The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

Lord, 2012, The DNA damage response and cancer therapy, Nature, 481, 287, 10.1038/nature10760 Helleday, 2008, DNA repair pathways as targets for cancer therapy, Nat Rev Cancer, 8, 193, 10.1038/nrc2342 Zhang, 2016, Integrated proteogenomic characterization of human high-grade serous ovarian cancer, Cell, 166, 755, 10.1016/j.cell.2016.05.069 Watkins, 2014, Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers, Breast Cancer Res, 16, 211, 10.1186/bcr3670 Weaver, 2013, Beyond DNA repair: additional functions of PARP-1 in cancer, Front Oncol, 3, 290, 10.3389/fonc.2013.00290 Robson, 2019, OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer, Ann Oncol, 30, 558, 10.1093/annonc/mdz012 Gonzalez-Martin, 2019, Niraparib in patients with newly diagnosed advanced ovarian cancer, N Engl J Med, 381, 2391, 10.1056/NEJMoa1910962 de Bono, 2020, Olaparib for metastatic castration-resistant prostate cancer, N Engl J Med, 382, 2091, 10.1056/NEJMoa1911440 Coleman, 2019, Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer, N Engl J Med, 381, 2403, 10.1056/NEJMoa1909707 Domchek, 2016, Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy, Gynecol Oncol, 140, 199, 10.1016/j.ygyno.2015.12.020 Kristeleit, 2017, A phase I-II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors, Clin Cancer Res, 23, 4095, 10.1158/1078-0432.CCR-16-2796 Ledermann, 2019, Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer, Ther Adv Med Oncol, 11, 10.1177/1758835919849753 Del Campo, 2019, Niraparib maintenance therapy in patients with recurrent ovarian cancer after a partial response to the last platinum-based chemotherapy in the ENGOT-OV16/NOVA trial, J Clin Oncol, 37, 2968, 10.1200/JCO.18.02238 Coleman, 2017, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet, 390, 1949, 10.1016/S0140-6736(17)32440-6 Banerjee, 2020, 811MO – maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1, Ann Oncol, 31, S551 Oaknin, 2019, 4350 – Time to second progression (PFS2) and second subsequent therapy (TSST) for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) treated with maintenance (mt) olaparib (ola) – Phase III SOLO1 trial, Ann Oncol, 30, v403 Ray-Coquard, 2019, Olaparib plus bevacizumab as first-line maintenance in ovarian cancer, N Engl J Med, 381, 2416, 10.1056/NEJMoa1911361 Ledermann, 2016, Homologous recombination deficiency and ovarian cancer, Eur J Cancer, 60, 49, 10.1016/j.ejca.2016.03.005 Lin, 2019, BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma, Cancer Discov, 9, 210, 10.1158/2159-8290.CD-18-0715 Konstantinopoulos, 2020, Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline, J Clin Oncol, 38, 1222, 10.1200/JCO.19.02960 Dougherty, 2017, Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting, Oncotarget, 8, 43653, 10.18632/oncotarget.17613 Mohyuddin, 2020, Similar response rates and survival with PARP inhibitors for patients with solid tumors harboring somatic versus germline BRCA mutations: a meta-analysis and systematic review, BMC Cancer, 20, 507, 10.1186/s12885-020-06948-5 Swisher, 2017, Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial, Lancet Oncol, 18, 75, 10.1016/S1470-2045(16)30559-9 Loveday, 2011, Germline mutations in RAD51D confer susceptibility to ovarian cancer, Nat Genet, 43, 879, 10.1038/ng.893 Pennington, 2014, Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas, Clin Cancer Res, 20, 764, 10.1158/1078-0432.CCR-13-2287 Takaya, 2020, Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma, Sci Rep, 10, 2757, 10.1038/s41598-020-59671-3 Ngoi, 2018, Reversal of bowel obstruction with platinum-based chemotherapy and olaparib in