Methods for predicting anti-cancer response

Abstract

The present invention is based, in part, on the identification of novel methods for defining predictive biomarkers of response to anti-cancer drugs.

What is claimed is: 
     
         1 . An assay for selecting therapy for a subject having cancer, the assay comprising
 subjecting a biological sample comprising a cancer cell or nucleic acid from a cancer cell taken from the subject to telomeric allelic imbalance (tAI) analysis;   detecting the number of telomeric allelic imbalance (NtAI) in the cancer cell or nucleic acid from the cancer cell, and   selecting a platinum-comprising therapy for the subject when the NtAI is detected to be above a reference value based on the recognition that platinum-comprising therapy is effective in patients who have NtAI above the reference value; and selecting a non-platinum-comprising cancer therapy for the subject when the NtAI is detected to be below a reference value based on the recognition that platinum-comprising cancer therapy is not effective in patients who have the NtAI below a reference value.   
     
     
         2 . The assay of  claim 1  further comprising the step of treating the subject with the selected therapy. 
     
     
         3 . The assay of  claim 1 , wherein the cancer is breast cancer or ovarian cancer. 
     
     
         4 . The assay of  claim 1 , wherein the reference value is 22. 
     
     
         5 . The assay of  claim 1 , wherein the reference value is 24. 
     
     
         6 . The assay of  claim 1 , wherein the reference value is 27. 
     
     
         7 . The assay of  claim 1 , wherein the cancer cell does not have mutations in the BRCA1 and/or BRCA2 gene. 
     
     
         8 . The assay of  claim 1  further comprising a step of assaying for BRCA1 mRNA expression or methylation status of the BRCA1 promoter, detecting the amount of BRCA1 mRNA expression or the amount of methylation of the BRCA1 promoter, wherein the platinum comprising therapy is selected when decreased expression of BRCA1 or increased methylation of BRCA1 promoter is detected. 
     
     
         9 . A method for selecting platinum-comprising therapy for a subject having cancer comprising
 subjecting a biological sample taken from the subject to allelic imbalance (AI) analysis;   detecting the number of AI; and   selecting platinum-comprising cancer therapy for the subject when the number of AIs is above a reference value based on the recognition that platinum-comprising cancer therapy is effective in patients who have the number of AIs is above a reference value.   
     
     
         10 . The method of  claim 9  further comprising the step of treating the subject with platinum-comprising cancer therapy when platinum-comprising cancer therapy is selected. 
     
     
         11 . The method of  claim 9 , wherein the cancer is selected from breast cancer and ovarian cancer. 
     
     
         12 . The method of  claim 11 , wherein the breast cancer does not have a BRCA1 mutations. 
     
     
         13 . The method of  claim 9 , wherein the allelic imbalance is within about 25 kB of a copy number variation (CNV). 
     
     
         14 . The method of  claim 13 , wherein the CNV is pericentromeric or subtelomeric CNV. 
     
     
         15 . The method of  claim 9 , wherein the allelic imbalance is telomeric allelic imbalance. 
     
     
         16 . A method comprising:
 detecting, in a cancer cell or genomic DNA derived therefrom, allelic imbalance in a representative number of pairs of human chromosomes of the cancer cell; and   determining the number of allelic imbalance.   
     
     
         17 . The method of  claim 16 , said representative number of pairs of human chromosomes is representative of the entire genome. 
     
     
         18 . The method of  claim 16 , further comprising correlating an increased number of allelic imbalance regions to an increased likelihood of deficiency in HDR. 
     
     
         19 . The method of  claim 16 , further comprising correlating an increased number of allelic imbalance regions to an increased likelihood of said cancer cell to respond to platinum comprising cancer therapy. 
     
     
         20 . The method of  claim 16 , further comprising correlating a non-increased number of allelic imbalance regions to a decreased likelihood of said cancer cell to respond to platinum comprising cancer therapy. 
     
     
         21 . The method of  claim 19  or  20 , wherein the platinum comprising cancer therapy comprises cisplatin, carboplatin, oxalaplatin, or picoplatin. 
     
     
         22 . A method comprising:
 a) detecting, in a cancer cell or genomic DNA derived therefrom, LOH regions in a representative number of pairs of human chromosomes of the cancer cell; and   b) determining the number and size of said LOH regions.   
     
