Assessing and treating prostate cancer

Abstract

This document provides methods and materials for assessing and / or treating mammals (e.g., humans) having prostate cancer. For example, methods and materials that can be used to determine whether or not a prostate cancer (e.g., a castration-resistant prostate cancer (CRPC)) is likely to respond to a particular cancer treatment (e.g., treatment with one or more one or more lutetium-177 (177Lu)-PSMA therapies) are provided. Methods and materials for using one or more cancer treatments to treat a mammal (e.g., a human) identified as likely to respond to a particular cancer treatment are also provided.

Description

[0001] ASSESSING AND TREATING PROSTATE CANCER

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Patent Application Serial No. 63 / 537,390, filed on September 8, 2023. The disclosure of the prior application is considered part of, and is incorporated by reference in, the disclosure of this application.

[0004] TECHNICAL FIELD

[0005] This document relates to methods and materials for assessing and / or treating mammals (e.g., humans) having cancer (e.g., prostate cancer). For example, this document provides methods and materials for determining whether or not a cancer (e.g., a prostate cancer such as a castration-resistant prostate cancer (CRPC)) is likely to respond to a particular cancer treatment (e.g., treatment with one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as lutetium-177 (177Lu) - prostate-specific membrane antigen (PSMA) therapies). In addition, this document provides methods and materials for assessing cancer (e.g., prostate cancer) and selecting one or more appropriate cancer treatments to treat a mammal (e.g., a human) identified as likely to respond to a particular cancer treatment.

[0006] BACKGROUND

[0007] 177LU-PSMA therapies use radioactive tracers designed to target and destroy cells having PSMA on their surface, such as prostate cancer cells, and are used in the treatment of patients with metastatic CRPC (mCRPC). However, while some patients respond well to this therapy, other patients have cancers that are resistant.

[0008] In addition, determining which prostate cancer patients most benefit from radioisotope therapies is of considerable interest given the costs for obtaining targeted radioisotope therapies such as177LU-PSMA.

[0009] SUMMARY

[0010] This document provides methods and materials for assessing and / or treating cancer (e.g., prostate cancer). In some cases, this document provides methods and materials for determining whether or not a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) is likely to respond to a particular cancer treatment (e.g., one or more radioisotope therapies such as177Lu-PSMA therapies), and, optionally, administering to the mammal one or more cancer treatments selected based, at least in part, on whether or not the mammal is likely to respond to a particular cancer treatment. For example, a sample (e.g., a blood sample) obtained from a mammal having cancer (e.g., prostate cancer) can be assessed to determine if the mammal is likely to respond or is unlikely to respond to a particular cancer treatment based, at least in part, on (1) the presence or absence of an amplification of a CCNE1 nucleic acid, (2) the presence or absence of an amplification of a FGFR1 nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in the sample.

[0011] As described herein, circulating tumor DNA (ctDNA) in blood samples from mammals having prostate cancer (e.g., CRPC such as mCRPC) that did not respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu- PSMA therapies) contained amplification of a CCNE1 nucleic acid, amplification of a FGFR1 nucleic acid, and / or one or more mutations present in a CDK12 nucleic acid (e.g., as compared to ctDNA in blood samples from mammals having prostate cancer (e.g., CRPC such as mCRPC) that did respond to one or more radioisotope therapies such as177Lu-PSMA therapies). Also as described herein, (1) the presence or absence of an amplification of a CCNE1 nucleic acid, (2) the presence or absence of an amplification of FGFRl nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from a mammal (e.g., a human) having prostate cancer can be used to determine whether or not that prostate cancer is likely to respond to a particular cancer treatment (e.g., one or more radioisotope therapies such as177Lu-PSMA therapies). For example, a mammal (e.g., a human) having prostate cancer (e.g., CRPC) can be identified as being likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177LU-PSMA therapies) based, at least in part, on (1) the absence of an amplification of a CCNE1 nucleic acid, (2) the absence of an amplification of aFGFRl nucleic acid, and (3) the absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from the mammal, and, optionally, one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu- PSMA therapies) can be administered to the mammal that was identified as having (l)-(3) (e.g., to treat the mammal).

[0012] Having the ability to identify a mammal as having cancer (e.g., prostate cancer) likely to respond to a177Lu-PSMA therapy based, at least in part, on (1) the absence of an amplification of a CCNE1 nucleic acid, (2) the absence of an amplification of a FGFR1 nucleic acid, and (3) the absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) (e.g., resulting in a mutated CDK12 polypeptide) in a sample (e.g., a blood sample) provides a unique and unrealized opportunity to provide a safe and effective use of a177Lu-PSMA therapy to treat cancer (e.g., prostate cancer) in this identified patient population.

[0013] Also, having the ability to identify a mammal as having cancer (e.g., prostate cancer) unlikely to respond to a177Lu-PSMA therapy based, at least in part, on (1) the presence of an amplification of a CCNE1 nucleic acid, (2) the presence of an amplification of a FGFR1 nucleic acid, and / or (3) the presence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) (e.g., resulting in a mutated CDK12 polypeptide) provides a unique and unrealized opportunity to provide a non-invasive assessment of a cancer (e.g., using a liquid biopsy) as well as an individualized approach in selecting effective cancer therapies other than a177Lu-PSMA therapy for this identified patient population.

[0014] In general, one aspect of this document features methods for assessing a mammal having a cancer where the methods can include, or consist essentially of, (a) determining if cancer cells of said cancer contain the absence of each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of & FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid; (b) classifying said cancer as being likely to respond to a radioisotope therapy. The mammal can be a human. The cancer can be a prostate cancer. The prostate cancer can be a CRPC such as a metastatic CRPC. The mutated CDK12 nucleic acid can encode a truncated CDK12 polypeptide or non-functional CDK12 polypeptide. The radioisotope therapy can include a beta-emitter. The radioisotope therapy can be a177Lu-PSMA therapy. The177Lu- PSMA therapy can be a177Lu-PSMA-617,177Lu- PSMAI&T,177Lu-PSMA-R2, or177Lu- PSMA-J591 therapy. The determining step can include determining if ctDNA in a blood sample from said mammal contains the absence of each of (1), (2), and (3). In another aspect, this document features methods for assessing a mammal having a cancer where the methods can include, or consist essentially of, (a) determining if cancer cells of said cancer contain the presence of at least one of (1) an amplification of a CCNEJ nucleic acid, (2) an amplification of a FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid; (b) classifying said cancer as being unlikely to respond to a radioisotope therapy. The mammal can be a human. The cancer can be a prostate cancer. The prostate cancer can be a CRPC such as a metastatic CRPC. The mutated CDK12 nucleic acid can encode a truncated CDK12 polypeptide or non-functional CDK12 polypeptide. The radioisotope therapy can include a beta-emitter. The radioisotope therapy can be a177Lu-PSMA therapy. The177Lu- PSMA therapy can be a177Lu-PSMA-617,177Lu- PSMAI&T,177Lu-PSMA-R2, or177Lu- PSMA-J591 therapy. The presence of said amplification of said CCNE1 nucleic acid can be determined. The presence of said amplification of said FGFR1 nucleic acid can be determined. The presence of said mutated CDK12 nucleic acid can be determined. The determining step can include determining if ctDNA in a blood sample from said mammal contains the presence of at least one of (1), (2), and (3).

[0015] In another aspect, this document features methods for selecting a treatment for a mammal having a cancer where the methods can include, or consist essentially of, (a) determining that cancer cells of said cancer lack each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of a FGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and (b) selecting a radioisotope therapy to be a treatment for said mammal. The mammal can be a human. The cancer can be a prostate cancer. The prostate cancer can be a CRPC such as a metastatic CRPC. The mutated CDK12 nucleic acid can encode a truncated CDK12 polypeptide or non-functional CDK12 polypeptide. The radioisotope therapy can include a beta-emitter. The radioisotope therapy can be a177Lu-PSMA therapy. The177Lu- PSMA therapy can be a177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, or177Lu- PSMA-J591 therapy. The determining step can include determining if ctDNA in a blood sample from said mammal lacks each of (1), (2), and (3).

