Cancer linear energy transfer (LET) sensitivity index and uses thereof

Abstract

The present disclosure relates to methods of selecting a treatment regimen for a subject having cancer (e.g., prostate cancer) by determining the presence of a mutation in the subject's tumor that makes the subject a candidate for particle therapy. Methods of treating the subject and determining relative dosage are also contemplated herein.

Description

[0001]CANCER LINEAR ENERGY TRANSFER (LET) SENSITIVITY INDEX AND USES THEREOF RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No.63 / 698,509, filed on September 24, 2024, which is incorporated herein by reference in its entirety. BACKGROUND One of the challenges faced in radiation oncology is the complex interplay of radiation dose delivery and the cellular response. Choosing the most effective treatment course can increase the chances of a successful outcome, and calibrating dose to each patient can allow physicians to administer sufficient treatments without exposing the patient to unnecessarily high levels of cancer therapy, which can lead to adverse side effects. Therefore, there is a need to develop methods for identifying patients who would benefit from a given therapy. There is also a need to develop methods for calibrating the dose of therapy to individual patients. SUMMARY Aspects of the disclosure relate, at least in part, to methods comprising a) determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject, and b) determining a relative biological effectiveness (RBE) dose of a therapy (e.g., a particle radiation therapy). Such methods can be useful, in some embodiments, to select a therapy (e.g., a photon or particle radiation therapy) for a subject, determine whether one or more subjects should be treated with particle radiation therapy (or photon radiation therapy), and / or select a dose of radiation (e.g., particle radiation) to administer to a subject in need thereof. In some aspects, the methods comprise a) determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject, b) determining a RBE dose (e.g., RBE-adjusted dose) of particle radiation for treatment of the subject, wherein the RBE dose is greater than a reference physical dose from megavoltage photon therapy, and c) administering the physical dose that corresponds to the RBE dose (e.g., an RBE-adjusted doses). In some aspects, the methods comprise a) determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject, b) determining a RBE dose (e.g., RBE-adjusted dose) of particle radiation for treatment of the subject, wherein the RBE dose is the same as a reference physical dose, and c) #14395076v1 administering the RBE dose. In some embodiments, the RBE dose (e.g., RBE-adjusted dose) is a lowered physical dose for both the cancer and healthy organs compared to the reference physical dose. In some aspects, determining a dose of particle radiation (e.g., an RBE dose or an RBE- adjusted dose) comprises using a linear energy transfer (LET) sensitivity index. In some aspects, the LET sensitivity index is based on the presence of a mutation in the one or more genes and a weighting factor. In some aspects, the weighing factor is a measure of the impact of the mutation in the one or more genes on the sensitivity of the tumor of the subject to linear energy transfer. In some aspects, the weighting factor is determined in cells of a cancer type similar to the cancer of the subject. In some aspects, the weighting factor is determined by determining a survival fraction of the cells treated with a single stranded DNA break repair inhibitor and determining a RBE dose (e.g., RBE-adjusted dose) of particle therapy in a tumor of the subject based on the RBE of the single stranded DNA break repair inhibitor in the cells of the similar cancer type. In some aspects, the determined RBE dose (e.g., RBE-adjusted dose) is inversely related to the LET sensitivity index. In some aspects, the method further comprises administering the particle radiation therapy to the subject at the selected dose of particle radiation (e.g., the RBE-adjusted dose). Aspects of the present disclosure provide a method comprising determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject, determining a dose of particle radiation for treatment of the subject using a linear energy transfer (LET) sensitivity index, wherein the LET sensitivity index is based on the presence of a mutation in the one or more genes and a weighting factor. In some aspects, the weighing factor is a measure of the impact of the mutation in the one or more genes on the sensitivity of the tumor of the subject to linear energy transfer; the weighting factor is determined in cells of a cancer type similar to the cancer of the subject by determining a survival fraction of the cells treated with a single stranded DNA break repair inhibitor and determining a RBE dose (e.g., RBE-adjusted dose) of particle therapy in the tumor of the subject based on the RBE of the single stranded DNA break repair inhibitor in the cells of the similar cancer type, wherein the RBE dose (e.g., RBE-adjusted dose) is proportional to the LET sensitivity index. In some aspects, the RBE dose (e.g., RBE-adjusted dose) is greater than the physical dose [J / kg], that would be administered to a subject without a mutation in the one or more genes. In some aspects, the RBE dose (e.g., RBE-adjusted dose) is equal to the physical dose [J / kg] that would be administered to a subject without a mutation in the one or more genes. In some aspects, the RBE dose (e.g., RBE-adjusted dose) is less than the physical dose [J / kg] that would be administered to a subject without a mutation in the one or more genes. In some aspects, the #14395076v1 method further comprises administering particle radiation therapy to the subject at the selected dose of particle radiation (e.g., the RBE-adjusted dose). In some aspects, a RBE dose (RBE-adjusted dose) is administered to a subject’s cancer target, which RBE dose (RBE-adjusted dose) is increased proportional to the LET sensitivity index of the subject’s cancer cells and / or the cancer cells of a similar cancer type as the subject’s cancer up to the limit of radiation toxicity in surrounding healthy organs. In some aspects, a method comprises administering a physical dose to a subject having a tumor that comprises a mutation in one or more double-stranded DNA break repair genes, which for the same physical dose results in a higher RBE dose (RBE-adjusted dose) in the tumor compared to a healthy organ of the subject not having a mutation in the one or more double-stranded DNA break repair genes. In some aspects, a physical dose is administered to a subject, which physical dose is lowered, inversely proportional (e.g., inversely related) to the LET sensitivity index, to achieve the same RBE in the subject’s cancer with reduced radiation toxicity in surrounding healthy organs. In some aspects, the cancer is prostate cancer. In some aspects, at least one of the one or more genes related to double-stranded DNA break repair is selected from: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), Cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase and tensin homolog (PTEN) and tumor protein 53 gene (TP53). In some embodiments, mutations are identified in two or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, mutations are identified in three or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, mutations are identified in four or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, mutations are identified in AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, particle radiation therapy comprises proton therapy, carbon therapy, and / or helium therapy. In some aspects, a higher RBE dose (RBE-adjusted dose) of particle therapy is administered to a subject having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53 DNA repair genes with administration of a same physical dose of particle therapy as is administered to a subject of unknown mutation status or a subject not having a mutation in the one or more DNA repair genes. In some aspects, a lower physical dose of particle therapy is administered to a subject having a mutation in one or more of AR, ATM, #14395076v1 BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53 DNA repair genes compared to a physical dose administered to a subject of unknown mutation status or a subject not having a mutation in the one or more DNA repair genes. In some aspects, a linear energy transfer (LET) sensitivity index (LSI) is determined by multiplying the coefficient of sensitivity caused by the presence of each genetic mutation, Ci, by one if the mutation is present or zero if the mutation is not present, and then summing the products for each double-stranded DNA repair genes. In some embodiments, an LSI (e.g., a PCLSI; prostate cancer LSI) is determined using the following equation: The LSI (e.g., PCLSI) is a metric of LET sensitivity created by multiplying the coefficient of sensitivity caused by the presence of each genetic mutation, by one if the mutation is present or zero if the mutation is not present and then summing the products for each double- stranded DNA repair genes. As an example, the coefficients for each of the genes in the context of prostate cancer are provided below (the PCLSI is the prostate cancer linear energy transfer sensitivity index). Prostate Cancer: ^^^^^ = (0.0309 ∙ ^^) + (0.0309 ∙ ^^^) + (0.0075 ∙ ^^^^^) + (0.0384 ∙ ^^^^!) …+ (0.0309 ∙ ^#$^) + (0.0478 ∙ %^&^) + (0.0478 ∙ '^%() + (0.0384 ∙ ^')*)Prostate Cancer Intercept RBE:+,-. / 012 = 1.16 + ^^^^^ × ^-5+,-6789 = (1.16 + ^^^^^ × ^-5) : ;<=^>?@8^ABCProstate Cancer Conservative RBE):+,-012 = 1.0 + ^^^ × ^-5+,-6789 = (1.0 + ^^^ × ^-5) : ;<=^>?@8^ABCAspects of the present disclosure provide a method comprising: administering particle therapy to a subject, wherein the subject has a tumor known to comprise a mutation in one or more genes (e.g., 2, 3, 4, 5, 6, 7, 8 or more genes) related to double stranded DNA break repair. In some aspects, at least one of the one or more genes related to double-stranded DNA break repair are selected from: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein #14395076v1 (BRCA2), Cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase and tensin homolog (PTEN) and tumor protein 53 gene (TP53). Aspects of the present disclosure provide a method comprising: administering particle therapy to a subject, wherein the subject has a tumor comprising a mutation in one or more genes (e.g., 2, 3, 4, 5, 6, 7, 8 or more genes) related to double stranded DNA break repair. In some aspects, at least one of the one or more genes related to double stranded DNA break repair are selected from androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), Cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase and tensin homolog (PTEN) and tumor protein 53 gene (TP53). In some aspects, a method wherein tissue-specific LSI coefficients are scaled inversely to PARP inhibitor resistance is provided. As is demonstrated in Example 2 and Table 6, LSI coefficients have been determined for different tissues. In some aspects, CNS tumor coefficients are reduced to 0.20-0.25× of prostate values. In some aspects, lung cancer coefficients are maintained at 1.0-1.2× of prostate values. In some aspects, breast cancer coefficients are maintained at 0.8-1.0× of prostate values. In some aspects, pancreatic cancer coefficients are reduced to 0.35-0.40× of prostate values. In some aspects, maximum achievable RBE decreases with tissue resistance. In some aspects, the disclosure provides a method comprising determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject, and administering a dose of particle radiation therapy to the subject. In some embodiments, the particle radiation therapy comprises proton therapy, carbon therapy, or helium therapy. In some embodiments, one of the one or more genes related to double-stranded DNA break repair is selected from the group consisting of: androgen receptor (AR), ataxia- telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase, and tensin homolog (PTEN) and tumor protein 53 gene (TP53). In some embodiments, mutations are identified in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, mutations are identified in four or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, mutations are identified in AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, the method further comprises determining the presence of a mutation in one or more genes selected from the group consisting of: partner and localizer of #14395076v1 BRCA2 (PALB2), cyclin-dependent kinase 12 (CDK12), RAD51 recombinase (RAD51), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Kirsten rat sarcoma virus (KRAS), and neurofibromin 2 (NF2). In some embodiments, the method further comprises determining the presence of a mutation in three or more genes selected from the group consisting of: PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some embodiments, the dose of particle radiation therapy is a relative biological effectiveness (RBE) dose determined for the tumor in the subject. In some embodiments, the RBE dose is determined using a linear energy transfer (LET) sensitivity index. In some embodiments, the LET sensitivity index is based on the presence of at least one mutation in the one or more genes and a weighting factor. In some embodiments, the weighting factor is a measure of the impact of the mutation in the one or more genes on the sensitivity of the tumor of the subject to LET. In some embodiments, the weighting factor is determined in cells of a cancer type similar to the cancer of the subject. In some embodiments, the weighting factor is determined by determining a survival fraction of the cells treated with a single-stranded DNA break repair inhibitor and determining a RBE-adjusted dose of a physical dose of particle therapy in the tumor of the subject based on an RBE of the single-stranded DNA break repair inhibitor in the cells of the similar cancer type. In some embodiments, the determined RBE dose is proportional to the LET sensitivity index. In some embodiments, the RBE dose of particle radiation is a RBE-adjusted dose and is 1.1 to 1.8 times less than a standard dose of photon radiation. In some embodiments, the subject has prostate cancer, Ewing’s sarcoma, chronic lymphocytic leukemia, synovial sarcoma, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, neuroblastoma, acute myeloid leukemia, small cell lung cancer, multiple myeloma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, breast cancer, head and neck cancer, ovarian cancer, lung adenocarcinoma, glioblastoma, bladder cancer, colorectal cancer, and / or pancreatic cancer. In some embodiments, the subject has prostate cancer. In some aspects, the disclosure provides a method comprising determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject, and administering a relative biological effectiveness (RBE) dose of particle radiation therapy to the subject. In some embodiments, the particle radiation therapy comprises proton therapy, carbon therapy, or helium therapy. In some embodiments, one of the one or more genes related to double-stranded DNA break repair is selected from the group consisting of: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), #14395076v1 breast cancer type 2 susceptibility protein (BRCA2), cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase, and tensin