     
         23 . The method of  claim 22 , said representative number of pairs of human chromosomes is representative of the entire genome. 
     
     
         24 . The method of  claim 22 , further comprising correlating an increased number of LOH regions of a particular size to an increased likelihood of deficiency in HDR. 
     
     
         25 . The method of  claim 24 , wherein said particular size is longer than about 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 75, or 100 megabases and less than the length of the entire chromosome that contains the LOH region. 
     
     
         26 . The method of either of  claim 24  or  25 , wherein 6, 7, 8, 9, 10, 11, 12 or 13 or more LOH regions of said particular size are correlated to an increased likelihood of deficiency in HDR. 
     
     
         27 . A method of determining prognosis in a patient comprising:
 a) determining whether the patient comprises cancer cells having an LOH signature, wherein the presence of more than a reference number of LOH regions in at least one pair of human chromosomes of a cancer cell of the cancer patient that are longer than a first length but shorter than the length of the whole chromosome containing the LOH region indicates that the cancer cells have the LOH signature, wherein the at least one pair of human chromosomes is not a human X/Y sex chromosome pair, wherein the first length is about 1.5 or more megabases, an   b) (1) determining, based at least in part on the presence of the LOH signature, that the patient has a relatively good prognosis, or b)(2) determining, based at least in part on the absence of the LOH signature, that the patient has a relatively poor prognosis   
     
     
         28 . A composition comprising a therapeutic agent selected from the group consisting of DNA damaging agent, anthracycline, topoisomerase I inhibitor, and PARP inhibitor for use in treating a cancer selected from the group consisting of breast cancer, ovarian cancer, liver cancer, esophageal cancer, lung cancer, head and neck cancer, prostate cancer, colon cancer, rectal cancer, colorectal cancer, and pancreatic cancer in a patient with more than a reference number of LOH regions in at least one pair of human chromosomes of a cancer cell of the patient that are longer than a first length but shorter than the length of the whole chromosome containing the LOH region, wherein the at least one pair of human chromosomes is not a human X/Y sex chromosome pair, wherein the first length is about 1.5 or more megabases. 
     
     
         29 . The composition of  claim 28 , wherein said LOH regions are determined in at least two, five, ten or 21 pairs of human chromosomes. 
     
     
         30 . The composition of  claim 28 , wherein the total number of said LOH regions is 9, 15, 20 or more. 
     
     
         31 . The composition of  claim 28 , wherein said first length is about 6, 12, or 15 or more megabases. 
     
     
         32 . The composition of  claim 28 , wherein said reference number is 6, 7, 8, 9, 10, 11, 12 or 13 or greater. 
     
     
         33 . A method of treating cancer in a patient, comprising:
 a) determining in a sample from said patient the number of LOH regions in at least one pair of human chromosomes of a cancer cell of the cancer patient that are longer than a first length but shorter than the length of the whole chromosome containing the LOH region indicates that the cancer cells have the LOH signature, wherein the at least one pair of human chromosomes is not a human X/Y sex chromosome pair, wherein the first length is about 1.5 or more megabases;   b) providing a test value derived from the number of said LOH regions;   c) comparing said test value to one or more reference values derived from the number of said LOH regions in a reference population (e.g., mean, median, terciles, quartiles, quintiles, etc.); and   d) administering to said patient an anti-cancer drug, or recommending or prescribing or initiating a treatment regimen comprising chemotherapy and/or a synthetic lethality agent based at least in part on said comparing step revealing that the test value is greater (e.g., at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-fold greater; at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 standard deviations greater) than at least one said reference value; or   e) recommending or prescribing or initiating a treatment regimen not comprising chemotherapy and/or a synthetic lethality agent based at least in part on said comparing step revealing that the test value is not greater (e.g., not more than 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-fold greater; not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 standard deviations greater) than at least one said reference value.   
     
     
         34 . The method of  claim 33 , wherein said LOH regions are determined in at least two, five, ten or 21 pairs of human chromosomes. 
     
     
         35 . The method of  claim 33 , wherein the total number of said LOH regions is 9, 15, 20 or more. 
     