[0016] In another aspect, this document features methods for selecting a treatment for a mammal having a cancer where the methods can include, or consist essentially of, (a) determining that cancer cells of said cancer contain at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and (b) selecting a cancer treatment for said mammal, wherein said cancer treatment does not include a radioisotope therapy. The mammal can be a human. The cancer can be a prostate cancer. The prostate cancer can be a CRPC such as a metastatic CRPC. The presence of said amplification of said CCNE1 nucleic acid can be determined. The presence of said amplification of said FGFR1 nucleic acid can be determined. The presence of said mutated CDK12 nucleic acid can be determined. The mutated CDK12 nucleic acid can encode a truncated CDK12 polypeptide or non-functional CDK12 polypeptide. The cancer treatment can include treatment with an anti-cancer agent. The anticancer agent can be abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel, bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, or combinations thereof. The treatment can include a surgery to remove said cancer, radiation treatment, and / or tissue ablation. The determining step can include determining if ctDNA in a blood sample from said mammal contains at least one of (1), (2), and (3).

[0017] In another aspect, this document features methods for treating a mammal having a cancer where the methods can include, or consist essentially of, (a) determining that cancer cells of said cancer lack each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid; and (b) administering a radioisotope therapy to said mammal. The mammal can be a human. The cancer can be a prostate cancer. The prostate cancer can be a CRPC such as a metastatic CRPC. The mutated CDK12 nucleic acid can encode a truncated CDK12 polypeptide or nonfunctional CDK12 polypeptide. The radioisotope therapy can include a beta-emitter. The radioisotope therapy can be a177Lu-PSMA therapy. The177Lu-PSMA therapy can be a177Lu- PSMA-617,177LU- PSMA I&T,177LU-PSMA-R2, or177Lu-PSMA-J591 therapy. The determining step can include determining if ctDNA in a blood sample from said mammal lacks each of (1), (2), and (3).

[0018] In another aspect, this document features methods for treating a cancer where the methods can include, or consist essentially of, administering a radioisotope therapy to a mammal that was identified as lacking each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid in cancer cells of said cancer. The mammal can be a human. The cancer can be a prostate cancer. The prostate cancer can be a CRPC such as a metastatic CRPC. The mutated CDK12 nucleic acid can encode a truncated CDK12 polypeptide or non-functional CDK12 polypeptide. The radioisotope therapy can include a beta-emitter. The radioisotope therapy can be a177Lu-PSMA therapy. The177Lu-PSMA therapy can be a177Lu-PSMA-617,177Lu- PSMAI&T,177LU-PSMA-R2, or177Lu-PSMA-J591 therapy. The mammal can have been identified as lacking each of (1), (2), and (3) in ctDNAin a blood sample from said mammal.

[0019] In another aspect, this document features methods for treating a mammal having a cancer where the methods can include, or consist essentially of, (a) determining that cancer cells of said cancer contain at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and (b) performing a cancer treatment on said mammal that does not include a radioisotope therapy. The mammal can be a human. The cancer can be a prostate cancer. The prostate cancer can be a CRPC such as a metastatic CRPC. The presence of said amplification of said CCNE1 nucleic acid can be determined. The presence of said amplification of said FGFR1 nucleic acid can be determined. The presence of said mutated CDK12 nucleic acid can be determined. The mutated CDK12 nucleic acid can encode a truncated CDK12 polypeptide or non-functional CDK12 polypeptide. The cancer treatment can include treatment with an anticancer agent. The anti-cancer agent can be abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel, bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, or combinations thereof. The treatment can include a surgery to remove said cancer, radiation treatment, and / or tissue ablation. The determining step can include determining if ctDNA in a blood sample from said mammal contains at least one of (1), (2), and (3).

[0020] In another aspect, this document features methods for treating a cancer where the methods can include, or consist essentially of, performing a treatment on a mammal that was identified as having at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of FGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid in cancer cells of said cancer, wherein said treatment does not include a radioisotope therapy. The mammal can be a human. The cancer can be a prostate cancer. The prostate cancer can be a CRPC such as a metastatic CRPC. The presence of said amplification of said CCNE1 nucleic acid can be determined. The presence of said amplification of said FGFR1 nucleic acid can be determined. The presence of said mutated CDK12 nucleic acid can be determined. The mutated CDK12 nucleic acid can encode a truncated CDK12 polypeptide or non-functional CDK12 polypeptide. The cancer treatment can include treatment with an anti-cancer agent. The anti-cancer agent can be abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel, bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, or combinations thereof. The treatment can include a surgery to remove said cancer, radiation treatment, and / or tissue ablation. The mammal can have been identified as having at least one of (1), (2), and (3) in ctDNA in a blood sample from said mammal.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0022] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0023] DETAILED DESCRIPTION

[0024] This document provides methods and materials for assessing and / or treating mammals (e.g., humans) having cancer (e.g., prostate cancer such as CRPC). In some cases, the methods and materials provided herein can be used to determine whether or not a mammal having cancer (e.g., prostate cancer such as CRPC) is likely to respond to a particular cancer treatment (e.g., one or more radioisotope therapies such as177Lu-PSMA therapies). For example, a sample (e.g., a blood sample) obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) can be assessed for (1) the presence or absence of an amplification of a CCNE1 nucleic acid, (2) the presence or absence of an amplification of aFGFRl nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) to determine whether or not the mammal is likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies). In some cases, the methods and materials provided herein also can include administering one or more cancer treatments to a mammal having cancer (e.g., prostate cancer such as CRPC) to treat the mammal (e.g., one or more cancer treatments selected based, at least in part, on whether or not the mammal is likely to respond to a particular cancer treatment such as one or more radioisotope therapies such as177LU-PSMA therapies).

[0025] A mammal (e g., a human) having cancer (e.g., prostate cancer such as CRPC) can be assessed to determine whether or not the cancer is likely to respond to a particular cancer treatment (e.g., one or more radioisotope therapies such as177Lu-PSMA therapies) by detecting (1) the presence or absence of an amplification of a CCNE1 nucleic acid, (2) the presence or absence of an amplification of aFGFRl nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from the mammal. As described herein, the absence of each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of a FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) can be used to determine that the mammal is likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177LU-PSMA therapies). Also as described herein, the presence of at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) can be used to determine that the mammal is unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177Lu-PSMA therapies). For example, the presence of an amplification of a CCNE1 nucleic acid in a sample obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) can be used to identify that mammal as being unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177Lu- PSMA therapies). In another example, the presence of an amplification of & FGFR1 nucleic acid in a sample obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) can be used to identify that mammal as being unlikely to respond to radioisotope therapies (e g., targeted radioisotope therapies such as177Lu-PSMA therapies). In yet another example, the presence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) can be used to identify that mammal as being unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177Lu-PSMA therapies).

[0026] Any appropriate mammal having cancer (e.g., prostate cancer such as CRPC) can be assessed and / or treated as described herein. Examples of mammals that can have cancer and can be assessed and / or treated as described herein include, without limitation, humans, nonhuman primates (e.g., monkeys), dogs, cats, horses, cows, pigs, sheep, mice, and rats. In some cases, a mammal can be a mammal that was treated with one or more (e.g., one, two, three, four, five, or more) agents capable of blocking and / or depleting androgens within the mammal. Examples of agents capable of blocking and / or depleting androgens within a mammal include, without limitation, abiraterone (e.g., ZYTIGA®), leuprolide (e.g., LUPRON DEPOT® and ELIGARD®), goserelin (e.g., ZOLADEX®), triptorelin (e g., TRELSTAR®), histrelin (e.g., VANTAS®), degarelix (e.g., FIRMAGON®), ketoconazole (e.g., NIZORAL®), flutamide (e.g., EULEXIN®), bicalutamide (e.g., CASODEX®), nilutamide (e.g., NILANDRON®), enzalutamide (e.g., XT ANDI®), apalutamide (e.g., ERLEADA®), and darolutamide (e.g., NUBEQ A®). In some cases, a mammal can be a mammal that was treated with one or more (e.g., one, two, three, four, five, or more) taxane- based chemotherapy agents. Examples of taxane-based chemotherapy agents include, without limitation, paclitaxel (e.g., ABRAXANE®), docetaxel (e.g., TAXOTERE® and DOCEFREZ®), and cabazitaxel (e.g., JEVTANA®). In some cases, a mammal can be a male mammal. For example, a male human having cancer (e.g., prostate cancer such as CRPC) can be assessed and / or treated as described herein.