homolog (PTEN) and tumor protein 53 gene (TP53). In some embodiments, mutations are identified in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, mutations are identified in four or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, mutations are identified in AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, the method further comprises determining the presence of a mutation in one or more genes selected from the group consisting of: partner and localizer of BRCA2 (PALB2), cyclin-dependent kinase 12 (CDK12), RAD51 recombinase (RAD51), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Kirsten rat sarcoma virus (KRAS), and neurofibromin 2 (NF2). In some embodiments, the method further comprises determining the presence of a mutation in three or more genes selected from the group consisting of: PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some embodiments, the RBE dose is determined using a linear energy transfer (LET) sensitivity index. In some embodiments, the LET sensitivity index is based on the presence of at least one mutation in the one or more genes and a weighting factor. In some embodiments, the weighting factor is a measure of the impact of the mutation in the one or more genes on the sensitivity of the tumor of the subject to LET. In some embodiments, the weighting factor is determined in cells of a cancer type similar to the cancer of the subject. In some embodiments, the weighting factor is determined by determining a survival fraction of the cells treated with a single-stranded DNA break repair inhibitor and determining a RBE-adjusted dose of a physical dose of particle therapy in the tumor of the subject based on an RBE of the single-stranded DNA break repair inhibitor in the cells of the similar cancer type. In some embodiments, the method further comprises determining the total energy transfer sensitivity index (LSI) by adding the weighting factor for each gene related to double- stranded DNA break repair having a mutation. In some embodiments, the method further comprises determining the RBE based on the total LSI and the linear energy transfer. In some embodiments, the RBE is determined by multiplying the total LSI by the linear energy transfer. In some embodiments, the method further comprises determining the RBE-adjusted dose as a function of the RBE. In some embodiments, determining the RBE-adjusted dose comprises dividing the 1.1 by the RBE. In some aspects, the disclosure provides a method of determining a radiation treatment regimen for a subject, wherein the subject has a tumor, the method comprising: performing a #14395076v1 biopsy on the tumor; analyzing the biopsy to determine whether the tumor has at least one mutation in at least one or more genes related to double-stranded DNA break repair selected from the group consisting of: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase, and tensin homolog (PTEN) and tumor protein 53 gene (TP53); for each gene related to double-stranded DNA break repair having mutation, determining a cancer-specific linear energy transfer sensitivity index (LSI) gene-specific coefficient; determining a total LSI as a function of the LSI coefficients; determining a relative biological effectiveness (RBE) dose based on the total LSI and the linear energy transfer; and determining the radiation treatment regimen for the subject based on the RBE dose. In some embodiments, the RBE is determined by multiplying the total LSI by the linear energy transfer. In some embodiments, determining the RBE-adjusted dose comprises dividing the 1.1 by the RBE. In some embodiments, if the RBE dose is greater than or equal to 1.1, the subject is administered particle radiation therapy with LET optimization. In some embodiments, if the RBE dose is greater than 1.1, the subject is administered particle radiation therapy with LET optimization. In some aspects, the cancer is sarcoma (Ewing), chronic lymphocytic leukemia, sarcoma (synovial), acute lymphoblastic leukemia, diffuse large B-cell lymphoma, neuroblastoma, acute myeloid leukemia, small cell lung cancer, multiple myeloma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, breast cancer, head and neck cancer, ovarian cancer, lung adenocarcinoma, glioblastoma, bladder cancer, colorectal cancer, and / or pancreatic cancer. BRIEF DESCRIPTION OF DRAWINGS For promoting an understanding of the principles of the disclosure, reference will now be made to the embodiments, or examples, illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Any alterations and further modifications in the described embodiments, and any further applications of the principles of the disclosure as described herein are contemplated as would normally occur to one of ordinary skill in the art to which the disclosure relates. FIGs. 1A-AB show overviews of non-limiting aspect of methods of the present disclosure. #14395076v1 FIGs. 2A-2B show data taken from the COSMIC database for a total of sixty-seven gene mutations. FIG. 2A shows the presence of DNA repair gene mutations (squares) in eachmodeled cell line. FIG. 2B shows the resultant coefficient Ci of(D%^ × EFGFH) ∙ ^H =(^^%'^DIJ − ^. ^L) of different gene mutations.FIG. 3 shows RBE = 1.1 dose (top) and LET (bottom) for single-field optimized (SFO) (left) and LET-optimized (right) PBS proton prostate cancer plans. The mean LET in the prostate is 2.2 KeV / µm in the single-field optimized (SFO) plan and 4.4 KeV / µm in the LET- optimized plan. FIG. 4 shows bladder and rectum target-to-organs at risk (OAR) dose ratios (TODRs) for both single-field optimized (SFO) and LET-optimized plans. FIG. 5 shows the relative sensitizations of different cell lines. FIG. 6 illustrates a system of determining a dose of particle radiation therapy, in accordance with some embodiments of the technology described herein. FIG. 7 illustrates a block diagram of an embodiment of a computer system, in accordance with some embodiments of the technology described herein. DETAILED DESCRIPTION The present disclosure provides methods of predicting, based on the presence of double- stranded DNA repair gene mutations in a subject’s tumor, whether particle therapy will be efficacious and, in some embodiments, the dose of particle radiation that may be administered (for example, a dose that is lower, e.g., a dose that is a specific percentage lower than that of traditional photon radiation and / or particle radiation). Without wishing to be bound by theory, it is thought that administering particle radiation to the selected subjects, as described herein, will lead to better outcomes (e.g., cure or remission) without the side effects of photon therapy (e.g., off-target effects on healthy organs or tissues). Particle therapy, such as proton therapy, differs from traditional radiation therapy (photon therapy) in that the mechanism of particle therapy produces more double-stranded DNA breaks than photon therapy, which causes mostly single-stranded breaks. This disclosure provides a method of using that difference to identify patients whose tumors are likely to be susceptible to particle therapy. By identifying patients who are likely to be good candidates for particle therapy, patients are given the most appropriate form of radiation and, in some embodiments, a dose of particle radiation that is relatively less than the dose of photon radiation that would be administered. In some embodiments, the methods described herein may be used to #14395076v1 select a therapy (e.g., particle radiation or photon radiation) for a subject based on the presence or absence of double-stranded DNA break repair genes having at least one mutation. Definitions As used herein, “LET” indicates linear energy transfer. Linear energy transfer indicates the average amount of energy that is lost per unit path-length as a charged particle travels through a material. As used herein, “SFO” indicates single field optimization. Single field optimization is an example of a standard method for treating patients with radiation. As used herein “RBE” means relative biological effectiveness. RBE is the ratio of biological effectiveness of one type of ionizing radiation relative to another given the same amount of absorbed energy. In some aspects, developing a personalized prediction of RBE allows for more effective treatment of a subject relative to standard methods of predicting RBE. In some embodiments, an RBE is the ratio of the biological effectiveness of particle radiation to photon radiation. As used herein, an “RBE-adjusted dose” is a dose of radiation that has been adjusted relative to an RBE value (for example, if an RBE value is 1.39; the RBE-adjusted dose would be 1.1 / 1.39 = 79%, meaning that a dose 79% of a full dose would be administered to the subject. In some embodiments, the full dose is the dose of photon radiation or the dose of particle radiation that would be administered to a subject if the subject did not have a mutation in one or more double-stranded DNA repair genes, as described herein. As used herein “PCLSI” indicates a prostate cancer LET sensitivity index. In some aspects, a PCLSI is used to predict sensitivity of a cancer cell to proton therapy. In some aspects, a PCLSI emphasizes the influence of genetic mutations. “LSI” refers to a cancer LET sensitivity index and may be used to predict the sensitivity of a cancer cell to proton therapy. As used herein “about” refers to a value that is similar to a stated value and within a range of values that fall within 20% in either direction (greater than or less than). As used herein a “reference dose” refers to a dose of radiation, e.g., particle radiation or photon radiation, that is administered to a subject having a tumor according to a standard treatment of care for the tumor of the subject. As used herein, a “subject” refers to a mammalian subject, a human subject, or a subject (e.g., a human subject) having a tumor or cancer. In some embodiment, the subject is a human subject. Particle Therapy #14395076v1 In some aspects, the present disclosure provides methods of selecting treatment regimens for a subject in need thereof. In some aspects, the treatment is radiotherapy, also referred to as radiation treatment. In some embodiments, the treatment is photon therapy. In some embodiments, the treatment is particle therapy. In some aspects, particle therapy can be administered using a device that directs particles, e.g., a proton beam, to a precise position in a subject’s body, e.g., a tumor. In some aspects, particle therapy is a form of radiation that uses neutrons, protons, or other positive ions, instead of the X-rays or photons used in traditional radiation therapy. In some aspects, the particle therapy comprises proton therapy. In some aspects, the particle therapy comprises helium therapy. In some aspects, the particle therapy comprises carbon therapy. Without intending to be bound by theory, particle therapy produces mostly double- stranded DNA breaks, while photon therapy produces largely single-stranded DNA breaks. Different DNA repair mechanisms are involved in single-stranded break repair compared to double-stranded break repair. Thus, mutations that render a subject’s cancer susceptible to photon therapy do not predictably indicate that the cancer will have the same susceptibility to particle therapy. Poly (ADP-ribose) polymerase (PARP) inhibitors such as Olaparib inhibit the single- stranded DNA break repair mechanism. In some aspects, as described herein, particle therapy dosing is based on the sensitivity of cells harboring certain mutations to linear energy transfer (LET) from particle therapy. In some aspects, sensitivity to LET from particle therapy is derived as described herein from measured sensitivity of cells harboring certain mutations to PARP inhibitor treatment. Methods of Selecting Treatment Regimens In some aspects, the present disclosure provides methods of selecting treatment regimens for patients in need of radiation therapy. In some aspects, particle radiation therapy is indicated or selected for a subject based on the presence of a mutation in at least of the one or more genes related to double-stranded DNA break repair in a tumor (e.g., the subject’s tumor). In some embodiments, the one or more genes related to double-stranded DNA break repair is selected from the group consisting of: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase, and tensin homolog (PTEN) and tumor protein 53 gene (TP53). #14395076v1 In some aspects, the subject has a proliferative disorder. In some aspects, the subject has cancer. In some aspects, the cancer is a solid tumor cancer. In some aspects, the solid tumor cancer is prostate cancer, lung cancer, head and neck cancer, liver cancer, esophageal cancer, brain cancer, breast cancer, cervical cancer, or pancreatic cancer. In some aspects, the cancer is a leukemia or a lymphoma. In some aspects, the cancer is an acute myelogenous leukemia (AML), an acute lymphocytic leukemia (ALL), a chronic lymphocytic leukemia (CLL), a chronic myelogenous leukemia (CML), a chronic myelomonocytic leukemia (CMML), or a myeloproliferative neoplasm (MPN). In some aspects, the lymphoma is a Hodgkin lymphoma or a non-Hodgkin lymphoma. In some aspects, the present disclosure provides determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject. In some aspects, the present disclosure provides measuring survival of a cell having a mutation in one or more genes related to double stranded DNA break repair in the presence of a PARP inhibitor. In some aspects, the present disclosure provides methods of determining the impact of each mutation in the one or more genes related to double-stranded DNA break repair present in a cell on the cell’s sensitivity to linear energy transfer from a particle therapy based on the cell’s survival capability in the presence of the PARP inhibitor. In some aspects, the present disclosure provides creating a linear energy transfer (LET) sensitivity index (LSI) from the impact of each mutation in the one or more genes related to double-stranded DNA break repair. In some aspects, the present disclosure provides determining a dose of particle radiation for treatment of the subject using the linear energy transfer (LET) sensitivity index. In some aspects, a linear energy transfer sensitivity index is determined for each specific cancer. In some aspects, the linear energy transfer sensitivity index is determined for prostate cancer. In some aspects, the LET sensitivity index is based on 1) the presence of a mutation in one or more genes and 2) a weighting factor. In some embodiments, the LET sensitivity index is based on the presence of a mutation in each of one gene, two genes, three genes, four genes, five genes, six genes, seven genes, eight genes, nine genes, ten genes, eleven genes, twelve genes, thirteen genes, or fourteen genes described herein. In some aspects, the weighting factor is determined in cells of a cancer type similar to the cancer of the subject by determining a survival fraction of the cells of the similar cancer type treated with a single-stranded DNA break repair inhibitor (e.g., PARP inhibitor) and determining a relative biological effectiveness of a dose of particle therapy in the tumor of the subject based on the relative biological effectiveness of the single-stranded DNA break repair inhibitor (e.g., PARP inhibitor) in the cells of the similar cancer type. The term “similar cancer type,” as used #14395076v1 