recurrent, platinum-free interval, RAD51C germline mutation–associated ovarian cancer, JCO Precision Oncology, 2, 1, 10.1200/PO.18.00008 McNeish, 2015, Results of ARIEL2: a phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis, J Clin Oncol, 33, 5508, 10.1200/jco.2015.33.15_suppl.5508 Swisher, 2020, Characterization of patients (pts) with long-term responses to rucaparib in recurrent ovarian cancer (OC), J Clin Oncol, 38, 6015, 10.1200/JCO.2020.38.15_suppl.6015 Hodgson, 2018, Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes, Br J Cancer, 119, 1401, 10.1038/s41416-018-0274-8 Moschetta, 2016, BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer, Ann Oncol, 27, 1449, 10.1093/annonc/mdw142 Konstantinopoulos, 2015, Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer, Cancer Discov, 5, 1137, 10.1158/2159-8290.CD-15-0714 Abkevich, 2012, Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer, Br J Cancer, 107, 1776, 10.1038/bjc.2012.451 George, 2013, Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations, Clin Cancer Res, 19, 3474, 10.1158/1078-0432.CCR-13-0066 Bernards, 2018, Clinical characteristics and outcomes of patients with BRCA1 or RAD51C methylated versus mutated ovarian carcinoma, Gynecol Oncol, 148, 281, 10.1016/j.ygyno.2017.12.004 Ruscito, 2014, BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients – a study of the tumour bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD), Eur J Cancer, 50, 2090, 10.1016/j.ejca.2014.05.001 Esteller, 2000, Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors, J Natl Cancer Inst, 92, 564, 10.1093/jnci/92.7.564 Sun, 2017, Genetic versus epigenetic BRCA1 silencing pathways: clinical effects in primary ovarian cancer patients: a study of the tumor bank ovarian cancer consortium, Int J Gynecol Cancer, 27, 1658, 10.1097/IGC.0000000000001071 Zhu, 2018, The BRCA1 methylation and PD-L1 expression in sporadic ovarian cancer, Int J Gynecol Cancer, 28, 1514, 10.1097/IGC.0000000000001334 Kondrashova, 2017, Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma, Cancer Discov, 7, 984, 10.1158/2159-8290.CD-17-0419 Patch, 2015, Whole-genome characterization of chemoresistant ovarian cancer, Nature, 521, 489, 10.1038/nature14410 Prieske, 2017, Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer, Oncotarget, 8, 83063, 10.18632/oncotarget.20945 Sakai, 2008, Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers, Nature, 451, 1116, 10.1038/nature06633 Timms, 2014, Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes, Breast Cancer Res, 16, 475, 10.1186/s13058-014-0475-x Birkbak, 2012, Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents, Cancer Discov, 2, 366, 10.1158/2159-8290.CD-11-0206 Popova, 2012, Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation, Cancer Res, 72, 5454, 10.1158/0008-5472.CAN-12-1470 Mills, 2016, Homologous recombination deficiency score shows superior association with outcome compared with its individual score components in platinum-treated serous ovarian cancer, Gynecol Oncol, 141, 2, 10.1016/j.ygyno.2016.04.034 Telli, 2016, Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer, Clin Cancer Res, 22, 3764, 10.1158/1078-0432.CCR-15-2477 2011, Integrated genomic analyses of ovarian carcinoma, Nature, 474, 609, 10.1038/nature10166 Moore, 2019, Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial, Lancet Oncol, 20, 636, 10.1016/S1470-2045(19)30029-4 Alexandrov, 2013, Signatures of mutational processes in human cancer, Nature, 500, 415, 10.1038/nature12477 Polak, 2017, A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer, Nat Genet, 49, 1476, 10.1038/ng.3934 Hillman, 2018, Genomic rearrangement signatures and