BRCA-guided therapy of ovarian cancer

Advanced (FIGO stages III and IV) epithelial ovarian cancer (aEOC) accounts for the majority of deaths from gynecological cancers in western countries. Although the prognosis of this disease has been considerably improved in the last two decades, the majority of women will still die from progression of EOC. Optimal cytoreductive surgery and cytotoxic chemotherapy remains the mainstay of treatment in the front-line setting. Approximately 18% of EOCs harbor germline mutations of the tumor suppressor genes Breast Cancer Susceptibility Gene 1 (BRCA1) and 2 (BRCA2), while another 3–6% of these tumors have somatic mutations of these genes. These mutations lead to increased predisposition of multiple cancers. In addition, BRCA1 and BRCA2 genes encode proteins that are implicated in the Homologous Recombination (HR) mechanism, which is responsible for the repair of DNA Double Strand Breaks (DSBs), which is a common mechanism of action of chemotherapy. The incorporation of BRCA-targeted therapies, such as poly ADP ribose polymerase (PARP) inhibitors in the treatment algorithm of advanced EOC has further improved outcomes and represents a successful strategy of individualization of treatment in EOC. In this review, we summarize current treatment recommendations for patients with EOC and a BRCA1/2 mutation.

BRCA; Ovarian cancer; PARP inhibitors

[1] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015; 136: E359–E386.

[2] Rosen DG, Yang G, Liu G, Mercado-Uribe I, Chang B, Xiao XS, et al. Ovarian cancer: pathology, biology, and disease models. Frontiers in Bioscience. 2009; 14: 2089–2102.

[3] Gadducci A, Guarneri V, Peccatori FA, Ronzino G, Scandurra G, Zamagni C, et al. Current strategies for the targeted treatment of high-grade serous epithelial ovarian cancer and relevance of BRCA mutational status. Journal of Ovarian Research. 2019; 12: 9.

[4] Terada KY, Ahn HJ, Kessel B. Differences in risk for type 1 and type 2 ovarian cancer in a large cancer screening trial. Journal of Gynecologic Oncology. 2016; 27: e25.

[5] Kossaï M, Leary A, Scoazec J, Genestie C. Ovarian cancer: a heterogeneous disease. Pathobiology. 2018; 85: 41–49.

[6] Norquist BM, Brady MF, Harrell MI, Walsh T, Lee MK, Gulsuner S, et al. Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG oncology/gynecologic oncology group study. Clinical Cancer Research. 2018; 24: 777–783.

[7] Caldecott KW. Single-strand break repair and genetic disease. Nature Reviews Genetics. 2008; 9: 619–631.

[8] Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017; 355: 1152–1158.

[9] Konstantinopoulos PA, Lheureux S, Moore KN. PARP inhibitors for ovarian cancer: current indications, future combinations, and novel assets in development to target DNA damage repair. American Society of Clinical Oncology Educational Book. 2020; 24: e116–e131.

[10] Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2- mutated and sporadic ovarian cancer: current practice and future directions. British Journal of Cancer. 2016; 115: 1157–1173.

[11] Milanesio MC, Giordano S, Valabrega G. Clinical implications of DNA repair defects in high-grade serous ovarian carcinomas. Cancers. 2020; 12: 1315.

[12] Gorodetska I, Kozeretska I, Dubrovska A. BRCA genes: the role in genome stability, cancer stemness and therapy resistance. Journal of Cancer. 2019; 10: 2109–2127.

[13] Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Science. 2004; 95: 866–871.

[14] Madariaga A, Lheureux S, Oza AM. Tailoring ovarian cancer treatment: implications of BRCA1/2 mutations. Cancers. 2019; 416.

[15] Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. The Journal of the American Medical Association. 2011; 306: 1557–1565.

[16] Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of Clinical Oncology. 2007; 25: 1329–1333.

[17] Stavropoulou AV, Fostira F, Pertesi M, Tsitlaidou M, Voutsinas GE, Triantafyllidou O, et al. Prevalence of BRCA1 mutations in familial and sporadic Greek ovarian cancer cases. PLoS ONE. 2013; 8: e58182.

[18] Bell D, Berchuck A, Birrer M, Chien J, Cramer DW, Dao F, et al. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474: 609–615.

[19] Woolderink JM, De Bock GH, de Hullu JA, Hollema H, Zweemer RP, Slangen BFM, et al. Characteristics of Lynch syndrome associated ovarian cancer. Gynecologic Oncology. 2018; 150: 324–330.

[20] Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clinical Cancer Re- search. 2014; 20: 764–775.

[21] Litton JK, Ready K, Chen H, Gutierrez-Barrera A, Etzel CJ, Meric-Bernstam F, et al. Earlier age of onset of BRCA mutation-related cancers in subsequent generations. Cancer. 2012; 118: 321–325.

[22] Apostolou P, Fostira F, Kouroussis C, Kalfakakou D, Delimitsou A, Agelaki S, et al. BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects. International Journal of Cancer. 2020; 147: 1334–1342.

