,the anti-cancer agent comprises a CDK4 / 6 inhibitor, including without limitation palbociclib, abemaciclib, ribociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-cancer agent comprises treatment with a SERD and a CDK4 / 6 inhibitor (see, e.g., Brett, J.O. et al. (2023) Oncologist 28(2): 172- 179). In some embodiments, the anti-cancer agent comprises a PI3K inhibitor, including without limitation GSK2636771, buparlisib, AZD8186, copanlisib, LY294002, PX-866, TGX115, TGX126, BEZ235, SF1126, idelalisib, pictilisib, GDC0032, IPI145, INK1117, SAR260301, KIN-193, duvelisib, GS-9820, GSK2636771, GDC-0980, AMG319, paxalisib, or alpelisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-cancer agent comprises an mTOR inhibitor, including without limitation temsirolimus, everolimus, ridaforolimus, dactolisib, GSK2126458, XL765, AZD8055, AZD2014, MLN128, PP242, NVP-BEZ235, LY3023414, PQR309, PKI587, or OSI027, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-cancer agent is a nucleic acid that inhibits the expression of an ESRI nucleic acid molecule (e.g., bearing an ESRI mutation), or an ESRI polypeptide encoded by the ESRI nucleic acid molecule, including without limitation a double- stranded RNA (dsRNA), a small interfering RNA (siRNA), or a small hairpin RNA (shRNA). In some embodiments, the anti-cancer agent is a cellular therapy that is an adoptive therapy, a T cellbased therapy, a natural killer (NK) cell-based therapy, a chimeric antigen receptor (CAR)-T cell therapy, a recombinant T cell receptor (TCR) T cell therapy, a macrophage-based therapy, an induced pluripotent stem cell-based therapy, a B cell-based therapy, or a dendritic cell (DC)-based therapy. In some embodiments, the anti-cancer agent can be a targeted therapy that targets, or is otherwise approved for use in treating a cancer comprising a mutation in, one or more oncogenic or tumor suppressor mutations, e.g., detected in a liquid biopsy sample as disclosed herein. In some embodiments, the anti-cancer agent other than a SERM or aromatase inhibitor is a targeted therapy targeting one of the one or more oncogenic or tumor suppressor mutations.

[0128] In some embodiments, an anti-cancer therapy of the disclosure is a small molecule inhibitor; an antibody; a cellular therapy; a nucleic acid; a virus-based therapy; an antibodydrug conjugate; a recombinant protein; a fusion protein; a natural compound; a peptide; a PROteolysis-TArgeting Chimera (PROTAC); a targeted therapy; or any combination thereof, e.g., a described in further detail below. In some embodiments, the anti-cancer therapy is an immunotherapy, such as any immunotherapy known in the art or described herein (e.g., a checkpoint inhibitor, cancer vaccine, cell-based therapy, T cell receptor (TCR)-based therapy, adjuvant immunotherapy, cytokine immunotherapy, or oncolytic virus therapy). In someembodiments, the anti-cancer therapy is an immune checkpoint inhibitor, such as any immune checkpoint inhibitor described herein or known in the art.

[0129] In some embodiments, the anti-cancer therapy comprises an immunotherapy (i.e., a cancer immunotherapy), such as a checkpoint inhibitor, cancer vaccine, cell-based therapy, T cell receptor (TCR)-based therapy, adjuvant immunotherapy, cytokine immunotherapy, and oncolytic virus therapy, as well as any combination thereof. In some embodiments, the cancer immunotherapy comprises a small molecule, nucleic acid, polypeptide, carbohydrate, toxin, cell-based agent, or cell-binding agent. Examples of cancer immunotherapies are described in greater detail herein but are not intended to be limiting. In some embodiments, the cancer immunotherapy activates one or more aspects of the immune system to attack a cell (e.g., a tumor cell) that expresses a neoantigen. The cancer immunotherapies of the present disclosure are contemplated for use as monotherapies, or in combination approaches comprising two or more in any combination or number, subject to medical judgement. Any of the cancer immunotherapies (optionally as monotherapies or in combination with another cancer immunotherapy or other therapeutic agent described herein) may find use in any of the methods described herein.

[0130] In some embodiments, the cancer immunotherapy comprises a cancer vaccine. A range of cancer vaccines have been tested that employ different approaches to promoting an immune response against a cancer (see, e.g., Emens L A, Expert Opin Emerg Drugs 13(2): 295-308 (2008) and US20190367613). Approaches have been designed to enhance the response of B cells, T cells, or professional antigen-presenting cells against tumors. Exemplary types of cancer vaccines include, but are not limited to, DNA-based vaccines, RNA-based vaccines, virus transduced vaccines, peptide-based vaccines, dendritic cell vaccines, oncolytic viruses, whole tumor cell vaccines, tumor antigen vaccines, etc. In some embodiments, the cancer vaccine can be prophylactic or therapeutic. In some embodiments, the cancer vaccine is formulated as a peptide-based vaccine, a nucleic acid-based vaccine, an antibody-based vaccine, or a cell-based vaccine. For example, a vaccine composition can include naked cDNA in cationic lipid formulations; lipopeptides (e.g., Vitiello, A. et al, J. Clin. Invest. 95:341, 1995); naked cDNA or peptides encapsulated, e.g., in poly(DL-lactide- co-glycolide) (“PLG”) microspheres (see, e.g., Eldridge, et ah, Molec. Immunol. 28:287-294, 1991: Alonso et al, Vaccine 12:299- 306, 1994; Jones et al, Vaccine 13:675-681, 1995); peptide composition contained in immune stimulating complexes (ISCOMS) (e.g., Takahashi et al, Nature 344:873-875, 1990; Hu et al, Clin. Exp. Immunol. 113:235-243, 1998); or multiple antigen peptide systems (MAPs) (see e.g., Tam, J. P., Proc. Natl Acad. Sci. U.S.A.85:5409-5413, 1988; Tam, J.P., J. Immunol. Methods 196: 17-32, 1996). In some embodiments, a cancer vaccine is formulated as a peptide-based vaccine, or nucleic acidbased vaccine in which the nucleic acid encodes the polypeptides. In some embodiments, a cancer vaccine is formulated as an antibody-based vaccine. In some embodiments, a cancer vaccine is formulated as a cell-based vaccine. In some embodiments, the cancer vaccine is a peptide cancer vaccine, which in some embodiments is a personalized peptide vaccine. In some embodiments, the cancer vaccine is a multivalent long peptide, a multiple peptide, a peptide mixture, a hybrid peptide, or a peptide pulsed dendritic cell vaccine (see, e.g., Yamada et al, Cancer Sci, 104: 14-21, 2013). In some embodiments, such cancer vaccines augment an anti-cancer response.

[0131] In some embodiments, the cancer vaccine comprises a polynucleotide that encodes a neoantigen, e.g., neoantigen(s) expressed by a cancer of the disclosure, such as a cancer in an individual. In some embodiments, the cancer vaccine comprises DNA that encodes the neoantigen(s). In some embodiments, the cancer vaccine comprises RNA that encodes the neoantigen(s). In some embodiments, the cancer vaccine comprises a polynucleotide that encodes the neoantigen(s). In some embodiments, the cancer vaccine further comprises one or more additional antigens, neoantigens, or other sequences that promote antigen presentation and / or an immune response. In some embodiments, the polynucleotide is complexed with one or more additional agents, such as a liposome or lipoplex. In some embodiments, the polynucleotide(s) are taken up and translated by antigen presenting cells (APCs), which then present the neoantigen(s) via MHC class I on the APC cell surface.

[0132] In some embodiments, the cancer vaccine is selected from sipuleucel-T (e.g., Provenge®, Dendreon / V aleant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate -resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (e.g., Imlygic®, BioVex / Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, the cancer vaccine is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (e.g., Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell cancer(NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117), metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676), and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV-lh68 / GLV-lhl53, Genelux GmbH), vaccinia viruses engineered to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCTO 1443260), fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818); anti-gplOO; STINGVAX; GV AX; DCVaxL; and DNX-2401. In some embodiments, the cancer vaccine is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TGO1 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT- 123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2F-delta24-hTNFa-IRES-hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8+ T cell response. In some embodiments, the cancer vaccine comprises a vector-based tumor antigen vaccine. Vectorbased tumor antigen vaccines can be used as a way to provide a steady supply of antigens to stimulate an anti-tumor immune response. In some embodiments, vectors encoding for tumor antigens are injected into an individual (possibly with pro-inflammatory or other attractants such as GM-CSF), taken up by cells in vivo to make the specific antigens, which then provoke the desired immune response. In some embodiments, vectors may be used to deliver more than one tumor antigen at a time, to increase the immune response. In addition, recombinant virus, bacteria or yeast vectors can trigger their own immune responses, which may also enhance the overall immune response.

[0133] In some embodiments, the cancer vaccine comprises a DNA-based vaccine. In some embodiments, DNA-based vaccines can be employed to stimulate an anti-tumor response.The ability of directly injected DNA that encodes an antigenic protein, to elicit a protective immune response has been demonstrated in numerous experimental systems. Vaccination through directly injecting DNA that encodes an antigenic protein, to elicit a protective immune response often produces both cell-mediated and humoral responses. Moreover, reproducible immune responses to DNA encoding various antigens have been reported in mice that last essentially for the lifetime of the animal (see, e.g., Yankauckas et al.(1993) DNA Cell Biol., 12: 771-776). In some embodiments, plasmid (or other vector) DNA that includes a sequence encoding a protein operably linked to regulatory elements required for gene expression is administered to individuals (e.g. human patients, non-human mammals, etc.). In some embodiments, the cells of the individual take up the administered DNA and the coding sequence is expressed. In some embodiments, the antigen so produced becomes a target against which an immune response is directed.

[0134] In some embodiments, the cancer vaccine comprises an RNA-based vaccine. In some embodiments, RNA-based vaccines can be employed to stimulate an anti-tumor response. In some embodiments, RNA-based vaccines comprise a self-replicating RNA molecule. In some embodiments, the self-replicating RNA molecule may be an alphavirus-derived RNA replicon. Self-replicating RNA (or "SAM") molecules are well known in the art and can be produced by using replication elements derived from, e.g., alphaviruses, and substituting the structural viral proteins with a nucleotide sequence encoding a protein of interest. A selfreplicating RNA molecule is typically a +-strand molecule which can be directly translated after delivery to a cell, and this translation provides a RNA-dependent RNA polymerase which then produces both antisense and sense transcripts from the delivered RNA. Thus, the delivered RNA leads to the production of multiple daughter RNAs. These daughter RNAs, as well as collinear subgenomic transcripts, may be translated themselves to provide in situ expression of an encoded polypeptide, or may be transcribed to provide further transcripts with the same sense as the delivered RNA which are translated to provide in situ expression of the antigen.

[0135] In some embodiments, the cancer immunotherapy comprises a cell-based therapy. In some embodiments, the cancer immunotherapy comprises a T cell-based therapy. In some embodiments, the cancer immunotherapy comprises an adoptive therapy, e.g., an adoptive T cell-based therapy. In some embodiments, the T cells are autologous or allogeneic to the recipient. In some embodiments, the T cells are CD 8+ T cells. In some embodiments, the T cells are CD4+ T cells. Adoptive immunotherapy refers to a therapeutic approach for treating cancer or infectious diseases in which immune cells are administered to a host with the aimthat the cells mediate either directly or indirectly specific immunity to (i.e., mount an immune response directed against) cancer cells. In some embodiments, the immune response results in inhibition of tumor and / or metastatic cell growth and / or proliferation, and in related embodiments, results in neoplastic cell death and / or resorption. The immune cells can be derived from a different organism / host (exogenous immune cells) or can be cells obtained from the subject organism (autologous immune cells). In some embodiments, the immune cells (e.g., autologous or allogeneic T cells (e.g., regulatory T cells, CD4+ T cells, CD8+ T cells, or gamma-delta T cells), NK cells, invariant NK cells, or NKT cells) can be genetically engineered to express antigen receptors such as engineered TCRs and / or chimeric antigen receptors (CARs). For example, the host cells (e.g., autologous or allogeneic T-cells) are modified to express a T cell receptor (TCR) having antigenic specificity for a cancer antigen. In some embodiments, NK cells are engineered to express a TCR. The NK cells may be further engineered to express a CAR. Multiple CARs and / or TCRs, such as to different antigens, may be added to a single cell type, such as T cells or NK cells. In some embodiments, the cells comprise one or more nucleic acids / expression constructs / vectors introduced via genetic engineering that encode one or more antigen receptors, and genetically engineered products of such nucleic acids. In some embodiments, the nucleic acids are heterologous, i.e., normally not present in a cell or sample obtained from the cell, such as one obtained from another organism or cell, which for example, is not ordinarily found in the cell being engineered and / or an organism from which such cell is derived. In some embodiments, the nucleic acids are not naturally occurring, such as a nucleic acid not found in nature (e.g. chimeric). In some embodiments, a population of immune cells can be obtained from a subject in need of therapy or suffering from a disease associated with reduced immune cell activity. Thus, the cells will be autologous to the subject in need of therapy. In some embodiments, a population of immune cells can be obtained from a donor, such as a histocompatibility-matched donor. In some embodiments, the immune cell population can be harvested from the peripheral blood, cord blood, bone marrow, spleen, or any other organ / tissue in which immune cells reside in said subject or donor. In some embodiments, the immune cells can be isolated from a pool of subjects and / or donors, such as from pooled cord blood. In some embodiments, when the population of immune cells is obtained from a donor distinct from the subject, the donor may be allogeneic, provided the cells obtained are subject-compatible, in that they can be introduced into the subject. In some embodiments, allogeneic donor cells may or may not be human-leukocyte-antigen (HLA)-compatible. Insome embodiments, to be rendered subject-compatible, allogeneic cells can be treated to reduce immunogenicity.

[0136] In some embodiments, the cell-based therapy comprises a T cell-based therapy, such as autologous cells, e.g., tumor-infiltrating lymphocytes (TILs); T cells activated ex-vivo using autologous DCs, lymphocytes, artificial antigen-presenting cells (APCs) or beads coated with T cell ligands and activating antibodies, or cells isolated by virtue of capturing target cell membrane; allogeneic cells naturally expressing anti-host tumor T cell receptor (TCR); and non-tumor- specific autologous or allogeneic cells genetically reprogrammed or "redirected" to express tumor-reactive TCR or chimeric TCR molecules displaying antibodylike tumor recognition capacity known as "T- bodies". Several approaches for the isolation, derivation, engineering or modification, activation, and expansion of functional anti-tumor effector cells have been described in the last two decades and may be used according to any of the methods provided herein. In some embodiments, the T cells are derived from the blood, bone marrow, lymph, umbilical cord, or lymphoid organs. In some embodiments, the cells are human cells. In some embodiments, the cells are primary cells, such as those isolated directly from a subject and / or isolated from a subject and frozen. In some embodiments, the cells include one or more subsets of T cells or other cell types, such as whole T cell populations, CD4+ cells, CD8+ cells, and subpopulations thereof, such as those defined by function, activation state, maturity, potential for differentiation, expansion, recirculation, localization, and / or persistence capacities, antigen- specificity, type of antigen receptor, presence in a particular organ or compartment, marker or cytokine secretion profile, and / or degree of differentiation. In some embodiments, the cells may be allogeneic and / or autologous. In some embodiments, such as for off-the-shelf technologies, the cells are pluripotent and / or multipotent, such as stem cells, such as induced pluripotent stem cells (iPSCs).

[0137] In some embodiments, the T cell-based therapy comprises a chimeric antigen receptor (CAR)-T cell-based therapy. This approach involves engineering a CAR that specifically binds to an antigen of interest and comprises one or more intracellular signaling domains for T cell activation. The CAR is then expressed on the surface of engineered T cells (CAR-T) and administered to a patient, leading to a T-cell-specific immune response against cancer cells expressing the antigen. In some embodiments, the CAR specifically binds a neoantigen, such as a neoantigen expressed in a cancer of a disclosure, e.g., in an individual.

[0138] In some embodiments, the T cell-based therapy comprises T cells expressing a recombinant T cell receptor (TCR). This approach involves identifying a TCR thatspecifically binds to an antigen of interest, which is then used to replace the endogenous or native TCR on the surface of engineered T cells that are administered to a patient, leading to a T-cell-specific immune response against cancer cells expressing the antigen. In some embodiments, the recombinant TCR specifically binds a neoantigen expressed in a cancer of a disclosure, e.g., in an individual.

[0139] In some embodiments, the T cell-based therapy comprises tumor-infiltrating lymphocytes (TILs). For example, TILs can be isolated from a tumor or cancer of the present disclosure, then isolated and expanded in vitro. Some or all of these TILs may specifically recognize an antigen expressed by the tumor or cancer of the present disclosure. In some embodiments, the TILs are exposed to one or more neoantigens, e.g., expressed in a cancer of a disclosure, in vitro after isolation. TILs are then administered to the patient (optionally in combination with one or more cytokines or other immune-stimulating substances).

[0140] In some embodiments, the cell-based therapy comprises a natural killer (NK) cellbased therapy. Natural killer (NK) cells are a subpopulation of lymphocytes that have spontaneous cytotoxicity against a variety of tumor cells, virus-infected cells, and some normal cells in the bone marrow and thymus. NK cells are critical effectors of the early innate immune response toward transformed and virus-infected cells. NK cells can be detected by specific surface markers, such as CD16, CD56, and CD8 in humans. NK cells do not express T-cell antigen receptors, the pan T marker CD3, or surface immunoglobulin B cell receptors. In some embodiments, NK cells are derived from human peripheral blood mononuclear cells (PBMC), unstimulated leukapheresis products (PBSC), human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), bone marrow, or umbilical cord blood by methods well known in the art.

[0141] In some embodiments, the cell-based therapy comprises a dendritic cell (DC)-based therapy, e.g., a dendritic cell vaccine. In some embodiments, the DC vaccine comprises antigen-presenting cells that are able to induce specific T cell immunity, which are harvested from the patient or from a donor. In some embodiments, the DC vaccine can then be exposed in vitro to a peptide antigen, for which T cells are to be generated in the patient. In some embodiments, dendritic cells loaded with the antigen are then injected back into the patient. In some embodiments, immunization may be repeated multiple times if desired. Methods for harvesting, expanding, and administering dendritic cells are known in the art; see, e.g., W02019178081. Dendritic cell vaccines (such as Sipuleucel-T, also known as APC8015 and PROVENGE®) are vaccines that involve administration of dendritic cells that act as APCs topresent one or more cancer- specific antigens to the patient’s immune system. In some embodiments, the dendritic cells are autologous or allogeneic to the recipient.

[0142] In some embodiments, the cancer immunotherapy comprises a TCR-based therapy. In some embodiments, the cancer immunotherapy comprises administration of one or more TCRs or TCR-based therapeutics that specifically bind an antigen expressed by a cancer of the present disclosure, e.g., a neoantigen expressed in a cancer of a disclosure, e.g., in an individual. The TCR-based therapeutic may further include a moiety that binds an immune cell (e.g., a T cell), such as an antibody or antibody fragment that specifically binds a T cell surface protein or receptor (e.g., an anti-CD3 antibody or antibody fragment).

[0143] In some embodiments, the immunotherapy comprises adjuvant immunotherapy. Adjuvant immunotherapy comprises the use of one or more agents that activate components of the innate immune system, e.g., HILTONOL® (imiquimod), which targets the TLR7 pathway.

[0144] In some embodiments, the immunotherapy comprises cytokine immunotherapy. Cytokine immunotherapy comprises the use of one or more cytokines that activate components of the immune system. Examples include, but are not limited to, aldesleukin (e.g., PROLEUKIN®; interleukin-2), interferon alfa-2a (e.g., ROFERON®-A), interferon alfa-2b (e.g., INTRON®-A), and peginterferon alfa-2b (e.g., PEGINTRON®).