[0027] When assessing and / or treating a mammal (e.g., a human) having cancer as described herein, the cancer can be any type of cancer. In some cases, a cancer assessed and / or treated as described herein can include one or more solid tumors. In some cases, a cancer assessed and / or treated as described herein can be a blood cancer. A cancer assessed and / or treated as described herein can be any stage of cancer (e.g., stage I, stage II, stage III, or stage IV). A cancer assessed and / or treated as described herein can be any grade of cancer (e.g., grade 1, grade 2, or grade 3). In some cases, a cancer assessed and / or treated as described herein can be a primary cancer (e.g., a localized primary cancer). In some cases, a cancer assessed and / or treated as described herein can have metastasized (e.g., can be a metastatic cancer). Examples of cancers that can be assessed and / or treated as described herein include, without limitation, prostate cancers, colon cancers, lung cancers, breast cancers, head and neck cancers, ovarian cancers, thyroid cancers, bile duct cancers, liver cancers, bone cancers, neuroendocrine cancers (e.g., neuroblastomas), and lymphomas. When a cancer that can be assessed and / or treated as described herein is a prostate cancer, the prostate cancer can be any type of prostate cancer. A prostate cancer can have any Gleason score. In some cases, a prostate cancer assessed and / or treated as described herein can be castration-sensitive prostate cancer (CSPC). In some cases, a prostate cancer assessed and / or treated as described herein can be CRPC. In some cases, a prostate cancer assessed and / or treated as described herein can have metastasized (e.g., can be a metastatic prostate cancer such as a mCRPC).

[0028] In some cases, the methods described herein can include identifying a mammal (e.g., a human) as having cancer (e.g., prostate cancer such as CRPC). Any appropriate method can be used to identify a mammal as having cancer. For example, physical examination (e.g., a digital rectal examination (DRE)), laboratory testing (e.g., blood tests for prostate-specific antigen (PSA) test), imaging techniques (e.g., ultrasound, magnetic resonance imaging (MRI), bone scans, computerized tomography (CT) scans, and positron emission tomography (PET) scans), and biopsy techniques can be used to identify a mammal (e.g., a human) as having prostate cancer.

[0029] In some cases, a sample (e.g., a blood sample) obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) can be assessed for the presence or absence of an amplification of a CCNE1 nucleic acid. The term “amplification” as used herein with respect to a level of a CCNE1 nucleic acid refers to any copy number of that CCNE1 nucleic acid that is greater than a number of CCNE1 nucleic acids typically observed in a comparable sample (e.g., a comparable control sample) from one or more mammals (e.g., humans) without cancer. For example, when a mammal is a diploid mammal, an amplification of a CCNE1 nucleic acid can include greater than two (e.g., three, four, five, six, or more) copies of a CCNE1 nucleic acid. In some cases, an amplification of a CCNE1 nucleic acid can include three or more copies (e.g., four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more copies) of a CCNE1 nucleic acid.

[0030] A sample (e.g., a blood sample) obtained from a mammal (e g., a human) having cancer (e.g., prostate cancer such as CRPC) can be assessed for an amplification of any appropriate CCNEJ nucleic acid. Examples of CCNE1 nucleic acids that can be assessed for an amplification of the CCNE1 nucleic acid in a sample obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) include, without limitation, those set forth in the National Center for Biotechnology Information (NCBI) databases at, for example, accession no. AC008798 (version AC008798.10), accession no. AF518727 (version AF518727.1), and accession no. AH003247 (version AH003247.2).

[0031] In some cases, a sample (e.g., a blood sample) obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) can be assessed for the presence or absence of an amplification of aFGFRl nucleic acid. The term “amplification” as used herein with respect to a level of a FGFR1 nucleic acid refers to any copy number of that FGFR1 nucleic acid that is greater than a number of FGFR1 nucleic acids typically observed in a comparable sample (e.g., a comparable control sample) from one or more mammals (e.g., humans) without cancer. For example, when a mammal is a diploid mammal, an amplification of a FGFR1 nucleic acid can include greater than two (e.g., three, four, five, six, or more) copies of a FGFR1 nucleic acid. In some cases, an amplification of a FGFR1 nucleic acid can include three or more copies (e.g., four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more copies) of aFGFRl nucleic acid.

[0032] A sample (e.g., a blood sample) obtained from a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) can be assessed for an amplification of any appropriate FGFR1 nucleic acid. Examples of FGFR1 nucleic acids that can be assessed for an amplification of the FGFR1 nucleic acid in a sample obtained from a mammal having cancer (e.g., prostate cancer such as CRPC) include, without limitation, those set forth in the NCBI databases at, for example, accession no. A29216 (version A29216.1), accession no. AC087623 (version AC087623.21), and accession no. AY585209 (version AY585209.1).

[0033] Any appropriate method can be used to detect the presence or absence of an amplification of a CCNE1 nucleic acid and / or an amplification of a FGFR1 nucleic acid within a sample (e.g., a blood sample) obtained from a mammal (e.g., a human such as a human having cancer such as prostate cancer). For example, DNA-based techniques (e.g., polymerase chain reaction (PCR) techniques, Southern blotting techniques, and nucleic acid sequence techniques such as next generation sequences, high throughput sequence, and deep sequencing techniques), and molecular cytogenetic techniques (e.g., fluorescence In Situ Hybridization (FISH)) can be used to determine the presence or absence of an amplification of a CCNE1 nucleic acid and / or an amplification of aFGFRl nucleic acid in a sample. In some cases, the presence or absence of an amplification of a CCNE1 nucleic acid and / or an amplification of aFGFRl nucleic acid within a sample from a mammal having cancer (e.g., prostate cancer) can be determined as described in Example 1 or Example 2.

[0034] In some cases, a sample (e g., a blood sample) obtained from a mammal having cancer (e g., prostate cancer such as CRPC) can be assessed for the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid). The term “mutated” as used herein with respect to a CDK12 nucleic acid can be any CDK12 nucleic acid that contains one or more mutations in its nucleic acid sequence.

[0035] Examples of mutations that can be present in a mutated CDK12 nucleic acid include, without limitation, mutations that alter the amino acid sequence of a CDK12 polypeptide from a wild-type CDK12 polypeptide found in the mammal’s somatic cells that are not cancerous to a different amino acid sequence, mutations present in non-coding sequences (e.g., introns) of CDK12 nucleic acid, and pathogenic CDK12 nucleic acid mutations. In some cases, a mutated CDK12 nucleic acid can have at least one, two, three, four, five, six, seven, eight, nine, ten, or more nucleotide changes per every 100 nucleotides of CDK12 nucleic acid being assessed. The term “pathologically mutated” as used herein with respect to a CDK12 nucleic acid can be any CDK12 nucleic acid mutation that results in a CDK12 polypeptide encoded by the mutated CDK12 nucleic acid having reduced or eliminated CDK12 polypeptide function (e.g., the ability to complex with cyclin K and phosphorylate RNA polymerase II (RNAP II)) and / or having a reduced or eliminated level of expression. The term “reduced level” as used herein with respect to a level of expression of a CDK12 polypeptide refers to any level that is lower than a reference level of the CDK12 polypeptide. In some cases, a reduced level of a CDK12 polypeptide can be a level that is at least 2 (e.g., about 3, about 4, about 5, about 10, about 20, about 25, about 30, about 40, about 50, or more) fold lower than a reference level of the CDK12 polypeptide. In some cases, a reduced level of a CDK12 polypeptide can be a level that is at least 10% (e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more) lower than a reference level of the CDK12 polypeptide. The term “reference level” as used herein with respect to a level of expression of a CDK12 polypeptide refers to the level of the CDK12 polypeptide typically observed in a control sample. Control samples are samples obtained from mammals not having cancer (e.g., healthy mammals such as healthy humans). It will be appreciated that levels of CDK12 polypeptides from comparable samples are used when determining whether or not a particular level is a reduced level of a CDK12 polypeptide. In some cases, a pathogenic CDK12 nucleic acid mutation can be as described elsewhere (see, e g., the cBioPortal for Cancer Genomics; Cerami et al., Cancer Discovery, 2:401 (2012); and Gao et al., Sci. Signal., 6:11 (2013)).

[0036] Any appropriate method can be used to detect the presence or absence of one or more mutations in a CDK12 nucleic acid within a sample (e.g., a blood sample) obtained from a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC). For example, sequencing techniques (e.g., nucleic acid sequence techniques such as next generation sequences, high throughput sequence, and deep sequencing techniques) can be used to identify the presence or absence of one or more mutations in a CDK12 nucleic acid.

[0037] Any appropriate method can be used to detect the presence, absence, or level of a CDK12 polypeptide within a sample (e.g., a blood sample) obtained from a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC). For example, western blotting techniques, mass spectrometry techniques, immunohistochemistry techniques, and flow cytometry techniques can be used to identify the presence, absence or level of a CDK12 polypeptide.