herein, refers to a cancer cell that originates from the same tissue as the cancer cell of a subject; a cancer cell that comprises the same or substantially the same genetic profile as the cancer cell of the subject; a cancer cell that comprises the same class of oncogenic mutation(s) as the cancer cell of the subject; and / or a cancer cell that comprises the same mutation or mutations as the cancer cell of the subject. In some aspects, substantially the same genetic profile means that the two cell types have the same class of oncogenic mutations. In some aspects, the same genetic profile means that the two cell types have the same oncogenic mutations. In some aspects, a weighting factor is determined in cells obtained from the subject. In some aspects, a weighting factor is determined in cells of a cancer obtained from the subject. Tissue-specific resistance to DNA damage repair inhibition affects the determination of the LET sensitivity and RBE-adjusted dose. Tissues with high resistance to PARP inhibitors (such as CNS tumors with IC50 ~221 μM) maintain functional DNA repair despite mutations, resulting in reduced coefficient values. Conversely, tissues with baseline repair deficiency (such as lung cancer with IC50~17.5 nM) show maintained or elevated sensitivity to LET optimization. In some aspects, the method comprises determining the sensitivity of cells derived from a subject to particle radiation. In some aspects, the method comprises determining a survival fraction of cells of a similar cancer type as a subject’s cancer type treated with a single-stranded DNA break repair inhibitor (e.g., a PARP inhibitor). In some aspects, the method further comprises using a mathematical model to determine a relative biological effectiveness of a dose of particle therapy in a tumor of a subject based on a relative biological effectiveness of a single stranded DNA break repair inhibitor in tumor cells of a similar cancer type to the subject’s cancer type. In some embodiments, the method comprises determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject. In some embodiments, the method further comprises determining a dose of particle radiation for treatment of the subject using a linear energy transfer (LET) sensitivity index. In some aspects, the LET sensitivity index is based on the presence of a mutation in the one or more genes and a weighting factor. In some embodiments, the weighting factor is determined in cells of a cancer type similar to the cancer of the subject by determining a survival fraction of the cells of the similar cancer type treated with a single stranded DNA break repair inhibitor. In some embodiments, the method comprises determining a relative biological effectiveness of a dose of particle therapy in the tumor of the subject based on the relative biological effectiveness of the single-stranded DNA break repair inhibitor in the cells of the similar cancer type. In some aspects, the determined RBE dose is directly related to the LET sensitivity index and is greater #14395076v1 than the physical dose that could be given to a subject without a mutation in the one or more genes. In some aspects, the required physical dose is lower than a dose that produces a similar biological effect in a tumor of a subject, which tumor does not have a mutation in the one or more genes. In some aspects, the method further comprises determining a radiation sensitivity index for the subject based on a mutation in the tumor of the subject. In some aspects, the radiation sensitivity index is an LET sensitivity index. In some aspects, determining a radiation sensitivity index for the subject comprises applying a rank-based linear regression model to the genetic profile of the subject and / or the genetic profile of a tumor of the subject. In some aspects, the genetic profile comprises a determined mutation. In some aspects, the subject and / or the subject’s tumor has been determined to comprise a mutation in one or more genes related to double-stranded DNA break repair. In some aspects, the determined mutation is weighted. The experimentally determined weighting factors for eight of the double-stranded DNA repair genes are shown below: +,-. / 012 = 1.16 + ^^^^^ × ^-5+,-6789 = (1.16 + ^^^^^ × ^-5) : ;<=^>?@8^ABCIn some aspects, the method further comprises administering a particle therapy to the subject. In some aspects, the particle therapy comprises a proton therapy, a carbon therapy, and / or helium therapy. In some aspects, the method comprises administering a particle therapy to the subject at a relative biological equivalent dose calculated as described herein. In some embodiments, the method further comprises one or more PARP inhibitors to the subject. Examples of PARP inhibitors include, but are not limited to, Olaparib (Lynparza), Rucaparib (Rubraca), Niraparib (Zejula), and Talazoparib (Talzenna). In some aspects, a lower dose of particle radiation therapy (e.g., the RBE dose or RBE- adjusted dose of particle therapy) is administered to a subject having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53 DNA repair genes relative to a subject not having a mutation in any of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53 DNA repair genes . In some aspects, the method further comprises selecting a dose of particle radiation for the subject that is lower than the dose that would have been given to a subject without a mutation in the one or more genes described herein. In some aspects, a subject without a mutation is a subject not having a mutation in one or more of AR, ATM, BRCA1, #14395076v1 BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, a subject without a mutation is a subject not having a mutation in any of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, the subject without a mutation in the one or more genes described herein is a comparable subject. In some aspects, a comparable subject is a subject of similar age, weight, disease progression, and / or other metric. In some aspects, the RBE dose (e.g., RBE- adjusted dose) can be 20%-80% percent (e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%) higher than that administered to a subject not having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, the RBE dose (e.g., the RBE-adjusted dose) can be 20%-80% percent (e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%) lower than that administered to a subject not having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some embodiments, if the subject does not have a mutation in any of the double-stranded DNA break repair genes, the subject is not administered particle radiation therapy. In some embodiments, if the subject does not have a mutation in any of the double- stranded DNA break repair genes, the subject is administered photon radiation therapy. In some embodiments, the RBE dose of proton (J / kg) is 1.1-2.0 times less than a photon dose (J / kg). For example, the RBE dose of proton is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 times less than a photon dose that would be administered according to standard practices. In some embodiments, the RBE dose (e.g., RBE-adjusted dose) of proton radiation (J / kg) is 20%- 80% percent (e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%) of a photon dose (J / kg). In some embodiments, the RBE dose (e.g., RBE-adjusted dose) of proton radiation (J / kg) is 20%-80% percent (e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%) of a reference particle therapy administered to a comparable subject (J / kg). In some embodiments, if the RBE value is greater than or equal to 1.1 (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0), particle therapy is indicated for the subject. In some aspects, the LET is between about 2 and about 6 keV / µm (e.g., about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, or about 6 keV / µm). In some aspects, the LET is about 2.1 keV / μm to about 5.9 keV / μm, or about 2.2 keV / μm to about 5.8 keV / μm, 2.3 keV / μm to about 5.7 keV / μm, 2.4 keV / μm to about 5.6 keV / μm, 2.5 keV / μm to about 5.5 keV / μm, or about 2.6 keV / μm to about 5.4 keV / μm; or about 2.3 keV / μm to about 2.8 keV / μm, about 2.6 keV / μm to about 3 keV / μm, about 2.8 keV / μm to about 3.5 keV / μm, about 3 keV / μm to about 3.8 keV / μm, about 3.9 keV / μm to about 4.5 keV / μm, about 4 keV / μm to about #14395076v1 4.8 keV / μm, about 4.9 keV / μm to about 5.5 keV / μm, about 5 keV / μm to about 5.8 keV / μm, or about 5.2keV / μm to about 6 keV / μm. In some aspects, the dose of radiation is between about 1 and about 10 Gy per fraction (e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 Gy per fraction). In some aspects, the dose of radiation is between about 1.5 and about 9.5 Gy per fraction, about 2 and about 9 Gy per fraction, about 2.5 and about 8.5 Gy per fraction, about 3 and about 8 Gy per fraction, or about 1 and about 1.5 Gy per fraction, about 1.6 and about 2 Gy per fraction, about 2.1 and about 2.5 Gy per fraction, about 2.6 and about 3 Gy per fraction, about 3.1 and about 3.5 Gy per fraction, about 3.6 and about 4 Gy per fraction, about 4.1 and about 4.5 Gy per fraction, about 4.6 and about 5 Gy per fraction, about 5.1 and about 5.5 Gy per fraction, or about 5.6 and about 6 Gy per fraction. In some aspects, the method comprises selecting a dose escalation treatment regimen for a subject. In some aspects, dose escalation comprises administering an initial dose of radiation, e.g., particle therapy, at a particular strength, e.g., a particular RBE, and subsequently administering one or more further dose of radiation at greater strength than the initial dose. In some aspects, the method comprises determining a lower initial dose of radiation relative to an initial dose calculated with standard means, and optionally administering said lower initial dose to a subject. In some aspects, the method comprises administering further escalating RBE doses (at increasingly higher levels of strength) to the subject. In some aspects, at least one of the further escalating doses is administered at lower strength than a dose provided to a comparable subject (e.g., the standard of care dose for a subject). Determination of Particle Radiation Therapy Dose The methods described herein, in some aspects, include determining whether a subject is a candidate for particle radiation therapy and optionally, an RBE-adjusted dose of particle radiation, based on the genetic profile of the subject’s tumor. FIG. 1A a non-limiting embodiment of the process of screening a subject’s tumor and administering a dose of particle therapy to the subject, including the steps of determining the mutation(s) in a subject’s tumor, determining the survival fraction in a similar cell population treated with an SSB repair inhibitor, applying a mathematical model to determine the dose of particle radiation for the subject, and administering the dose of particle radiation to the subject. FIG. 1B illustrates a non- limiting process pipeline 110 for screening a subject’s tumor and processing the data to determine whether the subject is a candidate for particle radiation therapy. Process pipeline 110 is performed by obtaining a biological sample (e.g., a tumor sample) from a subject having #14395076v1 cancer. The biological sample is screened to determine whether the subject’s tumor has mutation(s) in one or more genes related to double-stranded DNA break repair at act 111. For each mutation present, the cancer-specific linear energy transfer sensitivity index (LSI) gene- specific coefficient is determined at act 112. The LSI coefficients are added together, resulting in the total LSI at act 113. The total LSI is multiped by the linear energy transfer (3-4 keV / µm) at act 114. Finally, if the resulting RBE is greater than 1.1, the subject may benefit from particle radiation therapy with LET optimization at act 115. In some embodiments, the methods further comprise administering particle radiation therapy to the subject according to the RBE. In some embodiments, the process comprises the steps outlined in Example 2. In some embodiments, act 111 comprises obtaining bulk biopsy tissues of a subject or a patient. In some embodiments, act 111 comprises obtaining a blood sample of a subject or a patient. In some embodiments, act 111 comprises obtaining a single cell suspension. In some embodiments, act 111 comprises obtaining any types of sample that are suitable for preparing nucleic acids for subsequent sequencing analysis. In some embodiments, act 111 comprises obtaining more than one type of samples. In some embodiments, when the bulk biopsy tissues are obtained, the tissues are processed (e.g., homogenized in the presence of TriZol) to extract nucleic acids such as DNA or RNA. In some embodiments, when a single cell suspension is obtained, the suspension is processed to extract nucleic acids such as DNA or RNA. In some embodiments, nucleic acids can be extracted that are suitable for germline whole exome sequencing (WES). In some embodiments, nucleic acids can be extracted that are suitable for tumor whole exome sequencing (WES). In some embodiments, nucleic acids can be extracted that are suitable for tumor RNA sequencing. In some embodiments, nucleic acids can be extracted that are suitable for CYTOF (mass cytometry). In some embodiments, nucleic acids can be extracted that are suitable for any type of sequencing known in the art. In some embodiments, a method comprises all processes illustrated in FIG. 1B. However, in some embodiments, a subset of the processes is performed and any one or more of the processes may be omitted, duplicated, and / or performed in a different order than illustrated in FIG. 1B. In some embodiments, a method comprises a process, optionally including one or more steps, for preparing a nucleic acid from a biological sample, wherein the nucleic acid is sequenced on at least one sequencing platform. In some embodiments, a method comprises processing nucleic acid information obtained (e.g., received) from a sequencing platform to generate DNA or RNA sequence data for subsequent analysis (e.g., to generate a tumor profile). In some embodiments, one or more processes of FIG. 1B are implemented on a computer. In #14395076v1 some embodiments, a method comprises identifying a treatment (e.g., a particle radiation therapy dose) for a subject (e.g., a subject having cancer). In some embodiments, a method comprises administering the treatment to the subject. Determination of Mutations Aspects of the disclosure provide, at least in part, methods comprising determining mutations in one or more genes from a subject. In some aspects, the mutations are determined in a tumor from a subject (e.g., a tumor biopsy or a liquid biopsy). Mutations may be determined by any means in the art (e.g., through sequencing, tumor profiling, molecular profiling). In some embodiments, the mutations are determined using a commercially available kits or panels (e.g., NGS50+ gene panel, Precise Tumor®, Luminex® assays, etc.). In some aspects, a mutation is a loss of function mutation. In some aspects, a loss of function mutation is a frameshift mutation, a deletion, an insertion, a mutation in the promoter of a gene, a mutation in the coding sequence of the gene, or an early stop codon. In some aspects, a loss of function mutation results in reduced expression levels of the gene. In some aspects, expression levels of a gene related to double stranded break repair are measured (e.g., by RNA sequencing). In some aspects, the method comprises determining a reduced level of expression in a gene related to double stranded break repair. In some aspects, the level of expression is reduced by at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. In some aspects, the present disclosure provides a method, the method comprising determining a mutation in one or more of androgen receptor (AR), Ataxia-telangiectasia mutated serine / threonine kinase (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), e-cadherin (CDH1), ETS variant transcription factor 1 (ETV1), phosphatase and tensin homolog (PTEN), tumor protein p53 (TP53) or combinations thereof in a subject and administering a particle therapy to the subject. In some aspects, the method comprises determining one or more mutations in AR. In some aspects, the method comprises determining one or more mutations in ATM. In some aspects, the method comprises determining one or more mutations in BRCA1. In some aspects, the method comprises determining one or more mutations in BRCA2. In some aspects, the method comprises determining one or more mutations in CDH1. In some aspects, the method comprises determining one or more mutations in ETV1. In some aspects, the method comprises determining one or more mutations in PTEN. In some aspects, the method comprises determining one or more mutations in TP53. In some aspects, the method comprises determining mutations in two or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In #14395076v1 some aspects, the method comprises determining mutations in AR and ATM, AR and BRCA1, AR and BRCA2, AR and CDH1, AR and ETV1, AR and PTEN, AR and TP53, ATM and BRCA1, ATM and BRCA2, ATM and CDH1, ATM and ETV1, ATM and PTEN, ATM and TP53, BRCA1 and BRCA2, BRCA1 and CDH1, BRCA1 and ETV1, BRCA1 and PTEN, BRCA1 and TP53, BRCA2 and CDH1, BRCA2 and ETV1, BRCA2 and PTEN, BRCA2 and TP53, CDH1 and ETV1, CDH1 and PTEN, CDH1 and TP53, ETV1 and PTEN, ETV1 and TP53, or PTEN and TP53. In some aspects, the method comprises determining mutations in three or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. For example, in some aspects, the method comprises determining mutations in AR, ATM, and BRCA1; AR, ATM, and BRCA2; AR, ATM, and CDH1; AR, ATM, and ETV1; AR, ATM, and PTEN; AR, ATM, and TP53; ATM, BRCA1, and BRCA2; ATM, BRCA1, CDH1; ATM, BRCA1, and ETV1; ATM, BRCA1, and PTEN; ATM, BRCA1, and TP53; ATM, BRCA2, and CDH1; ATM, BRCA2, and ETV1; ATM, BRCA2, and PTEN; ATM, BRCA2, and TP53; ATM, CDH1, and ETV1; ATM, CDH1, and PTEN; ATM, CDH1, and TP53; ATM, ETV1, and PTEN; ATM, ETV1, and TP53; or ATM, PTEN, and TP53. In some aspects, the method comprises determining mutations in four or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, the method comprises determining mutations in five or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, the method comprises determining mutations in six or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, the method comprises determining mutations in seven or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, the method comprises determining mutations in AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. In some aspects, the method further comprises determining mutations in one or more of PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some aspects, the method further comprises determining mutations in two or more of PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some aspects, the method further comprises determining mutations in three or more of PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some aspects, the method further comprises determining mutations in four or more of PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some aspects, the method further comprises determining mutations in five or more of PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some aspects, the method further comprises determining mutations in PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some aspects, the method further comprises administering particle therapy to the subject. In some aspects, the particle therapy comprises proton therapy, carbon therapy, and / or #14395076v1 helium therapy. In some aspects, the dose of particle therapy (e.g., the RBE-adjusted dose) administered is determined based on the determination that mutations are present in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP5. In some aspects, the dose of particle therapy (e.g., the RBE-adjusted dose) administered is determined based on the determination that mutations are present in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN, TP5, PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. In some aspects, the method comprises administering a greater RBE dose (e.g., RBE- adjusted dose of particle therapy to the subject relative to the physical dose that would be given to a subject not having a mutation affecting double-stranded DNA break repair. In some aspects, the method comprises administering a lower physical dose (e.g., RBE-adjusted dose) of particle therapy to the subject relative to the physical dose that would be given to a subject not having a mutation affecting double stranded DNA break repair. In some aspects, the method comprises administering a lower physical dose (e.g., RBE-adjusted dose) of particle therapy to the subject relative to the physical dose that would be given to a subject not having a mutation of one or more genes described herein. In some aspects, the method comprises administering a lower physical dose (e.g., RBE-adjusted dose) of particle therapy to the subject relative to the physical dose that would be given to a subject whose genotype is not known. In some aspects, the method comprises administering a lower physical dose (e.g., RBE-adjusted dose) of particle therapy to the subject relative to the physical dose that would be given to a subject whose tumor’s genotype is not known. In some aspects, the method comprises administering a lower physical dose (e.g., RBE-adjusted dose) of particle therapy to the subject relative to a reference physical dose that would be given to a subject whose tumor’s genotype is not known. In some aspects, a reference physical dose is a physical dose that is predicted based on historical dosing practices and / or general clinical practice, e.g., standard of care. In some aspects, the method comprises administering a lower dose (e.g., RBE-adjusted dose) of particle therapy to the subject relative to a control subject not having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN, and TP53. In some embodiments, the control subject does not have a mutation in any of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN, and TP53. In some aspects, the subject is a comparable subject. In some aspects, a comparable subject is a subject of similar age, weight, disease progression, and / or other metric. In some aspects, the RBE dose (e.g., RBE- adjusted dose) is about 10% to about 50% higher than the physical dose, e.g., the physical reference dose, administered to a subject not having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN, and TP53. For example, the RBE dose (e.g., RBE- adjusted dose) is at least 8%, at least 9%, at least 10%, at least 12%, at least 15%, at least 20%, #14395076v1 at least 25%, at least 30%, at least 35%, at least 40%, at least 45% at least 50%, at least 55% or at least 60% higher than the physical dose, e.g. the physical reference dose, administered to a subject not having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN, and TP53. In some embodiments, the RBE dose (e.g., RBE-adjusted dose) is 10-40% percent lower (e.g., 10%, 20%, 30%, or 40% lower) than the physical dose, e.g., the physical reference dose, administered to a subject not having a mutation in any of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN, and TP53. In some aspects, the present disclosure provides methods of selecting treatment regimens for a subject having cancer (e.g., prostate cancer). In some aspects, the present disclosure provides methods of selecting treatment regimens for a subject having sarcoma (Ewing), chronic lymphocytic leukemia, sarcoma (synovial), acute lymphoblastic leukemia, diffuse large B-cell lymphoma, neuroblastoma, acute myeloid leukemia, small cell lung cancer, multiple myeloma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, breast cancer, head and neck cancer, ovarian cancer, lung adenocarcinoma, glioblastoma, bladder cancer, colorectal cancer, and / or pancreatic cancer. Core Genes Provided are methods comprising determining a mutation in one or more genes of a subject and administering a particle therapy to the subject. One or more of the following genes can be interrogated to determine the presence of one or more mutations in order to determine a level of particle radiation to use. In some aspects, the one or more genes include, but are not limited to, a gene encoding an androgen receptor (AR), Ataxia-telangiectasia mutated serine / threonine kinase (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), e-cadherin (CDH1), ETS variant transcription factor 1 (ETV1), phosphatase and tensin homolog (PTEN), tumor protein p53 (TP53) or combinations thereof. AR The Androgen Receptor (AR) gene had been indicated in the expression of many other DNA repair genes and is a cofactor to PARP1, an important enzyme for determining DNA strand breaks. AR receptor activity governs gene expression of several key process in repair of DNA damage. The AR gene is involved in the expression of other DNA repair genes and AR is also unknown cofactor of Poly ADR-Ribose Polymerase 1 (PARP1). PARP1 is one of the most #14395076v1 important enzymes for the determination and response to DNA damage. PARP1 serves as one of the first mechanisms to determine DNA damage and is also used in the selection of the subsequent DNA repair pathway. The success of PARP1 in the determination of DNA damage plays a significant role in the quality and efficiency of the resulting DNA Damage Repair (DDR). ATM The ATM gene encodes the Ataxia-telangiectasia mutated serine / threonine kinase. The ATM gene plays a key role in DNA damage repair by encoding the PI3K- related serine / threonine kinase. ATM loss hinders the DNA repair process either by germline or somatic mutations. It acts as a key signal transducer in DSB repair by sensing and cellular response. ATM mutation is also strongly associated with higher Gleason grades (higher-risk prostate cancers). BRCA1 The BRCA1 gene encodes breast cancer type 1 susceptibility protein. BRCA1 is also called breast cancer gene 1. BRCA1, like BRCA2 described below, is important to homologous recombination repair (HRR) and plays a significant role in the repair of double strand break (DSB) DNA damage. BRCA2 The BRCA2 gene encodes breast cancer type 2 susceptibility protein. BRCA2 is also called breast cancer gene 2. BRCA2 is important for homologous recombination repair (HRR) and plays a significant role in the repair of double strand break (DSB) DNA damage. HRR is one of the most common processes affected by DDR mutations in prostate cancer and BRCA2 is one of the most common mutations in DDR genes of prostate cancer cells. CDH1 E-cadherin, a protein encoded by CDH1 responsible for cell-to-cell adhesion. CDH1 acts as tumor suppressor gene having role in AR-dependent transcriptional regulation and recruiting HRR proteins for DNA DSB repairs. ETV1 #14395076v1 ETV1 plays a role in AR signaling and mutations can lead to overexpression and higher androgen metabolism and when combined with PTEN mutations lead to formation of prostate cancer in mice. ETV1 was associated with more aggressive disease and poorer outcomes. PTEN Mutations in PTEN are frequently found in genomic analysis of post prostatectomy and tumor biopsy samples. Similar to ATM, PTEN also regulates PI3K. Loss of the PTEN impacts many pathways that lead to tumorigenesis, particularly in prostate cancer. TP53 TP53 activates many cellular responses to stress including DNA repair and cell cycle arrest. TP53 mutations are one of the most common genetic mutations in cancer with TP53 mutations being reported in 50% of cancer cases. As described in the Examples below, TP53 was found to play a significant role in the total PCLSI with a coefficient of 0.0384. Extended Genes In some aspects, the methods described herein further comprise determining a mutation in one or more additional genes (“extended genes”) of a subject, in addition to one or more of the core genes described herein, and administering a particle therapy to the subject. One or more of the following genes can be interrogated to determine the presence of one or more mutations in order to determine a level of particle radiation to use. In some aspects, the one or more additional genes include, but are not limited to, a gene encoding partner and localizer of BRCA2 (PALB2), cyclin-dependent kinase 12 (CDK12), RAD51, or combinations thereof. PALB2 Partner and Localizer of BRCA2 (PALB2) encodes a protein that serves as a critical scaffold in the homologous recombination repair (HRR) pathway. PALB2 acts as a molecular bridge, linking BRCA1 and BRCA2 to facilitate the recruitment of recombination factors to sites of DNA double-strand breaks. Loss of function mutations in PALB2 severely compromise HRR efficiency, leading to increased sensitivity to DNA-damaging agents. In prostate cancer, PALB2 mutations have been associated with aggressive disease phenotypes and may confer enhanced sensitivity to particle therapy due to impaired DSB repair capacity. CDK12 #14395076v1 Cyclin-Dependent Kinase 12 (CDK12) encodes a transcriptional kinase that regulates the expression of several DNA damage response genes, particularly those involved in homologous recombination repair. CDK12 phosphorylates the C-terminal domain of RNA polymerase II, facilitating the transcription of long genes including BRCA1, ATM, and other HRR factors. Loss of CDK12 function results in decreased expression of multiple DDR genes simultaneously, creating a "BRCAness" phenotype. CDK12 mutations in prostate cancer are associated with genomic instability and may predict increased sensitivity to therapies that induce double-strand breaks. RAD51 RAD51 encodes the central recombinase enzyme in homologous recombination repair, catalyzing the critical strand invasion step during DSB repair. RAD51 forms nucleoprotein filaments on single-stranded DNA, facilitating the search for homologous sequences and subsequent DNA strand exchange. Mutations affecting RAD51 function or expression severely compromise HRR efficiency, leading to increased reliance on error-prone non-homologous end joining pathways. In the context of particle therapy, RAD51 deficiency would be expected to enhance sensitivity to high-LET radiation due to impaired repair of complex DSBs. Tissue-Specific Genes In some aspects, the methods described herein further comprise determining a mutation in one or more tissue-specific genes of a subject, in addition to one or more of the core genes and optionally, one or more of the additional genes described herein, and administering a particle therapy to the subject. One or more of the following genes can be interrogated to determine the presence of one or more mutations in order to determine a level of particle radiation to use. In some aspects, the one or more additional genes include, but are not limited to, a gene encoding phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Kirsten rat sarcoma virus (KRAS), neurofibromin 2 (NF2), or combinations thereof. PIK3CA Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) encodes the catalytic subunit of PI3K, a key component of the PI3K / AKT / mTOR signaling pathway. PIK3CA mutations lead to constitutive activation of PI3K signaling, affecting multiple cellular processes including DNA damage response coordination. In prostate cancer, PIK3CA #14395076v1 alterations interact with PTEN loss to amplify oncogenic signaling and may influence the cellular response to radiation-induced DNA damage. The dysregulation of PI3K signaling through PIK3CA mutations can affect both cell survival and DNA repair pathway choice following particle therapy. KRAS KRAS encodes a small GTPase that serves as a molecular switch in multiple signaling pathways, including those governing DNA damage response and cell survival. Oncogenic KRAS mutations result in constitutive activation of downstream signaling cascades that can influence DNA repair pathway selection and efficiency. In the context of radiation therapy, KRAS mutations have been associated with altered radiosensitivity through effects on both intrinsic DNA repair capacity and extrinsic factors such as tumor microenvironment. KRAS status may influence the therapeutic ratio of particle therapy through modulation of DSB repair kinetics. NF2 Neurofibromin 2 (NF2), also known as Merlin, encodes a tumor suppressor protein that links cytoskeletal dynamics to growth control signaling. NF2 loss disrupts multiple signaling pathways including those involved in DNA damage response and cell cycle checkpoint control. Recent evidence suggests NF2 deficiency can compromise genomic stability through effects on mitotic fidelity and DNA repair pathway regulation. In tumors with NF2 mutations, the impaired coordination of DNA damage signaling may enhance sensitivity to particle therapy, particularly to high-LET radiation that generates complex DNA lesions. Systems and Implementation FIG. 6 illustrates an embodiment of a system 600 for administering a dose of particle radiation therapy for the tumor of a subject in accordance with some embodiments of the technology described herein. As shown in FIG. 6, the system 600 may comprise a controller 610, a particle radiation system 620, and a user interface 630. The controller 610 may be configured to facilitate performance of the particle radiation system. The controller 610 may be configured to receive dose information, and in response to receiving the dose information, perform a process for administration of the particle radiation therapy dose, as described herein. In some embodiments, the controller 610 may be configured to receive a subject’s tumor profile (e.g., information regarding whether the tumor has mutations #14395076v1 in any one of the genes described herein) and, using the methods described herein, the controller 610 may determine a dose of particle radiation therapy specific to the subject’s tumor. The dose information may comprise an interaction from a user. In some embodiments, the dose information comprises an explicit input from a user to perform particle radiation therapy, such as pushing a button, turning a dial, clicking, and / or clicking an icon (e.g., to set and / or administer the dose of particle radiation therapy). In some embodiments, the dose information may be implicit, such as turning on the particle therapy system, connecting to a network, and / or logging into a user interface. The particle radiation system 620 may include an accelerator, a beam transport system, a gantry, and a nozzle. The accelerator, in some embodiments, is a cyclotron. In some embodiments, the cyclotron is a superconducting cyclotron. The accelerator, in some embodiments, is a synchrotron. The beam transport system, in some embodiments, comprises dipole (bending) magnets and / or quadrupole (focusing) magnets). The nozzle, in some embodiments, guides the beam to the patient. In some embodiments, the nozzle comprises scanning magnets, an aperture, and / or a compensator. In some embodiments, the particle radiation system 620, further comprises a patient positioning system (e.g., robotic treatment couch and / or stabilization / immobilization devices). In some embodiments, the particle radiation system 620 further comprises an imaging system, such as an X-ray, CT, and / or prompt gamma imaging system. In some embodiments, a user may interact with the particle radiation system 620 via a user interface 630. In some embodiments, the user interface may be on a display. The display may provide visual presentation of one or more outputs of the particle radiation therapy described herein. In some embodiments, the method for performing particle radiation therapy with a selected dose begins with receiving a tumor profile, indicating mutations in specific genes. In some embodiments, the tumor profile is added directly to the user interface and / or controller. In some embodiments, the tumor profile is added to a general computer. In either embodiment, the dose of particle radiation therapy is determined based on the methods described herein. With respect to the particle radiation therapy, in some embodiments, the dose may comprise an input by a user (e.g., via the press of a button or entry of values). In some embodiments, the dose may comprise a single input from a user (e.g., when the dose is determined on a general computer, the dose may comprise input of the dose into the particle therapy system). In response to receiving the dose for the subject’s tumor, one or more of performing subject loading and positioning, performing automated alignment of the particle #14395076v1 therapy system, selecting a protocol and dose, and administering the particle radiation therapy dose to the subject may be performed autonomously or with user input. In some embodiments, each of performing subject loading and positioning, performing automated alignment of the particle therapy system, selecting a protocol and dose, and administering the particle radiation therapy dose to the subject are performed. In other embodiments, one or more of performing subject loading and positioning, performing automated alignment of the particle therapy system, selecting a protocol and dose, and administering the particle radiation therapy dose to the subject may be omitted. The acts described herein may be performed in any suitable order. In some embodiments, the user interfaces may be used in accordance with some embodiments of the technology described herein. The user interface, in some embodiments, displays the dose of particle radiation and, optionally, other related parameters (e.g., patient position, linear energy transfer, range, stopping power, particle type, particle mass, and particle charge). In some embodiments, the controller also interacts with a computing device programmed to process data received regarding the subject’s tumor profile (e.g., the presence or absence of mutations in selected genes described herein). In some embodiments, the computing device may process the data using any one of the methods described herein in order to determine a dose of particle radiation therapy. In some embodiments, the controller and the computing device are the same device. In some embodiments, the controller and the computing device are different devices. The computing device may be any electronic device configured to process tumor profile data and determine a dose of particle radiation therapy based on the same. In some embodiments, the computing device may be located in a same room as the particle radiation therapy system and / or coupled to the particle radiation therapy system. In some embodiments, the computing device may be a fixed electronic device such as a desktop computer, a server, a rack-mounted computer, or any other suitable fixed electronic device that may be configured to process tumor profile data and determine a dose of particle radiation therapy based on the same. Alternatively, the computing device may be a portable device such as a smart phone, a personal digital assistant, a laptop computer, a tablet computer, or any other portable device that may be configured to process tumor profile data and determine a dose of particle radiation therapy based on the same. In some embodiments, the computing device may comprise multiple computing devices of any suitable type, as aspects of the disclosure provided herein are not limited in this respect. #14395076v1 FIG. 7 shows a block diagram of an embodiment of a computer system 700 that may be used to implement embodiments of the technology described herein. In some aspects, the particle radiation therapy system is controlled by a computer system that allows for user input to target and align the patient with the particle therapy. For example, in some aspects the components of the particle therapy system are controlled via a computer system that allows a user to identify the location of a tumor, target the particle beam dose to the tumor, and adjust the targeting based on patient movement (e.g., breathing, etc.). In some aspects, a computer system receives inputs from a scanner, an imager, and a cyclotron. In some aspects, information from the scanner and / or imager are displayed to help a user align a patient with a particle beam (e.g., a pencil beam). In some aspects, a computer system receives inputs from a scanner, an imager, and a cyclotron and automatically generates outputs to a robotic positioner and a cyclotron. In some aspects, a computer system receives inputs from a scanner and an imager of the position of a patient surface and a patient tumor, respectively, and a cyclotron on the delivery of a particle beam (e.g., a pencil beam). In some aspects, based on the inputs, a computer system automatically generates outputs to a robotic positioner and a cyclotron to position the patient positioning device to a position in which the tumor is positioned in a predetermined area for optimal particle beam (e.g., a pencil beam) scanning. An illustrative implementation of a computer system 700 that may be used in connection with any of the aspects of the technology described herein is shown in FIG. 7. The computer system 700 includes one or more processors 701 and one or more articles of manufacture that comprise non-transitory computer-readable storage media (e.g., memory 702 and one or more non-volatile storage media 703). In some aspects, a processor 701 receives inputs 706, e.g., connected to a scanner, an imager, and a cyclotron (e.g., the particle radiation system 620). In some aspects, a processor 701 receives inputs from a scanner, an imager, and a cyclotron through a network input / output (I / O) interface 704. The processor 701 may control writing data to and reading data from the memory 702 and the non-volatile storage device 703 in any suitable manner, as the aspects of the technology described herein are not limited in this respect. To perform any of the functionality described herein, the processor 701 may receive input data from the scanner, imager, and / or cyclotron and execute one or more processor-executable instructions stored in one or more non-transitory computer-readable storage media (e.g., the memory 702), which may serve as non-transitory computer-readable storage media storing processor- executable instructions for execution by the processor 701. Computing device 700 may also include a network input / output (I / O) interface 704 via which the computing device may communicate with other computing devices (e.g., over a network), e.g., the scanner, imager #14395076v1 and / or cyclotron and may also include one or more user I / O interfaces 705, via which the computing device may provide output to and receive input from a user. The user I / O interfaces may include devices such as a keyboard, a mouse, a microphone, a display device (e.g., a monitor or touch screen), speakers, a camera, and / or various other types of I / O devices. The embodiments described herein, can be implemented in any of numerous ways. For example, the embodiments may be implemented using hardware, software or a combination thereof. When implemented in software, the software code can be executed on any suitable processor (e.g., a microprocessor) or collection of processors, whether provided in a single computing device or distributed among multiple computing devices. It should be appreciated that any component or collection of components that perform the functions described above can be generically considered as one or more controllers that control the above-described functions. The one or more controllers can be implemented in numerous ways, such as with dedicated hardware, or with general purpose hardware (e.g., one or more processors) that is programmed using microcode or software to perform the functions recited above. In this respect, it should be appreciated that one implementation of the embodiments described herein comprises at least one computer-readable storage medium (e.g., RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical disk storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or other tangible, non-transitory computer-readable storage medium) encoded with a computer program (i.e., a plurality of executable instructions) that, when executed on one or more processors, performs the above-described functions of one or more embodiments. The computer- readable medium may be transportable such that the program stored thereon can be loaded onto any computing device to implement aspects of the techniques described herein. In addition, it should be appreciated that the reference to a computer program which, when executed, performs any of the above- described functions, is not limited to an application program running on a host computer. Rather, the terms computer program and software are used herein in a generic sense to reference any type of computer code (e.g., application software, firmware, microcode, or any other form of computer instruction) that can be employed to program one or more processors to implement aspects of the techniques described herein. Aspects of the technology described herein provide computer implemented methods for evaluating, generating, visualizing, and / or targeting a tumor in a patient. In some embodiments, a software program may provide a user with a visual representation of a subject’s tumor and / or other information related to a subject’s medical condition (e.g., cancer) using an interactive graphical user interface (GUI). Such a software program may execute in any suitable computing environment including, but not limited #14395076v1 to, a cloud-computing environment, a device co-located with a user (e.g., the user’s laptop, desktop, smartphone, etc.), one or more devices remote from the user (e.g., one or more servers), etc. In some aspects, a software program also provides a user with options for selecting the appropriate intensity of a particle beam and positioning the subject using the patient positioning device. In some aspects, a software program also processes feedback from a scanner and / or imager and sends instructions to patient positioning device to adjust the position of the subject relative to the position of the particle beam. Determining the location of the target tumor tissue, positioning the subject, controlling the particle beam (e.g., a pencil beam), and optionally adjusting the subject’s position during