[0145] In some embodiments, the immunotherapy comprises oncolytic virus therapy. Oncolytic virus therapy uses genetically modified viruses to replicate in and kill cancer cells, leading to the release of antigens that stimulate an immune response. In some embodiments, replication-competent oncolytic viruses expressing a tumor antigen comprise any naturally occurring (e.g., from a “field source”) or modified replication-competent oncolytic virus. In some embodiments, the oncolytic virus, in addition to expressing a tumor antigen, may be modified to increase selectivity of the virus for cancer cells. In some embodiments, replication-competent oncolytic viruses include, but are not limited to, oncolytic viruses that are a member in the family of myoviridae, siphoviridae, podpviridae, teciviridae, corticoviridae, plasmaviridae, lipothrixviridae, fuselloviridae, poxyiridae, iridoviridae, phycodnaviridae, baculoviridae, herpesviridae, adnoviridae, papovaviridae, polydnaviridae, inoviridae, microviridae, geminiviridae, circoviridae, parvoviridae, hcpadnaviridae, retroviridae, cyctoviridae, reoviridae, birnaviridae, paramyxoviridae, rhabdoviridae, filoviridae, orthomyxoviridae, bunyaviridae, arenaviridae, Leviviridae, picornaviridae, sequiviridae, comoviridae, potyviridae, caliciviridae, astroviridae, nodaviridae, tetraviridae, tombusviridae, coronaviridae, glaviviridae, togaviridae, and bamaviridae. In someembodiments, replication-competent oncolytic viruses include adenovirus, retrovirus, reovirus, rhabdovirus, Newcastle Disease virus (NDV), polyoma virus, vaccinia virus (VacV), herpes simplex virus, picomavirus, coxsackie virus and parvovirus. In some embodiments, a replicative oncolytic vaccinia virus expressing a tumor antigen may be engineered to lack one or more functional genes in order to increase the cancer selectivity of the virus. In some embodiments, an oncolytic vaccinia virus is engineered to lack thymidine kinase (TK) activity. In some embodiments, the oncolytic vaccinia virus may be engineered to lack vaccinia virus growth factor (VGF). In some embodiments, an oncolytic vaccinia virus may be engineered to lack both VGF and TK activity. In some embodiments, an oncolytic vaccinia virus may be engineered to lack one or more genes involved in evading host interferon (IFN) response such as E3L, K3L, B18R, or B8R. In some embodiments, a replicative oncolytic vaccinia virus is a Western Reserve, Copenhagen, Lister or Wyeth strain and lacks a functional TK gene. In some embodiments, the oncolytic vaccinia virus is a Western Reserve, Copenhagen, Lister or Wyeth strain lacking a functional B18R and / or B8R gene. In some embodiments, a replicative oncolytic vaccinia virus expressing a tumor antigen may be locally or systemically administered to a subject, e.g. via intratumoral, intraperitoneal, intravenous, intra-arterial, intramuscular, intradermal, intracranial, subcutaneous, or intranasal administration.

[0146] In some embodiments, the anti-cancer therapy comprises an immune checkpoint inhibitor. In some embodiments, the methods provided herein comprise administering to an individual an effective amount of an immune checkpoint inhibitor. As is known in the art, a checkpoint inhibitor targets at least one immune checkpoint protein to alter the regulation of an immune response. Immune checkpoint proteins include, e.g., CTLA4, PD-L1, PD-1, PD- L2, VISTA, B7-H2, B7-H3, B7-H4, B7-H6, 2B4, ICOS, HVEM, CEACAM, LAIR1, CD80, CD86, CD276, VTCN1, MHC class I, MHC class II, GALS, adenosine, TGFR, CSF1R, MICA / B, arginase, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, LAG-3, BTLA, IDO, 0X40, and A2aR. In some embodiments, molecules involved in regulating immune checkpoints include, but are not limited to: PD-1 (CD279), PD-L1 (B7- Hl, CD274), PD-L2 (B7-CD, CD273), CTLA-4 (CD152), HVEM, BTLA (CD272), a killercell immunoglobulin-like receptor (KIR), LAG-3 (CD223), TIM-3 (HAVCR2), CEACAM, CEACAM-1, CEACAM-3, CEACAM-5, GAL9, VISTA (PD-1H), TIGIT, LAIR1, CD160, 2B4, TGFRbeta, A2AR, GITR (CD357), CD80 (B7-1), CD86 (B7-2), CD276 (B7-H3), VTCNI (B7-H4), MHC class I, MHC class II, GALS, adenosine, TGFR, B7-H1, 0X40(CD134), CD94 (KLRD1), CD137 (4-1BB), CD137L (4-1BBL), CD40, IDO, CSF1R, CD40L, CD47, CD70 (CD27L), CD226, HHLA2, ICOS (CD278), ICOSL (CD275), LIGHT (TNFSF14, CD258), NKG2a, NKG2d, OX40L (CD134L), PVR (NECL5, CD155), SIRPa, MICA / B, and / or arginase. In some embodiments, an immune checkpoint inhibitor (i.e., a checkpoint inhibitor) decreases the activity of a checkpoint protein that negatively regulates immune cell function, e.g., in order to enhance T cell activation and / or an anti-cancer immune response. In other embodiments, a checkpoint inhibitor increases the activity of a checkpoint protein that positively regulates immune cell function, e.g., in order to enhance T cell activation and / or an anti-cancer immune response. In some embodiments, the checkpoint inhibitor is an antibody. Examples of checkpoint inhibitors include, without limitation, a PD- 1 axis binding antagonist, a PD-L1 axis binding antagonist (e.g., an anti-PD-Ll antibody, e.g., atezolizumab (MPDL3280A)), an antagonist directed against a co-inhibitory molecule (e.g., a CTLA4 antagonist (e.g., an anti-CTLA4 antibody), a TIM-3 antagonist (e.g., an anti- TIM-3 antibody), or a LAG-3 antagonist (e.g., an anti-LAG-3 antibody)), or any combination thereof. In some embodiments, the immune checkpoint inhibitors comprise drugs such as small molecules, recombinant forms of ligand or receptors, or antibodies, such as human antibodies (see, e.g., International Patent Publication W02015016718; Pardoll, Nat Rev Cancer, 12(4): 252-64, 2012; both incorporated herein by reference). In some embodiments, known inhibitors of immune checkpoint proteins or analogs thereof may be used, in particular chimerized, humanized or human forms of antibodies may be used.

[0147] In some embodiments, the checkpoint inhibitor is a PD-L1 axis binding antagonist. PD-1 (programmed death 1) is also referred to in the art as "programmed cell death 1," "PDCD1," "CD279," and "SLEB2." An exemplary human PD-1 is shown in UniProtKB / Swiss-Prot Accession No. Q15116. PD-L1 (programmed death ligand 1) is also referred to in the art as "programmed cell death 1 ligand 1,” "PDCD1 LG1," "CD274," "B7- H," and "PDL1." An exemplary human PD-L1 is shown in UniProtKB / Swiss-Prot Accession No.Q9NZQ7.1. PD-L2 (programmed death ligand 2) is also referred to in the art as "programmed cell death 1 ligand 2," "PDCD1 LG2," "CD273," "B7-DC," "Btdc," and "PDL2." An exemplary human PD-L2 is shown in UniProtKB / Swiss-Prot Accession No. Q9BQ51. In some instances, PD-1, PD-L1, and PD-L2 are human PD-1, PD-L1 and PD-L2.

[0148] In some embodiments, the checkpoint inhibitor is a PD-1 binding antagonist / inhibitor. In some embodiments, the PD-1 binding antagonist / inhibitor is a molecule that inhibits the binding of PD-1 to its ligand binding partners. In a specific embodiment, the PD-1 ligand binding partners are PD-L1 and / or PD-L2. In someembodiments, the checkpoint inhibitor is a PD-L1 binding antagonist / inhibitor. In some embodiments, a PD-L1 binding antagonist / inhibitor is a molecule that inhibits the binding of PD-L1 to its binding ligands. In a specific embodiment, PD-L1 binding partners are PD-1 and / or B7-1. In some embodiments, the checkpoint inhibitor is a PD-L2 binding antagonist / inhibitor. In some embodiments, the PD-L2 binding antagonist / inhibitor is a molecule that inhibits the binding of PD-L2 to its ligand binding partners. In a specific embodiment, the PD-L2 binding ligand partner is PD- 1. The antagonist or inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. In some embodiments, the PD-1, PD-L1, or PD-L1 binding antagonist or inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., antibody), a carbohydrate, a lipid, a metal, or a toxin.

[0149] In some instances, the PD-1 binding antagonist or inhibitor is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), for example, as described below. In some instances, the anti-PD-1 antibody is one or more of MDX-1 106 (nivolumab), MK-3475 (pembrolizumab, e.g., Keytruda®), MEDI-0680 (AMP-514), PDR001, REGN2810, MGA-012, JNJ-63723283, BI 754091, BGB-108, BGB-A317, JS-001, STI-Al l 10, INCSHR-1210, PF-06801591, TSR-042, AM0001, ENUM 244C8, ENUM 388D4, cemiplimab, or dostarlimab. In other instances, the PD-1 binding antagonist or inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence)). In some instances, the PD-1 binding antagonist or inhibitor is AMP- 224. Other examples of anti-PD-1 antibodies include, but are not limited to, MEDI- 0680 (AMP-514; AstraZeneca), PDR001 (CAS Registry No. 1859072-53-9; Novartis), REGN2810 (e.g., LIBTAYO® or cemiplimab-rwlc; Regeneron), BGB-108 (BeiGene), BGB- A317 (BeiGene), BI 754091, JS-001 (Shanghai Junshi), STI-Al l 10 (Sorrento), INCSHR- 1210 (Incyte), PF-06801591 (Pfizer), TSR-042 (also known as ANB011;Tesaro / AnaptysBio), AM0001 (ARMO Biosciences), ENUM 244C8 (Enumeral Biomedical Holdings), or ENUM 388D4 (Enumeral Biomedical Holdings). In some embodiments, the PD-1 axis binding antagonist or inhibitor comprises tislelizumab (BGB-A317), BGB-108, STI-Al l 10, AM0001, BI 754091, sintilimab (IBI308), cetrelimab (JNJ-63723283), toripalimab (JS-001), camrelizumab (SHR-1210, INCSHR-1210, HR-301210), MEDI-0680 (AMP-514), MGA-012 (INCMGA 0012), nivolumab (BMS-936558, MDX1106, ONO-4538), spartalizumab (PDR001), pembrolizumab (MK-3475, SCH 900475, e.g., Keytruda®), PF-06801591, cemiplimab (REGN-2810, REGEN2810), dostarlimab (TSR-042, ANB011),FITC-YT-16 (PD-1 binding peptide), APL-501 or CBT-501 or genolimzumab (GB-226), AB- 122, AK105, AMG 404, BCD- 100, F520, HLX10, HX008, JTX-4014, LZM009, Sym021, PSB205, AMP-224 (fusion protein targeting PD-1), CX-188 (PD-1 probody), AGEN-2034, GLS-010, budigalimab (ABBV-181), AK-103, BAT-1306, CS-1003, AM- 0001, TILT-123, BH-2922, BH-2941, BH-2950, ENUM-244C8, ENUM-388D4, HAB-21, H EISCOI 11-003, IKT-202, MCLA-134, MT-17000, PEGMP-7, PRS-332, RXI-762, STI- 1110, VXM-10, XmAb-23104, AK-112, HLX-20, SSI-361, AT-16201, SNA-01, AB122, PD1-PIK, PE-06936308, RG-7769, CAB PD-1 Abs, AK-123, MEDI-3387, MEDI-5771, 4H1128Z-E27, REMD-288, SG-001, BY-24.3, CB-201, IBL319, ONCR-177, Max-1, CS- 4100, JBL426, CCC-0701, or CCX- 4503, or derivatives thereof, or an antibody that competes with any of the preceding.

[0150] In some embodiments, the PD-L1 binding antagonist or inhibitor is a small molecule that inhibits PD-1. In some embodiments, the PD-L1 binding antagonist or inhibitor is a small molecule that inhibits PD-L1. In some embodiments, the PD-L1 binding antagonist or inhibitor is a small molecule that inhibits PD-L1 and VISTA or PD-L1 and TIM3. In some embodiments, the PD-L1 binding antagonist or inhibitor is CA-170 (also known as AUPM- 170). In some embodiments, the PD-L1 binding antagonist or inhibitor is an anti-PD-Ll antibody. In some embodiments, the anti-PD-Ll antibody can bind to a human PD-L1, for example a human PD-L1 as described above herein and / or as shown in UniProtKB / Swiss- Prot Accession No.Q9NZQ7.1, or a variant thereof. In some embodiments, the PD-L1 binding antagonist or inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., antibody), a carbohydrate, a lipid, a metal, or a toxin.

[0151] In some instances, the PD-L1 binding antagonist or inhibitor is an anti-PD-Ll antibody, for example, as described below. In some instances, the anti-PD-Ll antibody is capable of inhibiting the binding between PD-L1 and PD-1, and / or between PD-L1 and B7-1. In some instances, the anti-PD-Ll antibody is a monoclonal antibody. In some instances, the anti-PD-Ll antibody is an antibody fragment selected from a Lab, Eab'-SH, Ev, scEv, or (Eab')2 fragment. In some instances, the anti-PD-Ll antibody is a humanized antibody. In some instances, the anti-PD-Ll antibody is a human antibody. In some instances, the anti- PD-Ll antibody is selected from YW243.55.S70, MPDL3280A (atezolizumab), MDX-1 105, MEDI4736 (durvalumab), MSB0010718C (avelumab), LY3300054, STI-A1014, KN035, EAZ053, or CX-072. In some embodiments, the PD-L1 axis binding antagonist or inhibitor comprises atezolizumab, avelumab, durvalumab (imfinzi), BGB-A333, SHR-1316 (HTI- 1088), CK-301, BMS-936559, envafolimab (KN035, ASC22), CS1001, MDX-1105 (BMS-936559), LY3300054, STI-A1014, FAZ053, CX-072, INCB086550, GNS-1480, CA-170, CK-301, M-7824, HTI-1088 (HTI-131, SHR-1316), MSB-2311, AK- 106, AVA-004, BBI- 801, CA-327, CBA-0710, CBT-502, FPT-155, IKT-201, IKT-703, 10-103, JS-003, KD-033, KY-1003, MCLA-145, MT-5050, SNA-02, BCD-135, APL-502 (CBT-402 or TQB2450), IMC-001, KD-045, INBRX-105, KN-046, IMC-2102, IMC-2101, KD-005, IMM-2502, 89Zr-CX-072, 89Zr-DFO-6El l, KY-1055, MEDI-1109, MT-5594, SL-279252, DSP- 106, Gensci-047, REMD-290, N-809, PRS-344, FS-222, GEN-1046, BH-29xx, or FS-118, or a derivative thereof, or an antibody that competes with any of the preceding.

[0152] In some embodiments, the checkpoint inhibitor is an antagonist or inhibitor of CTLA4. In some embodiments, the checkpoint inhibitor is a small molecule antagonist or inhibitor of CTLA4. In some embodiments, the checkpoint inhibitor is an anti-CTLA4 antibody. CTLA4 is part of the CD28-B7 immunoglobulin superfamily of immune checkpoint molecules that acts to negatively regulate T cell activation, particularly CD28- dependent T cell responses. CTLA4 competes for binding to common ligands with CD28, such as CD80 (B7-1) and CD86 (B7-2), and binds to these ligands with higher affinity than CD28. Blocking CTLA4 activity (e.g., using an anti-CTLA4 antibody) is thought to enhance CD28-mediated costimulation (leading to increased T cell activation / priming), affect T cell development, and / or deplete Tregs (such as intratumoral Tregs). In some embodiments, the CTLA4 antagonist or inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., antibody), a carbohydrate, a lipid, a metal, or a toxin. In some embodiments, the CTLA-4 antagonist or inhibitor comprises ipilimumab (IBB 10, BMS-734016, MDX010, MDX- CTLA4, MEDI4736), tremelimumab (CP-675, CP-675,206), APL-509, AGEN1884, CS1002, AGEN1181, Abatacept (Orencia, BMS-188667, RG2077), BCD-145, ONC-392, ADU-1604, REGN4659, ADG116, KN044, KN046, or a derivative thereof, or an antibody that competes with any of the preceding.

[0153] In some embodiments, the immune checkpoint inhibitor comprises a LAG-3 antagonist or inhibitor (e.g., an antibody, an antibody conjugate, or an antigenbinding fragment thereof). In some embodiments, the LAG-3 antagonist or inhibitor comprises a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In some embodiments, the LAG-3 antagonist or inhibitor comprises a small molecule. In some embodiments, the LAG-3 antagonist or inhibitor comprises a LAG-3 binding agent. In some embodiments, the LAG-3 antagonist or inhibitor comprises an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In some embodiments, the LAG-3 antagonist or inhibitor comprises eftilagimod alpha (IMP321,IMP-321, EDDP-202, EOC-202), relatlimab (BMS-986016), GSK2831781 (IMP-731), LAG525 (IMP701), TSR-033, EVIP321 (soluble LAG-3 protein), BI 754111, IMP761, REGN3767, MK-4280, MGD-013, XmAb22841, INCAGN-2385, ENUM-006, AVA-017, AM-0003, iOnctura anti-LAG-3 antibody, Arcus Biosciences LAG-3 antibody, Sym022, a derivative thereof, or an antibody that competes with any of the preceding.

[0154] In some embodiments, the immune checkpoint inhibitor is monovalent and / or monospecific. In some embodiments, the immune checkpoint inhibitor is multivalent and / or multispecific.

[0155] In some embodiments, an anti-cancer therapy of the disclosure (e.g., an immunotherapy) is administered in combination with an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is any anti-cancer therapy known in the art or described herein. In some embodiments, the additional anti-cancer therapy comprises one or more of a small molecule inhibitor, a chemotherapeutic agent, a cancer immunotherapy, an antibody, a cellular therapy, a nucleic acid, a surgery, a radiotherapy, an anti-angiogenic therapy, an anti-DNA repair therapy, an anti-inflammatory therapy, an anti- neoplastic agent, a growth inhibitory agent, a cytotoxic agent, a vaccine, a small molecule agonist, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a PROteolysis-TArgeting Chimera (PROTAC), or any combination thereof.

[0156] In some embodiments, an anti-cancer therapy of the disclosure comprises a cyclin- dependent kinase (CDK) inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the CDK inhibitor inhibits CDK4. In some embodiments, the CDK inhibitor inhibits Cyclin D / CDK4. In some embodiments, the CDK inhibitor is (a) a small molecule that inhibits one or more enzymatic activities of CDK4, (b) an antibody that inhibits one or more activities of CDK4 (e.g., by binding to and inhibiting one or more activities of CDK4, binding to and inhibiting expression of CDK4, and / or binding to and inhibiting one or more activities of a cell expressing CDK4, such as by inducing antibody-dependent cellular cytotoxicity, ADCC, or phagocytosis, ADCP), or (c) a nucleic acid that inhibits expression of CDK4 (e.g., an antisense oligonucleotide, miRNA, siRNA, morpholino, CRISPR-based therapeutic, and the like). In some embodiments, the CDK inhibitor inhibits CDK4 and CDK6. In some embodiments, the CDK inhibitor is a small molecule inhibitor of CDK4 (e.g., a competitive or non-competitive inhibitor). Non-limiting examples of CDK inhibitors include palbociclib, ribociclib, and abemaciclib, as well as pharmaceutically acceptable salts thereof.

[0157] In some embodiments, an anti-cancer therapy of the disclosure comprises a murine double minute 2 homolog (MDM2) inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the MDM2 inhibitor is (a) a small molecule that inhibits one or more activities of MDM2 (e.g., binding to p53), (b) an antibody that inhibits one or more activities of MDM2 (e.g., by binding to and inhibiting one or more activities of MDM2, binding to and inhibiting expression of MDM2, and / or binding to and inhibiting one or more activities of a cell expressing MDM2, such as by inducing antibody-dependent cellular cytotoxicity, ADCC, or phagocytosis, ADCP), or (c) a nucleic acid that inhibits expression of MDM2 (e.g., an antisense oligonucleotide, miRNA, siRNA, morpholino, CRISPR-based therapeutic, and the like). In some embodiments, the MDM2 inhibitor is a small molecule inhibitor of MDM2 (e.g., a competitive or noncompetitive inhibitor). Non-limiting examples of MDM2 inhibitors include nutlin-3a, RG7112, idasanutlin (RG7388), AMG-232, MI-63, MI-291, MI-391, MI-77301 (SAR405838), APG-115, DS-3032b, NVP-CGM097, and HDM-201 (siremadlin), as well as pharmaceutically acceptable salts thereof. In some embodiments, the MDM2 inhibitor inhibits or disrupts interaction between MDM2 and p53.