[23] Rubin SC, Benjamin I, Behbakht K, Takahashi H, Morgan MA, LiVolsi VA, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. The New England Journal of Medicine. 1996; 335: 1413–1416.

[24] Aida H, Takakuwa K, Nagata H, Tsuneki I, Takano M, Tsuji S, et al. Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clinical Cancer Research. 1998; 4: 235–240.

[25] Boyd J, Sonoda Y, Federici MG, Bogomolniy F, Rhei E, Maresco DL, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. The Journal of the American Medical Association. 2000; 283: 2260–2265.

[26] Ben David Y, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck BD, Beller U, et al. Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. Journal of Clinical Oncology. 2002; 20: 463–466.

[27] Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer. 2003; 97: 2187–2195.

[28] Jóhannsson OT, Ranstam J, Borg A, Olsson H. Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. Journal of Clinical Oncology. 1998; 16: 397– 404.

[29] Pharoah PD, Easton DF, Stockton DL, Gayther S, Ponder BA. Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Research. 1999; 59: 868–871.

[30] Kotsopoulos J, Rosen B, Fan I, Moody J, McLaughlin JR, Risch H, et al. Ten-year survival after epithelial ovarian cancer is not associated with BRCA mutation status. Gynecologic Oncology. 2016; 140: 42–47.

[31] Zhong Q, Peng HL, Zhao X, Zhang L, Hwang WT. Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis. Clinical Cancer Research. 2015; 21: 211–220.

[32] Hyman DM, Zhou Q, Iasonos A, Grisham RN, Arnold AG, Phillips MF, et al. Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1- associated serous ovarian cancer. Cancer. 2012; 118: 3703–3709.

[33] Liu G, Yang D, Sun Y, Shmulevich I, Xue F, Sood AK, et al. Differing clinical impact of BRCA1 and BRCA2 mutations in serous ovarian cancer. Pharmacogenomics. 2012; 13: 1523–1535.

[34] Earle CC, Schrag D, Neville BA, Yabroff KR, Topor M, Fahey A, et al. Effect of surgeon specialty on processes of care and outcomes for ovarian cancer patients. Journal of the National Cancer Institute. 2006; 98: 172–180.

[35] Chan JK, Kapp DS, Shin JY, Husain A, Teng NN, Berek JS, et al. Influence of the gynecologic oncologist on the survival of ovarian cancer patients. Obstetrics & Gynecology. 2007; 109: 1342–1350.

[36] Aletti GD, Gostout BS, Podratz KC, Cliby WA. Ovarian cancer surgical resectability: relative impact of disease, patient status, and surgeon. Gynecologic Oncology. 2006; 100: 33–37.

[37] Pan Z, Xie X. BRCA mutations in the manifestation and treatment of ovarian cancer. Oncotarget. 2017; 8: 97657–97670.

[38] Eisen A, Rebbeck TR, Wood WC, Weber BL. Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer. Journal of Clinical Oncology. 2000; 18: 1980–1995.

[39] Petrillo M, Marchetti C, De Leo R, Musella A, Capoluongo E, Paris I, et al. BRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study. American Journal of Obstetrics and Gynecology. 2017; 217: 334.e1–334.e9.

[40] Johnstone TC, Park GY, Lippard SJ. Understanding and improving platinum anticancer drugs-phenanthriplatin. Anticancer Research. 2014; 34: 471–476.

[41] Samouëlian V, Maugard CM, Jolicoeur M, Bertrand R, Arcand SL, Tonin PN, et al. Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2, TGFbeta-RII, KRAS2, TP53 and/or CDNK2a. Cancer Chemotherapy and Pharmacology. 2004; 54: 497–504.

[42] Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. Journal of Clinical Oncology. 2012; 30: 2654–2663.

[43] Mahdi H, Gockley A, Esselen K, Marquard J, Nutter B, Yang B, et al. Outcome of neoadjuvant chemotherapy in BRCA1/2 mutation positive women with advanced-stage Mullerian cancer. Gynecologic Oncology. 2015; 139: 407–412.

[44] Lee YJ, Kim HS, Rim JH, Lee JY, Nam EJ, Kim SW, et al. Germline BRCA, chemotherapy response scores, and survival in the neoadjuvant treatment of ovarian cancer. BMC Cancer. 2020; 20: 185.

[45] Howell SB, Pfeifle CL, Wung WE, Olshen RA, Lucas WE, Yon JL, et al. Intraperitoneal cisplatin with systemic thiosulfate protection. Annals of Internal Medicine. 1982; 97: 845–851.

[46] Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New England Journal of Medicine. 2006; 354: 34–43.

[47] Walker JL, Brady MF, Wenzel L, Fleming GF, Huang HQ, DiSilvestro PA, et al. Randomized trial of intravenous versus intraperitoneal chemotherapy plus bevacizumab in advanced ovarian carcinoma: an NRG oncology/gynecologic oncology group study. Journal of Clinical Oncology. 2019; 37: 1380–1390.

[48] Lesnock JL, Darcy KM, Tian C, Deloia JA, Thrall MM, Zahn C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a gynecologic oncology group study. British Journal of Cancer. 2013; 108: 1231–1237.