treatment can be performed via user input and / or automatically using the computer system. In some aspects, the computer system also can generate a report of the therapeutic conditions for the subject’s medical record. EXAMPLES Example 1. Prostate Cancer Surviving Fraction Sensitivity to DNA Repair Mutations Cell Lines and PARP Inhibitor Five prostate carcinoma cell lines with published Olaparib survival data were investigated: LNCaP, VCaP, 22Rv1, PC3, and Du145. These cell lines are derived from a lymph node metastasis, spinal cord metastasis xenograft, primary prostate cancer xenograft, bone metastasis and brain metastasis, respectively. The LNCaP, VCaP, and 22Rv1 cell lines were AR positive, while PC3 and Du145 cells were AR negative. LNCaP and VCaP are PSA positive, while PC3 and Du145 are PSA negative; 22Rv1 is negative for the PSA protein but positive for PSA mRNA. The cell lines evaluated in this study were purchased from the American Type Culture Collection (ATCC). Olaparib (C24H23FN4O3, MW: 434 g / mol), a PARPi, has been studied for the treatment of adult patients with germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC). Olaparib's mechanism induces synthetic lethality in cancer cells, particularly those with HRR deficiencies, such as BRCA1 or BRCA2 mutations. In HRR- deficient cells, Olaparib-induced loss of base excision repair (BER) results in the accumulation of unrepaired SSBs. During DNA replication in S phase, these SSBs lead to replication fork collapse, ultimately generating deleterious DSBs. In cells with intact HRR, these DSBs can be effectively repaired. However, in HRR-deficient cells, such as those with BRCA mutations, these DSBs either remain unrepaired or are mended through error-prone DNA repair #14395076v1 mechanisms (i.e., nonhomologous end joining), ultimately triggering genomic instability and apoptotic cell death. Data Source The model also uses the published data regarding the Du145 prostate cancer cell line sensitivity to proton beam LET and the DNA repair mutation profile included from the COSMIC cell line project’s mutations database (FIG. 2A). Du145 was used as the common calibration cell line to estimate the change in LET required to produce a similar sensitization from the available spectrum of a PARPi, Olaparib, doses. Of the five cell lines included in the Olaparib data, three cell lines were used to fit the model, Du145, 22Rv1 and LNCaP. These three cell lines had mutations with published incidence frequency from genetic screening of prostate cancer patients. PSLSI Model Development Relating Olaparib Sensitization to LET Sensitization Published α and β values for Du145 response to photon therapy were used as reference values from which ∆α values were calculated by modeling sensitization by exploitation of mutations in DSB repair pathways by Olaparib or LET. The change in α required to produce the relative change in surviving fraction (SF) at the published doses of Olaparib was calculated using Equation 2 for a dose of 2Gy. This sensitization model chose α because α is dependent on LET, this is also consistent with LET dependent cell survival curves. To calculate RBE from ∆α, the dose required to produce a SF of 10% was calculated using Equation 3 with an αref=0.14 and β=0.03 taken from published clonogenic assay data. The ∆α used in the model are shown in Table 1 and relative sensitization of the SF in Figure 5. The change in RBE was then calculated using Equation 4. The LET range that would produce the corresponding #14395076v1 ∆RBE was calculated using the linear model of Du145 sensitivity to LET. The LET increase required to produce the RBE enhancement was estimated by dividing the change in RBE by the published Du145 coefficient of LET sensitivity of 0.084. Using the estimated LET range, the RBE response to LET of each cell line was estimated using least-squares fit. The reference RBE of each cell line at 1.9 keV / µm was calculated using Equation 5 and added to the RBE enhancement values. The values of LET and RBE used in fitting the PCLSI model are shown in Table 2. (3) ; (4) P∆+,- = ghi;(PghiR∆P)(5)+,-a9b = 1.16 + j ∗ 1.9 [j^l / µo]Establishing Coefficients for DNA Repair Mutation Sensitivity To capture the relationship between RBE sensitivity and HRR mutations, a linear system of equations was devised. A system of equations was created such that the RBE as a function of LET of a cell line with a known DNA repair mutation profile could be calculated from its PCLSI (Equation 6). The PCLSI is a metric of LET sensitivity created by multiplying the coefficient of sensitivity caused by the presence of each genetic mutation, ^^, by one if the mutation is present or zero if the mutation is not present, denoted by ^^^^^. A system of equations was created from DNA repair mutations presented in the COSMIC database from the cell lines Du145, 22Rv1 and LNCaP. The system of equations was solved such that the coefficients of each genetic mutation best fit the RBE at each LET. The system of equations was solved with a linear least square in MATLAB to best fit the coefficients to the reference SF data. #14395076v1 Prostate Cancer LET Sensitivity Index (PCLSI) & Coefficient Determination The model utilizes the tissue-specific DNA repair mutation profile to estimate the sensitivity of RBE to LET from the SF of prostate cancer cell lines with varying DNA repair mutation profiles. The RBE multiple when compared to the reference dose expressed in Cobalt Gray Equivalent (CGE) is given in Equation 7, denoted as +,-. / 012. The equivalent biological impact in CGE, +,-6789, is given as +,-. / 012multiplied by ;<=^>?@8^ABCand is shown in Equation 8. The linear model intercept for LET=0 was taken from the published fit of Du145 LET sensitivity. +,-. / 012 = 1.16 + ^^^^^ × ^-5 (7)+,-6789 = (1.16 + ^^^^^ × ^-5) : ;<=^>?@8^ABC (8)To calculate the coefficients of sensitivity to each genetic mutation, ^^, a system of equations was evaluated using least squares to fit the coefficients, using the MATLAB function lsqr.Equation 9 shows the conversion of Equation 7, +,-. / 012, into the form of q ∙ : = r to besolved by MATLAB. (^-5 × ^^^^Z) ∙ ^Z = (+,-^^^^^ − 1.16) <[ sℎ^ [<uo q ∙ : = r (9)RBE Model Comparison The PCLSI model was compared to two published LET-dependent RBE models. The first model is the McMahon model, a linear LET-dependent model with the RBE calculated as RBEyzy = 1 + { ∙ LET (10)where { = 0.055 µm / keV is a constant fit to cell survival data from non-prostate cell lines. Thisfitted {-factor is consistent with the optimized {-factor that minimized the variability in the modeled McNamara RBE-dose for W / Xs ranging from 2 Gy to 10 Gy can be considered a generalized-tissue model. The second model is the McNamara model, a phenomenological LET-dependent model based on the linear-quadratic cell survival model with the RBE calculated as #14395076v1 where ;>is the proton dose per fraction, (W / X)^is for X-rays, and +,-^B^and +,-^^^are calculated as +,-o^: = 0.99064 (12) +,-oZ^ = 1.1012 − 0.0038703d(W / X):LET^ (13)and are the asymptotic values of RBE^A^ as ;> → 0 and ;> → ∞, respectively. The McNamaramodel is specific and depends on the dose per fraction. It was fit to 287 W / X data points at various values of LET, of which only two data points at one value of LET are prostate cancer (Du145). Notably, the McNamara model underpredicted the Du145 RBE in multiple studies. Clinical Case Study SFO and LET-optimized prostate pencil beam scanning (PBS) proton therapy plans were created to compare the PCLSI model to the McMahon and McNamara models (approved by an IRB). The dose to the planning target volume (PTV) prostate / seminal vesicles (PSV) was prescribed at 46 Gy (RBE=1.1) in 23 fractions and 32 Gy (RBE=1.1) in 16 fractions in sequential two-phase treatment with pelvic nodes irradiated in the first phase. A Monte Carlo dose engine (RayStation 12B Research Non-Clinical, RaySearch Laboratories, Stockholm) was used to robustly optimize the dose to target volumes. The dose and LET were optimized with 50000 ions / spot and 0.5% statistical uncertainty for the final dose / LET calculation. Python scripts were written to apply the RBE models to the plan based on the voxelwise physical dose and LET. The(W / X)^s used in the McNamara model were 1.5 Gy for the prostate / PTV PSV, 5 Gy for the bladder, and 5.4 Gy for the rectum. Dose-volume histograms (DVHs) were used to compare the RBE doses between models. Using the published prevalence of prostate cancer DNA repair mutations, particularly AR (84.86%) and BRCA2 (46.85%), a PCLSI expected value of 0.165 was used in the applied RBE model. To quantify how the PCLSI model may predict improved dosimetry over the McMahon or McNamara models, we define the target-to-OAR dose ratios (TODRs) for the bladder and rectum as #14395076v1 and respectively. The TODRs represent how much dose can be given to the PTV PSV D95 region per unit dose in the bladder D20 or rectum D10 regions and were based on the clinical dose goals that at least 95% of the PTV PSV should receive 100% of the prescribed dose, and no more than 20% of the bladder or 10% of the rectum should receive more than 70 Gy (RBE = 1.1). The TODRs were calculated for the McMahon, McNamara, and PCLSI models for both SFO and LET-optimized plans; because the PCLSI model is only applicable to the prostate, the McNamara model was used for the OARs since it is W / X specific. The TODR serves as an analog of the therapeutic ratio, where increases in the TODR are likely to result in an improved therapeutic ratio and benefit patient outcomes. A higher TODR value indicates a better ratio between tumor coverage and dose to normal tissue. Results Mutations in the DNA repair genes, AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53, had positive coefficients (FIG. 2B) relating LET to RBE. The increase in LET sensitivity appears to be a cumulative effect where the greater the number of mutations in DNA repair genes within a cell line, the greater the sensitivity to LET. Certain DNA repair mutations were found to have greater impact than others as shown in equation 16. ^^^^^ = (0.0309 ∙ ^^) + (0.0309 ∙ ^^^) + (0.0075 ∙ ^^^^^) + (0.0384 ∙ ^^^^!) …+(0.0309 ∙ ^#$^)+(0.0478 ∙ %^&^)+(0.0478 ∙ '^%()+(0.0384 ∙ ^')*)(16) ETV1 and PTEN mutations had the largest coefficients of 0.0478, demonstrating that cells with these mutations have the greatest reduction in surviving fraction as LET increases. The next largest coefficient was for mutations in the DNA repair genes BRCA2 and TP53, with values of 0.0384. BRCA1 mutations had the smallest coefficient of any of the mutations identified, with a value of only 0.0075. Given the DNA repair mutation profile present in each of these prostate cancer cell lines, LNCaP had the largest total PSLSI score of 0.265. As shown in Table 3, this indicates that LNCaP cells are likely to have the greatest sensitivity to LET and LET-optimized proton therapy. At an LET of 2 KeV / µm, LNCaP would experience an RBE of 1.69, and at an LET of 4 #14395076v1 KeV / µm, it is indicated to experience an RBE of 2.22. Cell lines that have relatively high PCLSI scores, above average reference values such as 0.055, are likely to experience RBE values well above the 1.1 typically used to scale the physical dose of proton therapy treatment plans. These data reveal the distinct sensitivity of these cell lines to varying LETs, underscoring the importance of adapting patient-specific radiation treatment. The PCLSI calculated from the frequency of DNA repair mutations in non-metastatic prostate cancer patients was 0.055, the same value published from averaging LET sensitivity across multiple cell lines. FIG. 4 shows the RBE dose (top) and LET (bottom) for the SFO (left) and LET- optimized (right) plans. The SFO dose field to the PTV PSV is more uniform than the LET- optimized field. The average LET in the PTV PSV beam set, however, is 4.4 keV / µm in the LET-optimized plan and only 2.2 keV / µm in the SFO plan; meanwhile, the change in OAR LET is modest. This results in the LET-optimized plan having higher TODRs than the SFO plan (FIG. 4). It is also evident that the choice of RBE model affects the TODRs. In both the SFO and LET-optimized plans, the TODRs for both the bladder and rectum were improved using the PCLSI model. Additionally, the percent improvement in TODRs between the McNamara and PCLSI models was 26.1% for both the bladder and rectum in the SFO plan and 36.1% in the LET-optimized plan. The improvement in TODR illustrates the increased divergence of tumor mutation-specific models, such as PCLSI, from general RBE models and the importance of developing patient- and tumor-specific models when using LET optimization. Table 1: Calculated values of ∆α and α / β using Olaparib surviving fraction (SF) and Du145 using Cell lines Dose 0 100 100 100 100 100 2.5 55 87 61 80 92 5.0 41 87 52 79 90 10.0 35 81 43 69 80 20.0 35 82 55 70 59 ∆α0 0.000 0.000 0.000 0.000 0.000 2.5 0.299 0.07 0.247 0.112 0.042 5.0 0.446 0.07 0.327 0.118 0.053 #14395076v1 10.0 0.525 0.105 0.422 0.186 0.112 20.0 0.525 0.099 0.299 0.178 0.264 α / β αref= 0.14 α / βref= 4.7 βref= 0.03 0 4.7 4.7 4.7 4.7 4.7 2.5 14.6 7.0 12.9 8.4 6.1 5.0 19.5 7.0 15.6 8.6 6.4 10.0 22.2 8.2 18.7 10.9 8.4 20.0 22.2 8.0 14.6 10.6 13.5 Table 2: RBE values of each equivalent LET value estimated by calculating the dose at SF=0.1 for each ∆α. The RBE and LET equivalent values were used to model the PCLSI. klsqr is a least squares regression of the relationship between LET and RBE for each cell line. The ∆RBE values were added to the RBEref values calculated using equation 5 for an LET of 1.9 keV / µm. ∆RBE klsqr 0.244 0.040 0.151 0.073 0.084 ∆LET [keV / µm] LNCaP VCaP 22Rv1 PC3 Du145 0.00 0.000 0.000 0.000 0.000 0.000 0.94 0.643 0.134 0.521 0.220 0.079 1.19 1.008 0.134 0.711 0.233 0.100 2.62 1.212 0.207 0.947 0.380 0.220 6.67 1.212 0.194 0.643 0.364 0.560 RBE 1.900 1.625 1.244 1.449 1.307 1.322 2.841 2.268 1.378 1.970 1.527 1.400 3.097 2.633 1.378 2.160 1.540 1.422 4.526 2.837 1.451 2.396 1.687 1.542 8.584 2.837 1.439 2.093 1.671 1.881 Abbreviations: radiobiological biological effectiveness (RBE), linear energy transfer (LET), prostate cancer LET sensitivity index (PCLSI). #14395076v1 Table 3: RBE values calculated using PCLSI. RBE value calculated using resultant coefficient at various LETs for the DNA repair mutations present in each cell line. Met: metastatic. nonMet: non-metastatic. Expected value were calculated using the PCLSI and published DNA repair mutation frequencies in prostate cancer patients. Example 2. Tissue-Specific LSI Model Extension Using PARP Inhibitor Sensitivity: A Biological Basis for Tissue-Specific Scaling While the prostate cancer LET sensitivity index (PCLSI) was validated using prostate cancer cell lines, the fundamental relationship between DNA repair deficiency and particle therapy sensitivity extends to other cancer types. To develop tissue-specific LSI models, Olaparib IC50values were utilized as a quantitative measure of intrinsic DNA repair capacity across different tissue types. The key biological principle underlying this extension is that tissues with intact DNA repair mechanisms (high Olaparib IC50) show reduced impact from mutations on LET sensitivity, while repair-deficient tissues (low Olaparib IC50) demonstrate maintained or enhanced mutation impact. This inverse relationship reflects that resistant tissues maintain functional DNA repair through