[0158] In some embodiments, an anti-cancer therapy of the disclosure comprises (alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor) one or more of an antimetabolite, DNA-damaging agent, or platinum-containing therapeutic (e.g., 5- azacitadine, 5-fluorouracil, acadesine, busulfan, carboplatin, cisplatin, chlorambucil, CPT-11, cytarabine, daunorubicin, decitabine, doxorubicin, etoposide, fludarabine, gemcitabine, idarubicin, radiation, oxaliplatin, temozolomide, topotecan, trabectedin, GSK2830371, or rucaparib); a pro-apoptotic agent (e.g., a BCL2 inhibitor or downregulator, SMAC mimetic, or TRAIL agonist such as ABT-263, ABT-737, oridonin, venetoclax, combination of venetoclax and an anti-CD20 antibody such as obinutuzumab or rituximab, 1396-11, ABT- 10, SM-164, D269H / E195R, or rhTRAIL); a tyrosine kinase inhibitor; an inhibitor of RAS, RAF, MEK, or the MAPK pathway (e.g., AZD6244, dabrafenib, LGX818, PD0325901, pimasertib, trametinib, or vemurafenib); an inhibitor of PI3K, mTOR, or Akt; a CDK inhibitor; a PKC inhibitor (e.g., LXS196 or sotrastaurin); an antibody-based therapeutic (e.g., an anti-PD-1 or anti-PDLl antibody such as atezolizumab, pembrolizumab, nivolumab, or spartalizumab; an anti-CD20 antibody such as obinutuzumab or rituximab; or an anti-DR5 antibody such as drozitumab); a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or MG- 132); an HD AC inhibitor (e.g., SAHA or VPA); an antibiotic (e.g., actinomycin D); a zinc-containing therapeutic (e.g., zinc or ZMC1); an HSP inhibitor (e.g.,geldanamycin); an ATPase inhibitor (e.g., archazolid); a mitotic inhibitor (e.g., paclitaxel or vincristine); metformin; methotrexate; tanshinone IIA; and / or P5091.

[0159] In some embodiments, the anti-cancer therapy comprises an immunoregulatory molecule or a cytokine, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. An immunoregulatory profile is required to trigger an efficient immune response and balance the immunity in a subject. Examples of suitable immunoregulatory cytokines include, but are not limited to, interferons (e.g., IFNa, IFNP and IFNy), interleukins (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL- 10, IL- 12 and IL-20), tumor necrosis factors (e.g., TNFa and TNFP), erythropoietin (EPO), FLT-3 ligand, glplO, TCA-3, MCP-1, MIF, MIP-la, MIP-ip, Rantes, macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), or granulocyte-macrophage colony stimulating factor (GM-CSF), as well as functional fragments thereof. In some embodiments, any immunomodulatory chemokine that binds to a chemokine receptor, i.e., a CXC, CC, C, or CX3C chemokine receptor, can be used in the context of the present disclosure. Examples of chemokines include, but are not limited to, MIP-3a (Lax), MIP-3P, Hcc-1, MPIF-1, MPIF- 2, MCP-2, MCP-3, MCP-4, MCP-5, Eotaxin, Tare, Elc, 1309, IL-8, GCP-2 Groa, Gro-P, Nap-2, Ena-78, Ip-10, MIG, LTac, SDF-1, or BCA-1 (Bic), as well as functional fragments thereof. In some embodiments, the immunoregulatory molecule is included with any of the treatments provided herein.

[0160] In some embodiments, an anti-cancer therapy of the disclosure comprises a tyrosine kinase inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the tyrosine kinase inhibitor is (a) a small molecule that inhibits one or more enzymatic activities of a tyrosine kinase, (b) an antibody that inhibits one or more activities of a tyrosine kinase (e.g., by binding to and inhibiting one or more activities of the tyrosine kinase, binding to and inhibiting expression, such as cell surface expression, of the tyrosine kinase, and / or binding to and inhibiting one or more activities of a cell expressing the tyrosine kinase, such as by inducing antibody-dependent cellular cytotoxicity, ADCC, or phagocytosis, ADCP), or (c) a nucleic acid that inhibits expression of a tyrosine kinase (e.g., an antisense oligonucleotide, miRNA, siRNA, morpholino, CRISPR-based therapeutic, and the like). In some embodiments, the tyrosine kinase inhibitor is a small molecule inhibitor of a tyrosine kinase (e.g., a competitive or noncompetitive inhibitor). Non-limiting examples of tyrosine kinase inhibitors include imatinib, crenolanib, linifanib, ninetedanib, axitinib, dasatinib, imetelstat, midostaurin, pazopanib, sorafenib, sunitinb, motesanib, masitinib, vatalanib, cabozanitinib, tivozanib, OSL930,K18751, telatinib, dovitinib, tyrphostin AG 1296, and amuvatinib, as well as pharmaceutically acceptable salts thereof.

[0161] In some embodiments, an anti-cancer therapy of the disclosure comprises a mitogen- activated protein kinase (MEK) inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the MEK inhibitor inhibits one or more activities of MEK1 and / or MEK2. In some embodiments, the anti-cancer therapy / MEK inhibitor is (a) a small molecule that inhibits one or more enzymatic activities of MEK, (b) an antibody that inhibits one or more activities of MEK (e.g., by binding to and inhibiting one or more activities of MEK, binding to and inhibiting expression of MEK, and / or binding to and inhibiting one or more activities of a cell expressing MEK, such as by inducing antibody-dependent cellular cytotoxicity, ADCC, or phagocytosis, ADCP), or (c) a nucleic acid that inhibits expression of MEK (e.g., an antisense oligonucleotide, miRNA, siRNA, morpholino, CRISPR-based therapeutic, and the like). In some embodiments, the MEK inhibitor is a small molecule inhibitor of MEK (e.g., a competitive or non-competitive inhibitor). Non-limiting examples of MEK inhibitors include trametinib, cobimetinib, binimetinib, CI-1040, PD0325901, selumetinib, AZD8330, TAK- 733, GDC-0623, refametinib, pimasertib, RO4987655, RO5126766, WX-544, and HL-085, as well as pharmaceutically acceptable salts thereof. In some embodiments, the anti-cancer therapy inhibits one or more activities of the Raf / MEK / ERK pathway, including inhibitors of Raf, MEK, and / or ERK.

[0162] In some embodiments, an anti-cancer therapy of the disclosure comprises a mammalian target of rapamycin (mTOR) inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the mTOR inhibitor is (a) a small molecule that inhibits one or more enzymatic activities of mTOR, (b) an antibody that inhibits one or more activities of mTOR (e.g., by binding to and inhibiting one or more activities of mTOR, binding to and inhibiting expression of mTOR, and / or binding to and inhibiting one or more activities of a cell expressing mTOR, such as by inducing antibody-dependent cellular cytotoxicity, ADCC, or phagocytosis, ADCP), or (c) a nucleic acid that inhibits expression of mTOR (e.g., an antisense oligonucleotide, miRNA, siRNA, morpholino, CRISPR-based therapeutic, and the like). In some embodiments, the mTOR inhibitor is a small molecule inhibitor of mTOR (e.g., a competitive inhibitor, such as an ATP-competitive inhibitor, or a non-competitive inhibitor, such as a rapamycin analog). Non-limiting examples of mTOR inhibitors include temsirolimus, everolimus, ridaforolimus, dactolisib, GSK2126458, XL765, AZD8055, AZD2014, MLN128, PP242, NVP-BEZ235,LY3023414, PQR309, PKI587, and OSI027, as well as pharmaceutically acceptable salts thereof. In some embodiments, the anti-cancer therapy inhibits one or more activities of the Akt / mTOR pathway, including inhibitors of Akt and / or mTOR.

[0163] In some embodiments, an anti-cancer therapy of the disclosure comprises a PI3K inhibitor or Akt inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the PI3K inhibitor inhibits one or more activities of PI3K. In some embodiments, the anti-cancer therapy / PI3K inhibitor is (a) a small molecule that inhibits one or more enzymatic activities of PI3K, (b) an antibody that inhibits one or more activities of PI3K (e.g., by binding to and inhibiting one or more activities of PI3K, binding to and inhibiting expression of PI3K, and / or binding to and inhibiting one or more activities of a cell expressing PI3K, such as by inducing antibodydependent cellular cytotoxicity, ADCC, or phagocytosis, ADCP), or (c) a nucleic acid that inhibits expression of PI3K (e.g., an antisense oligonucleotide, miRNA, siRNA, morpholino, CRISPR-based therapeutic, and the like). In some embodiments, the PI3K inhibitor is a small molecule inhibitor of PI3K (e.g., a competitive or non-competitive inhibitor). Nonlimiting examples of PI3K inhibitors include GSK2636771, buparlisib (BKM120), AZD8186, copanlisib (BAY80-6946), LY294002, PX-866, TGX115, TGX126, BEZ235, SF1126, idelalisib (GS-1101, CAL-101), pictilisib (GDC-094), GDC0032, IPI145, INK1117 (MLN1117), SAR260301, KIN-193 (AZD6482), duvelisib, GS-9820, GSK2636771, GDC- 0980, AMG319, paxalisib, and alpelisib (BYL719, Piqray), as well as pharmaceutically acceptable salts thereof. In some embodiments, the AKT inhibitor inhibits one or more activities of AKT (e.g., AKT1). In some embodiments, the AKT inhibitor is (a) a small molecule that inhibits one or more enzymatic activities of AKT1, (b) an antibody that inhibits one or more activities of AKT1 (e.g., by binding to and inhibiting one or more activities of AKT1, binding to and inhibiting expression of AKT1, and / or binding to and inhibiting one or more activities of a cell expressing AKT1, such as by inducing antibody-dependent cellular cytotoxicity, ADCC, or phagocytosis, ADCP), or (c) a nucleic acid that inhibits expression of AKT1 (e.g., an antisense oligonucleotide, miRNA, siRNA, morpholino, CRISPR-based therapeutic, and the like). In some embodiments, the AKT1 inhibitor is a small molecule inhibitor of AKT1 (e.g., a competitive or non-competitive inhibitor). Non-limiting examples of AKT1 inhibitors include GSK690693, GSK2141795 (uprosertib), GSK2110183 (afuresertib), AZD5363, GDC-0068 (ipatasertib), AT7867, CCT128930, MK-2206, BAY 1125976, AKT1 and AKT2-IN-1, perifosine, and VIII, as well as pharmaceutically acceptable salts thereof. In some embodiments, the AKT1 inhibitor is a pan-Akt inhibitor.

[0164] In some embodiments, an anti-cancer therapy of the disclosure comprises a hedgehog (Hh) inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the Hh inhibitor is (a) a small molecule that inhibits one or more enzymatic activities of Hh, (b) an antibody that inhibits one or more activities of Hh (e.g., by binding to and inhibiting one or more activities of Hh, binding to and inhibiting expression of Hh, and / or binding to and inhibiting one or more activities of a cell expressing Hh, such as by inducing antibody-dependent cellular cytotoxicity, ADCC, or phagocytosis, ADCP), or (c) a nucleic acid that inhibits expression of Hh (e.g., an antisense oligonucleotide, miRNA, siRNA, morpholino, CRISPR-based therapeutic, and the like). In some embodiments, the Hh inhibitor is a small molecule inhibitor of Hh (e.g., a competitive or non-competitive inhibitor). Non-limiting examples of Hh inhibitors include sonidegib, vismodegib, erismodegib, saridegib, BMS833923, PF-04449913, and LY2940680, as well as pharmaceutically acceptable salts thereof.

[0165] In some embodiments, an anti-cancer therapy of the disclosure comprises a heat shock protein (HSP) inhibitor, a MYC inhibitor, an HD AC inhibitor, an immunotherapy, a neoantigen, a vaccine, or a cellular therapy, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor.

[0166] In some embodiments, the anti-cancer therapy comprises one or more of a chemotherapy, a VEGF inhibitor, an Integrin P3 inhibitor, a statin, an EGFR inhibitor, an mTOR inhibitor, a PI3K inhibitor, a MAPK inhibitor, or a CDK4 / 6 inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor.

[0167] In some embodiments, the anti-cancer therapy comprises a kinase inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the kinase inhibitor is crizotinib, alectinib, ceritinib, lorlatinib, brigatinib, ensartinib (X-396), repotrectinib (TPX-005), entrectinib (RXDX-101), AZD3463, CEP- 37440, belizatinib (TSR-011), ASP3026, KRCA-0008, TQ-B3139, TPX-0131, or TAE684 (NVP-TAE684). In some embodiments, the kinase inhibitor is an ALK kinase inhibitor, e.g., as described herein and / or in examples 3-39 of W02005016894.

[0168] In some embodiments, the anti-cancer therapy comprises a heat shock protein (HSP) inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the HSP inhibitor is a Pan-HSP inhibitor, such as KNK423. In some embodiments, the HSP inhibitor is an HSP70 inhibitor, such as cmHsp70.1, quercetin, VER155008, or 17-AAD. In some embodiments, the HSP inhibitor is a HSP90 inhibitor. In some embodiments, the HSP90 inhibitor is 17-AAD, Debio0932,ganetespib (STA-9090), retaspimycin hydrochloride (retaspimycin, IPI-504), AUY922, alvespimycin (KOS- 1022, 17-DMAG), tanespimycin (KOS-953, 17-AAG), DS 2248, or AT13387 (onalespib). In some embodiments, the HSP inhibitor is an HSP27 inhibitor, such as Apatorsen (OGX-427).

[0169] In some embodiments, the anti-cancer therapy comprises a MYC inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the MYC inhibitor is MYCi361 (NUCC-0196361), MYCi975 (NUCC- 0200975), Omomyc (dominant negative peptide), ZINC16293153 (Min9), 10058-F4, JKY-2- 169, 7594-0035, or inhibitors of MYC / MAX dimerization and / or MYC / MAX / DNA complex formation.

[0170] In some embodiments, the anti-cancer therapy comprises a histone deacetylase(HD AC) inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the HDAC inhibitor is belinostat (PXD101, e.g., Beleodaq®), SAHA (vorinostat, suberoylanilide hydroxamine, e.g., Zolinza®), panobinostat (LBH589, LAQ-824), ACY1215 (Rocilinostat), quisinostat (JNJ-26481585), abexinostat (PCI-24781), pracinostat (SB939), givinostat (ITF2357), resminostat (4SC-201), trichostatin A (TSA), MS-275 (etinostat), Romidepsin (depsipeptide, FK228), MGCD0103 (mocetinostat), BML-210, CAY10603, valproic acid, MC1568, CUDC-907, CI-994 (Tacedinaline), Pivanex (AN-9), AR-42, Chidamide (CS055, HBI-8000), CUDC-101, CHR- 3996, MPT0E028, BRD8430, MRLB-223, apicidin, RGFP966, BG45, PCI-34051, C149 (NCC149), TMP269, Cpd2, T247, T326, LMK235, CIA, HPOB, Nexturastat A, Befexamac, CBHA, Phenylbutyrate, MC1568, SNDX275, Scriptaid, Merck60, PX089344, PX105684, PX117735, PX117792, PX117245, PX105844, compound 12 as described by Li et al., Cold Spring Harb Perspect Med (2016) 6(10):a026831, or PX117445.

[0171] In some embodiments, the anti-cancer therapy comprises a VEGF inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the VEGF inhibitor is Bevacizumab (e.g., Avastin®), BMS-690514, or aflibercept. In some embodiments, the anti-cancer therapy comprises a VEGFR inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the VEGFR inhibitor is ramucirumab, pazopanib, sorafenib, sunitinib, golvatinib, vandetanib, cabozantinib, levantinib, axitinib, cediranib, tivozanib, lucitanib, semaxanib, nindentanib, or regorafenib.

[0172] In some embodiments, the anti-cancer therapy comprises an integrin P3 inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. Insome embodiments, the integrin P3 inhibitor is anti-avb3 (clone LM609), cilengitide (EMD121974, NSC, 707544), an siRNA, GLPG0187, MK-0429, CNTO95, TN-161, etaracizumab (MEDI-522), intetumumab (CNTO95) (anti-alphaV subunit antibody), abituzumab (EMD 525797 / DI17E6) (anti-alphaV subunit antibody), JSM6427, SJ749, BCH- 15046, SCH221153, or SC56631. In some embodiments, the anti-cancer therapy comprises an allbp3 integrin inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the allbp3 integrin inhibitor is abciximab, eptifibatide (e.g., Integrilin®), or tirofiban (e.g., Aggrastat®).

[0173] In some embodiments, the anti-cancer therapy comprises an mTOR inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the mTOR inhibitor is temsirolimus (CCI-779), KU-006379, PP242, Torinl, Torin2, ICSN3250, Rapalink-1, CC-223, sirolimus (rapamycin), everolimus (RAD001), dactosilib (NVP-BEZ235), GSK2126458, WAY-001, WAY-600, WYE-687, WYE-354, SF1126, XL765, INK128 (MLN012), AZD8055, OSI027, AZD2014, or AP- 23573.

[0174] In some embodiments, the anti-cancer therapy comprises a statin or a statin-based agent, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the statin or statin-based agent is simvastatin, atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or cerivastatin.

[0175] In some embodiments, the anti-cancer therapy comprises a MAPK inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the MAPK inhibitor is SB203580, SKF-86002, BIRB-796, SC-409, RJW-67657, BIRB-796, VX-745, RO3201195, SB-242235, or MW181.

[0176] In some embodiments, the anti-cancer therapy comprises an EGFR inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the EGFR inhibitor is cetuximab, panitumumab, lapatinib, gefitinib, vandetanib, dacomitinib, icotinib, osimertinib (AZD9291), afatanib, olmutinib, EGF816 (nazartinib), avitinib (AC0010), rociletinib (CO-1686), BMS-690514, YH5448, PF- 06747775, ASP8273, PF299804, AP26113, necitumumab (e.g., Portrazza®), BLU-945, amivantamab, or erlotinib. In some embodiments, the EGFR inhibitor is gefitinib or cetuximab.

[0177] In some embodiments, the anti-cancer therapy comprises a nucleic acid molecule, such as a dsRNA, an siRNA, or an shRNA, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. As is known in the art, dsRNAshaving a duplex structure are effective at inducing RNA interference (RNAi). In some embodiments, the anti-cancer therapy comprises a small interfering RNA molecule (siRNA). dsRNAs and siRNAs can be used to silence gene expression in mammalian cells (e.g., human cells). In some embodiments, a dsRNA of the disclosure comprises any of between about 5 and about 10 base pairs, between about 10 and about 12 base pairs, between about 12 and about 15 base pairs, between about 15 and about 20 base pairs, between about 20 and 23 base pairs, between about 23 and about 25 base pairs, between about 25 and about 27 base pairs, or between about 27 and about 30 base pairs. As is known in the art, siRNAs are small dsRNAs that optionally include overhangs. In some embodiments, the duplex region of an siRNA is between about 18 and 25 nucleotides, e.g., any of 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. siRNAs may also include short hairpin RNAs (shRNAs), e.g., with approximately 29-base-pair stems and 2-nucleotide 3’ overhangs. Methods for designing, optimizing, producing, and using dsRNAs, siRNAs, or shRNAs, are known in the art.

[0178] In some embodiments, the anti-cancer therapy comprises a chemotherapy, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor.Examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclo sphosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites, such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues, such as denopterin, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6- mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals, such as mitotane and trilostane; folic acid replenishers such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; taxoids, e.g., paclitaxel and docetaxel gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-1 1); topoisomerase inhibitor RFS 2000; difluorometlhylomithine (DMFO); retinoids, such as retinoic acid; capecitabine; carboplatin, procarbazine, plicomycin, gemcitabine, navelbine, famesyl-protein tansferase inhibitors, transplatinum, and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0179] Some non-limiting examples of chemotherapeutic drugs which can be combined with anti-cancer therapies of the present disclosure are carboplatin (Paraplatin), cisplatin (Platinol, Platinol-AQ), cyclophosphamide (Cytoxan, Neosar), docetaxel (Taxotere), doxorubicin (Adriamycin), etoposide (VePesid), fluorouracil (5-FU), gemcitabine (Gemzar), irinotecan(Camptosar), methotrexate (Folex, Mexate, Amethop terin), paclitaxel (Taxol, Abraxane), topotecan (Hycamtin), vincristine (Oncovin, Vincasar PFS), and vinblastine (Velban).