[0038] Any appropriate sample from a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) can be assessed as described herein (e.g., for (1) the presence or absence of an amplification of a CCNE1 nucleic acid, (2) the presence or absence of an amplification of &FGFR1 nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid)). In some cases, a sample can be a biological sample. For example, a sample can contain one or more biological molecules (e.g., nucleic acids such as DNA and RNA, polypeptides, carbohydrates, lipids, hormones, and / or metabolites). Examples of samples that can be assessed as described herein include, without limitation, fluid samples (e.g., urine samples, pleural fluid samples, and blood samples such as whole blood samples, plasma samples, and serum samples), and tissue samples (e.g., prostate tissue samples) such as cancer tissue biopsies. A sample can be a fresh sample or a fixed sample (e.g., a formaldehyde-fixed sample or a formalin-fixed sample). In some cases, one or more biological molecules can be isolated from a sample. For example, nucleic acid (e.g., DNA such ctDNA) can be isolated from a sample and can be assessed as described herein.

[0039] In some cases, a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) can be identified as being likely to respond to a particular cancer treatment (e.g., one or more radioisotope therapies such as177Lu-PSMA therapies) based, at least in part, on (1) the presence or absence of an amplification of a CCNE1 nucleic acid, (2) the presence or absence of an amplification of & FGFR1 nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid).

[0040] In some cases, a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) identified as being likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) based, at least in part, on (1) the absence of an amplification of a CCNE1 nucleic acid, (2) the absence of an amplification of FGFR1 nucleic acid, and (3) the absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) can be selected to receive one or more cancer treatments that include one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies).

[0041] In some cases, a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) can be identified as being likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) based, at least in part, on the absence of each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of SL FGFRI nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from the mammal. For example, a mammal having cancer (e.g., prostate cancer such as CRPC) can be identified as being likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) based, at least in part, on a sample (e.g., a blood sample) obtained from the mammal lacking each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of & FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid).

[0042] In some cases, a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) and identified as being likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) as described herein (e.g., based, at least in part, on the absence of each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from the mammal) can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies). For example, a mammal having cancer (e.g., prostate cancer such as CRPC) and identified as lacking each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from the mammal can be administered or instructed to selfadminister one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies).

[0043] In cases where a radioisotope therapy is a targeted radioisotope therapy, the targeted radioisotope therapy can include one or more targeting moieties. A targeting moiety can be any appropriate type of molecule. In some cases, a targeting moiety can be a polypeptide (e.g., an antibody) that can target (e.g., target and bind) a target polypeptide such as a tumor antigen (e.g., tumor-specific antigen). For example, a targeting moiety included in a targeted radioisotope therapy can target (e.g., target and bind) a tumor-specific antigen (e.g., a cell surface tumor-specific antigen) expressed by a cancer cell in a mammal having cancer. Examples of target polypeptides that can be recognized by a targeting moiety included in a targeted radioisotope therapy as described herein include, without limitation, PMSA, cluster of differentiation 19 (CD 19), mucin 1 (MUC-1), human epidermal growth factor receptor 2 (HER-2), estrogen receptor (ER), epidermal growth factor receptor (EGFR), alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, epithelial tumor antigen (ETA), melanoma-associated antigen (MAGE), CD33, CD 123, CLL-1, E-Cadherin, folate receptor alpha, folate receptor beta, IL13R, EGFRviii, CD22, CD20, kappa light chain, lambda light chain, desmopressin, CD44v, CD45, CD30, CD5, CD7, CD2, CD38, BCMA, CD138, FAP, CS-1, C-met, SSTR2, TR0P2, CLDN18.2, LAT1, MET, EPHA3, B7H3, HK2, STEAP1, PSCA, DLL3, GPC3, FAP, GRPR, NTSR-1, and integrins. For example, a targeting moiety included in a targeted radioisotope therapy can target (e.g., target and bind) cancer cells expressing a PMSA polypeptide on their surface.

[0044] A targeted radioisotope therapy can include any appropriate radioisotope. In some cases, a radioisotope present in a targeted radioisotope therapy can be a beta-emitter. Examples of radioisotopes that can be used in a targeted radioisotope therapy include, without limitation,177Lu, gallium-68 (Ga68), iodine-131 (1131), Actinium-224, Lead-212, Astatine-211, gallium plus Lutetium-177, Samarium-153, Samarium-153 plus radium-224, bismuth-213, terbium-149, yttrium-90, copper-64, copper 67, terbium-161, and iodine-125.

[0045] When a targeted radioisotope therapy is a177Lu-PSMA therapy, the177Lu-PSMA therapy can include any appropriate177Lu-PSMA therapy. Examples of177Lu-PSMA therapies that can be administered to a mammal having cancer (e.g., prostate cancer such as CRPC) and identified as being likely to respond to one or more177Lu-PSMA therapies as described herein include, without limitation,177Lu-PSMA-617,177Lu- PSMA I&T,177Lu- PSMA-R2,177LU-PSMA-J591, and combinations thereof. In some cases, a177Lu-PSMA therapy can be as described in Example 1 or Example 2. In some cases, a177Lu-PSMA therapy can be as described elsewhere (see, e.g., Aalbersberg et al., EJNMMI Radiopharmacy and Chemistry, 7:24 (2022)).

[0046] In some cases, a mammal (e g., a human) having cancer (e.g., prostate cancer such as CRPC) and identified as being likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) as described herein (e.g., based, at least in part, on the absence of each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of a FGFRJ nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from the mammal) can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) in combination with one or more (e.g., one, two, three, four, five, or more) additional cancer treatments effective against cancer (e.g., prostate cancer). In some cases, an additional cancer treatment that can be used together with one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can include administering one or more cancer drugs (e.g., chemotherapeutic agents, targeted cancer drugs, immunotherapy drugs, radioactive agents, and anti-androgens) other than a targeted radioisotope therapy. Examples of cancer drugs that are not an177Lu-PSMA therapy include, without limitation, abiraterone (e.g., ZYTIGA®), enzalutamide (e.g., XTANDI®), radium-223, docetaxel (e.g., TAXOTERE®), cabazitaxel (e.g., JEVTANA®), mitoxantrone (e.g., NOVANTRONE®), pembrolizumab (e.g., KEYTRUDA®), sipuleucel-T (e.g., PROVENGE®), olaparib (e.g., LYNPARZA®), rucaparib (e.g., RUBRACA®), talazoparib (e.g., TALZENNA®), carboplatin (e.g., PARAPLATIN®), paclitaxel (e.g., TAXOL®), bicalutamide (e.g., CASODEX®), leuprolide (e.g., LUPRON DEPOT® and ELIGARD®), darolutamide (e.g., NUBEQA®), apalutamide (e.g., ERLEADA®), flutamide (e.g., EULEXIN®), degarelix (e.g., FIRMAGON®), gosarelin (e.g., ZOLADEX®), and combinations thereof. For example, one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can be administered to a mammal (e.g., a human) having prostate cancer (e.g., CRPC) together with olaparib and abiraterone. In another example, one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can be administered to a mammal (e.g., a human) having prostate cancer (e.g., CRPC) together with talozaparib and enzalutamide. In another example, one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can be administered to a mammal (e.g., a human) having prostate cancer (e.g., CRPC) together with docetaxel and carboplatin. In yet another example, one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can be administered to a mammal (e.g., a human) having prostate cancer (e.g., CRPC) together with cabazitaxel and carboplatin. In some cases, an additional cancer treatment that can be used together with one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177LU-PSMA therapies) can include surgery. Examples of surgeries that can be performed on a mammal having prostate cancer (e.g., CRPC) include, without limitation, radical prostatectomies (removal of the prostate gland). In some cases, an additional cancer treatment that can be used together with one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can include radiation treatment (e.g., external beam radiation and brachytherapy). In some cases, an additional cancer treatment that can be used together with one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can be an androgen deprivation therapy (ADT). In some cases, an additional cancer treatment that can be used together with one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can include prostate tissue ablation. Examples of ablative therapies that can be performed on a mammal having prostate cancer to treat the mammal as described herein include, without limitation, freezing prostate tissue (e.g., cryoablation or cryotherapy), heating prostate tissue (e g., thermal ablation), and high intensity focused ultrasound (HIFU).