     
         36 . The method of  claim 33 , wherein said first length is about 6, 12, or 15 or more megabases. 
     
     
         37 . The method of  claim 33 , wherein said reference number is 6, 7, 8, 9, 10, 11, 12 or 13 or greater. 
     
     
         38 . The method of  claim 33 , wherein said chemotherapy is selected from the group consisting of a DNA damaging agent, an anthracycline, and a topoisomerase I inhibitor and/or wherein said synthetic lethality agent is a PARP inhibitor drug. 
     
     
         39 . The method of  claim 33 , wherein said DNA damaging agent is cisplatin, carboplatin, oxalaplatin, or picoplatin, said anthracycline is epirubincin or doxorubicin, said topoisomerase I inhibitor is campothecin, topotecan, or irinotecan, and/or said PARP inhibitor is iniparib, olaparib or velapirib. 
     
     
         40 . A composition comprising a therapeutic agent selected from the group consisting of platinum comprising cancer therapy and anthracycline for use in treating a cancer selected from the group consisting of breast cancer, ovarian cancer, liver cancer, esophageal cancer, lung cancer, head and neck cancer, prostate cancer, colon cancer, rectal cancer, colorectal cancer, and pancreatic cancer in a patient with increased allelic imbalance. 
     
     
         41 . The composition of  claim 40 , wherein the allelic imbalance is telomeric allelic imbalance. 
     
     
         42 . The composition of  claim 40 , wherein the allelic imbalance is within about 25 kB of a copy number variation (CNV). 
     
     
         43 . The composition of  claim 40 , wherein the patient is further determined not to carry a BRCA1 and/or BRCA2 mutation. 
     
     
         44 . The composition of  claim 40  or  43 , wherein the patient is further determined to have decreased BRCA1 mRNA amount in the cancer cell and/or is further determined to have increased methylation of the BRCA1 promoter region. 
     
     
         45 . A method for predicting the outcome of anti-cancer treatment of a subject with a cell hyperproliferative disorder, comprising determining a global chromosomal aberration score (GCAS), comprising obtaining a biological sample from the subject and determining whether a plurality of chromosomal regions displaying a chromosomal aberration exists within a plurality of chromosomal loci, wherein said chromosomal aberrations are selected from the group consisting of allelic imbalance (NAI), loss of heterozygosity (NLOH), copy number aberrations (NCNA), copy number gain (NCNG), copy number decrease (NCND) and combinations thereof, relative to a control, and wherein the presence of a plurality of chromosomal regions displaying said chromosomal aberrations predicts the outcome of anti-cancer treatment of the subject. 
     
     
         46 . The method of  claim 45 , wherein the anti-cancer treatment is chemotherapy treatment. 
     
     
         47 . The method of  claim 46 , wherein the chemotherapy treatment comprises platinum-based chemotherapeutic agents. 
     
     
         48 . The method of  claim 47 , wherein the platinum-based chemotherapeutic agents are selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, and iproplatin. 
     
     
         49 . The method of  claim 45 , wherein the subject is a human. 
     
     
         50 . The method of  claim 45 , wherein the cell hyperproliferative disorder is selected from the group consisting of breast cancer, ovarian cancer, transitional cell bladder cancer, bronchogenic lung cancer, thyroid cancer, pancreatic cancer, prostate cancer, uterine cancer, testicular cancer, gastric cancer, soft tissue and osteogenic sarcomas, neuroblastoma, Wilms' tumor, malignant lymphoma (Hodgkin's and non-Hodgkin's), acute myeloblastic leukemia, acute lymphoblastic leukemia, Kaposi's sarcoma, Ewing's tumor, refractory multiple myeloma, and squamous cell carcinomas of the head, neck, cervix, colon cancer, melanoma, and vagina. 
     
     
         51 . The method of  claim 45 , wherein the biological sample is selected from the group consisting of cells, cell lines, histological slides, frozen core biopsies, paraffin embedded tissues, formalin fixed tissues, biopsies, whole blood, nipple aspirate, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, and bone marrow. 
     
     
         52 . The method of  claim 45 , wherein the biological sample is enriched for the presence of hyperproliferative cells to at least 75% of the total population of cells. 
     