[0180] In some embodiments, the anti-cancer therapy comprises a kinase inhibitor, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor.Examples of kinase inhibitors include those that target one or more receptor tyrosine kinases, e.g., EGFR, HER-2 / ERBB2, IGF-IR, PDGFR-a, PDGFR- 0, cKIT, FLT4, FLT3, FGFR1, FGFR2, FGFR3, FGFR4, CSF1R, c-MET, ROS1, RON, c-RET, NTRK1, NTRK2, NTRK3, AXL or ALK; one or more cytoplasmic tyrosine kinases, e.g., c-SRC, c-YES, ABL, BCR- ABL, or JAK-2; one or more serine / threonine kinases, e.g., ATM, Aurora A & B, CDKs, mTOR, PKCi, PLKs, BRAF, CRAF, S6K, or STK11 / LKB1; or one or more lipid kinases, e.g., PI3K or SKI. Small molecule kinase inhibitors include PHA-739358, nilotinib, dasatinib, PD166326, NSC 743411, lapatinib (GW-572016), canertinib (CI-1033), semaxinib (SU5416), vatalanib (PTK787 / ZK222584), sunitinib (SU1 1248), sorafenib (BAY 43-9006), or leflunomide (SU101). Additional non-limiting examples of tyrosine kinase inhibitors include erlotinib (Tarceva), imatinib (Gleevec / Glivec), sorafenib (Nexavar), sunitinib (Sutent), deucravacitinib, avapritinib, capmatinib, pemigatinib, ripretinib, selpercatinib, selumetinib, tucatinib, entrectinib, erdafitinib, fedratinib, pexidartinib, upadacitinib, zanubrutinib, dasatinib, nilotinib, lapatinib, pazopanib, vandetanib, ruxolitinib, crizotinib, tofacitinib, regorafenib, ponatinib, cabozantinib, bosutinib, axitinib, trametinib, ibrutinib, afatinib, nintedanib, ceritinib, osimertinib, lenvatinib, cobimetinib, alectinib, neratinib, midostaurin, brigatinib, acalabrutinib, lorlatinib, larotrectinib, gilteritinib, fostamatinib, dacomitinib, binimetinib, baricitinib and gefitinib (Iressa).

[0181] In some embodiments, the anti-cancer therapy comprises an anti-angiogenic agent, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. Angiogenesis inhibitors prevent the extensive growth of blood vessels (angiogenesis) that tumors require to survive. Non-limiting examples of angiogenesismediating molecules or angiogenesis inhibitors which may be used in the methods of the present disclosure include soluble VEGF (for example: VEGF isoforms, e.g., VEGF121 and VEGF165; VEGF receptors, e.g., VEGFR1, VEGFR2; and co-receptors, e.g., Neuropilin-1 and Neuropilin-2), NRP-1, angiopoietin 2, TSP-1 and TSP-2, angiostatin and related molecules, endostatin, vasostatin, calreticulin, platelet factor-4, TIMP and CD Al, Meth-1 and Meth-2, IFNa, IFN-0 and IFN-y, CXCL10, IL-4, IL- 12 and IL- 18, prothrombin (kringle domain-2), antithrombin III fragment, prolactin, VEGI, SPARC, osteopontin, maspin, canstatin, proliferin-related protein, restin and drugs such as bevacizumab, itraconazole,carboxyamidotriazole, TNP-470, CM101, IFN-a platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids and heparin, cartilage-derived angiogenesis inhibitory factor, matrix metalloproteinase inhibitors, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, prolactina v P3 inhibitors, linomide, or tasquinimod. In some embodiments, known therapeutic candidates that may be used according to the methods of the disclosure include naturally occurring angiogenic inhibitors, including without limitation, angiostatin, endostatin, or platelet factor-4. In another embodiment, therapeutic candidates that may be used according to the methods of the disclosure include, without limitation, specific inhibitors of endothelial cell growth, such as TNP-470, thalidomide, and interleukin- 12. Still other anti- angiogenic agents that may be used according to the methods of the disclosure include those that neutralize angiogenic molecules, including without limitation, antibodies to fibroblast growth factor, antibodies to vascular endothelial growth factor, antibodies to platelet derived growth factor, or antibodies or other types of inhibitors of the receptors of EGF, VEGF or PDGF. In some embodiments, anti-angiogenic agents that may be used according to the methods of the disclosure include, without limitation, suramin and its analogs, and tecogalan. In other embodiments, anti- angiogenic agents that may be used according to the methods of the disclosure include, without limitation, agents that neutralize receptors for angiogenic factors or agents that interfere with vascular basement membrane and extracellular matrix, including, without limitation, metalloprotease inhibitors and angiostatic steroids. Another group of anti- angiogenic compounds that may be used according to the methods of the disclosure includes, without limitation, anti-adhesion molecules, such as antibodies to integrin alpha v beta 3. Still other anti-angiogenic compounds or compositions that may be used according to the methods of the disclosure include, without limitation, kinase inhibitors, thalidomide, itraconazole, carboxyamidotriazole, CM101, IFN-a, IL-12, SU5416, thrombospondin, cartilage-derived angiogenesis inhibitory factor, 2-methoxyestradiol, tetrathiomolybdate, thrombospondin, prolactin, and linomide. In one particular embodiment, the anti-angiogenic compound that may be used according to the methods of the disclosure is an antibody to VEGF, such as AvastinO / bevacizumab (Genentech).

[0182] In some embodiments, the anti-cancer therapy comprises an anti-DNA repair therapy, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the anti-DNA repair therapy is a PARP inhibitor (e.g., talazoparib, rucaparib, olaparib), a RAD51 inhibitor (e.g., RI-1), or an inhibitor of a DNAdamage response kinase, e.g., CHCK1 (e.g., AZD7762), ATM (e.g., KU-55933, KU-60019, NU7026, or VE-821), and ATR (e.g., NU7026).

[0183] In some embodiments, the anti-cancer therapy comprises a radiosensitizer, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. Exemplary radiosensitizers include hypoxia radiosensitizers such as misonidazole, metronidazole, and trans-sodium crocetinate, a compound that helps to increase the diffusion of oxygen into hypoxic tumor tissue. The radiosensitizer can also be a DNA damage response inhibitor interfering with base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), recombinational repair comprising homologous recombination (HR) and non-homologous end-joining (NHEJ), and direct repair mechanisms. Single strand break (SSB) repair mechanisms include BER, NER, or MMR pathways, while double stranded break (DSB) repair mechanisms consist of HR and NHEJ pathways. Radiation causes DNA breaks that, if not repaired, are lethal. SSBs are repaired through a combination of BER, NER and MMR mechanisms using the intact DNA strand as a template. The predominant pathway of SSB repair is BER, utilizing a family of related enzymes termed poly-(ADP-ribose) polymerases (PARP). Thus, the radiosensitizer can include DNA damage response inhibitors such as PARP inhibitors.

[0184] In some embodiments, the anti-cancer therapy comprises an anti-inflammatory agent, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, the anti-inflammatory agent is an agent that blocks, inhibits, or reduces inflammation or signaling from an inflammatory signaling pathway In some embodiments, the anti-inflammatory agent inhibits or reduces the activity of one or more of any of the following: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-23; interferons (ILNs), e.g., ILNa, IENP, ILNy, ILN-y inducing factor (IGIE); transforming growth factor-P (TGE-P); transforming growth factor-a (TGE-a); tumor necrosis factors, e.g., TNE-a, TNE-p, TNE-RI, TNE-RII; CD23; CD30; CD40L; EGE; G- CSE; GDNE; PDGE-BB; RANTES / CCL5; IKK; NL-KB; TLR2; TLR3; TLR4; TL5; TLR6; TLR7; TLR8; TLR8; TLR9; and / or any cognate receptors thereof. In some embodiments, the anti-inflammatory agent is an IL-1 or IL-1 receptor antagonist, such as anakinra (e.g., Kineret®), rilonacept, or canakinumab. In some embodiments, the anti-inflammatory agent is an IL-6 or IL-6 receptor antagonist, e.g., an anti-IL-6 antibody or an anti-IL-6 receptor antibody, such as tocilizumab (e.g., ACTEMRA®), olokizumab, clazakizumab, sarilumab, sirukumab, siltuximab, or ALX-0061. In some embodiments, the anti-inflammatory agent is a TNE-a antagonist, e.g., an anti-TNEa antibody, such as infliximab (Remicade®), golimumab(Simponi®), adalimumab (e.g., Humira®), certolizumab pegol (e.g., Cimzia®) or etanercept. In some embodiments, the anti-inflammatory agent is a corticosteroid. Exemplary corticosteroids include, but are not limited to, cortisone (hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, e.g., Ala-Cort®, Hydrocort Acetate®, hydrocortone phosphate Lanacort®, Solu-Cortef®), decadron (dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, e.g., Dexasone®, Diodex®, Hexadrol®, Maxidex®), methylprednisolone (6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, e.g., Duralone®, Medralone®, Medrol®, M- Prednisol®, Solu-Medrol®), prednisolone (e.g., Delta-Cortef®, ORAPRED®, Pediapred®, Prezone®), and prednisone (e.g., Deltasone®, Liquid Pred®, Meticorten®, Orasone®), and bisphosphonates (e.g., pamidronate (Aredia®), and zoledronic acid (e.g., Zometac®).

[0185] In some embodiments, the anti-cancer therapy comprises an antimetabolite chemotherapeutic agent, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. Antimetabolite chemotherapeutic agents are agents that are structurally similar to a metabolite, but cannot be used by the body in a productive manner. Many antimetabolite chemotherapeutic agents interfere with the production of RNA or DNA. Examples of antimetabolite chemotherapeutic agents include gemcitabine (e.g., GEMZAR®), 5 -fluorouracil (5-FU), capecitabine (e.g., XELODA™), 6-mercaptopurine, methotrexate, 6- thioguanine, pemetrexed, raltitrexed, arabinosylcytosine ARA-C cytarabine (e.g., CYTOSAR-U®), dacarbazine (DTIC-DOMED), azacytosine, deoxycytidine, pyrimidine, fludarabine (e.g., FLUDARA®), cladribine, and 2-deoxy-D-glucose. In some embodiments, an antimetabolite chemotherapeutic agent is gemcitabine. Gemcitabine HC1 is sold by Eli Lilly under the trademark GEMZAR®.

[0186] In some embodiments, the anti-cancer therapy comprises a platinum-based chemotherapeutic agent, e.g., alone or in combination with an immunotherapy, such as an immune checkpoint inhibitor. Platinum-based chemotherapeutic agents are chemotherapeutic agents that comprise an organic compound containing platinum as an integral part of the molecule. In some embodiments, a chemotherapeutic agent is a platinum agent. In some such embodiments, the platinum agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.

[0187] In some embodiments of any of the methods provided herein, the treatment or the one or more treatment options further comprise an additional anti-cancer therapy. In some embodiments of any of the methods provided herein, the treatment or the one or more treatment options further comprise administering an additional anti-cancer therapy to theindividual. In some embodiments, the additional anti-cancer therapy is any anti-cancer therapy known in the art or described herein. In some embodiments, the additional anticancer therapy comprises one or more of a small molecule inhibitor, a chemotherapeutic agent, a cancer immunotherapy, an antibody, a cellular therapy, a nucleic acid, a surgery, a radiotherapy, an anti-angiogenic therapy, an anti-DNA repair therapy, an anti-inflammatory therapy, an anti-neoplastic agent, a growth inhibitory agent, a cytotoxic agent, a vaccine, a small molecule agonist, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a PROteolysis-TArgeting Chimera (PROTAC), or any combination thereof. In some embodiments, the additional anti-cancer therapy is an immunotherapy. In some embodiments, the additional anti-cancer therapy is a heat shock protein 90 inhibitor (Golding et al., Molecular cancer vol. 17,1 52, 2018; Pall, Current opinion in oncology vol. 27,2 (2015): 118-24), an EGFR inhibitor (Golding et al., Molecular cancer vol. 17,1 52, 2018), a SHP2 inhibitor (Dardaei et al., Nature medicine vol. 24,4 (2018): 512-517), a MEK inhibitor (Shrestha et al., Scientific reports vol. 9,1 18842, 2019; Shrestha et al., The Journal of pharmacology and experimental therapeutics vol. 374,1 (2020): 134-140), an IGF-1R inhibitor (George, Journal of hematology & oncology vol. 12,1 80, 2019), a vascular endothelial growth factor (VEGF)-targeted therapy (Makimoto et al., Acta medica Okayama vol. 74,5 (2020): 371-379; Gristina et al., Pharmaceuticals (Basel, Switzerland) vol. 13,12474, 2020), an mTOR inhibitor (Kim et al., Anticancer research vol. 40,3 (2020): 1395-1403), or any combination thereof.

[0188] In some embodiments of any of the methods provided herein, the methods further comprise acquiring knowledge of or detecting in a sample from the individual a base substitution, a short insertion / deletion (indel), a copy number alteration, or a genomic rearrangement in one or more genes or based on genetic information. In some embodiments, the one or more genes or genetic information comprise the ABL1, ACVR1B, AKT1, AKT2, AKT3, ALK, ALOX12B, AMER1, APC, AR, ARAF, ARFRP1, ARID1A, ASXL1, ATM, ATR, ATRX, AURKA, AURKB, AXIN1, AXL, BAP1, BARD1, BCL2, BCL2L1, BCL2L2, BCL6, BCOR, BCORL1, BCR, BRAF, BRCA1, BRCA2, BRD4, BRIP1, BTG1, BTG2, BTK, CALR, CARD11, CASP8, CBFB, CBL, CCND1, CCND2, CCND3, CCNE1, CD22, CD274, CD70, CD74, CD79A, CD79B, CDC73, CDH1, CDK12, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CEBPA, CHEK1, CHEK2, CIC, CREBBP, CRKL, CSF1R, CSF3R, CTCF, CTNNA1, CTNNB1, CUL3, CUL4A, CXCR4, CYP17A1, DAXX, DDR1, DDR2, DIS3, DNMT3A, DOT1L, EED, EGFR, EMSY (CllorfSO), EP300, EPHA3, EPHB1, EPHB4, ERBB2, ERBB3, ERBB4, ERCC4, ERG, ERRFI1, ESRI, ETV4, ETV5,ETV6, EWSR1, EZH2, EZR, FAM46C, FANCA, FANCC, FANCG, FANCL, FAS, FBXW7, FGF10, FGF12, FGF14, FGF19, FGF23, FGF3, FGF4, FGF6, FGFR1, FGFR2, FGFR3, FGFR4, FH, FLCN, FLT1, FLT3, F0XL2, FUBP1, GABRA6, GATA3, GATA4, GATA6, GID4 (C17orf39), GNA11, GNA13, GNAQ, GNAS, GRM3, GSK3B, H3F3A, HDAC1, HGF, HNF1A, HRAS, HSD3B1, ID3, IDH1, IDH2, IGF1R, IKBKE, IKZF1, INPP4B, IRF2, IRF4, IRS2, JAK1, JAK2, JAK3, JUN, KDM5A, KDM5C, KDM6A, KDR, KEAP1, KEL, KIT, KLHL6, KMT2A (MLL), KMT2D (MLL2), KRAS, LTK, LYN, MAF, MAP2K1, MAP2K2, MAP2K4, MAP3K1, MAP3K13, MAPK1, MCL1, MDM2, MDM4, MED12, MEF2B, MEN1, MERTK, MET, MITF, MKNK1, MLH1, MPL, MRE11A, MSH2, MSH3, MSH6, MST1R, MTAP, MTOR, MUTYH, MYB, MYC, MYCL, MYCN, MYD88, NBN, NF1, NF2, NFE2L2, NFKBIA, NKX2-1, N0TCH1, N0TCH2, N0TCH3, NPM1, NRAS, NT5C2, NTRK1, NTRK2, NTRK3, NUTM1, P2RY8, PALB2, PARK2, PARP1, PARP2, PARP3, PAX5, PBRM1, PDCD1, PDCD1LG2, PDGFRA, PDGFRB, PDK1, PIK3C2B, PIK3C2G, PIK3CA, PIK3CB, PIK3R1, PIM1, PMS2, POLDI, POLE, PPARG, PPP2R1A, PPP2R2A, PRDM1, PRKAR1A, PRKCI, PTCHI, PTEN, PTPN11, PTPRO, QKI, RAC1, RAD21, RAD51, RAD51B, RAD51C, RAD51D, RAD 52, RAD54L, RAFI, RARA, RBI, RBM10, REL, RET, RICTOR, RNF43, R0S1, RPTOR, RSP02, SDC4, SDHA, SDHB, SDHC, SDHD, SETD2, SF3B1, SGK1, SLC34A2, SMAD2, SMAD4, SMARCA4, SMARCB1, SMO, SNCAIP, S0CS1, S0X2, S0X9, SPEN, SPOP, SRC, STAG2, STAT3, STK11, SUFU, SYK, TBX3, TEK, TERC, TERT, TET2, TGFBR2, TIPARP, TMPRSS2, TNFAIP3, TNFRSF14, TP53, TSC1, TSC2, TYR03, U2AF1, VEGFA, VHL, WHSCI, WHSC1L1, WT1, XP01, XRCC2, ZNF217, or ZNF703 gene, or any combination thereof. In some embodiments, the one or more genes comprise the ABL, ALK, ALL, B4GALNT1, BAFF, BCL2, BRAF, BRCA, BTK, CD19, CD20, CD3, CD30, CD319, CD38, CD52, CDK4, CDK6, CML, CRACC, CS1, CTLA-4, dMMR, EGFR, ERBB1, ERBB2, FGFR1-3, FLT3, GD2, HDAC, HER1, HER2, HR, IDH2, IL-ip, IL-6, IL-6R, JAK1, JAK2, JAK3, KIT, KRAS, MEK, MET, MSI-H, mTOR, PARP, PD-1, PDGFR, PDGFRa, PDGFRP, PD-L1, PI3K5, PIGF, PTCH, RAF, RANKL, RET, ROS1, SLAMF7, VEGF, VEGFA, or VEGFB gene, or any combination thereof.

[0189] In some embodiments of any of the methods provided herein, the treatment or the one or more treatment options further comprise an additional anti-cancer therapy. In some embodiments of any of the methods provided herein, the treatment or the one or more treatment options further comprise administering an additional anti-cancer therapy to the individual. In some embodiments, the additional anti-cancer therapy is any anti-cancer therapy known in the art or described herein. In some embodiments, the additional anti-cancer therapy comprises one or more of a small molecule inhibitor, a chemotherapeutic agent, a cancer immunotherapy, an antibody, a cellular therapy, a nucleic acid, a surgery, a radiotherapy, an anti-angiogenic therapy, an anti-DNA repair therapy, an anti-inflammatory therapy, an anti-neoplastic agent, a growth inhibitory agent, a cytotoxic agent, a vaccine, a small molecule agonist, a virus-based therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a PROteolysis-TArgeting Chimera (PROTAC), or any combination thereof.

[0190] In some embodiments, the individual has been previously treated, or is being treated, for cancer with a treatment for cancer, e.g., an anti-cancer therapy described herein or any other anti-cancer therapy or treatment known in the art, such as an endocrine therapy.

[0191] In some embodiments according to any of the embodiments described herein, the cancer is breast cancer. In some embodiments, the breast cancer is hormone receptor positive (HR+) breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is advanced or metastatic.Detection of ESDI Fusion Nucleic A cid Molecules and FSP1 Fusion Polypeptides

[0192] Certain aspects of the present disclosure relate to detection of an ESRI fusion nucleic acid molecule of the disclosure, e.g., in a patient sample. In some embodiments, the ESRI fusion nucleic acid molecule is detected in vitro.

[0193] Other aspects of the present disclosure relate to detection of an ESRI fusion polypeptide of the disclosure, e.g., an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule of the disclosure, e.g., in a patient sample. In some embodiments, the ESRI fusion polypeptide is detected in vitro.

[0194] Methods for detecting an ESRI fusion nucleic acid molecule of the disclosure are known in the art. For example, in some embodiments, an ESRI fusion nucleic acid molecule is detected by sequencing part or all of a gene involved in the fusion nucleic acid molecule, e.g., an ESRI gene, and / or a corresponding fusion partner gene described herein (e.g., any of CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5), by next-generation or other sequencing of DNA, RNA, or cDNA. In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected by PCR amplification of DNA, RNA, or cDNA. In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected by in situ hybridization using one or more polynucleotides that hybridize to a locus involved in the fusion nucleic acid molecule, e.g., anESRI locus, and / or a corresponding fusion partner gene locus described herein (e.g., any of CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfi5), e.g., using fluorescence in situ hybridization (FISH). In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected in a cancer or tumor cell, e.g., using tumor tissue, such as from a tumor biopsy or other tumor specimen; in a circulating cancer or tumor cell, e.g., using a liquid biopsy, such as from blood, plasma, cerebrospinal fluid, sputum, stool, urine, or saliva; or in circulating tumor DNA (ctDNA), e.g., using a liquid biopsy, such as from blood, plasma, cerebrospinal fluid, sputum, stool, urine, or saliva.

[0195] Exemplary and non-limiting methods for detecting an ESRI fusion nucleic acid molecule of the disclosure are provided below.