[0047] In some cases, a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) can be identified as being unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177Lu-PSMA therapies) based, at least in part, on the presence of at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of a FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from the mammal. For example, a mammal having cancer (e.g., prostate cancer such as CRPC) can be identified as being unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177LU-PSMA therapies) based, at least in part, on a sample (e.g., a blood sample) obtained from the mammal having the presence of an amplification of a CCNE1 nucleic acid. In another example, a mammal having cancer (e.g., prostate cancer such as CRPC) can be identified as being unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177Lu-PSMA therapies) based, at least in part, on a sample (e.g., a blood sample) obtained from the mammal having a presence of an amplification of a FGFR1 nucleic acid. In yet another example, a mammal having cancer (e.g., prostate cancer such as CRPS) can be identified as being unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177Lu-PSMA therapies) based, at least in part, on a sample (e.g., a blood sample) obtained from the mammal having a presence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid).

[0048] In some cases, a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) and identified as being unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177Lu-PSMA therapies) as described herein (e.g., based, at least in part, on the presence of at least one of (1) an amplification of a CCNEJ nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in a sample (e.g., a blood sample) obtained from the mammal) can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) alternative cancer treatments that do not include an177Lu-PSMA therapy. In some cases, an alternative cancer treatment that can be used as described herein can include administering one or more cancer drugs (e.g., chemotherapeutic agents, targeted cancer drugs, and immunotherapy drugs) other than an177Lu-PSMA therapy to a mammal in need thereof. Examples of cancer drugs that are not an177Lu-PSMA therapy and that can be administered to a mammal having cancer (e.g., prostate cancer such as CRPC) that was identified as being unlikely to respond to an177Lu-PSMA therapy as described herein include, without limitation, abiraterone (e.g., ZYTIGA®), enzalutamide (e.g., XT ANDI®), radium-223, docetaxel (e.g., TAXOTERE®), cabazitaxel (e.g., JEVTANA®), mitoxantrone (e.g., NOVANTRONE®), pembrolizumab (e.g., KEYTRUDA®), sipuleucel-T (e.g., PROVENGE®), olaparib (e.g., LYNPARZA®), rucaparib (e.g., RUBRACA®), talazoparib (e.g., TALZENNA®), carboplatin (e.g., PARAPLATIN®), paclitaxel (e.g., TAXOL®), bicalutamide (e.g., CASODEX®), leuprolide (e g., LUPRON DEPOT® and ELIGARD®), darolutamide (e.g., NUBEQA®), apalutamide (e.g., ERLEADA®), flutamide (e.g., EULEXIN®), degarelix (e.g., FIRMAGON®), gosarelin (e.g., ZOLADEX®), and combinations thereof. In some cases, an alternative cancer treatment that can be used as described herein can include surgery. Examples of surgeries that can be performed on a mammal having prostate cancer (e.g., CRPC) include, without limitation, radical prostatectomies (removal of the prostate gland). In some cases, an alternative cancer treatment that can be used as described herein can include radiation treatment (e.g., external beam radiation and brachytherapy). In some cases, an alternative cancer treatment that can be used as described herein can be an ADT. In some cases, an alternative cancer treatment that can be used as described herein can include prostate tissue ablation. Examples of ablative therapies that can be performed on a mammal having prostate cancer to treat the mammal as described herein include, without limitation, freezing prostate tissue (e.g., cryoablation or cryotherapy), heating prostate tissue (e.g., thermal ablation), and HIFU.

[0049] In some cases, when treating a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) as described herein, the treatment can be effective to reduce the size of a cancer (e.g., to reduce the number of cancer cells in the mammal and / or to reduce the volume of one or more tumors in the mammal) within a mammal (e.g., a human). For example, the methods and materials described herein can be used to reduce the size of the cancer by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. For example, the methods and materials described herein can be used to reduce the size of the cancer by at least 2-fold (e.g., by 2-fold, 3-fold, 4-fold, 5-fold, or more). In some cases, the methods and materials described herein can be used such that the size (e.g., the number of cancer cells and / or the volume) of one or more tumors present within a mammal does not increase.

[0050] In some cases, when treating a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) as described herein, the treatment can be effective to improve survival of the mammal. For example, the methods and materials described herein can be used to improve disease-free survival (e.g., relapse-free survival). For example, the methods and materials described herein can be used to improve progression-free survival. For example, the methods and materials described herein can be used to improve the survival of a mammal having cancer (e g., prostate cancer) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. For example, the materials and methods described herein can be used to improve the survival of a mammal having cancer (e.g., prostate cancer) by, for example, at least 2 months (e.g., about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 1 year, or more).

[0051] In some cases, when treating a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) as described herein, the treatment can be effective to reduce one or more symptoms of the cancer. Examples of symptoms of prostate cancer that can be reduced using the methods and materials described herein include, without limitation, trouble urinating, decreased force in the stream of urine, blood in the urine, blood in the semen, pain (e.g., bone pain), losing weight without trying, erectile dysfunction, fatigue, and loss of appetite. For example, the materials and methods described herein can be used to reduce one or more symptoms within a mammal having prostate cancer by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, when treating a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) as described herein (e.g., by administering one or more radioisotope therapies such as177Lu-PSMA therapies), the one or more radioisotope therapies (e g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can be the sole cancer treatment(s) administered to the mammal.

[0052] In some cases, when treating a mammal (e.g., a human) having cancer (e.g., prostate cancer such as CRPC) as described herein (e.g., by administering one or more radioisotope therapies such as177Lu-PSMA therapies), the mammal also can be treated with one or more additional agents / therapies used to treat cancer. Examples of additional agents / therapies that can be used to treat cancer as described herein include, without limitation, surgery, chemotherapies, targeted therapies (e g., monoclonal antibody therapies), hormone therapies (e.g., ADTs), radioisotopes (e.g., radioisotopes other than177Lu), angiogenesis inhibitors, immunotherapies, checkpoint blockade therapies, radiopharmaceuticals, and / or adoptive cell therapies (e.g., chimeric antigen receptor (CAR) T-cell therapies). In cases where one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu- PSMA therapies) are used in combination with one or more additional agents / therapies, the one or more additional agents / therapies can be administered at the same time or independently. For example, the one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies) can be administered first, and the one or more additional agents / therapies can be administered second, or vice versa.

[0053] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

[0054] EXAMPLES

[0055] Example 1: Predicting Resistance to1 , 7Lu-PSMA by Circulating Tumor DNA Biomarkers

[0056] Response to radiopharmaceuticals remains incompletely understood despite pretreatment imaging being a well-established biomarker. This Example describes using circulating tumor DNA (ctDNA) as a biomarker for whether metastatic castrate resistant prostate cancer (mCRPC) responds to177Lu-PSMA therapy. Materials and Methods

[0057] Blood for ctDNA (Guardant360 assays) was obtained before treatment with177Lu- PSMA therapy. This assay used deep sequencing to assess mutations in 83 genes, deletions in 7 genes, and amplification in 17 genes. All assessed genes were implicated in cancer growth, progression, and / or metastases.177Lu-PSMA therapy responses were assessed by PSA declines (>50% decline or not).

[0058] Results

[0059] Forty-four patients had baseline ctDNA. Of these, 28 / 44 (63.6%) had a PSA response, whereas 16 / 44 (36.3%) did not. Unresponsive patients were more likely to have amplifications detected in their ctDNA assays; 75% vs 39.2% (P=0.03). When examining alterations on a gene by gene basis, three genes were distinct. Amplification in CCNEJ and FGFR1 and pathogenic mutations in CDK12 were more frequently detected in patients without a PSA response. A total of 0% of responders had CCNE1 amplification vs 31.2% of non-responders (P=0.004). Responders had 0% FGFR1 amplifications vs 25% of nonresponders (P=0.01). For CDK12, 3.6% of responders were pathologically mutated compared to 25% of non-responders (P=0.05).

[0060] Together, these results demonstrate that CCNE1 and FGFR1 amplifications and CDK12 pathogenic mutations were associated with resistance to177Lu-PSMA therapy in mCRPC patients.

[0061] Example 2: Resistance to1 7Lu-PSMA Therapies and Circulating Tumor DNA Biomarkers

[0062] In the phase III VISION trial,177Lu-PSMA prolonged radiographic progression free survival (rPFS) and overall survival (OS) in PSMA-positive mCRPC patients (Sartor et al., N. Engl. J. Med., 385: 1091-1103 (2021)). With supporting data from the phase III VISION trial, both the U.S. Food and Drug Administration (FDA) and the European Commission approved177Lu-PSMA in 2022 for mCRPC patients previously treated with an androgenreceptor pathway inhibitor and taxane-based chemotherapy.