clinical outcomes in high-grade serous ovarian cancer, J Natl Cancer Inst, 110, 265, 10.1093/jnci/djx176 Gulhan, 2019, Detecting the mutational signature of homologous recombination deficiency in clinical samples, Nat Genet, 51, 912, 10.1038/s41588-019-0390-2 Davies, 2017, HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures, Nat Med, 23, 517, 10.1038/nm.4292 Mukhopadhyay, 2010, Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors, Clin Cancer Res, 16, 2344, 10.1158/1078-0432.CCR-09-2758 Fuh, 2020, Homologous recombination deficiency real-time clinical assays, ready or not?, Gynecol Oncol, 159, 877, 10.1016/j.ygyno.2020.08.035 van Wijk, 2020, The RECAP test rapidly and reliably identifies homologous recombination-deficient ovarian carcinomas, Cancers (Basel), 12, 2805, 10.3390/cancers12102805 Tumiati, 2018, A functional homologous recombination assay predicts primary chemotherapy response and long-term survival in ovarian cancer patients, Clin Cancer Res, 24, 4482, 10.1158/1078-0432.CCR-17-3770 Naipal, 2014, Functional ex vivo assay to select homologous recombination-deficient breast tumors for PARP inhibitor treatment, Clin Cancer Res, 20, 4816, 10.1158/1078-0432.CCR-14-0571 Waks, 2020, Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer, Ann Oncol, 31, 590, 10.1016/j.annonc.2020.02.008 Timms, 2020, Comparison of genomic instability test scores used for predicting PARP activity in ovarian cancer, J Clin Oncol, 38, 1586, 10.1200/JCO.2020.38.15_suppl.1586 Matulonis, 2019, Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study, Ann Oncol, 30, 1080, 10.1093/annonc/mdz135 Cohen, 2019, Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: a systematic review and meta-analysis of individual patient data, Gynecol Oncol, 154, 441, 10.1016/j.ygyno.2019.04.679 Oza, 2015, Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial, Lancet Oncol, 16, 928, 10.1016/S1470-2045(15)00086-8 Calléns, 2020, Concordance between tumor and germline BRCA status in high-grade ovarian carcinoma patients in the phase III PAOLA-1/ENGOT-ov25 trial, J Natl Cancer Inst Courtney, 2019, Impact of free cancer predisposition cascade genetic testing on uptake in Singapore, NPJ Genom Med, 4, 22, 10.1038/s41525-019-0096-5 Yoon, 2011, Genetic counseling for patients and families with hereditary breast and ovarian cancer in a developing Asian country: an observational descriptive study, Fam Cancer, 10, 199, 10.1007/s10689-011-9420-7 Cheung, 2010, Communication of BRCA results and family testing in 1103 high-risk women, Cancer Epidemiol Biomarkers Prev, 19, 2211, 10.1158/1055-9965.EPI-10-0325 Stover, 2020, Clinical assays for assessment of homologous recombination DNA repair deficiency, Gynecol Oncol, 159, 887, 10.1016/j.ygyno.2020.09.029 Pilié, 2019, State-of-the-art strategies for targeting the DNA damage response in cancer, Nat Rev Clin Oncol, 16, 81, 10.1038/s41571-018-0114-z Norquist, 2011, Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas, J Clin Oncol, 29, 3008, 10.1200/JCO.2010.34.2980 Swisher, 2008, Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance, Cancer Res, 68, 2581, 10.1158/0008-5472.CAN-08-0088 Drost, 2016, BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1, J Clin Invest, 126, 2903, 10.1172/JCI70196 Mirza, 2020, The forefront of ovarian cancer therapy: update on PARP inhibitors, Ann Oncol, 31, 1148, 10.1016/j.annonc.2020.06.004 Ngoi, 2020, Exploiting replicative stress in gynecological cancers as a therapeutic strategy, Int J Gynecol Cancer, 30, 1224, 10.1136/ijgc-2020-001277 Farkkila, 2020, Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer, Nat Commun, 11, 1459, 10.1038/s41467-020-15315-8