[0196] In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected using any suitable method known in the art, such as a nucleic acid hybridization assay, an amplification-based assay e.g., polymerase chain reaction, PCR), a PCR-RFLP assay, real-time PCR, sequencing (e.g., Sanger sequencing or next-generation sequencing), a screening analysis (e.g., using karyotype methods), fluorescence in situ hybridization (FISH), break away FISH, spectral karyotyping, multiplex-FISH, comparative genomic hybridization, in situ hybridization, single specific primer-polymerase chain reaction (SSP-PCR), high performance liquid chromatography (HPLC), or mass-spectrometric genotyping. Methods of analyzing samples, e.g., to detect a nucleic acid molecule, are described in U.S. Patent No. 9,340,830 and in WO2012092426A1, which are hereby incorporated by reference in their entirety. In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected by sequencing. In some embodiments, the sequencing comprises a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique. In some embodiments, the massively parallel sequencing (MPS) technique comprises nextgeneration sequencing (NGS).

[0197] In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected using an in situ hybridization method, such as a fluorescence in situ hybridization (FISH) method.

[0198] In some embodiments, FISH analysis is used to identify the chromosomal rearrangement resulting in an ESRI fusion nucleic acid molecule as described herein. In some embodiments, FISH analysis is used to identify an RNA molecule comprising or encoding an ESRI fusion nucleic acid molecule of the disclosure. Methods for performing FISH are known in the art and can be used in nearly any type of tissue. In FISH analysis, nucleic acidprobes which are detectably labeled, e.g. fluorescently labeled, are allowed to bind to specific regions of DNA, e.g., a chromosome, or an RNA, e.g., an mRNA, and then examined, e.g., through a microscope. See, for example, U.S. Patent No. 5,776,688. DNA or RNA molecules are first fixed onto a slide, the labeled probe is then hybridized to the DNA or RNA molecules, and then visualization is achieved, e.g., using enzyme-linked label-based detection methods known in the art. Generally, the resolution of FISH analysis is on the order of detection of 60 to 100000 nucleotides, e.g., 60 base pairs (bp) up to 100 kilobase pairs of DNA. Nucleic acid probes used in FISH analysis comprise single stranded nucleic acids. Such probes are typically at least about 50 nucleotides in length. In some embodiments, probes comprise about 100 to about 500 nucleotides. Probes that hybridize with centromeric DNA and locus- specific DNA or RNA are available commercially, for example, from Vysis, Inc. (Downers Grove, Ill.), Molecular Probes, Inc. (Eugene, Oreg.) or from Cytocell (Oxfordshire, UK). Alternatively, probes can be made non-commercially from chromosomal or genomic DNA or other sources of nucleic acids through standard techniques. Examples of probes, labeling and hybridization methods are known in the art.

[0199] Several variations of FISH methods are known in the art and are suitable for use according to the methods of the disclosure, including single-molecule RNA FISH, Fiber FISH, Q-FISH, Flow-FISH, MA-FISH, break-away FISH, hybrid fusion-FISH, and multifluor FISH or mFISH. In some embodiments, “break-away FISH” is used in the methods provided herein. In break-away FISH, at least one probe targeting a fusion junction or breakpoint and at least one probe targeting an individual gene of the fusion, e.g., at one or more exons and or introns of the gene, are utilized. In normal cells (i.e., cells not having a fusion nucleic acid molecule described herein), both probes are observed (or a secondary color is observed due to the close proximity of the two genes of the gene fusion); and in cells having a fusion nucleic acid molecule described herein, only a single gene probe is observed due to the presence of a rearrangement resulting in the fusion nucleic acid molecule.

[0200] In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected using an array-based method, such as array-based comparative genomic hybridization (CGH) methods. In array-based CGH methods, a first sample of nucleic acids (e.g., from a sample, such as from a tumor, or a tissue or liquid biopsy) is labeled with a first label, while a second sample of nucleic acids (e.g., a control, such as from a healthy cell / tissue) is labeled with a second label. In some embodiments, equal quantities of the two samples are mixed and co-hybridized to a DNA microarray of several thousand evenly spaced cloned DNA fragments or oligonucleotides, which have been spotted in triplicate onthe array. After hybridization, digital imaging systems are used to capture and quantify the relative fluorescence intensities of each of the hybridized fluorophores. The resulting ratio of the fluorescence intensities is proportional to the ratio of the copy numbers of DNA sequences in the two samples. In some embodiments, where there are chromosomal deletions or multiplications, differences in the ratio of the signals from the two labels are detected and the ratio provides a measure of the copy number. Array-based CGH can also be performed with single-color labeling. In single color CGH, a control (e.g., control nucleic acid sample, such as from a healthy cell / tissue) is labeled and hybridized to one array and absolute signals are read, and a test sample (e.g., a nucleic acid sample obtained from an individual or from a tumor, or a tissue or liquid biopsy) is labeled and hybridized to a second array (with identical content) and absolute signals are read. Copy number differences are calculated based on absolute signals from the two arrays.

[0201] In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected using an amplification-based method. As is known in the art, in such amplificationbased methods, a sample of nucleic acids, such as a sample obtained from an individual, a tumor or a tissue or liquid biopsy, is used as a template in an amplification reaction (e.g., Polymerase Chain Reaction (PCR)) using one or more oligonucleotides or primers, e.g., such as one or more oligonucleotides or primers provided herein. The presence of a fusion nucleic acid molecule of the disclosure in the sample can be determined based on the presence or absence of an amplification product. Quantitative amplification methods are also known in the art and may be used according to the methods provided herein. Methods of measurement of DNA copy number at microsatellite loci using quantitative PCR analysis are known in the art. The known nucleotide sequence for genes is sufficient to enable one of skill in the art to routinely select primers to amplify any portion of the gene. Fluorogenic quantitative PCR can also be used. In fluorogenic quantitative PCR, quantitation is based on the amount of fluorescence signals, e.g., TaqMan and Sybr green.

[0202] Other amplification methods suitable for use according to the methods provided herein include, e.g., ligase chain reaction (LCR), transcription amplification, self-sustained sequence replication, dot PCR, and linker adapter PCR.

[0203] In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected using a sequencing method. Any method of sequencing known in the art can be used to detect an ESRI fusion nucleic acid molecule provided herein. Exemplary sequencing methods that may be used to detect a fusion nucleic acid molecule provided herein includethose based on techniques developed by Maxam and Gilbert or Sanger. Automated sequencing procedures may also be used, e.g., including sequencing by mass spectrometry.

[0204] In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected using hybrid capture-based sequencing (hybrid capture-based NGS), e.g., using adaptor ligation-based libraries. See, e.g., Frampton, G.M. et al. (2013) Nat. Biotech. 31:1023-1031, which is hereby incorporated by reference. In some embodiments, an ESRI fusion nucleic acid molecule of the disclosure is detected using next-generation sequencing (NGS). Next- generation sequencing includes any sequencing method that determines the nucleotide sequence of either individual nucleic acid molecules or clonally expanded proxies for individual nucleic acid molecules in a highly parallel fashion (e.g., greater than 105molecules may be sequenced simultaneously). Next generation sequencing methods suitable for use according to the methods provided herein are known in the art and include, without limitation, massively parallel short-read sequencing, template-based- sequencing, pyrosequencing, real-time sequencing comprising imaging the continuous incorporation of dye-labeling nucleotides during DNA synthesis, nanopore sequencing, sequencing by hybridization, nano-transistor array based sequencing, polony sequencing, scanning tunneling microscopy (STM)-based sequencing, or nanowire-molecule sensor based sequencing. See, e.g., Metzker, M. (2010) Nature Biotechnology Reviews 11:31-46, which is hereby incorporated by reference. Exemplary NGS methods and platforms that may be used to detect an ESRI fusion nucleic acid molecule provided herein include, without limitation, the HeliScope Gene Sequencing system from Helicos BioSciences (Cambridge, MA., USA), the PacBio RS system from Pacific Biosciences (Menlo Park, CA, USA), massively parallel short-read sequencing such as the Solexa sequencer and other methods and platforms from Illumina Inc. (San Diego, CA, USA), 454 sequencing from 454 LifeSciences (Branford, CT, USA), Ion Torrent sequencing from ThermoFisher (Waltham, MA, USA), or the SOLiD sequencer from Applied Biosystems (Foster City, CA, USA). Additional exemplary methods and platforms that may be used to detect a fusion nucleic acid molecule provided herein include, without limitation, the Genome Sequencer (GS) FLX System from Roche (Basel, CHE), the G.007 polonator system, the Solexa Genome Analyzer, HiSeq 2500, HiSeq3000, HiSeq 4000, and NovaSeq 6000 platforms from Illumina Inc. (San Diego, CA, USA).

[0205] In some embodiments of any of the methods provided herein, the methods may comprise one or more of the steps of: (i) obtaining a sample from an individual (e.g., an individual suspected of having or determined to have cancer), (ii) extracting nucleic acid molecules (e.g., a mixture of tumor or cancer nucleic acid molecules and non-tumor or non-cancer nucleic acid molecules) from the sample, (iii) ligating one or more adapters to the nucleic acid molecules extracted from the sample (e.g., one or more amplification primers, flow cell adaptor sequences, substrate adapter sequences, sample index sequences, or unique molecular identifier (UMI) sequences), (iv) amplifying the nucleic acid molecules (e.g., using a polymerase chain reaction (PCR) amplification technique, a non-PCR amplification technique, or an isothermal amplification technique), (v) capturing nucleic acid molecules from the amplified nucleic acid molecules (e.g., by hybridization to one or more bait molecules, where the bait molecules each comprise one or more nucleic acid molecules (e.g., capture nucleic acid molecules) that each comprise a region that is complementary to a region of a captured nucleic acid molecule), (vi) sequencing the nucleic acid molecules extracted from the sample (or library proxies derived therefrom) using, e.g., a next-generation (massively parallel) sequencing technique, a whole genome sequencing (WGS) technique, a whole exome sequencing technique, a targeted sequencing technique, a direct sequencing technique, or a Sanger sequencing technique) using, e.g., a next-generation (massively parallel) sequencer, and (vii) generating, displaying, transmitting, and / or delivering a report (e.g., an electronic, web-based, or paper report) to the individual (or patient), a caregiver, a healthcare provider, a physician, an oncologist, an electronic medical record system, a hospital, a clinic, a third-party payer, an insurance company, or a government office. In some instances, the report comprises output from the methods described herein. In some instances, all or a portion of the report may be displayed in a graphical user interface of an online or web-based healthcare portal. In some instances, the report is transmitted via a computer network or peer-to-peer connection.

[0206] In some embodiments of any of the methods provided herein, the methods may comprise one or more of the steps of: (a) providing a plurality of nucleic acid molecules obtained from a sample from an individual (e.g., an individual suspected of having or determined to have cancer), wherein the plurality of nucleic acid molecules comprises nucleic acid molecules corresponding to an ESRI fusion nucleic acid molecule of the disclosure; (b) ligating one or more adapters onto one or more nucleic acid molecules from the plurality of nucleic acid molecules; (c) amplifying the one or more ligated nucleic acid molecules from the plurality of nucleic acid molecules; (d) capturing amplified nucleic acid molecules from the amplified nucleic acid molecules; (e) sequencing, by a sequencer, the captured nucleic acid molecules to obtain a plurality of sequence reads that represent the captured nucleic acid molecules, wherein one or more of the plurality of sequence reads correspond to the ESRI fusion nucleic acid molecule; (f) analyzing the plurality of sequence reads; and (g) based onthe analysis, detecting the presence or absence of the ESRI fusion nucleic acid molecule in the sample. In some embodiments, the methods further comprise receiving, at one or more processors, sequence read data for the plurality of sequence reads. In some embodiments, the analyzing the plurality of sequence reads comprises identifying, using the one or more processors, the presence or absence of sequence reads corresponding to the ESRI fusion nucleic acid molecule. In some embodiments, the amplified nucleic acid molecules are captured by hybridization with one or more bait molecules.

[0207] In some embodiments of any of the methods provided herein, the methods may comprise one or more of the steps of: (a) providing a sample from an individual (e.g., an individual suspected of having or determined to have cancer), wherein the sample comprises a plurality of nucleic acid molecules; (b) preparing a nucleic acid sequencing library from the plurality of nucleic acid molecules in the sample; (c) amplifying said library; (d) selectively enriching for one or more nucleic acid molecules comprising nucleotide sequences corresponding to an ESRI fusion nucleic acid molecule of the disclosure in said library to produce an enriched sample; (e) sequencing the enriched sample, thereby producing a plurality of sequence reads; (f) analyzing the plurality of sequence reads for the presence of the ESRI fusion nucleic acid molecule; (g) detecting, based on the analyzing step, the presence or absence of the ESRI fusion nucleic acid molecule in the sample from the individual.

[0208] In some embodiments of any of the methods provided herein, the plurality of nucleic acid molecules comprises a mixture of cancer nucleic acid molecules and non-cancer nucleic acid molecules. In some embodiments, the cancer nucleic acid molecules are derived from a tumor portion of a heterogeneous tissue biopsy sample, and the non-cancer nucleic acid molecules are derived from a normal portion of the heterogeneous tissue biopsy sample. In some embodiments, the sample comprises a liquid biopsy sample, and the cancer nucleic acid molecules are derived from a circulating tumor DNA (ctDNA) fraction of the liquid biopsy sample; and the non-cancer nucleic acid molecules are derived from a non-tumor fraction of the liquid biopsy sample or a cell-free DNA (cfDNA) fraction of the liquid biopsy sample.

[0209] In some embodiments of any of the methods, the one or more adapters comprise amplification primers, flow cell adaptor sequences, substrate adapter sequences, sample index sequences, or unique molecular identifier (UMI) sequences. In some embodiments, the one or more adapters comprise one or more sample index sequences. As is known in the art, sample indexes allow the sequencing of multiple samples on the same instrument flow cell or chip (i.e., multiplexing). Sample indexes are typically between about 8 and about 10 bases inlength, and comprise a nucleotide sequence specific to a sample that is used to assign sequence reads to the correct sample during data analysis. In some embodiments, the one or more adapters comprise one or more unique molecule identifiers (UMIs). As is known in the art, UMIs comprise short nucleotide sequences that include a unique barcode that is incorporated into each molecule in a given sample library. UMIs are useful for identifying PCR duplicates created during library amplification steps, and / or for reducing the rate of false-positive variant calls and increasing variant detection, since variant alleles present in the original sample (true variants) can be distinguished from errors introduced during library preparation, target enrichment, or sequencing.

[0210] In some embodiments, the selectively enriching comprises: (a) combining one or more bait molecules with the library, thereby hybridizing the one or more bait molecules to one or more nucleic acid molecules comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule and producing nucleic acid hybrids; and (b) isolating the nucleic acid hybrids to produce the enriched sample. In some embodiments, the captured nucleic acid molecules are captured from the amplified nucleic acid molecules by hybridization to one or more bait molecules. In some embodiments, the amplifying comprises performing a polymerase chain reaction (PCR) amplification technique, a non-PCR amplification technique, or an isothermal amplification technique. In some embodiments, the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique. In some embodiments, the sequencing comprises a massively parallel sequencing technique, and the massively parallel sequencing technique comprises next generation sequencing (NGS). In some embodiments, the sequencer comprises a next generation sequencer.

[0211] In some embodiments of any of the methods provided herein, the methods further comprise selectively enriching for one or more nucleic acids in the sample comprising nucleotide sequences corresponding to an ESRI fusion nucleic acid molecule of the disclosure. In some embodiments, the selectively enriching produces an enriched sample. In some embodiments, the selectively enriching comprises: (a) combining one or more bait molecules with the sample, thereby hybridizing the one or more bait molecules to one or more nucleic acids in the sample comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule and producing nucleic acid hybrids; and (b) isolating the nucleic acid hybrids to produce the enriched sample. In some embodiments, the selectively enriching comprises amplifying the one or more nucleic acids comprising nucleotide sequencescorresponding to the ESRI fusion nucleic acid molecule using a polymerase chain reaction (PCR) to produce an enriched sample. In some embodiments, the methods further comprise sequencing the enriched sample.

[0212] In some embodiments of any of the methods provided herein, the methods further comprise analyzing sequence data (e.g., obtained from sequencing as described above), for the presence or absence of one or more alterations (e.g., a base substitution, a short insertion / deletion (indel), a copy number alteration, or a genomic rearrangement) in one or more genes (e.g., one or more cancer-related genes, or a panel of known / suspected oncogenes and / or tumor suppressors, or any combination thereof). In some embodiments, the presence or absence of one or more gene alterations of the disclosure is detected using any suitable method known in the art, e.g., as described in Frampton et al., (2013) Nat Biotechnol, 31:1023-1031. In some embodiments, base substitution alterations are detected using Bayesian methodology, which allows detection of novel somatic mutations at low mutant allele frequency (MAF) and increased sensitivity for mutations at hotspot sites through the incorporation of tissue- specific prior expectations. See, e.g., Kim et al., Cancer Discov (2011) 1:44-53 and Frampton et al., (2013) Nat Biotechnol, 31:1023-1031. In some embodiments, insertion / deletion (indel) alterations are detected using any suitable method, such as de novo local assembly, e.g., using the de Bruijn approach, see, e.g., Compeau et al., Nat Biotechnol (2011) 29:987-991 and Frampton et al., (2013) Nat Biotechnol, 31:1023-1031. In some embodiments, gene fusion and genomic rearrangement alterations are detected using any suitable method, such as by analyzing chimeric read pairs (read pairs for which reads map to separate chromosomes, or at a distance of over 10 Mbp), see, e.g., Frampton et al., (2013) Nat Biotechnol, 31:1023-1031. In some embodiments, rearrangements are annotated for predicted function (e.g., creation of fusion gene or tumor suppressor inactivation).

[0213] In some embodiments of any of the methods provided herein, the methods further comprise generating a molecular profile for the individual or the sample, based, at least in part, on detecting the presence or absence of an ESRI fusion nucleic acid molecule of the disclosure. In some embodiments, the molecular profile for the individual or sample further comprises results from a comprehensive genomic profiling (CGP) test, a gene expression profiling test, a cancer hotspot panel test, a DNA methylation test, a DNA fragmentation test, an RNA fragmentation test, or any combination thereof. In some embodiments, the molecular profile further comprises results from a nucleic acid sequencing-based test. In some instances, a molecular profile may comprise information on the presence of genes (or variant sequences thereof), copy number variations, epigenetic traits, proteins (or modifications thereof), and / orother biomarkers in an individual’s genome and / or proteome, as well as information on the individual’s corresponding phenotypic traits and the interaction between genetic or genomic traits, phenotypic traits, and environmental factors.

[0214] In some embodiments of any of the methods provided herein, the methods further comprise selecting a treatment, administering a treatment, or applying a treatment to the individual based on the generated molecular profile, wherein the treatment comprises an anticancer therapy, e.g., as described herein. In some embodiments of any of the methods provided herein, the methods further comprise generating a report indicating the presence or absence of an ESRI fusion nucleic acid molecule of the disclosure in the sample. In some embodiments of any of the methods provided herein, the methods further comprise generating, by one or more processors, a report indicating the presence or absence of an ESRI fusion nucleic acid molecule of the disclosure in the sample. In some embodiments, the report comprises the generated molecular profile. In some embodiments, the methods further comprise providing or transmitting the report, e.g., as described below. In some embodiments, the report is transmitted via a computer network or a peer-to-peer connection. In some instances, all or a portion of the report may be displayed in a graphical user interface of an online or web-based healthcare portal.

[0215] In some embodiments of any of the methods provided herein, the methods for determining the presence or absence of an ESRI fusion nucleic acid molecule, may be implemented as part of a genomic profiling process that comprises identification of the presence of variant sequences at one or more gene loci (e.g., one or more gene loci as listed above) in a sample derived from an individual as part of detecting, monitoring, predicting a risk factor, or selecting a treatment for a particular disease, e.g., cancer. In some instances, the variant panel selected for genomic profiling may comprise the detection of variant sequences at a selected set of gene loci (e.g., one or more gene loci as listed above). In some instances, the variant panel selected for genomic profiling may comprise detection of variant sequences at a number of gene loci (e.g., one or more gene loci as listed above) through comprehensive genomic profiling (CGP), a next-generation sequencing (NGS) approach used to assess hundreds of genes (including relevant cancer biomarkers) in a single assay.Inclusion of the disclosed methods for determining the presence or absence of an ESRI fusion nucleic acid molecule as part of a genomic profiling process can improve the validity of, e.g., disease detection calls by, for example, independently confirming the presence of the ESRI fusion nucleic acid molecule in a given patient sample.