[0063] This Example describes the discovery that the presence or absence of particular markers present in ctDNA of mCRPC patients can be used to predict response or resistance to177LU-PSMA therapy. Materials and Methods

[0064] Blood for ctDNA assays to assess selected somatic mutations, amplifications, deletions, and fusions were obtained <50 days prior to treatment with177Lu-PSMA. All assays were performed using a commercial assay (Guardant 360, Redwood City, CA). This assay assessed 83 cancer-associated genes for mutations, 7 genes for deletions, 18 genes for amplifications, and 10 genes for various pathogenic fusions.

[0065] All patients had mCRPC, and all patients had PET positive metastatic disease (greater than liver uptake). All patients had prior treatment with abiraterone / enzalutamide (or both). The vast majority had at least one taxane based chemotherapy. Standard-of-care therapies were used in combination with177Lu- PSMA. All but four patients were treated with one of177LU-PSMA-617,177LU- PSMA I&T, and177Lu-PSMA-R2.

[0066] PSA was assessed at baseline (prior to177Lu-PSMA therapy) and at every treatment cycle (e.g., once every 6-8 weeks). PSA declines at any point post-treatment were assessed. Those with a PSA decline of >50% were “responders.” Those with a lesser PSA decline were “non-responders.” This analysis compared responders and non-responders relative to baseline ctDNA findings and demographics to assess differences in the two subsets using Fisher’s Exact methodology or Mann-Whitney test (where appropriate). The comparisons in Table 2 and p values reported therein represent a direct comparison of the individual genetic alterations in the responder versus non-responder groups.

[0067] Results

[0068] As shown in Table 1, the patient population included 44 mCPRC patients including 4 African Americans, 38 Caucasians, 1 Hispanic, and 1 “other.” The baseline PSA was 71.5 ng / mL and 88.9 ng / mL in the non-responders and responders, respectively. The responders and non-responders had several distinctions in their baseline variables. Non-responders were more likely to have liver metastases (25% vs 3.6%; / ?=0.05), higher serum lactate dehydrogenase (LDH) (median 249.5 vs 192.0; ?=0.009), and higher serum alkaline phosphatase (median 163 vs 81; =0.003).

[0069] Table 1. Patient demographics at baseline. The ctDNA findings were first assessed for amplifications, deletions, mutations, and splice variations (Table 2). No differences were noted between responders and non- responders for the frequency of deletions, mutations, or splice variations reported by the Guardant 360 testing. Amplifications, however, were distinct between the two groups. Those with no response to177Lu-PSMA were more likely to have amplifications as compared to non-responders (39.2% vs. 75.0%; p=0.03). When examining the amplifications using a gene-by-gene analysis, two specific amplifications were distinct between the two subsets. Non-responders were more likely to have amplification in CCNE1 (31.2% vs. 0%; =0.004) or FGFR1 (25% vs. 0%; / ?=0.01).

[0070] Table 2. All Lu- 177 responders and non-responders by gene. Guardant results for all Lu- 177 responders vs non-responders (responder defined as a PSA decline >50%) prior to initiation of Lu- 177 treatment.

[0071] As noted above, there was no difference in the patients with regard to the frequency of pathogenic mutations in responders / non responders. However, a gene-by-gene analysis indicated that CDK12 mutations were more frequent in the non-responders as compared to the responder (25% vs 3.7%; ?=0.05).

[0072] Together, these results demonstrate that a sample (e.g., a blood sample) obtained from a mammal having prostate cancer can be assessed to determine if the mammal is likely to respond or is unlikely to respond to177Lu-PSMA therapy based, at least in part, on (1) the presence or absence of an amplification of a CCNEl nucleic acid, (2) the presence or absence of an amplification of FGFR1 nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in the sample.

[0073] Example 3: Assessing prostate cancers

[0074] A blood sample is obtained from a human having prostate cancer (e.g., CRPC such as mCRPC). ctDNA in the obtained blood sample is examined for (1) the presence or absence of an amplification of a CCNE1 nucleic acid, (2) the presence or absence of an amplification of a EGER 1 nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid).

[0075] If the ctDNA in the sample lacks each of (1) an amplification of a CCNEl nucleic acid, (2) an amplification of & FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid), then the human is classified as being likely to respond to one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies).

[0076] If the ctDNA in the sample contains the presence of at least one of (1) an amplification of a CCNEl nucleic acid, (2) an amplification of &FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid), then the human is classified as being unlikely to respond to radioisotope therapies (e.g., targeted radioisotope therapies such as177Lu-PSMA therapies).

[0077] Example 4: Treating prostate cancer

[0078] A blood sample is obtained from a human having prostate cancer (e.g., CRPC such as mCRPC). ctDNA present in the obtained blood sample is examined for the (1) the presence or absence of an amplification of a CCNEl nucleic acid, (2) the presence or absence of an amplification of &FGFR1 nucleic acid, and / or (3) the presence or absence of a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid).

[0079] If the ctDNA in the sample lacks each of (1) an amplification of a CCNEl nucleic acid, (2) an amplification of &FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid), then the human is administered one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu- PSMA therapies).

[0080] If the ctDNA in the sample contains the presence of at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid), then the human is administered one or more alternative cancer treatment that do not include a177Lu- PSMA therapy.

[0081] Example 5: Treating prostate cancers

[0082] A human that was identified as having the absence of each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of &FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in ctDNA in a blood sample obtained from the human is administered one or more radioisotope therapies (e.g., one or more targeted radioisotope therapies such as177Lu-PSMA therapies). The administered radioisotope therapies can reduce the size of a prostate cancer (e.g., reduce the number of prostate cancer cells and / or reduce the volume of one or more prostate tumors) present within the human.

[0083] Example 6: Treating prostate cancers

[0084] A human identified as having the presence of one or more of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of &FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid (e.g., pathologically mutated CDK12 nucleic acid) in ctDNA in the blood sample obtained from the human is administered one or more alternative cancer treatments that do not include a targeted radioisotope therapy (e.g., a177Lu-PSMA therapy). The administered cancer treatment s) can reduce the size of a prostate cancer (e.g., reduce the number of prostate cancer cells and / or reduce the volume of one or more prostate tumors) present within the human.

[0085] Example 7: Exemplary embodiments

[0086] Embodiment 1. A method for assessing a mammal having a cancer, wherein said method comprises: (a) determining if cancer cells of said cancer contain the absence of each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of & G R1 nucleic acid, and (3) a mutated CDK12 nucleic acid;

[0087] (b) classifying said cancer as being likely to respond to a radioisotope therapy.

[0088] Embodiment 2. The method of embodiment 1, wherein said mammal is a human.

[0089] Embodiment 3. The method of any one of embodiments 1-2, wherein said cancer is a prostate cancer.

[0090] Embodiment 4. The method of embodiment 3, wherein said prostate cancer is a castration -resistant prostate cancer (CRPC).

[0091] Embodiment 5. The method of embodiment 4, wherein said CRPC is a metastatic

[0092] CRPC.

[0093] Embodiment 6. The method of any one of embodiments 1-5, wherein said mutated CDK12 nucleic acid encodes a truncated CDK12 polypeptide or non-functional CDK12 polypeptide.

[0094] Embodiment 7. The method of any one of embodiments 1-6, where said radioisotope therapy comprises a beta-emitter.

[0095] Embodiment 8. The method of any one of embodiments 1-6, wherein said radioisotope therapy is a177Lu-PSMA therapy.

[0096] Embodiment 9. The method of embodiment 8, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177LU-PSMA-J591 therapy. Embodiment 10. The method of any one of embodiments 1-9, wherein said determining step comprises determining if circulating tumor DNA (ctDNA) in a blood sample from said mammal contains the absence of each of (1), (2), and (3).

[0097] Embodiment 11. A method for assessing a mammal having a cancer, wherein said method comprises:

[0098] (a) determining if cancer cells of said cancer contain the presence of at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid;

[0099] (b) classifying said cancer as being unlikely to respond to a radioisotope therapy.

[0100] Embodiment 12. The method of embodiment 11, wherein said mammal is a human.

[0101] Embodiment 13. The method of any one of embodiments 11-12, wherein said cancer is a prostate cancer.

[0102] Embodiment 14. The method of embodiment 13, wherein said prostate cancer is a

[0103] CRPC.

[0104] Embodiment 15. The method of embodiment 14, wherein said CRPC is a metastatic

[0105] CRPC.

[0106] Embodiment 16. The method of any one of embodiments 11-15, wherein said mutated CDK12 nucleic acid encodes a truncated CDK12 polypeptide or non-functional CDK12 polypeptide.

[0107] Embodiment 17. The method of any one of embodiments 11-16, where said radioisotope therapy comprises a beta-emitter.

