The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median = 27) than those with germline ATM or CHEK2 mutations (median = 16.5 [p = 0.029] and 9 [p < 0.001], respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median = 28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs. 11; p = 0.015); this finding was confirmed in the PROGENE cohort (24 vs. 16; p = 0.001). Finally, among eight BRCA2-altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs. 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2-altered cases have significantly higher HRD scores than germline ATM-altered or CHEK2-altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.
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Chung JH, Dewal N, Sokol E, Mathew P, Whitehead R, Millis SZ, et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis Oncol. 2019;3. https://doi.org/10.1200/PO.18.00283.
Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708.
de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382:2091–102.
Abida W, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res. 2020;26:2487–96.
Smith MR, Sandhu SK, Kelly WK, Scher HI, Efstathiou E, Lara P, et al. Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): preliminary results of GALAHAD. J Clin Oncol. 2019;37. https://doi.org/10.1200/JCO.2019.37.7_suppl.202.
Bono JSD, Mehra N, Higano CS, Saad F, Buttigliero C, Mata M, et al. TALAPRO-1: a phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA). J Clin Oncol. 2020;38. https://doi.org/10.1200/JCO.2020.38.6_suppl.119.
Abida W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38:3763–72.
Marshall CH, Sokolova AO, McNatty AL, Cheng HH, Eisenberger MA, Bryce AH, et al. Differential response to olaparib treatment among men with metastatic castration-resistant prostate cancer harboring BRCA1 or BRCA2 versus ATM mutations. Eur Urol. 2019;76:452–8.
Antonarakis ES, Wang H, Teply BA, Kelly WK, Willms J, Sullivan R, et al. Interim results from a phase 2 study of olaparib (without ADT) in men with biochemically-recurrent prostate cancer after prostatectomy, with integrated biomarker analysis. J Clin Oncol. 2019;37. https://doi.org/10.1200/JCO.2019.37.15_suppl.5045.
Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res. 2016;22:3764–73.
Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443–53.
Nicolosi P, Ledet E, Yang S, Michalski S, Freschi B, O’Leary E, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5:523–8.
Marshall CH, Antonarakis ES. Therapeutic targeting of the DNA damage response in prostate cancer. Curr Opin Oncol. 2020;32:216–22.
Na R, Zheng SL, Han M, Yu H, Jiang D, Shah S, et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur Urol. 2017;71:740–7.
Velho PI, Lim D, Wang H, Park JC, Kaur HB, Almutairi F, et al. Molecular characterization and clinical outcomes of primary gleason pattern 5 prostate cancer after radical prostatectomy. JCO Precis Oncol. 2019;3. https://doi.org/10.1200/PO.19.00081.
Kaur H, Salles DC, Murali S, Hicks JL, Nguyen M, Pritchard CC, et al. Genomic and clinical-pathologic characterization of ATM-deficient prostate cancer. Clin Cancer Res. 2020;26:4869–81.
Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.
Leon P, Cancel-Tassin G, Drouin S, Audouin M, Varinot J, Comperat E, et al. Comparison of cell cycle progression score with two immunohistochemical markers (PTEN and Ki-67) for predicting outcome in prostate cancer after radical prostatectomy. World J Urol. 2018;36:1495–500.
Stronach EA, Paul J, Timms KM, Hughes E, Brown K, Neff C, et al. Biomarker assessment of HR deficiency, tumor BRCA1/2 mutations, and CCNE1 copy number in ovarian cancer: associations with clinical outcome following platinum monotherapy. Mol Cancer Res. 2018;16:1103–11.
Patel JN, Braicu I, Timms KM, Solimeno C, Tshiaba P, Reid J, et al. Characterisation of homologous recombination deficiency in paired primary and recurrent high-grade serous ovarian cancer. Br J Cancer. 2018;119:1060–6.
Timms KM, Abkevich V, Hughes E, Neff C, Reid J, Morris B, et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 2014;16:475–83.
Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19:4–23.
Morais CL, Herawi M, Toubaji A, Albadine R, Hicks J, Netto GJ, et al. PTEN loss and ERG protein expression are infrequent in prostatic ductal adenocarcinomas and concurrent acinar carcinomas. Prostate. 2015;75:1610–9.
Chaux A, Albadine R, Toubaji A, Hicks J, Meeker A, Platz EA, et al. Immunohistochemistry for ERG expression as a surrogate for TMPRSS2-ERG fusion detection in prostatic adenocarcinomas. Am J Surg Pathol. 2011;35:1014–20.
Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MD, Wendl MC, et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun. 2014;5:3156.
Guedes LB, Antonarakis ES, Schweizer MT, Mirkheshti N, Almutairi F, Park JC, et al. MSH2 loss in primary prostate cancer. Clin Cancer Res. 2017;23:6863–74.