[0216] The disclosed methods may be used with any of a variety of samples, e.g., as described in further detail below. For example, in some instances, the sample may comprise a tissue biopsy sample, a liquid biopsy sample, or a normal control. In some instances, the sample may be a liquid biopsy sample and may comprise blood, plasma, cerebrospinal fluid, sputum, stool, urine, or saliva. In some instances, the sample may be a liquid biopsy sample and may comprise circulating tumor cells (CTCs). In some instances, the sample may be a liquid biopsy sample and may comprise cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), or any combination thereof.

[0217] In some instances, the nucleic acid molecules extracted from a sample may comprise a mixture of tumor or cancer nucleic acid molecules and non-tumor or non-cancer nucleic acid molecules. In some instances, the tumor nucleic acid molecules may be derived from a tumor portion of a heterogeneous tissue biopsy sample, and the non-tumor nucleic acid molecules may be derived from a normal portion of the heterogeneous tissue biopsy sample. In some instances, the sample may comprise a liquid biopsy sample, and the tumor or cancer nucleic acid molecules may be derived from a circulating tumor DNA (ctDNA) fraction of the liquid biopsy sample while the non-tumor or non-cancer nucleic acid molecules may be derived from a non-tumor or non-cancer, cell-free DNA (cfDNA) fraction of the liquid biopsy sample.

[0218] In some embodiments of any of the methods provided herein, the method further comprises determining the circulating tumor DNA (ctDNA) fraction of a liquid biopsy sample.

[0219] Also provided herein are methods of detecting an ESRI fusion polypeptide of the disclosure, or a fragment thereof, e.g., an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule of the disclosure, or a fragment thereof.

[0220] An ESRI fusion polypeptide provided herein, or a fragment thereof, may be detected or measured, e.g., in a sample obtained from an individual, using any method known in the art, such as using antibodies (e.g., an antibody described herein), mass spectrometry (e.g., tandem mass spectrometry), a reporter assay (e.g., a fluorescence-based assay), immunoblots such as a Western blot, immunoassays such as enzyme-linked immunosorbent assays (ELISA), immunohistochemistry, other immunological assays (e.g., fluid or gel precipitin reactions, immunodiffusion, immunoelectrophoresis, radioimmunoassay (RIA), immunofluorescent assays), and analytic biochemical methods (e.g., electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography).

[0221] In some embodiments, an ESRI fusion polypeptide provided herein, or a fragment thereof, can be distinguished from a reference polypeptide, e.g., a non-mutant or wild type protein or polypeptide, with an antibody or antibody fragment that reacts differentially with a mutant protein or polypeptide (e.g., an ESRI fusion polypeptide provided herein or a fragment thereof) as compared to a reference protein or polypeptide. In some embodiments, an ESRI fusion polypeptide of the disclosure, or a fragment thereof, can be distinguished from a reference polypeptide, e.g., a non-mutant or wild type protein or polypeptide, by binding to estradiol and / or DNA binding activity.

[0222] In some aspects, methods of detection of an ESRI fusion polypeptide of the disclosure (e.g., an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule of the disclosure), or a fragment thereof, are provided, comprising contacting a sample, e.g., a sample described herein, comprising an ESRI fusion polypeptide described herein, with a detection reagent provided herein (e.g., an antibody of the disclosure), and determining if the ESRI fusion polypeptide is present in the sample.

[0223] In some aspects, provided herein are reagents for detecting an ESRI fusion nucleic acid molecule of the disclosure, or a fragment thereof, e.g., according to the methods of detection provided herein. In some embodiments, a detection reagent provided herein comprises a nucleic acid molecule, e.g., a DNA, RNA, or mixed DNA / RNA molecule, comprising a nucleotide sequence that is complementary to a nucleotide sequence on a target nucleic acid molecule, e.g., a nucleic acid molecule that is or comprises an ESRI fusion nucleic acid molecule described herein or a fragment or portion thereof.

[0224] In other aspects, provided herein are reagents for detecting an ESRI fusion polypeptide of the disclosure, or a fragment thereof, e.g., an ESRI fusion polypeptide encoded by an ESRI fusion nucleic acid molecule of the disclosure, or a fragment thereof, e.g., according to the methods of detection provided herein. In some embodiments, a detection reagent provided herein comprises an antibody or antibody fragment that specifically binds to an ESRI fusion polypeptide of the disclosure, or to a fragment thereof.

[0225] In some embodiments, nucleic acids corresponding to a gene involved in an ESRI fusion nucleic acid molecule described herein, e.g., an ESRI gene, and / or a corresponding gene fusion partner as described herein (e.g., e.g., any of CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5), are captured (e.g., from amplified nucleic acids) by hybridization with a bait molecule. Provided herein are bait molecules suitable for the detection of an ESRI fusion nucleic acid molecule of the disclosure.

[0226] In some embodiments, a bait molecule comprises a capture nucleic acid molecule configured to hybridize to a target nucleic acid molecule comprising an ESRI fusion nucleic acid molecule of the disclosure, or a fragment or portion thereof. In some embodiments, the capture nucleic acid molecule is configured to hybridize to the ESRI fusion nucleic acid molecule of the target nucleic acid molecule.

[0227] In some embodiments, the capture nucleic acid molecule is configured to hybridize to a fragment of an ESRI fusion nucleic acid molecule of the disclosure. In some embodiments, the fragment comprises (or is) between about 5 and about 25 nucleotides, between about 5 and about 300 nucleotides, between about 100 and about 300 nucleotides, between about 130 and about 230 nucleotides, or between about 150 and about 200 nucleotides. In some embodiments, the fragment comprises (or is) about 100 nucleotides, about 125 nucleotides, about 150 nucleotides, about 175 nucleotides, about 200 nucleotides, about 225 nucleotides, about 250 nucleotides, about 275 nucleotides, or about 300 nucleotides in length. In some embodiments, the fragment comprises a breakpoint or fusion junction of an ESRI fusion nucleic acid molecule of the disclosure.

[0228] In some embodiments, the capture nucleic acid molecule comprises (or is) between about 5 and about 25 nucleotides, between about 5 and about 300 nucleotides, between about 100 and about 300 nucleotides, between about 130 and about 230 nucleotides, or between about 150 and about 200 nucleotides. In some embodiments, the capture nucleic acid molecule comprises (or is) about 100 nucleotides, about 125 nucleotides, about 150 nucleotides, about 175 nucleotides, about 200 nucleotides, about 225 nucleotides, about 250 nucleotides, about 275 nucleotides, or about 300 nucleotides in length.

[0229] In some embodiments, the capture nucleic acid molecule is configured to hybridize to a breakpoint of an ESRI fusion nucleic acid molecule of the disclosure, and may further hybridize to between about 10 and about 100 nucleotides or more, e.g., any of between about 10 and about 20, about 20 and about 30, about 30 and about 40, about 40 and about 50, about 50 and about 60, about 60 and about 70, about 70 and about 80, about 80 and about 90, or about 90 and about 100, or more nucleotides flanking either side of the breakpoint.

[0230] In some embodiments, the capture nucleic acid molecule is configured to hybridize to a nucleotide sequence in an intron or an exon of an ESRI gene, or in a breakpoint joining the introns or exons of an ESRI gene (e.g., plus or minus any of between about 10 and about 20, about 20 and about 30, about 30 and about 40, about 40 and about 50, about 50 and about 60, about 60 and about 70, about 70 and about 80, about 80 and about 90, or about 90 and about 100, or more nucleotides) to an intron or exon of another gene, such as a corresponding genefusion partner as described herein (e.g., any of CCDC170, SMAD4, LOCI 00422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5).

[0231] In some embodiments, the capture nucleic acid molecule is a DNA, RNA, or a DNA / RNA molecule. In some embodiments, the capture nucleic acid molecule comprises any of between about 50 and about 1000 nucleotides, between about 50 and about 500 nucleotides, between about 100 and about 500 nucleotides, between about 100 and about 300 nucleotides, between about 130 and about 230 nucleotides, or between about 150 and about 200 nucleotides. In some embodiments, the capture nucleic acid molecule comprises any of between about 50 nucleotides and about 100 nucleotides, about 100 nucleotides and about 150 nucleotides, about 150 nucleotides and about 200 nucleotides, about 200 nucleotides and about 250 nucleotides, about 250 nucleotides and about 300 nucleotides, about 300 nucleotides and about 350 nucleotides, about 350 nucleotides and about 400 nucleotides, about 400 nucleotides and about 450 nucleotides, about 450 nucleotides and about 500 nucleotides, about 500 nucleotides and about 550 nucleotides, about 550 nucleotides and about 600 nucleotides, about 600 nucleotides and about 650 nucleotides, about 650 nucleotides and about 700 nucleotides, about 700 nucleotides and about 750 nucleotides, about 750 nucleotides and about 800 nucleotides, about 800 nucleotides and about 850 nucleotides, about 850 nucleotides and about 900 nucleotides, about 900 nucleotides and about 950 nucleotides, or about 950 nucleotides and about 1000 nucleotides. In some embodiments, the capture nucleic acid molecule comprises between about 10 and about 30 nucleotides, between about 50 and about 1000 nucleotides, between about 100 and about 500 nucleotides, between about 100 and about 300 nucleotides, or between about 100 and about 200 nucleotides. In some embodiments, the capture nucleic acid molecule comprises about 150 nucleotides. In some embodiments, the capture nucleic acid molecule is about 150 nucleotides. In some embodiments, the capture nucleic acid molecule comprises about 170 nucleotides. In some embodiments, the capture nucleic acid molecule is about 170 nucleotides.

[0232] In some embodiments, a bait provided herein comprises a DNA, RNA, or a DNA / RNA molecule. In some embodiments, a bait provided herein includes a label, a tag or detection reagent. In some embodiments, the label, tag or detection reagent is a radiolabel, a fluorescent label, an enzymatic label, a sequence tag, biotin, or another ligand. In some embodiments, a bait provided herein includes a detection reagent such as a fluorescent marker. In some embodiments, a bait provided herein includes (e.g., is conjugated to) an affinity tag or reagent, e.g., that allows capture and isolation of a hybrid formed by a bait anda nucleic acid molecule hybridized to the bait. In some embodiments, the affinity tag or reagent is an antibody, an antibody fragment, biotin, or any other suitable affinity tag or reagent known in the art. In some embodiments, a bait is suitable for solution phase hybridization.

[0233] Baits can be produced and used according to methods known in the art, e.g., as described in WO2012092426 Al and / or or in Frampton et al (2013) Nat Biotechnol, 31:1023- 1031, incorporated herein by reference. For example, biotinylated baits (e.g., RNA baits) can be produced by obtaining a pool of synthetic long oligonucleotides, originally synthesized on a microarray, and amplifying the oligonucleotides to produce the bait sequences. In some embodiments, the baits are produced by adding an RNA polymerase promoter sequence at one end of the bait sequences, and synthesizing RNA sequences using RNA polymerase. In one embodiment, libraries of synthetic oligodeoxynucleotides can be obtained from commercial suppliers, such as Agilent Technologies, Inc., and amplified using known nucleic acid amplification methods.

[0234] In some embodiments, a bait provided herein is between about 100 nucleotides and about 300 nucleotides. In some embodiments, a bait provided herein is between about 130 nucleotides and about 230 nucleotides. In some embodiments, a bait provided herein is between about 150 nucleotides and about 200 nucleotides. In some embodiments, a bait provided herein comprises a target- specific bait sequence (e.g., a capture nucleic acid molecule described herein) and universal tails on each end. In some embodiments, the targetspecific sequence, e.g., a capture nucleic acid molecule described herein, is between about 40 nucleotides and about 300 nucleotides. In some embodiments, the target- specific sequence, e.g., a capture nucleic acid molecule described herein, is between about 100 nucleotides and about 200 nucleotides. In some embodiments, the target- specific sequence, e.g., a capture nucleic acid molecule described herein, is between about 120 nucleotides and about 170 nucleotides. In some embodiments, the target- specific sequence, e.g., a capture nucleic acid molecule described herein, is about 150 nucleotides or about 170 nucleotides. In some embodiments, a bait provided herein comprises an oligonucleotide comprising about 200 nucleotides, of which about 150 nucleotides or about 170 nucleotides are target- specific (e.g., a capture nucleic acid molecule described herein), and the other 50 nucleotides or 30 nucleotides (e.g., 25 or 15 nucleotides on each end of the bait) are universal arbitrary tails, e.g., suitable for PCR amplification.

[0235] In some embodiments, a bait provided herein hybridizes to a nucleotide sequence corresponding to an intron or an exon of one gene of an ESRI fusion molecule describedherein (e.g., an ESRI gene), in an intron or an exon of the other gene of a fusion molecule described herein (e.g., a corresponding gene fusion partner as described herein, e.g., any of CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5 and / or a breakpoint joining the introns and / or exons.

[0236] The baits described herein can be used for selection of exons and short target sequences.

[0237] In some embodiments, a bait of the disclosure distinguishes a nucleic acid molecule, e.g., a genomic or transcribed nucleic acid molecule, e.g., a cDNA or RNA, having a breakpoint of an ESRI fusion nucleic acid molecule described herein, from a reference nucleotide sequence, e.g., a nucleotide sequence not having the breakpoint.

[0238] In some embodiments, the bait hybridizes to a breakpoint of an ESRI fusion nucleic acid molecule described herein, and to a sequence on either side of the breakpoint (e.g., any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides on either side of the breakpoint, or any of between 1 and about 5, about 5 and about 10, about 10 and about 15, about 15 and about 20, about 20 and about 25, about 25 and about 30, about 30 and about 35, about 35 and about 40, about 40 and about 45, about 45 and about 50, about 50 and about 55, about 55 and about 60, about 60 and about 65, about 70 and about 75, about 75 and about 80, about 80 and about 85, about 85 and about 90, about 90 and about 95, or about 95 and about 100, or more nucleotides on either side of the breakpoint).

[0239] Also provided herein are probes, e.g., nucleic acid molecules, suitable for the detection of an ESRI fusion nucleic acid molecule of the disclosure. In some embodiments, a probe provided herein comprises a nucleic acid sequence configured to hybridize to a target nucleic acid molecule that is or comprises an ESRI fusion nucleic acid molecule of the disclosure, or a fragment or portion thereof. In some embodiments, the probe comprises a nucleic acid sequence configured to hybridize to the ESRI fusion nucleic acid molecule of the disclosure, or the fragment or portion thereof, of the target nucleic acid molecule. In some embodiments, the probe comprises a nucleic acid sequence configured to hybridize to a fragment or portion of the ESRI fusion nucleic acid molecule of the target nucleic acid molecule. In some embodiments, the fragment or portion comprises between about 5 and about 25 nucleotides, between about 5 and about 300 nucleotides, between about 100 and about 300 nucleotides, between about 130 and about 230 nucleotides, or between about 150 and about 200 nucleotides.

[0240] In some embodiments, the probe comprises a nucleotide sequence configured to hybridize to a breakpoint of an ESRI fusion nucleic acid molecule of the disclosure, and maybe further configured to hybridize to between about 10 and about 100 nucleotides or more, e.g., any of between about 10 and about 20, about 20 and about 30, about 30 and about 40, about 40 and about 50, about 50 and about 60, about 60 and about 70, about 70 and about 80, about 80 and about 90, or about 90 and about 100, or more nucleotides flanking either side of the breakpoint.

[0241] In some embodiments, the probe comprises a nucleotide sequence configured to hybridize to a nucleotide sequence in an intron or an exon of a gene involved in an ESRI fusion nucleic acid molecule described herein, e.g., an ESRI gene, or in a breakpoint joining the introns or exons of the gene (e.g., plus or minus any of between about 10 and about 20, about 20 and about 30, about 30 and about 40, about 40 and about 50, about 50 and about 60, about 60 and about 70, about 70 and about 80, about 80 and about 90, or about 90 and about 100, or more nucleotides) to an intron or exon of another gene e.g., a corresponding gene fusion partner as described herein, e.g., any of CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2. IYD, IMPG1, STAG2, TNRC6B, or C6orfl5).

[0242] In some embodiments, the probe comprises a nucleic acid molecule which is a DNA, RNA, or a DNA / RNA molecule. In some embodiments, the probe comprises a nucleic acid molecule comprising any of between about 10 and about 20 nucleotides, between about 12 and about 20 nucleotides, between about 10 and about 1000 nucleotides, between about 50 and about 500 nucleotides, between about 100 and about 500 nucleotides, between about 100 and about 300 nucleotides, between about 130 and about 230 nucleotides, or between about 150 and about 200 nucleotides. In some embodiments, the probe comprises a nucleic acid molecule comprising any of 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides. In some embodiments, the probe comprises a nucleic acid molecule comprising any of between about 40 nucleotides and about 50 nucleotides, about 50 nucleotides and about 100 nucleotides, about 100 nucleotides and about 150 nucleotides, about 150 nucleotides and about 200 nucleotides, about 200 nucleotides and about 250 nucleotides, about 250 nucleotides and about 300 nucleotides, about 300 nucleotides and about 350 nucleotides, about 350 nucleotides and about 400 nucleotides, about 400 nucleotides and about 450 nucleotides, about 450 nucleotides and about 500 nucleotides, about 500 nucleotides and about 550 nucleotides, about 550 nucleotides and about 600 nucleotides, about 600 nucleotides and about 650 nucleotides, about 650 nucleotides and about 700 nucleotides, about 700nucleotides and about 750 nucleotides, about 750 nucleotides and about 800 nucleotides, about 800 nucleotides and about 850 nucleotides, about 850 nucleotides and about 900 nucleotides, about 900 nucleotides and about 950 nucleotides, or about 950 nucleotides and about 1000 nucleotides. In some embodiments, the probe comprises a nucleic acid molecule comprising between about 12 and about 20 nucleotides.

[0243] In some embodiments, a probe provided herein comprises a DNA, RNA, or a DNA / RNA molecule. In some embodiments, a probe provided herein includes a label or a tag. In some embodiments, the label or tag is a radiolabel (e.g., a radioisotope), a fluorescent label (e.g., a fluorescent compound), an enzymatic label, an enzyme co-factor, a sequence tag, biotin, or another ligand. In some embodiments, a probe provided herein includes a detection reagent such as a fluorescent marker. In some embodiments, a probe provided herein includes (e.g., is conjugated to) an affinity tag, e.g., that allows capture and isolation of a hybrid formed by a probe and a nucleic acid molecule hybridized to the probe. In some embodiments, the affinity tag is an antibody, an antibody fragment, biotin, or any other suitable affinity tag or reagent known in the art. In some embodiments, a probe is suitable for solution phase hybridization.

[0244] In some embodiments, probes provided herein may be used according to the methods of detection of ESRI fusion nucleic acid molecules provided herein. For example, a probe provided herein may be used for detecting an ESRI fusion nucleic acid molecule of the disclosure in a sample, e.g., a sample obtained from an individual. In some embodiments, the probe may be used for identifying cells or tissues that express an ESRI fusion nucleic acid molecule of the disclosure, e.g., by measuring levels of the ESRI fusion nucleic acid molecule. In some embodiments, the probe may be used for detecting levels of an ESRI fusion nucleic acid molecule of the disclosure, e.g., mRNA levels, in a sample of cells from an individual.

[0245] In some embodiments, a probe provided herein specifically hybridizes to a nucleic acid molecule comprising a rearrangement (e.g., a deletion, inversion, insertion, duplication, or other rearrangement) resulting in an ESRI fusion nucleic acid molecule of the disclosure.

[0246] In some embodiments, a probe of the disclosure distinguishes a nucleic acid, e.g., a genomic or transcribed nucleic acid, e.g., a cDNA or RNA, having a breakpoint of an ESRI fusion nucleic acid molecule of the disclosure from a reference nucleotide sequence, e.g., a nucleotide sequence not having the breakpoint.

[0247] Also provided herein are isolated pairs of allele-specific probes, wherein, for example, the first probe of the pair specifically hybridizes to an ESRI fusion nucleic acid molecule ofthe disclosure, and the second probe of the pair specifically hybridizes to a corresponding wild type sequence (e.g., a wild type ESRI nucleic acid molecule; and / or a wild type nucleic acid molecule corresponding to a gene fusion partner as described herein, e.g., any of CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfi5). Probe pairs can be designed and produced for any of the ESRI fusion nucleic acid molecules described herein and are useful in detecting a somatic mutation in a sample. In some embodiments, a first probe of a pair specifically hybridizes to a mutation (e.g., the breakpoint of an alteration, rearrangement, inversion, duplication, deletion, insertion or translocation resulting in an ESRI fusion nucleic acid molecule described herein), and a second probe of a pair specifically hybridizes to a sequence upstream or downstream of the mutation.