[0108] Embodiment 18. The method of any one of embodiments 11-16, wherein said radioisotope therapy is a177Lu-PSMA therapy. Embodiment 19. The method of embodiment 8, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177LU-PSMA-J591 therapy.

[0109] Embodiment 20. The method of any one of embodiments 11-19, wherein the presence of said amplification of said CCNE1 nucleic acid is determined.

[0110] Embodiment 21. The method of any one of embodiments 11-19, wherein the presence of said amplification of said FGFR1 nucleic acid is determined.

[0111] Embodiment 22. The method of any one of embodiments 11-19, wherein the presence of said mutated CDK12 nucleic acid is determined.

[0112] Embodiment 23. The method of any one of embodiments 11-22, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal contains the presence of at least one of (1), (2), and (3).

[0113] Embodiment 24. A method for selecting a treatment for a mammal having a cancer, wherein said method comprises:

[0114] (a) determining that cancer cells of said cancer lack each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of a FGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and

[0115] (b) selecting a radioisotope therapy to be a treatment for said mammal.

[0116] Embodiment 25. The method of embodiment 24, wherein said mammal is a human.

[0117] Embodiment 26. The method of any one of embodiments 24-25, wherein said cancer is a prostate cancer. Embodiment 27. The method of embodiment 26, wherein said prostate cancer is a

[0118] CRPC.

[0119] Embodiment 28. The method of embodiment 27, wherein said CRPC is a metastatic CRPC.

[0120] Embodiment 29. The method of any one of embodiments 24-28, wherein said mutated CDK12 nucleic acid encodes a truncated CDK12 polypeptide or non-functional CDK12 polypeptide.

[0121] Embodiment 30. The method of any one of embodiments 24-29, where said radioisotope therapy comprises a beta-emitter.

[0122] Embodiment 31. The method of any one of embodiments 24-29, wherein said radioisotope therapy is a177Lu-PSMA therapy.

[0123] Embodiment 32. The method of embodiment 31, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177LU-PSMA-J591 therapy.

[0124] Embodiment 33. The method of any one of embodiments 24-32, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal lacks each of (1), (2), and (3).

[0125] Embodiment 34. A method for selecting a treatment for a mammal having a cancer, wherein said method comprises:

[0126] (a) determining that cancer cells of said cancer contain at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and

[0127] (b) selecting a cancer treatment for said mammal, wherein said cancer treatment does not include a radioisotope therapy. Embodiment 35. The method of embodiment 34, wherein said mammal is a human.

[0128] Embodiment 36. The method of any one of embodiments 34-35, wherein said cancer is a prostate cancer.

[0129] Embodiment 37. The method of embodiment s 36, wherein said prostate cancer is a CRPC.

[0130] Embodiment 38. The method of embodiment 37, wherein said CRPC is a metastatic

[0131] CRPC

[0132] Embodiment 39. The method of any one of embodiments 34-38, wherein the presence of said amplification of said CCNE1 nucleic acid is determined.

[0133] Embodiment 40. The method of any one of embodiments 34-38, wherein the presence of said amplification of said FGFR1 nucleic acid is determined.

[0134] Embodiment 41. The method of any one of embodiments 34-38, wherein the presence of said mutated CDK12 nucleic acid is determined.

[0135] Embodiment 42. The method of any one of embodiments 34-41, wherein said mutated CDK12 nucleic acid encodes a truncated CDK12 polypeptide or non-functional CDK12 polypeptide.

[0136] Embodiment 43. The method of any one of embodiments 34-42, wherein said cancer treatment comprises treatment with an anti-cancer agent.

[0137] Embodiment 44. The method of embodiment 43, wherein said anti-cancer agent is selected from the group consisting of abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel, bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, and combinations thereof.

[0138] Embodiment 45. The method of any one of embodiments 34-42, wherein said cancer treatment comprises a surgery to remove said cancer, radiation treatment, and / or tissue ablation.

[0139] Embodiment 46. The method of any one of embodiments 34-45, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal contains at least one of (1), (2), and (3).

[0140] Embodiment 47. A method for treating a mammal having a cancer, wherein said method comprises:

[0141] (a) determining that cancer cells of said cancer lack each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and

[0142] (b) administering a radioisotope therapy to said mammal.

[0143] Embodiment 48. The method of embodiment 47, wherein said mammal is a human.

[0144] Embodiment 49. The method of any one of embodiments 47-48, wherein said cancer is a prostate cancer.

[0145] Embodiment 50. The method of embodiment 49, wherein said prostate cancer is a

[0146] CRPC.

[0147] Embodiment 51. The method of embodiment 50, wherein said CRPC is a metastatic

[0148] CRPC. Embodiment 52. The method of any one of embodiments 47-51, wherein said mutated CDK12 nucleic acid encodes a truncated CDK12 polypeptide or non-functional CDK12 polypeptide.

[0149] Embodiment 53. The method of any one of embodiments 47-52, where said radioisotope therapy comprises a beta-emitter.

[0150] Embodiment 54. The method of any one of embodiments 47-52, wherein said radioisotope therapy is a177Lu-PSMA therapy.

[0151] Embodiment 55. The method of embodiment 54, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177LU-PSMA-J591 therapy.

[0152] Embodiment 56. The method of any one of embodiments 47-55, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal lacks each of (1), (2), and (3).

[0153] Embodiment 57. A method for treating a cancer, wherein said method comprises administering a radioisotope therapy to a mammal that was identified as lacking each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of a FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid in cancer cells of said cancer.

[0154] Embodiment 58. The method of embodiment 57, wherein said mammal is a human.

[0155] Embodiment 59. The method of any one of embodiments 57-585, wherein said cancer is a prostate cancer.

[0156] Embodiment 60. The method of embodiment 59, wherein said prostate cancer is a

[0157] CRPC Embodiment 61. The method of embodiment 60, wherein said CRPC is a metastatic

[0158] CRPC.

[0159] Embodiment 62. The method of any one of embodiments 57-61, wherein said mutated CDK12 nucleic acid encodes a truncated CDK12 polypeptide or non-functional CDK12 polypeptide.

[0160] Embodiment 63. The method of any one of embodiments 57-62, where said radioisotope therapy comprises a beta-emitter.

[0161] Embodiment 64. The method of any one of embodiments 57-62, wherein said radioisotope therapy is a177Lu-PSMA therapy.

[0162] Embodiment 65. The method of embodiment 64, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177LU-PSMA-J591 therapy.

[0163] Embodiment 66. The method of any one of embodiments 57-65, wherein said mammal was identified as lacking each of (1), (2), and (3) in ctDNA in a blood sample from said mammal.

[0164] Embodiment 67. A method for treating a mammal having a cancer, wherein said method comprises:

[0165] (a) determining that cancer cells of said cancer contain at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and

[0166] (b) performing a cancer treatment on said mammal that does not include a radioisotope therapy.

[0167] Embodiment 68. The method of embodiment 67, wherein said mammal is a human. Embodiment 69. The method of any one of embodiments 67-68, wherein said cancer is a prostate cancer.

[0168] Embodiment 70. The method of embodiment 69, wherein said prostate cancer is a

[0169] CRPC.

[0170] Embodiment 71. The method of embodiment 70, wherein said CRPC is a metastatic

[0171] CRPC.

[0172] Embodiment 72. The method of any one of embodiments 67-71, wherein the presence of said amplification of said CCNE1 nucleic acid is determined.

[0173] Embodiment 73. The method of any one of embodiments 67-71, wherein the presence of said amplification of said FGFR1 nucleic acid is determined.

[0174] Embodiment 74. The method of any one of embodiments 67-71, wherein the presence of said mutated CDK12 nucleic acid is determined.

[0175] Embodiment 75. The method of any one of embodiments 67-74, wherein said mutated CDK12 nucleic acid encodes a truncated CDK12 polypeptide or non-functional CDK12 polypeptide.

[0176] Embodiment 76. The method of any one of embodiments 67-75, wherein said cancer treatment comprises treatment with an anti-cancer agent.

[0177] Embodiment 77. The method of embodiment 76, wherein said anti-cancer agent is selected from the group consisting of abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel, bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, and combinations thereof. Embodiment 78. The method of any one of embodiments 67-75, wherein said cancer treatment comprises a surgery to remove said cancer, radiation treatment, and / or tissue ablation.

[0178] Embodiment 79. The method of any one of embodiments 67-78, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal contains at least one of (1), (2), and (3).