redundant pathways despite harboring mutations, whereas sensitive tissues cannot compensate for repair gene defects. Methodology for Tissue-Specific Coefficient Scaling The Genomics of Drug Sensitivity in Cancer (GDSC2) database provides a systematic foundation for determining cancer-specific Linear Energy Transfer Sensitivity Index (LSI) #14395076v1 coefficients through quantitative measurement of Olaparib sensitivity across 967 human cancer cell lines representing 34 distinct cancer types. The mechanistic basis for utilizing Olaparib IC50 values as a scaling metric derives from the shared dependency on homologous recombination repair pathways: Olaparib induces synthetic lethality by inhibiting single-stranded DNA break repair through PARP inhibition, thereby forcing cellular reliance on the same double-stranded DNA break repair mechanisms that are overwhelmed by the clustered DNA damage characteristic of particle therapy at therapeutic LET ranges of 3-4 keV / μm. The mathematical model employs a logarithmic scaling factor incorporating a 0.7 power coefficient, expressed in the scaling factor equation below, wherein the reference IC50 corresponds to prostate cancer cell lines as established herein. This exponential dampening factor of 0.7 serves to modulate the relationship between pharmacological sensitivity to PARP inhibition and predicted radiobiological response to high-LET radiation, accounting for the non- linear correlation between drug response and radiation sensitivity while preventing extrapolation to biologically implausible coefficient values. The resulting LSI scaling maintains proportional relationships between cancer types while preserving four significant figure precision, generating coefficient ranges from 0.0061 to 0.0942 that produce clinically reasonable RBE predictions when applied to the fundamental equation RBE = 1.00 + (LSI × LET). This methodology enables tissue-specific and mutation-specific optimization of particle therapy dosimetry across diverse malignancies while maintaining consistency with the validated prostate cancer model. Table 4 shows cancer-specific linear energy transfer sensitivity index (LSI) coefficients derived from the GDSC2 Olaparib IC50Analysis. Logarithmic scaling of prostate cancer reference coefficients was performed using 967 cancer cell lines across 34 distinct cancer types from the Genomics of Drug Sensitivity in Cancer database (GDSC2, October 2023 release). The scaling factor was calculated as shown above, where IC50_prostate = 122.5 µM represents the median value from six prostate cancer cell lines. Individual gene coefficients (AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN, TP53) maintain four significant figures. The Total LSI represents the sum of all eight coefficients when all genes are mutated, enabling calculation of cancer-specific relative biological effectiveness using the formula RBE = 1.00 + (LSI × LET). Cancer types are ordered by decreasing total LSI values, with sarcoma subtypes distinguished from the 18-sample aggregate. The n column indicates the number of cell lines analyzed per cancer type in the GDSC2 database. #14395076v1 Table 4. #14395076v1 Example Calculation: Breast Cancer Patient:Patient with BRCA2, PTEN, and TP53 mutations: PCLSI = 0.0396 + 0.0492 + 0.0396 = 0.1284 At 3 keV / µm: RBE = 1.00 + (0.1284 × 3) = 1.39 This represents a 26% increase in biological effectiveness compared to standard RBE of 1.1 These values can be extended to additional genes (for example, the extended genes and / or the tissue-specific genes), as exemplified below: Extended Tissue Specific LET Sensitivity Indexes (LSI): Prostate Cancer: Lung Cancer: Breast Cancer: Pancreatic Cancer: Central Nervous System Cancers: ^^^ / ^1O^^= (0.0 ∙ ^^) + (0.0062 ∙ ^^^) + (0.0015 ∙ ^^^^^) + (0.0077 ∙ ^^^^!) …+ (0.0062 ∙ ^#$^) + (0.0 ∙ %^&^) + (0.0096 ∙ '^%() + (0.0077 ∙ ^')*) …#14395076v1+ (0.0065 ∙ '^D^!) + (0.0070 ∙ ^#^^!) + (0.0055 ∙ ^^#)^) …+ (0.0040 ∙ 'J^*^^) + (0.0 ∙ ^^^I) + (0.0080 ∙ (^!)Head and Neck Cancers: Sarcomas: Methodology for Tissue-Specific Coefficient Scaling: Tissue-specific coefficients are derived using: Ci,tissue=Ci,prostate×SFtissueCi,tissue=Ci,prostate×SFtissue Where SFtissue (Sensitivity Factor) is determined by the tissue's Olaparib IC50 relative to the prostate baseline (58.24 μM): • For sensitive tissues (IC50 < 1 μM): SF = 1.0-1.2 • For intermediate tissues (1-50 μM): SF = 0.8-1.0 • For resistant tissues (>100 μM): SF inversely proportional to IC50 Table 5: Tissue-Specific Olaparib Sensitivity and Scaling Factors #14395076v1 Table 6: Tissue-Specific LSI Coefficients for Common DNA Repair Genes Examples are provided below: Example A: Lung Cancer (Sensitive) Patient: NSCLC with common mutations • Mutations: TP53, KRAS • HRD score: 50 • LSI = 0.0422 + 0.0180 + 0.080 × (50-42) / 58 = 0.0602 + 0.0110 = 0.0712 • At LET=3.5: RBE = 1.0 + 0.0712×3.5 = 1.25 • Biological interpretation: Sensitive tissue shows meaningful benefit Example B: CNS Tumor (Resistant) Patient: Glioblastoma with typical mutations • Mutations: TP53, PTEN, NF2 • HRD score: 60 • LSI = 0.0077 + 0.0096 + 0.0080 + 0.015 × (60-42) / 58 = 0.0253 + 0.0047 = 0.0300 • At LET=3.5: RBE = 1.0 + 0.0300×3.5 = 1.105 • Biological interpretation: Resistant tissue shows minimal benefit despite mutations Example C: Pancreatic Cancer (Resistant) Patient: BRCA2-mutant pancreatic • Mutations: BRCA2, TP53 • HRD score: 65 • LSI = 0.0134 + 0.0134 + 0.020 × (65-42) / 58 = 0.0268 + 0.0079 = 0.0347 • At LET=3.5: RBE = 1.0 + 0.0347×3.5 = 1.121 • Biological interpretation: Limited benefit due to tissue resistance Example D: Prostate Cancer (Baseline) Patient: High-risk with multiple mutations #14395076v1 • Mutations: BRCA2, PTEN, TP53 • HRD score: 55 • LSI = 0.0384 + 0.0478 + 0.0384 + 0.050 × (55-42) / 58 = 0.1246 + 0.0112 = 0.1358 • At LET=3.5: RBE = 1.0 + 0.1358×3.5 = 1.475 • Biological interpretation: Validated model shows substantial benefit ADDITIONAL EMBODIMENTS 1. A method comprising a) determining the presence of a mutation in one or more genes related to double stranded DNA break repair in a tumor in a subject, and b) determining a relative biological effectiveness (RBE) dose of particle radiation. 2. The method of paragraph 1, wherein determining a RBE dose of particle radiation comprises using a linear energy transfer (LET) sensitivity index. 3. The method of paragraph 2, wherein the LET sensitivity index is based on the presence of a mutation in the one or more genes and a weighting factor. 4. The method of paragraph 3, wherein the weighing factor is a measure of the impact of the mutation in the one or more genes on the sensitivity of the tumor of the subject to linear energy transfer. 5. The method of paragraph 4, wherein the weighting factor is determined in cells of a cancer type similar to the cancer of the subject. 6. The method of paragraph 5, wherein the weighting factor is determined by determining a survival fraction of the cells treated with a single stranded DNA break repair inhibitor and using a mathematical model to determine a relative biological effectiveness of a physical dose of particle therapy in the tumor of the subject based on the relative biological effectiveness of the single stranded DNA break repair inhibitor in the cells of the similar cancer type. 7. The method of any one of paragraphs 1-6, wherein the determined RBE dose is proportional to the LET sensitivity index. #14395076v1 8. The method of any one of paragraphs 1-7, wherein the method further comprising administering particle therapy to the subject at the determined RBE dose of particle radiation. 9. The method of any one of paragraphs 1-8, wherein the cancer is prostate cancer. 10. The method of any one of the preceding paragraphs, wherein at least one of the one or more genes related to double stranded DNA break repair is selected from: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), Cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase and tensin homolog (PTEN) and tumor protein 53 gene (TP53). 11. The method of paragraph 10, wherein mutations are identified in two or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. 12. The method of paragraph 10, wherein mutations are identified in three or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. 13. The method of paragraph 10, wherein mutations are identified in four or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. 14. The method of paragraph 10, wherein mutations are identified in AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53. 15. The method of any one of the preceding paragraphs, wherein particle therapy comprises proton therapy, carbon therapy, or helium therapy. 16. The method of any one of the preceding paragraphs, wherein a lower physical dose of particle therapy is administered relative to a subject not having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53, wherein the lower physical dose is at least 10% lower, at least 15% lower, at least 20% lower, or at least 50% lower. #14395076v1 17. The method of any one of the preceding paragraphs, wherein a greater RBE dose of particle therapy is administered relative to a subject not having a mutation in one or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53, wherein the RBE dose is at least 10% greater, at least 15% greater, at least 20% greater, or at least 50% greater. 18. The method of paragraph 17, wherein the greater RBE dose of particle therapy administered corresponds to a same physical dose administered to a subject not having a mutation in one or more double stranded DNA break repair genes. 19. The method of any one of the preceding paragraphs, wherein the mathematical model is represented by one or more of the following algorithms: +,-. / 012 = 1.16 + ^^^^^ × ^-5 (7)+,-6789 = (1.16 + ^^^^^ × ^-5) : ;<=^>?@8^ABC (8)20. A method comprising: administering particle therapy to a subject, wherein the subject has a tumor known to comprise a mutation in one or more genes related to double stranded DNA break repair. 21. The method of paragraph 20, wherein at least one of the one or more genes related to double stranded DNA break repair are selected from: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), Cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase and tensin homolog (PTEN) and tumor protein 53 gene (TP53). 22. A method comprising: administering particle therapy to a subject, wherein the subject has a tumor comprising a mutation in one or more genes related to double stranded DNA break repair. #14395076v1 23. The method of paragraph 22, wherein at least one of the one or more genes related to double stranded DNA break repair are selected from androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), Cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase and tensin homolog (PTEN) and tumor protein 53 gene (TP53). 24. A method comprising determining the presence of a mutation in one or more genes related to double stranded DNA break repair in a tumor in a subject, and administering a dose of particle radiation to the subject, wherein the dose is an RBE- adjusted dose determined for the tumor in the subject. 25. The method of paragraph 24, wherein at least one of the one or more genes related to double stranded DNA break repair are selected from: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), Cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase and tensin homolog (PTEN) and tumor protein 53 gene (TP53). 26. The method of paragraph 24 or 25, wherein determining a RBE-adjusted dose of particle radiation comprises using a linear energy transfer (LET) sensitivity index. 27. The method of paragraph 26, wherein the LET sensitivity index is based on the presence of a mutation in the one or more genes and a weighting factor. 28. The method of paragraph 27, wherein the weighing factor is a measure of the impact of the mutation in the one or more genes on the sensitivity of the tumor of the subject to linear energy transfer. 29. The method of paragraph 27 or 28, wherein the weighting factor is determined in cells of a cancer type similar to the cancer of the subject. #14395076v1 30. The method of any one of paragraphs 27-29, wherein the weighting factor is determined by determining a survival fraction of the cells treated with a single stranded DNA break repair inhibitor and using a mathematical model to determine a relative biological effectiveness of a physical dose of particle therapy in the tumor of the subject based on the relative biological effectiveness of the single stranded DNA break repair inhibitor in the cells of the similar cancer type. 31. The method of any one of paragraphs 27-30, wherein the determined RBE- adjusted dose is proportional to the LET sensitivity index. 32. The method of any one of the paragraphs 24-31, wherein particle therapy comprises proton therapy, carbon therapy, or helium therapy. 33. The method of any one of paragraphs 24-32, wherein the mathematical model is represented by one or more of the following algorithms: +,-. / 012 = 1.16 + ^^^^^ × ^-5 (7)+,-6789 = (1.16 + ^^^^^ × ^-5) : ;<=^>?@8^ABC (8)34. A method wherein tissue-specific LSI coefficients are scaled inversely to PARP inhibitor resistance. 35. The method of paragraph 34, wherein CNS tumor coefficients are reduced to 0.20-0.25× of prostate values. 36. The method of paragraph 34, wherein lung cancer coefficients are maintained at 1.0-1.2× of prostate values. 37. The method of paragraph 34, wherein breast cancer coefficients are maintained at 0.8- 1.0× of prostate values. #14395076v1 38. The method of paragraph 34, wherein pancreatic cancer coefficients are reduced to 0.35- 0.40× of prostate values. 39. The method of any one of paragraphs 1-38, wherein maximum achievable RBE decreases with tissue resistance. 40. The method of any one of paragraphs 1-8 and 10-39, wherein the cancer is sarcoma (Ewing), chronic lymphocytic leukemia, sarcoma (synovial), acute lymphoblastic leukemia, diffuse large B-cell lymphoma, neuroblastoma, acute myeloid leukemia, small cell lung cancer, multiple myeloma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, breast cancer, head and neck cancer, ovarian cancer, lung adenocarcinoma, glioblastoma, bladder cancer, colorectal cancer, and / or pancreatic cancer. EQUIVALENTS While several inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the function and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be illustrative examples, and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure. #14395076v1 All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms. All references, patents and patent applications disclosed herein are incorporated by reference with respect to the subject matter for which each is cited, which in some cases may encompass the entirety of the document. The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements #14395076v1 and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. It should be appreciated that embodiments described in this document using an open-ended transitional phrase (e.g., “comprising”) are also contemplated, in alternative embodiments, as “consisting of” and “consisting essentially of” the feature described by the open-ended transitional phrase. For example, if the disclosure describes “a composition comprising A and B”, the disclosure also contemplates the alternative embodiments “a composition consisting of A and B” and “a composition consisting essentially of A and B”. #14395076v1