[0248] In some embodiments, one or more probes provided herein are suitable for use in in situ hybridization methods, e.g., as described above, such as FISH.

[0249] Chromosomal probes, e.g., for use in the FISH methods described herein, are typically about 50 to about 105nucleotides in length. Longer probes typically comprise smaller fragments of about 100 to about 500 nucleotides. Probes that hybridize with centromeric DNA and locus-specific DNA are available commercially, for example, from Vysis, Inc. (Downers Grove, Ill.), Molecular Probes, Inc. (Eugene, Oreg.) or from Cytocell (Oxfordshire, UK). Alternatively, probes can be made non-commercially from chromosomal or genomic DNA through standard techniques. For example, sources of DNA that can be used include genomic DNA, cloned DNA sequences, somatic cell hybrids that contain one, or a part of one, chromosome (e.g., human chromosome) along with the normal chromosome complement of the host, and chromosomes purified by flow cytometry or microdissection. The region of interest can be isolated through cloning, or by site-specific amplification via the polymerase chain reaction (PCR). Probes of the disclosure may also hybridize to RNA molecules, e.g., mRNA, such as an RNA that is or comprises an ESRI fusion nucleic acid molecule of the disclosure.

[0250] In some embodiments, probes, such as probes for use in the FISH methods described herein, are used for determining whether a cytogenetic abnormality is present in one or more cells, e.g., in a region of a chromosome or an RNA bound by one or more probes provided herein. The cytogenetic abnormality may be a cytogenetic abnormality that results in an ESRI fusion nucleic acid molecule of the disclosure. Examples of such cytogenetic abnormalities include, without limitation, deletions (e.g., deletions of entire chromosomes or deletions of fragments of one or more chromosomes), duplications (e.g., of entire chromosomes, or ofregions smaller than an entire chromosome), translocations (e.g., non-reciprocal translocations, balanced translocations, reciprocal translocations), intra-chromosomal inversions, point mutations, deletions, gene copy number changes, germ-line mutations, and gene expression level changes.

[0251] In some embodiments, probes, such as probes for use in the FISH methods described herein, are labeled such that a chromosomal region or a region on an RNA to which the probes hybridize can be detected. Probes typically are directly labeled with a fluorophore, allowing the probe to be visualized without a secondary detection molecule. Probes can also be labeled by nick translation, random primer labeling or PCR labeling. Labeling may be accomplished using fluorescent (direct)-or haptene (indirect)-labeled nucleotides. Representative, non-limiting examples of labels include: AMCA-6-dUTP, CascadeBlue-4- dUTP, Fluorescein- 12-dUTP, Rhodamine-6-dUTP, TexasRed-6-dUTP, Cy3-6-dUTP, Cy5- dUTP, Biotin(BIO)-l l-dUTP, Digoxygenin(DIG)-l l-dUTP and Dinitrophenyl (DNP)-l l- dUTP. Probes can also be indirectly labeled with biotin or digoxygenin, or labeled with radioactive isotopes such as32P and3H, and secondary detection molecules may be used, or further processing may be performed, to visualize the probes. For example, a probe labeled with biotin can be detected by avidin conjugated to a detectable marker, e.g., avidin can be conjugated to an enzymatic marker such as alkaline phosphatase or horseradish peroxidase. Enzymatic markers can be detected in standard colorimetric reactions using a substrate and / or a catalyst for the enzyme. Catalysts for alkaline phosphatase include 5-bromo-4-chloro-3- indolylphosphate and nitro blue tetrazolium. Diaminobenzoate can be used as a catalyst for horseradish peroxidase. Probes can also be prepared such that a fluorescent or other label is added after hybridization of the probe to its target to detect that the probe hybridized to the target. For example, probes can be used that have antigenic molecules incorporated into the nucleotide sequence. After hybridization, these antigenic molecules are detected, for example, using specific antibodies reactive with the antigenic molecules. Such antibodies can, for example, themselves incorporate a fluorochrome, or can be detected using a second antibody with a bound fluorochrome. For fluorescent probes, e.g., used in FISH techniques, fluorescence can be viewed with a fluorescence microscope equipped with an appropriate filter for each fluorophore, or by using dual or triple band-pass filter sets to observe multiple fluorophores. Alternatively, techniques such as flow cytometry can be used to examine the hybridization pattern of the chromosomal probes.

[0252] In some embodiments, the probe hybridizes to a breakpoint of an ESRI fusion nucleic acid molecule of the disclosure and a sequence on either side of the breakpoint (e.g., any of 1,2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides on either side of the breakpoint, or any of between 1 and about 5, about 5 and about 10, about 10 and about 15, about 15 and about 20, about 20 and about 25, about 25 and about 30, about 30 and about 35, about 35 and about 40, about 40 and about 45, about 45 and about 50, about 50 and about 55, about 55 and about 60, about 60 and about 65, about 70 and about 75, about 75 and about 80, about 80 and about 85, about 85 and about 90, about 90 and about 95, or about 95 and about 100, or more nucleotides on either side of the breakpoint).

[0253] In some aspects, provided herein are oligonucleotides, e.g., useful as primers. In some embodiments, an oligonucleotide, e.g., a primer, provided herein comprises a nucleotide sequence configured to hybridize to a target nucleic acid molecule that is or comprises an ESRI fusion nucleic acid molecule of the disclosure, or a fragment or portion thereof. In some embodiments, the oligonucleotide comprises a nucleotide sequence configured to hybridize to the ESRI fusion nucleic acid molecule of the target nucleic acid molecule. In some embodiments, the oligonucleotide comprises a nucleotide sequence configured to hybridize to a fragment or portion of the ESRI fusion nucleic acid molecule of the target nucleic acid molecule.

[0254] In some embodiments, the oligonucleotide, e.g., the primer, comprises a nucleotide sequence configured to hybridize to a breakpoint of an ESRI fusion nucleic acid molecule of the disclosure, and may be further configured to hybridize to between about 10 and about 12, about 12 and about 15, about 15 and about 17, about 17 and about 20, about 20 and about 25, or about 25 and about 30, or more nucleotides flanking either side of the breakpoint.

[0255] In some embodiments, the oligonucleotide, e.g., the primer, comprises a nucleotide sequence configured to hybridize to a nucleotide sequence in an intron or an exon of a gene involved in an ESRI fusion nucleic acid mole of the disclosure (e.g., an ESRI gene), to a breakpoint of an ESRI fusion nucleic acid molecule described herein, and / or to an intron or exon of another gene e.g., a corresponding gene fusion partner as described herein, e.g., any of CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5~).

[0256] In some embodiments, the oligonucleotide comprises a nucleotide sequence corresponding to an ESRI fusion nucleic acid molecule of the disclosure. In some embodiments, the oligonucleotide comprises a nucleotide sequence corresponding to a fragment or a portion of the ESRI fusion nucleic acid molecule. In some embodiments, the fragment or portion comprises between about 10 and about 30 nucleotides, between about 12 and about 20 nucleotides, or between about 12 and about 17 nucleotides. In someembodiments, the oligonucleotide comprises a nucleotide sequence complementary to an ESRI fusion nucleic acid molecule provided herein. In some embodiments, the oligonucleotide comprises a nucleotide sequence complementary to a fragment or a portion of the ESRI fusion nucleic acid molecule provided herein. In some embodiments, the fragment or portion comprises between about 10 and about 30 nucleotides, between about 12 and about 20 nucleotides, or between about 12 and about 17 nucleotides.

[0257] In some embodiments, an oligonucleotide, e.g., a primer, provided herein comprises a nucleotide sequence that is sufficiently complementary to its target nucleotide sequence such that the oligonucleotide specifically hybridizes to a nucleic acid molecule comprising the target nucleotide sequence, e.g., under high stringency conditions. In some embodiments, an oligonucleotide, e.g., a primer, provided herein comprises a nucleotide sequence that is sufficiently complementary to its target nucleotide sequence such that the oligonucleotide specifically hybridizes to a nucleic acid molecule comprising the target nucleotide sequence under conditions that allow a polymerization reaction (e.g., PCR) to occur.

[0258] In some embodiments, an oligonucleotide, e.g., a primer, provided herein may be useful for initiating DNA synthesis via PCR (polymerase chain reaction) or a sequencing method. In some embodiments, the oligonucleotide may be used to amplify a nucleic acid molecule that is or comprises an ESRI fusion nucleic acid molecule of the disclosure, or a fragment thereof, e.g., using PCR. In some embodiments, the oligonucleotide may be used to sequence a nucleic acid molecule that is or comprises an ESRI fusion nucleic acid molecule provided herein, or a fragment thereof. In some embodiments, the oligonucleotide may be used to amplify a nucleic acid molecule comprising a breakpoint of an ESRI fusion nucleic acid molecule described herein, e.g., using PCR. In some embodiments, the oligonucleotide may be used to sequence a nucleic acid molecule comprising a breakpoint of an ESRI fusion nucleic acid molecule described herein.

[0259] In some embodiments, pairs of oligonucleotides, e.g., pairs of primers, are provided herein, which are configured to hybridize to a nucleic acid molecule that is or comprises an ESRI fusion nucleic acid molecule of the disclosure, or a fragment thereof. In some embodiments, a pair of oligonucleotides of the disclosure may be used for directing amplification of the ESRI fusion nucleic acid molecule or fragment thereof, e.g., using a PCR reaction. In some embodiments, pairs of oligonucleotides, e.g., pairs of primers, are provided herein, which are configured to hybridize to a nucleic acid molecule comprising a breakpoint of an ESRI fusion nucleic acid molecule described herein, e.g., for use in directingamplification of the corresponding ESRI fusion nucleic acid molecule or fragment thereof, e.g., using a PCR reaction.

[0260] In some embodiments, an oligonucleotide, e.g., a primer, provided herein is a single stranded nucleic acid molecule, e.g., for use in sequencing or amplification methods. In some embodiments, an oligonucleotide provided herein is a double stranded nucleic acid molecule. In some embodiments, a double stranded oligonucleotide is treated, e.g., denatured, to separate its two strands prior to use, e.g., in sequencing or amplification methods. Oligonucleotides provided herein comprise a nucleotide sequence of sufficient length to hybridize to their target, e.g., an ESRI fusion nucleic acid molecule of the disclosure, or a fragment thereof, and to prime the synthesis of extension products, e.g., during PCR or sequencing.

[0261] In some embodiments, an oligonucleotide, e.g., a primer, provided herein comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or more deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises at least about 8 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises at least about 10 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises at least about 12 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises at least about 15 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises at least about 20 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises at least about 30 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises between about 10 and about 30 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises between about 10 and about 25 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises between about 10 and about 20 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleotide provided herein comprises between about 10 and about 15 deoxyribonucleotides or ribonucleotides. In some embodiments, an oligonucleo...

Claims

CLAIMSWhat is claimed is:

1. A method for selecting a therapy for an individual having breast cancer or for identifying an individual having breast cancer who may benefit from a treatment comprising an anti-cancer agent other than a selective estrogen receptor modulator (SERM) or an aromatase inhibitor, the method comprising detecting in a sample from the individual an estrogen receptor 1 (ESRI) fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; wherein detection of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample identifies the individual as one who may benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor.

2. A method of identifying one or more treatment options for an individual having breast cancer, the method comprising detecting or acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and generating a report comprising one or more treatment options identified for the individual based, at least in part, on detection or on acquiring knowledge of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample, wherein the one or more treatment options comprise an anti-cancer agent other than a SERM or an aromatase inhibitor.

3. A method of selecting a treatment for an individual having breast cancer, comprising acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; wherein responsiveto the acquisition of said knowledge: (i) the individual is classified as a candidate to receive a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor; and / or (ii) the individual is identified as likely to respond to a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

4. A method of predicting survival of an individual having breast cancer, or an individual having breast cancer treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, the method comprising acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; wherein responsive to the acquisition of said knowledge, the individual is predicted to have longer survival when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor.

5. A method of treating or delaying progression of breast cancer, comprising:(1) acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from an individual having breast cancer, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof; and(2) responsive to said knowledge, administering to the individual an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

6. A method of treating or delaying progression of breast cancer, comprising administering to an individual having breast cancer an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor, wherein the anti-cancer agent is administered responsive to acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acidmolecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP9I, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof.

7. A method of treating or delaying progression of breast cancer, comprising:(1) detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from an individual having breast cancer, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and(2) administering to the individual an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

8. A method of monitoring, evaluating or screening an individual having breast cancer, comprising acquiring knowledge of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof; wherein responsive to the acquisition of said knowledge, the individual is predicted to benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor and / or to have longer survival when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor, as compared to an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide when treated with a treatment comprising a SERM or an aromatase inhibitor.

9. A method of assessing an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide, in breast cancer in an individual, the method comprising:(1) detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP9I, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and(2) providing an assessment of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample.

10. A method of detecting an ESRI fusion nucleic acid molecule or an ESRI fusion polypeptide in breast cancer, the method comprising detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from an individual having breast cancer, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof.

11. A method of detecting the presence or absence of breast cancer in an individual, the method comprising:(1) detecting the presence or absence of breast cancer in a sample from the individual; and(2) detecting an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP9I, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof.

12. The method of claim 11, comprising detecting the presence of breast cancer in a sample from the individual; and / or detecting the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in a sample from the individual.

13. A method for monitoring progression or recurrence of breast cancer in an individual, the method comprising:(1) detecting, in a first sample obtained from the individual at a first time point, the presence or absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule;(2) detecting, in a second sample obtained from the individual at a second time point after the first time point, the presence or absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; and(3) providing an assessment of breast cancer progression or breast cancer recurrence in the individual based, at least in part, on the presence or absence of the ESRI fusion nucleic acidmolecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the first sample and / or in the second sample; wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B. or C6orfl5, or a portion thereof.

14. The method of claim 13, wherein the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the first sample and / or in the second sample identifies the individual as having decreased risk of breast cancer progression or breast cancer recurrence when treated with a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor.

15. The method of claim 13 or claim 14, further comprising selecting a treatment, administering a treatment, adjusting a treatment, adjusting a dose of a treatment, or applying a treatment to the individual based, at least in part, on detecting the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the first sample and / or in the second sample, wherein the treatment comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

16. A method for monitoring resistance to endocrine therapy in an individual with breast cancer, the method comprising:(1) detecting, in a sample obtained from the individual during or after treatment with an endocrine therapy, an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; and(2) providing an assessment of resistance to endocrine therapy in the individual based, at least in part, on the detection of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample; wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2. IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof.

17. The method of claim 16, further comprising, after providing the assessment of resistance to endocrine therapy, administering to the individual an effective amount of a treatment that comprises an anti-cancer agent other than a SERM or an aromatase inhibitor; wherein optionally the method further comprises halting administration of an endocrinetherapy to the individual based, at least in part, on the detection of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample.

18. A method for monitoring sensitivity to endocrine therapy in an individual with breast cancer, the method comprising:(1) detecting, in a sample obtained from the individual before, during, or after treatment with an endocrine therapy, absence of an ESRI fusion nucleic acid molecule, or an ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule; and(2) providing an assessment of sensitivity to endocrine therapy in the individual based, at least in part, on the detection of the absence of an ESRI fusion nucleic acid molecule, or ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample; wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC100422737, SNAP91, ZBTB2, IYD, IMPGI, STAG2, TNRC6B. or C6orfl5, or a portion thereof.

19. The method of claim 18, further comprising, after providing the assessment of sensitivity to endocrine therapy, administering to the individual an effective amount of an endocrine therapy.

20. The method of any one of claims 16-19, further comprising, prior to the detection, administering to the individual an effective amount of an endocrine therapy.

21. The method of any one of claims 16-20, wherein the endocrine therapy comprises treatment with a SERM or an aromatase inhibitor.

22. A method of detecting an ESRI fusion nucleic acid molecule, the method comprising:(a) providing a plurality of nucleic acid molecules obtained from a sample from an individual having breast cancer, wherein the plurality of nucleic acid molecules comprises nucleic acid molecules corresponding to an ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOCI 00422737, SNAP9I, ZBTB2, IYD, IMPGI, STAG2, TNRC6B, or C6oifl5, or a portion thereof;(b) optionally, ligating one or more adapters onto one or more nucleic acid molecules from the plurality of nucleic acid molecules;(c) optionally, amplifying the one or more ligated nucleic acid molecules from theplurality of nucleic acid molecules;(d) optionally, capturing amplified nucleic acid molecules from the amplified nucleic acid molecules;(e) sequencing, by a sequencer, the captured nucleic acid molecules to obtain a plurality of sequence reads that represent the captured nucleic acid molecules, wherein one or more of the plurality of sequence reads correspond to the ESRI fusion nucleic acid molecule;(f) analyzing the plurality of sequence reads for the presence or absence of the ESRI fusion nucleic acid molecule; and(g) based on the analyzing step, detecting the presence or absence of the ESRI fusion nucleic acid molecule in the sample.

23. The method of claim 22, wherein the sequencer comprises a next- generation sequencer.

24. A method of detecting an ESRI fusion nucleic acid molecule, the method comprising:(a) providing a sample from an individual having breast cancer, wherein the sample comprises a plurality of nucleic acid molecules;(b) preparing a nucleic acid sequencing library from the plurality of nucleic acid molecules in the sample;(c) amplifying said library;(d) selectively enriching for one or more nucleic acid molecules comprising nucleotide sequences corresponding to an ESRI fusion nucleic acid molecule in said library to produce an enriched sample, wherein the an ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOCI 00422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof;(e) sequencing the enriched sample, thereby producing a plurality of sequence reads;(f) analyzing the plurality of sequence reads for the presence or absence of the ESRI fusion nucleic acid molecule; and(g) detecting, based on the analyzing step, the presence or absence of the ESRI fusion nucleic acid molecule in the sample from the individual.

25. The method of claim 22 or claim 24, wherein the one or more adapters compriseamplification primers, flow cell adapter sequences, substrate adapter sequences, sample index sequences, or unique molecular identifier (UMI) sequences.

26. The method of claim 24, wherein the selectively enriching comprises: (a) combining one or more bait molecules with the library, thereby hybridizing the one or more bait molecules to one or more nucleic acid molecules comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule, and producing nucleic acid hybrids; and (b) isolating the nucleic acid hybrids to produce the enriched sample.

27. The method of any one of claims 22-26, wherein the amplified nucleic acid molecules are captured by hybridization with one or more bait molecules.

28. The method of any one of claims 22-27, wherein the amplifying comprises performing a polymerase chain reaction (PCR) amplification technique, a non-PCR amplification technique, or an isothermal amplification technique.

29. The method of any one of claims 1, 2, 7, and 9-21, further comprising selectively enriching for one or more nucleic acid molecules in the sample comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule; wherein the selectively enriching produces an enriched sample.

30. The method of claim 29, wherein the selectively enriching comprises: (a) combining one or more bait molecules with the sample, thereby hybridizing the one or more bait molecules to one or more nucleic acid molecules in the sample comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule and producing nucleic acid hybrids; and (b) isolating the nucleic acid hybrids to produce the enriched sample.

31. The method of any one of claims 26-28 and 30, wherein the one or more bait molecules comprise a capture nucleic acid molecule configured to hybridize to a nucleotide sequence corresponding to the ESRI fusion nucleic acid molecule.

32. The method of claim 31, wherein the capture nucleic acid molecule comprises between about 10 and about 30 nucleotides, between about 50 and about 1000 nucleotides, between about 100 and about 500 nucleotides, between about 100 and about 300 nucleotides, or between about 100 and about 200 nucleotides.

33. The method of any one of claims 26-28 and 30-32, wherein the one or more baitmolecules are conjugated to an affinity reagent or to a detection reagent.

34. The method of claim 33, wherein the affinity reagent is an antibody, an antibody fragment, or biotin, or wherein the detection reagent is a fluorescent marker.

35. The method of any one of claims 31-34, wherein the capture nucleic acid molecule comprises a DNA, RNA, or mixed DNA / RNA molecule.

36. The method of any one of claims 24-25 and 29, wherein the selectively enriching comprises amplifying the one or more nucleic acid molecules comprising nucleotide sequences corresponding to the ESRI fusion nucleic acid molecule using a polymerase chain reaction (PCR) to produce an enriched sample.

37. The method of any one of claims 29-36, further comprising sequencing the enriched sample.

38. The method of any one of claims 22-37, wherein the plurality of nucleic acid molecules comprises a mixture of cancer nucleic acid molecules and non-cancer nucleic acid molecules.

39. The method of claim 38, wherein the cancer nucleic acid molecules are derived from a tumor portion of a heterogeneous tissue biopsy sample, and the non-cancer nucleic acid molecules are derived from a normal portion of the heterogeneous tissue biopsy sample.