[49] Naumann RW, Morris JC, Tait DL, Higgins RV, Crane EK, Drury LK, et al. Patients with BRCA mutations have superior outcomes after intraperitoneal chemotherapy in optimally resected high grade ovarian cancer. Gynecologic Oncology. 2018; 151: 477–480.

[50] Keung MYT, Wu Y, Vadgama JV. PARP inhibitors as a therapeutic agent for homologous recombination deficiency in breast cancers. Journal of Clinical Medicine. 2019; 8: 435.

[51] Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005; 434: 913– 917.

[52] Montemorano L, Lightfoot MD, Bixel K. Role of olaparib as maintenance treatment for ovarian cancer: the evidence to date. OncoTargets and Therapy. 2019; 12: 11497–11506.

[53] Moore K, Colombo N, Scambia G, Kim B, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. The New England Journal of Medicine. 2018; 379: 2495–2505.

[54] González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. New England Journal of Medicine. 2019; 381: 2391–2402.

[55] Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. New England Journal of Medicine. 2019; 381: 2416–2428.

[56] Vergote IB, Moore KN, Hettle R, Rhodes K, Ouwens M, Ray- Coquard I. Population adjusted indirect comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 studies of olaparib with or without bevacizumab, bev alone and placebo in the maintenance treatment of women with newly diagnosed stage III/IV ovarian cancer with BRCA mutation. Gynecologic Oncology. 2020; 159: 19–20.

[57] Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. New England Journal of Medicine. 2019; 381: 2403–2415.

[58] Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinumsensitive relapsed ovarian cancer. New England Journal of Medicine. 2012; 366: 1382–1392.

[59] Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncology. 2014; 15: 852–861.

[60] Ledermann JA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebocontrolled, double-blind, phase 2 trial. Lancet Oncology. 2017; 17: 1579–1589.

[61] Matulonis UA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: overall survival adjusted for postprogression poly (adenosine diphosphate ribose) polymerase inhibitor therapy. Cancer. 2017; 122: 1844–1852.

[62] Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncology. 2017; 18: 1274–1284.

[63] Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. The New England Journal of Medicine. 2016; 375: 2154–2164.

[64] Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 390: 1949–1961.

[65] Bartoletti M, Pelizzari G, Gerratana L, Bortot L, Lombardi D, Nicoloso M, et al. Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive recurrent ovarian cancer: a network meta-analysis. International Journal of Molecular Sciences. 2020; 21: 3805.

[66] Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: a randomized, double-blind, placebocontrolled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. Journal of Clinical Oncology. 2012; 30: 2039–2045.

[67] Coleman RL, B. R., Herzog TJ. A phase III randomized, controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary and Fallopian tube cancer. The Society of Gynecologic Oncolog. 2015; 137: 3–4.

[68] Penson RT, Valencia RV, Cibula D, Colombo N, Leath CA, Bidziński M, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. Journal of Clinical Oncology. 2020; 38: 1164–1174.

[69] Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, McNeish IA, Swisher EM, et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecologic Oncology. 2017; 147: 267–275.

[70] Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncology. 2017; 18: 75–87.

[71] Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. Journal of Clinical Oncology. 2015; 33: 244–250.

[72] Matulonis UA, Penson RT, Domchek SM, Kaufman B, Shapira-Frommer R, Audeh MW, et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Annals of Oncology. 2016; 27: 1013–1019.

[73] Moore KN, Geller M, Miller DS, Cloven NG, Fleming GF, Wahner Hendrickson AE, et al. QUADRA: a phase 2, open-label, single-arm study to evaluate niraparib in patients with relpased ovarian cancer in 4th or later line of therapy: results from the BRCAmut subset. Annals of Oncology. 2018.

[74] LaFargue CJ, Dal Molin GZ, Sood AK, Coleman RL. Exploring and comparing adverse events between PARP inhibitors. Lancet Oncology. 2019; 20: e15–e28.

[75] Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nature Structural & Molecular Biology. 2010; 17: 688–695.

[76] Barber LJ, Sandhu S, Chen L, Campbell J, Kozarewa I, Fenwick K, et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. The Journal of Pathology. 2013; 229: 422–429.

[77] Liu Y, Burness ML, Martin-Trevino R, Guy J, Bai S, Harouaka R, et al. RAD51 mediates resistance of cancer stem cells to PARP inhibition in triple-negative breast cancer. Clinical Cancer Research. 2017; 23: 514–522.

[78] Yamaguchi H, Du Y, Nakai K, Ding M, Chang S, Hsu JL, et al. EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer. Oncogene. 2018; 37: 208–217.

[79] Wakefield MJ, Nesic K, Kondrashova O, Scott CL. Diverse mechanisms of PARP inhibitor resistance in ovarian cancer. Biochimica et Biophysica Acta Reviews on Cancer. 2019; 1872: 188307.

[80] L Hollis R, L Hollis R, Gourley C, Gourley C. Genetic and molecular changes in ovarian cancer. Cancer Biology & Medicine. 2016; 13: 236–247.