[0179] Embodiment 80. A method for treating a cancer, wherein said method comprises performing a treatment on a mammal that was identified as having at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of a FGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid in cancer cells of said cancer, wherein said treatment does not include a radioisotope therapy.

[0180] Embodiment 81. The method of embodiment 80, wherein said mammal is a human.

[0181] Embodiment 82. The method of any one of embodiments 80-81, wherein said cancer is a prostate cancer.

[0182] Embodiment 83. The method of embodiment 82, wherein said prostate cancer is a

[0183] CRPC.

[0184] Embodiment 84. The method of embodiment 83, wherein said CRPC is a metastatic

[0185] CRPC.

[0186] Embodiment 85. The method of any one of embodiments 80-84, wherein the presence of said amplification of said CCNE1 nucleic acid is determined.

[0187] Embodiment 86. The method of any one of embodiments 80-84, wherein the presence of said amplification of said FGFR1 nucleic acid is determined. Embodiment 87. The method of any one of embodiments 80-84, wherein the presence of said mutated CDK12 nucleic acid is determined.

[0188] Embodiment 88. The method of any one of embodiments 80-87, wherein said mutated CDK12 nucleic acid encodes a truncated CDK12 polypeptide or non-functional CDK12 polypeptide.

[0189] Embodiment 89. The method of any one of embodiments 80-88, wherein said cancer treatment comprises treatment with an anti-cancer agent.

[0190] Embodiment 90. The method of embodiment 89, wherein said anti-cancer agent is selected from the group consisting of abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel, bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, and combinations thereof.

[0191] Embodiment 91. The method of any one of embodiments 80-88, wherein said cancer treatment comprises a surgery to remove said cancer, radiation treatment, and / or tissue ablation.

[0192] Embodiment 92. The method of any one of embodiments 80-91, wherein said mammal was identified as having at least one of (1), (2), and (3) in ctDNA in a blood sample from said mammal.

[0193] OTHER EMBODIMENTS

[0194] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for assessing a mammal having a cancer, wherein said method comprises:(a) determining if cancer cells of said cancer contain the absence of each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of & FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid;(b) classifying said cancer as being likely to respond to a radioisotope therapy.

2. The method of claim 1, wherein said mammal is a human.

3. The method of any one of claims 1-2, wherein said cancer is a prostate cancer.

4. The method of claim 3, wherein said prostate cancer is a castration-resistant prostate cancer (CRPC).

5. The method of claim 1, wherein said radioisotope therapy is a177Lu-PSMA therapy.

6. The method of claim 5, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177Lu-PSMA-J591 therapy.

7. The method of any one of claims 1-6, wherein said determining step comprises determining if circulating tumor DNA (ctDNA) in a blood sample from said mammal contains the absence of each of (1), (2), and (3).

8. A method for assessing a mammal having a cancer, wherein said method comprises:(a) determining if cancer cells of said cancer contain the presence of at least one of(1) an amplification of a CCNE1 nucleic acid, (2) an amplification of FGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid;(b) classifying said cancer as being unlikely to respond to a radioisotope therapy.

9. The method of claim 8, wherein said mammal is a human.

10. The method of claim 8, wherein said cancer is a prostate cancer.

11. The method of claim 10, wherein said prostate cancer is a CRPC.

12. The method of claim 8, wherein said radioisotope therapy is a177Lu-PSMA therapy.

13. The method of claim 12, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177Lu-PSMA-J591 therapy.

14. The method of any one of claims 8-13, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal contains the presence of at least one of (1), (2), and (3).

15. A method for selecting a treatment for a mammal having a cancer, wherein said method comprises:(a) determining that cancer cells of said cancer lack each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and(b) selecting a radioisotope therapy to be a treatment for said mammal.

16. The method of claim 15, wherein said mammal is a human.

17. The method of claim 15, wherein said cancer is a prostate cancer.

18. The method of claim 17, wherein said prostate cancer is a CRPC.

19. The method of claim 15, wherein said radioisotope therapy is a177Lu-PSMA therapy.

20. The method of claim 19, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177Lu-PSMA-J591 therapy.

21. The method of any one of claims 15-20, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal lacks each of (1), (2), and (3).

22. A method for selecting a treatment for a mammal having a cancer, wherein said method comprises:(a) determining that cancer cells of said cancer contain at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of a FGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and(b) selecting a cancer treatment for said mammal, wherein said cancer treatment does not include a radioisotope therapy.

23. The method of claim 22, wherein said mammal is a human.

24. The method of claim 22, wherein said cancer is a prostate cancer.

25. The method of claim 22, wherein said cancer treatment comprises treatment with an anti-cancer agent.

26. The method of claim 25, wherein said anti-cancer agent is selected from the group consisting of abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel, bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, and combinations thereof.

27. The method of claim 22, wherein said treatment comprises a surgery to remove said cancer, radiation treatment, and / or tissue ablation.

28. The method of any one of claims 22-27, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal contains at least one of (1), (2), and (3).

29. A method for treating a mammal having a cancer, wherein said method comprises:(a) determining that cancer cells of said cancer lack each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and(b) administering a radioisotope therapy to said mammal.

30. The method of claim 29, wherein said mammal is a human.

31. The method of claim 29, wherein said cancer is a prostate cancer.

32. The method of claim 31, wherein said prostate cancer is a CRPC.

33. The method of claim 29, wherein said radioisotope therapy is a177Lu-PSMA therapy.

34. The method of claim 33, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177Lu-PSMA-J591 therapy.

35. The method of any one of claims 29-34, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal lacks each of (1), (2), and (3).

36. A method for treating a cancer, wherein said method comprises administering a radioisotope therapy to a mammal that was identified as lacking each of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of FGFR1 nucleic acid, and (3) a mutated CDK12 nucleic acid in cancer cells of said cancer.

37. The method of claim 36, wherein said mammal is a human.

38. The method of claim 36, wherein said cancer is a prostate cancer.

39. The method of claim 38, wherein said prostate cancer is a CRPC.

40. The method of claim 36, wherein said radioisotope therapy is a177Lu-PSMA therapy.

41. The method of claim 40, wherein said177Lu-PSMA therapy is selected from the group consisting of177Lu-PSMA-617,177Lu- PSMA I&T,177Lu-PSMA-R2, and177Lu-PSMA-J591 therapy.

42. The method of any one of claims 36-41, wherein said mammal was identified as lacking each of (1), (2), and (3) in ctDNAin a blood sample from said mammal.

43. A method for treating a mammal having a cancer, wherein said method comprises:(a) determining that cancer cells of said cancer contain at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of aFGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid; and(b) performing a cancer treatment on said mammal that does not include a radioisotope therapy.

44. The method of claim 43, wherein said mammal is a human.

45. The method of claim 43, wherein said cancer is a prostate cancer.

46. The method of claim 45, wherein said prostate cancer is a CRPC.

47. The method of claim 43, wherein said cancer treatment comprises treatment with an anti-cancer agent.

48. The method of claim 47, wherein said anti-cancer agent is selected from the group consisting of abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel, bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, and combinations thereof.

49. The method of claim 43, wherein said cancer treatment comprises a surgery to remove said cancer, radiation treatment, and / or tissue ablation.

50. The method of any one of claims 43-49, wherein said determining step comprises determining if ctDNA in a blood sample from said mammal contains at least one of (1), (2), and (3).

51. A method for treating a cancer, wherein said method comprises performing a treatment on a mammal that was identified as having at least one of (1) an amplification of a CCNE1 nucleic acid, (2) an amplification of FGFRl nucleic acid, and (3) a mutated CDK12 nucleic acid in cancer cells of said cancer, wherein said treatment does not include a radioisotope therapy.

52. The method of claim 51, wherein said mammal is a human.

53. The method of claim 51, wherein said cancer is a prostate cancer.

54. The method of claim 53, wherein said prostate cancer is a CRPC.

55. The method of claim 51, wherein said cancer treatment comprises treatment with an anti-cancer agent.

56. The method of claim 55, wherein said anti-cancer agent is selected from the group consisting of abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, mitoxantrone, pembrolizumab, sipuleucel-T, olaparib, rucaparib, talazoparib, carboplatin, paclitaxel,bicalutamide, leuprolide, darolutamide, apalutamide, flutamide, degarelix, gosarelin, and combinations thereof.

57. The method of claim 51, wherein said cancer treatment comprises a surgery to remove said cancer, radiation treatment, and / or tissue ablation.

58. The method of any one of claims 51-57, wherein said mammal was identified as having at least one of (1), (2), and (3) in ctDNA in a blood sample from said mammal.

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