40. The method of claim 38, wherein the sample comprises a liquid biopsy sample, and wherein the cancer nucleic acid molecules are derived from a circulating tumor DNA (ctDNA) fraction of the liquid biopsy sample, and the non-cancer nucleic acid molecules are derived from a non-tumor fraction of the liquid biopsy sample.

41. The method of claim 40, wherein the ctDNA fraction of the liquid biopsy sample comprises at least 1% of nucleic acid molecules in the liquid biopsy sample.

42. The method of any one of claims 16-41, wherein the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; optionally wherein the sequencing comprises a massively parallel sequencing technique, and the massively parallel sequencing technique comprises next-generationsequencing (NGS).

43. A method of identifying a candidate treatment for breast cancer in an individual in need thereof, comprising: performing DNA sequencing on a sample obtained from the individual to determine a sequencing mutation profile, wherein the sequencing mutation profile identifies presence of an ESRI fusion nucleic acid molecule in the sample, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6oifl5, or a portion thereof; wherein the treatment comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

44. The method of claim 43, wherein the presence of the ESRI fusion nucleic acid molecule in the sample identifies the individual as one who may benefit from a treatment comprising an anti-cancer agent other than a SERM or an aromatase inhibitor; and / or predicts the individual to have longer survival when treated with a treatment comprising an anticancer agent other than a SERM or an aromatase inhibitor, as compared to survival of an individual whose breast cancer comprises an ESRI fusion nucleic acid molecule when treated with a treatment comprising a SERM or an aromatase inhibitor.

45. The method of claim 43 or claim 44, wherein the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; optionally wherein the sequencing comprises a massively parallel sequencing technique, and the massively parallel sequencing technique comprises next generation sequencing (NGS).

46. The method of any one of claims 43-45, wherein the sequencing mutation profile identifies a fragment of the ESRI fusion nucleic acid molecule comprising a breakpoint or fusion junction.

47. The method of any one of claims 1-46, further comprising generating a report, wherein the report: (a) indicates the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample from the individual; and / or (b) indicates a treatment or one or more treatment options identified or selected for the individual based, at least in part, on the presence of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusionnucleic acid molecule, in the sample from the individual, wherein the treatment or the one or more treatment options comprise an anti-cancer agent other than a SERM or an aromatase inhibitor.

48. The method of any one of claims 1-47, further comprising generating a molecular profile for the individual, based, at least in part, on detecting or acquiring knowledge of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample from the individual.

49. The method of claim 48, wherein the molecular profile for the individual further comprises results from a comprehensive genomic profiling (CGP) test, a gene expression profiling test, a cancer hotspot panel test, a DNA methylation test, a DNA fragmentation test, an RNA fragmentation test, or any combination thereof.

50. The method of claim 48 or claim 49, wherein the molecular profile for the individual further comprises results from a nucleic acid sequencing-based test.

51. The method of any one of claims 48-50, further comprising selecting a treatment, administering a treatment, or applying a treatment to the individual based on the generated molecular profile, wherein the treatment comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

52. The method of any one of claims 48-51, further comprising generating a report, wherein the report comprises the molecular profile for the individual.

53. The method of claim 52, wherein the report further comprises information on a treatment or one or more treatment options identified or selected for the individual based, at least in part, on the molecular profile for the individual, wherein the treatment or one or more treatment options comprise an anti-cancer agent other than a SERM or an aromatase inhibitor.

54. The method of any one of claims 2 and 47-53, further comprising providing the report to the individual, a caregiver, a healthcare provider, a physician, an oncologist, an electronic medical record system, a hospital, a clinic, a third-party payer, an insurance company, or a government office.

55. The method of any one of claims 1-54, wherein the individual is a human.

56. The method of any one of claims 1-55, further comprising obtaining the sample from the individual.

57. The method of any one of claims 1-56, wherein the sample is obtained or derived from the breast cancer.

58. The method of any one of claims 1-57, wherein the sample comprises a tissue biopsy sample, a liquid biopsy sample, or a normal control.

59. The method of any one of claims 1-57, wherein the sample is from a tumor biopsy, tumor specimen, or circulating tumor cell.

60. The method of any one of claims 1-57, wherein the sample is a liquid biopsy sample comprising blood, plasma, cerebrospinal fluid, sputum, stool, urine, or saliva.

61. The method of any one of claims 1-60, wherein the sample comprises cells and / or nucleic acids from the breast cancer.

62. The method of claim 61, wherein the sample comprises mRNA, DNA, circulating tumor DNA (ctDNA), cell-free DNA, or cell-free RNA from the breast cancer.

63. The method of any one of claims 1-57, wherein the sample is a liquid biopsy sample comprising circulating tumor cells (CTCs).

64. The method of any one of claims 1-57, wherein the sample is a liquid biopsy sample comprising cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), or any combination thereof.

65. The method of any one of claims 2-6, 8, and 47-64, wherein the acquiring knowledge of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, comprises detecting the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample.

66. The method of any one of claims 1, 2, 7, and 9-65, wherein detecting the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule, in the sample comprises detecting a fragment of the ESRI fusion nucleic acid molecule, or of the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acidmolecule, comprising a breakpoint or fusion junction.

67. The method of any one of claims 1, 2, 7, and 9-66, wherein the ESRI fusion nucleic acid molecule is detected in the sample by one or more of: a nucleic acid hybridization assay, an amplification-based assay, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, real-time PCR, a screening analysis, fluorescence in situ hybridization (FISH), spectral karyotyping, multicolor FISH (mFISH), comparative genomic hybridization, in situ hybridization, sequence- specific priming (SSP) PCR, high-performance liquid chromatography (HPLC), mass-spectrometric genotyping, or sequencing.

68. The method of claim 67, wherein the sequencing comprises a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; optionally wherein the massively parallel sequencing (MPS) technique comprises next-generation sequencing (NGS).

69. The method of any one of claims 1, 2, 7, 9-21, and 47-66, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule is detected in the sample by one or more of: immunoblotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry, or mass spectrometry.

70. The method of any one of claims 1-69, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule is oncogenic; optionally wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule promotes cancer cell survival, angiogenesis, cancer cell proliferation, and any combination thereof.

71. The method of any one of claims 1-70, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule confers resistance to an endocrine therapy.

72. The method of any one of claims 1-71, wherein the anti-cancer agent comprises one or more of a small molecule inhibitor, an antibody, a cellular therapy, a nucleic acid, a virusbased therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a PROteolysis-TArgeting Chimera (PROTAC), a treatment for cancer comprising an ESRI gene fusion or rearrangement, an anti-cancer agent being tested in a clinical trial, a treatment for cancer comprising an ESRI gene fusion or rearrangement being tested in a clinical trial, or any combination thereof.

73. The method of any one of claims 1-71, wherein the anti-cancer agent comprises a selective estrogen receptor covalent antagonist (SERCA).

74. The method of claim 73, wherein the anti-cancer agent is H3B-5942 or H3B-6545.

75. The method of any one of claims 1-71, wherein the anti-cancer agent comprises a selective estrogen receptor degrader (SERD).

76. The method of claim 75, wherein the anti-cancer agent is fulvestrant, elacestrant, amcenestrant, camizestrant, giredestrant, rintodestrant, imlunestrant, ZB-716, Zn-c5, LSZ102, LY3484356, or D-0502, or a pharmaceutically acceptable salt thereof.

77. The method of any one of claims 1-71, wherein the anti-cancer agent comprises a PROTAC.

78. The method of claim 77, wherein the PROTAC is ARV-471.

79. The method of any one of claims 1-71, wherein the anti-cancer agent comprises a CDK4 / 6 inhibitor.

80. The method of claim 79, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, ribociclib, or a pharmaceutically acceptable salt thereof.

81. The method of any one of claims 1-71, wherein the anti-cancer agent comprises a SERD and a CDK4 / 6 inhibitor.

82. The method of any one of claims 1-71, wherein the anti-cancer agent comprises a PI3K inhibitor.

83. The method of claim 82, wherein the PI3K inhibitor is GSK2636771, buparlisib, AZD8186, copanlisib, LY294002, PX-866, TGX115, TGX126, BEZ235, SF1126, idelalisib, pictilisib, GDC0032, IPI145, INK1117, SAR260301, KIN-193, duvelisib, GS-9820, GSK2636771, GDC-0980, AMG319, paxalisib, or alpelisib, or a pharmaceutically acceptable salt thereof.

84. The method of any one of claims 1-71, wherein the anti-cancer agent comprises an mTOR inhibitor.

85. The method of claim 84, wherein the mTORCl inhibitor is temsirolimus, everolimus,ridaforolimus, dactolisib, GSK2126458, XL765, AZD8055, AZD2014, MLN128, PP242, NVP-BEZ235, LY3023414, PQR309, PKI587, or OSI027, or a pharmaceutically acceptable salt thereof.

86. The method of claim 72, wherein the nucleic acid inhibits the expression of the ESRI fusion nucleic acid molecule, or the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule.

87. The method of claim 86, wherein the nucleic acid is a double-stranded RNA (dsRNA), a small interfering RNA (siRNA), or a small hairpin RNA (shRNA).

88. The method of claim 72, wherein the cellular therapy is an adoptive therapy, a T cellbased therapy, a natural killer (NK) cell-based therapy, a chimeric antigen receptor (CAR)-T cell therapy, a recombinant T cell receptor (TCR) T cell therapy, a macrophage-based therapy, an induced pluripotent stem cell-based therapy, a B cell-based therapy, or a dendritic cell (DC) -based therapy.

89. The method of any one of claims 1-8, 14, 15, 17, and 43-88, wherein the treatment or the one or more treatment options further comprise an additional anti-cancer therapy.

90. The method of claim 89, wherein the additional anti-cancer therapy comprises one or more of a small molecule inhibitor, a chemotherapeutic agent, a cancer immunotherapy, an antibody, a cellular therapy, a nucleic acid, a surgery, a radiotherapy, an anti- angiogenic therapy, an anti-DNA repair therapy, an anti-inflammatory therapy, an anti-neoplastic agent, a growth inhibitory agent, a cytotoxic agent, a vaccine, a small molecule agonist, a virusbased therapy, an antibody-drug conjugate, a recombinant protein, a fusion protein, a natural compound, a peptide, a PROteolysis-TArgeting Chimera (PROTAC), or any combination thereof.

91. The method of claim 90, wherein the anti-cancer agent comprises a SERD, and wherein the additional anti-cancer therapy comprises a CDK4 / 6 inhibitor.

92. The method of claim 90, wherein the cellular therapy is an adoptive therapy, a T cellbased therapy, a natural killer (NK) cell-based therapy, a chimeric antigen receptor (CAR)-T cell therapy, a recombinant T cell receptor (TCR) T cell therapy, a macrophage-based therapy, an induced pluripotent stem cell-based therapy, a B cell-based therapy, or a dendriticcell (DC) -based therapy.

93. The method of claim 90, wherein the nucleic acid comprises a double-stranded RNA (dsRNA), a small interfering RNA (siRNA), or a small hairpin RNA (shRNA).

94. The method of any one of claims 1-8, 14, 15, 17, 21, and 43-93, wherein the SERM is tamoxifen, raloxifene, EM652, GW7604, keoxifene, toremifene, bazedoxifene, broparestrol, clomifene, cyclofenil, lasofoxifene, ormeloxifene, or ospemifene.

95. The method of any one of claims 1-8, 14, 15, 17, 21, and 43-94, wherein the aromatase inhibitor is aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1, 4, 6-androstatrien-3, 17-dione (ATD), or 4-Androstene-3, 6, 17-trione (“6-OXO”).

96. The method of any one of claims 1-95, wherein the breast cancer is advanced or metastatic.

97. The method of any one of claims 1-96, wherein the breast cancer is hormone receptor positive (HR+) breast cancer.

98. The method of any one of claims 1-97, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, encoding an ESRI DNA binding domain, or a portion thereof, to any one of genes CCDC170, SMAD4, LOCI 00422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof.

99. The method of any one of claims 1-98, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI DNA binding domain, or a portion thereof, fused to a polypeptide encoded by any one of genes CCDC170, SMAD4, LOC100422737, SNAP9I, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof.

100. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a CCDC170 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a CCDC170 gene, or a portion thereof.

101. The method of claim 100, wherein the ESRI fusion nucleic acid molecule comprises the CCDC170 gene, or a portion thereof, fused to exon 2 of the ESRI gene.

102. The method of claim 100 or claim 101, wherein the ESRI fusion nucleic acid molecule comprises the CCDC170 gene, or a portion thereof, fused to exons 1-2 of the ESRI gene.

103. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a CCDC170 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a CCDC170 polypeptide, or a portion thereof.

104. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a SMAD4 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a SMAD4 gene, or a portion thereof.

105. The method of claim 104, wherein the ESRI fusion nucleic acid molecule comprises the SMAD4 gene, or a portion thereof, fused to exon 4 of the ESRI gene.

106. The method of claim 104 or claim 105, wherein the ESRI fusion nucleic acid molecule comprises the SMAD4 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene.

107. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a SMAD4 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a SMAD4 polypeptide, or a portion thereof.

108. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a EOC100422737 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to aLOCI 00422737 gene, or a portion thereof.

109. The method of claim 108, wherein the ESRI fusion nucleic acid molecule comprises the LOC100422737 gene, or a portion thereof, fused to exon 4 of the ESRI gene.

110. The method of claim 108 or claim 109, wherein the ESRI fusion nucleic acid molecule comprises the EOC 100422737 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene.

111. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a EOC 100422737 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a EOC 100422737 polypeptide, or a portion thereof.

112. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a SNAP91 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a SNAP91 gene, or a portion thereof.

113. The method of claim 112, wherein the ESRI fusion nucleic acid molecule comprises the SNAP91 gene, or a portion thereof, fused to exon 4 of the ESRI gene.

114. The method of claim 112 or claim 113, wherein the ESRI fusion nucleic acid molecule comprises the SNAP91 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene.

115. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a SNAP91 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a SNAP91 polypeptide, or a portion thereof.

116. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a ZBTB2 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, inthe 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a ZBTB2 gene, or a portion thereof.

117. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a ZBTB2 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a ZBTB2 polypeptide, or a portion thereof.

118. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to an IYD gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to an IYD gene, or a portion thereof.

119. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to an IYD polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to an IYD polypeptide, or a portion thereof.

120. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to an IMPG1 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to an IMPG1 gene, or a portion thereof.

121. The method of claim 120, wherein the ESRI fusion nucleic acid molecule comprises the IMPG1 gene, or a portion thereof, fused to exon 4 of the ESRI gene.

122. The method of claim 120 or claim 121, wherein the ESRI fusion nucleic acid molecule comprises the IMPG1 gene, or a portion thereof, fused to exons 1-4 of the ESRI gene.

123. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide,or a portion thereof, fused to an 1MPG1 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to an 1MPG1 polypeptide, or a portion thereof.

124. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a STAG2 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction an ESRI gene, or a portion thereof, fused to a STAG2 gene, or a portion thereof.

125. The method of claim 124, wherein the ESRI fusion nucleic acid molecule comprises the STAG2 gene, or a portion thereof, fused to exon 5 of the ESRI gene.

126. The method of claim 124 or claim 125, wherein the ESRI fusion nucleic acid molecule comprises the STAG2 gene, or a portion thereof, fused to exons 1-5 of the ESRI gene.

127. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a STAG2 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a STAG2 polypeptide, or a portion thereof.

128. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a TNRC6B gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a TNRC6B gene, or a portion thereof.

129. The method of claim 128, wherein the ESRI fusion nucleic acid molecule comprises the TNRC6B gene, or a portion thereof, fused to exon 4 of the ESRI gene.

130. The method of claim 128 or claim 129, wherein the ESRI fusion nucleic acid molecule comprises the TNRC6B gene, or a portion thereof, fused to exons 1-4 of the ESRI gene.

131. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encodedby the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a TNRC6B polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a TNRC6B polypeptide, or a portion thereof.

132. The method of any one of claims 1-99, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to a C6orfl5 gene, or a portion thereof, and wherein the ESRI fusion nucleic acid molecule comprises, in the 5’ to 3’ direction, an ESRI gene, or a portion thereof, fused to a C6orfl5 gene, or a portion thereof.

133. The method of claim 132, wherein the ESRI fusion nucleic acid molecule comprises the C6orfl5 gene, or a portion thereof, fused to exon 5 of the ESRI gene.

134. The method of claim 132 or claim 133, wherein the ESRI fusion nucleic acid molecule comprises the C6orfl5 gene, or a portion thereof, fused to exons 1-5 of the ESRI gene.

135. The method of any one of claims 1-99, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI polypeptide, or a portion thereof, fused to a C6orfl5 polypeptide, or a portion thereof, and wherein the ESRI fusion polypeptide comprises, in the N- to C-terminus direction, an ESRI polypeptide, or a portion thereof, fused to a C6orfl5 polypeptide, or a portion thereof.

136. A system, comprising: a memory configured to store one or more program instructions, and one or more processors configured to execute the one or more program instructions, the one or more program instructions when executed by the one or more processors are configured to:(a) obtain a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from an individual having breast cancer;(b) analyze the plurality of sequence reads for presence of an ESRI fusionnucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOCI 00422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and(c) detect, based on the analyzing, the ESRI fusion nucleic acid molecule in the sample.

137. The system of claim 136, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule confers resistance to an endocrine therapy.

138. The system of claim 136 or claim 137, wherein the plurality of sequence reads is obtained by sequencing; optionally wherein the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; and optionally wherein the massively parallel sequencing technique comprises next generation sequencing (NGS).

139. The system of any one of claims 136-138, wherein the one or more program instructions when executed by the one or more processors are further configured to generate, based at least in part on the detecting, a genomic profile for the sample.

140. The system of claim 139, wherein the individual is administered a treatment based at least in part on the genomic profile; optionally wherein the treatment comprises an anticancer agent other than a SERM or an aromatase inhibitor.

141. The system of claim 139 or claim 140, wherein the genomic profile further comprises results from a comprehensive genomic profiling (CGP) test, a gene expression profiling test, a cancer hotspot panel test, a DNA methylation test, a DNA fragmentation test, an RNA fragmentation test, or any combination thereof.

142. The system of any one of claims 139-141, wherein the genomic profile further comprises results from a nucleic acid sequencing-based test.

143. A non-transitory computer readable storage medium comprising one or more programs executable by one or more computer processors for performing a method, the method comprising:(a) obtaining, using the one or more processors, a plurality of sequence reads of one or more nucleic acid molecules, wherein the one or more nucleic acid molecules are derived from a sample obtained from an individual having breast cancer;(b) analyzing, using the one or more processors, the plurality of sequence reads for presence of an ESRI fusion nucleic acid molecule, wherein the ESRI fusion nucleic acid molecule comprises a fusion between an ESRI gene, or a portion thereof, fused to any one of genes CCDC170, SMAD4, LOC 100422737, SNAP91, ZBTB2, IYD, IMPG1, STAG2, TNRC6B, or C6orfl5, or a portion thereof; and(c) detecting, using the one or more processors and based on the analyzing, the ESRI fusion nucleic acid molecule in the sample.

144. The non-transitory computer readable storage medium of claim 143, wherein the ESRI fusion polypeptide encoded by the ESRI fusion nucleic acid molecule confers resistance to an endocrine therapy.

145. The non-transitory computer readable storage medium of claim 143 or claim 144, wherein the plurality of sequence reads is obtained by sequencing; optionally wherein the sequencing comprises use of a massively parallel sequencing (MPS) technique, whole genome sequencing (WGS), whole exome sequencing, targeted sequencing, direct sequencing, or a Sanger sequencing technique; and optionally wherein the massively parallel sequencing technique comprises next generation sequencing (NGS).

146. The non-transitory computer readable storage medium of any one of claims 143-145, wherein the method further comprises generating, using the one or more processors, a genomic profile for the sample.

147. The non-transitory computer readable storage medium of claim 146, wherein the individual is administered a treatment based at least in part on the genomic profile; optionally wherein the treatment comprises an anti-cancer agent other than a SERM or an aromatase inhibitor.

148. The non-transitory computer readable storage medium of claim 146 or claim 147, wherein the genomic profile further comprises results from a comprehensive genomic profiling (CGP) test, a gene expression profiling test, a cancer hotspot panel test, a DNAmethylation test, a DNA fragmentation test, an RNA fragmentation test, or any combination thereof.

149. The non-transitory computer readable storage medium of any one of claims 146-148, wherein the genomic profile further comprises results from a nucleic acid sequencing-based test.

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