     
         53 . The method of  claim 52 , wherein the enrichment is performed according to at least one technique selected from the group consisting of needle microdissection, laser microdissection, fluorescence activated cell sorting, and immunological cell sorting. 
     
     
         54 . The method of  claim 52  or  53 , wherein an automated machine performs the at least one technique to thereby transform the biological sample into a purified form enriched for the presence of hyperproliferative cells. 
     
     
         55 . The method of  claim 45 , wherein the biological sample is obtained before the subject has received adjuvant chemotherapy. 
     
     
         56 . The method of  claim 45 , wherein the biological sample is obtained after the subject has received adjuvant chemotherapy. 
     
     
         57 . The method of  claim 45 , wherein the control is determined from a non-cell hyperproliferative cell sample from the patient or member of the same species to which the patient belongs. 
     
     
         58 . The method of  claim 45 , wherein the control is determined from the average frequency of genomic locus appearance of chromosomal regions of the same ethnic group within the species to which the patient belongs. 
     
     
         59 . The method of  claim 57  or  58 , wherein the control is from non-cancerous tissue that is the same tissue type as said cancerous tissue of the subject. 
     
     
         60 . The method of  claim 57  or  58 , wherein the control is from non-cancerous tissue that is not the same tissue type as said cancerous tissue of the subject. 
     
     
         61 . The method of  claim 45 , wherein NAI is determined using major copy proportion (MCP). 
     
     
         62 . The method of  claim 61 , wherein NAI for a given genomic region is counted when MCP is greater than 0.70. 
     
     
         63 . The method of  claim 45 , wherein the plurality of chromosomal loci are randomly distributed throughout the genome at least every 100 Kb of DNA. 
     
     
         64 . The method of  claim 45 , wherein the plurality of chromosomal loci comprise at least one chromosomal locus on each of the 23 human chromosome pairs. 
     
     
         65 . The method of  claim 45 , wherein the plurality of chromosomal loci comprise at least one chromosomal locus on each arm of each of the 23 human chromosome pairs. 
     
     
         66 . The method of  claim 65 , wherein the plurality of chromosomal loci comprise at least one chromosomal locus on at least one telomere of each of the 23 human chromosome pairs. 
     
     
         67 . The method of  claim 66 , wherein the plurality of chromosomal loci comprise at least one chromosomal locus on each telomere of each of the 23 human chromosome pairs. 
     
     
         68 . The method of  claim 45  or  67 , wherein the chromosomal aberrations have a minimum segment size of at least 1 Mb. 
     
     
         69 . The method of  claim 68 , wherein the chromosomal aberrations have a minimum segment size of at least 12 Mb. 
     
     
         70 . The method of  claim 45 , wherein the plurality of chromosomal aberrations comprises at least 5 chromosomal aberrations. 
     
     
         71 . The method of  claim 70 , wherein the plurality of chromosomal aberrations comprises at least 13 chromosomal aberrations. 
     
     
         72 . The method of  claim 45 , wherein the chromosomal loci are selected from the group consisting of single nucleotide polymorphisms (SNPs), restriction fragment length polymorphisms (RFLPs), and simple tandem repeats (STRs). 
     
     
         73 . The method of  claim 45 , wherein the chromosomal loci are analyzed using at least one technique selected from the group consisting of molecular inversion probe (MIP), single nucleotide polymorphism (SNP) array, in situ hybridization, Southern blotting, transcriptional arrays, array comparative genomic hybridization (aCGH), and next-generation sequencing. 
     
     
         74 . The method of  claim 45 , wherein outcome of treatment is measured by at least one criteria selected from the group consisting of survival until mortality, pathological complete response, semi-quantitative measures of pathologic response, clinical complete remission, clinical partial remission, clinical stable disease, recurrence-free survival, metastasis free survival, disease free survival, circulating tumor cell decrease, circulating marker response, and RECIST criteria. 
     
     
         75 . The method of  claim 45 , further comprising determining a suitable treatment regimen for the subject. 
     
     
         76 . The method of  claim 75 , wherein said suitable treatment regimen comprises at least one platinum-based chemotherapeutic agent when a plurality of genomic chromosomal aberrations is determined or does not comprise at least one platinum-based chemotherapeutic agent when no plurality of genomic chromosomal aberrations is determined.