Claims

CLAIMS What is claimed is:

1. A method comprising determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject, and administering a dose of particle radiation therapy to the subject.

2. The method of claim 1, wherein the particle radiation therapy comprises proton therapy, carbon therapy, or helium therapy.

3. The method of any one of claims 1-2, wherein one of the one or more genes related to double-stranded DNA break repair is selected from the group consisting of: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase, and tensin homolog (PTEN) and tumor protein 53 gene (TP53).

4. The method of claim 3, wherein mutations are identified in four or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53.

5. The method of claim 4, wherein mutations are identified in AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53.

6. The method of any one of claims 1-5, further comprising determining the presence of a mutation in one or more genes selected from the group consisting of: partner and localizer of BRCA2 (PALB2), cyclin-dependent kinase 12 (CDK12), RAD51 recombinase (RAD51), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Kirsten rat sarcoma virus (KRAS), and neurofibromin 2 (NF2).

7. The method of any one of claims 1-5, further comprising determining the presence of a mutation in three or more genes selected from the group consisting of: PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. #14395076v18. The method of any one of claims 1-7, wherein the dose of particle radiation therapy is a relative biological effectiveness (RBE) dose determined for the tumor in the subject.

9. The method of claim 8, wherein the RBE dose is determined using a linear energy transfer (LET) sensitivity index.

10. The method of claim 9, wherein the LET sensitivity index is based on the presence of at least one mutation in the one or more genes and a weighting factor.

11. The method of claim 10, wherein the weighting factor is a measure of the impact of the mutation in the one or more genes on the sensitivity of the tumor of the subject to LET.

12. The method of claim 11, wherein the weighting factor is determined in cells of a cancer type similar to the cancer of the subject.

13. The method of claim 12, wherein the weighting factor is determined by determining a survival fraction of the cells treated with a single-stranded DNA break repair inhibitor and determining a RBE-adjusted dose of a physical dose of particle therapy in the tumor of the subject based on an RBE of the single-stranded DNA break repair inhibitor in the cells of the similar cancer type.

14. The method of any one of claims 9-13, wherein the determined RBE dose is proportional to the LET sensitivity index.

15. The method of any one of claims 1-14, wherein the RBE dose of particle radiation is a RBE-adjusted dose and is 1.1 to 1.8 times less than a standard dose of photon radiation.

16. The method of any one of claims 1-15, wherein the subject has prostate cancer, Ewing’s sarcoma, chronic lymphocytic leukemia, synovial sarcoma, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, neuroblastoma, acute myeloid leukemia, small cell lung cancer, multiple myeloma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, breast cancer, head and neck cancer, ovarian cancer, lung adenocarcinoma, glioblastoma, bladder cancer, colorectal cancer, and / or pancreatic cancer. #14395076v117. The method of claim 16, wherein the subject has prostate cancer.

18. A method comprising determining the presence of a mutation in one or more genes related to double-stranded DNA break repair in a tumor in a subject, and administering a relative biological effectiveness (RBE) dose of particle radiation therapy to the subject.

19. The method of claim 18, wherein the particle radiation therapy comprises proton therapy, carbon therapy, or helium therapy.

20. The method of any one of claims 18-19, wherein one of the one or more genes related to double-stranded DNA break repair is selected from the group consisting of: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase, and tensin homolog (PTEN) and tumor protein 53 gene (TP53).

21. The method of claim 20, wherein mutations are identified in four or more of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53.

22. The method of claim 21, wherein mutations are identified in AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53.

23. The method of any one of claims 18-22, further comprising determining the presence of a mutation in one or more genes selected from the group consisting of: partner and localizer of BRCA2 (PALB2), cyclin-dependent kinase 12 (CDK12), RAD51 recombinase (RAD51), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Kirsten rat sarcoma virus (KRAS), and neurofibromin 2 (NF2).

24. The method of any one of claims 18-23, further comprising determining the presence of a mutation in three or more genes selected from the group consisting of: PALB2, CDK12, RAD51, PIK3CA, KRAS, and NF2. #14395076v125. The method of any one of claims 18-25, wherein the RBE dose is determined using a linear energy transfer (LET) sensitivity index.

26. The method of claim 25, wherein the LET sensitivity index is based on the presence of at least one mutation in the one or more genes and a weighting factor.

27. The method of claim 26, wherein the weighting factor is a measure of the impact of the mutation in the one or more genes on the sensitivity of the tumor of the subject to LET.

28. The method of claim 26 or claim 27, wherein the weighting factor is determined in cells of a cancer type similar to the cancer of the subject.

29. The method of claim 28, wherein the weighting factor is determined by determining a survival fraction of the cells treated with a single-stranded DNA break repair inhibitor and determining a RBE-adjusted dose of a physical dose of particle therapy in the tumor of the subject based on an RBE of the single-stranded DNA break repair inhibitor in the cells of the similar cancer type.

30. The method of any one of claims 26-29, further comprising determining the total energy transfer sensitivity index (LSI) by adding the weighting factor for each gene related to double- stranded DNA break repair having a mutation.

31. The method of claim 30, further comprising determining the RBE by multiplying the total LSI by the linear energy transfer.

32. The method of claim 31, further comprising determining the RBE-adjusted dose by dividing 1.1 by the RBE.

33. The method of claim 3, wherein mutations are identified at least one of AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53.

34. A method of determining a radiation treatment regimen for a subject, wherein the subject has a tumor, the method comprising: (a) performing a biopsy on the tumor; #14395076v1(b) analyzing the biopsy to determine whether the tumor has at least one mutation in at least one or more genes related to double-stranded DNA break repair selected from the group consisting of: androgen receptor (AR), ataxia-telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), cadherin-1 (CDH1), erythroblast transformation specific variant 1 (ETV1), phosphatase, and tensin homolog (PTEN) and tumor protein 53 gene (TP53); (c) for each gene related to double-stranded DNA break repair having mutation, determining a cancer-specific linear energy transfer sensitivity index (LSI) gene-specific coefficient; (d) determining a total LSI as a function of the LSI coefficients; (e) determining a relative biological effectiveness (RBE) dose based on the total LSI and the linear energy transfer; and (f) determining the radiation treatment regimen for the subject based on the RBE dose.

35. The method of claim 34, wherein if the RBE dose is greater than or equal to 1.1, the subject is administered particle radiation therapy with LET optimization.

36. The method of claim 35, wherein, if the RBE dose is greater than 1.1, the subject is administered particle radiation therapy with LET optimization. #14395076v1

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