Lalonde E, Ishkanian AS, Sykes J, Fraser M, Ross-Adams H, Erho N, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 2014;15:1521–32.
Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011;19:664–78.
Hussain M, Daignault-Newton S, Twardowski PW, Albany C, Stein MN, Kunju LP, et al. Targeting androgen receptor and DNA repair in metastatic castration-resistant prostate cancer: results from NCI 9012. J Clin Oncol. 2018;36:991–9.
Spratt DE, Alshalalfa M, Fishbane N, Weiner AB, Mehra R, Mahal BA, et al. Transcriptomic heterogeneity of androgen receptor activity defines a de novo low AR-active subclass in treatment naive primary prostate cancer. Clin Cancer Res. 2019;25:6721–30.
Jonsson P, Bandlamudi C, Cheng ML, Srinivasan P, Chavan SS, Friedman ND, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571:576–9.
Polak P, Kim J, Braunstein LZ, Karlic R, Haradhavala NJ, Tiao G, et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet. 2017;49:1476–86.
Hughley R, Karlic R, Joshi H, Turnbull C, Foulkes WD, Polak P. Etiologic index: a case-only measure of BRCA1/2-associated cancer risk. N Engl J Med. 2020;383:286–8.
Poti A, Gyergyak H, Nemeth E, Rusz O, Toth S, Kovacshazi C, et al. Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents. Genome Biol. 2019;20:240–52.
Sztupinszki Z, Diossy M, Krzystanek M, Borcsok J, Pomerantz MM, Tisza V, et al. Detection of molecular signatures of homologous recombination deficiency in prostate cancer with or without BRCA1/2 mutations. Clin Cancer Res. 2020;26:2673–80.
Galbiati A, Beausejour C, d’Adda, di Fagagna F. A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues. Aging Cell. 2017;16:422–7.
Guidugli L, Carreira A, Caputo SM, Ehlen A, Galli A, Monteiro AN, et al. Functional assays for analysis of variants of uncertain significance in BRCA2. Hum Mutat. 2014;35:151–64.
Pomerantz MM, Spisak S, Jia L, Cronin AM, Csabai I, Ledet E, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer. 2017;123:3532–9.
Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, et al. Genomic hallmarks and structural variation in metastatic prostate. Cancer Cell. 2018;174:758–69.
Lheureux S, Lai Z, Dougherty BA, Runswick S, Hodgson DR, Timms KM, et al. Long-term responders on olaparib maintenance in high-grade serous ovarian cancer: clinical and molecular characterization. Clin Cancer Res. 2017;23:4086–94.
Markowski MC, Antonarakis ES. BRCA1 versus BRCA2 and PARP inhibitor sensitivity in prostate cancer: more different than alike? J Clin Oncol. 2020;38:3735–9.
Weigelt B, Bi R, Kumar R, Blecua P, Mandelker DL, Geyer FC, et al. The landscape of somatic genetic alterations in breast cancers from ATM germline mutation carriers. J Natl Cancer Inst. 2018;110:1030–4.
Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11:220–8.
Greiner TC, Dasgupta C, Ho VV, Weisenburger DD, Smith LM, Lynch JC, et al. Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. Proc Natl Acad Sci USA. 2006;103:2352–7.
Pettitt AR, Sherrington PD, Stewart G, Cawley JC, Taylor AM, Stankovic T. p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation. Blood. 2001;98:814–22.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.
Markowski MC, Antonarakis ES. PARP inhibitors in prostate cancer: time to narrow patient selection? Expert Rev Anticancer Ther. 2020;20:523–6.
This work was supported by the Patrick C. Walsh Prostate Cancer Research Fund (ESA, TLL), the Prostate Cancer Foundation (ESA), NIH/NCI Prostate SPORE P50 CA58236; and the NCI Cancer Center Support Grant 5P30 CA006973-52. ALR is supported by a grant from the Breast Cancer Research Foundation.
Conflict of interest
TLL has received research support from Roche/Ventana Medical Systems and DeepBio for other studies. ESA has served as a paid consultant/advisor for Janssen, Pfizer, Sanofi, Dendreon, Merck, Bristol-Myers Squibb, AstraZeneca, Clovis, Eli Lilly and Amgen; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Merck, Bristol-Myers Squibb, AstraZeneca, and Constellation; and is a co-inventor of an AR-V7 biomarker technology that has been licensed to Qiagen. JSL and KMT are employees and shareholders in Myriad Genetics. RB has received research support from Myriad Genetics and AstraZeneca.
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Lotan, T.L., Kaur, H.B., Salles, D.C. et al. Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer. Mod Pathol (2021). https://doi.org/10.1038/s41379-020-00731-4