New treatment strategy for ovarian cancer with a BRCA gene mutation

Mutated BRCA1/2 genes have been identified as causative genes for ovarian cancer, and it has been reported that 10%–20% of all epithelial ovarian cancers have a BRCA mutation. As novel treatment drugs utilizing this BRCA gene mutation, significant attention has been paid to adenine dinucleotide poly (ADP-ribose) polymerase inhibitors. Among them, olaparib has been reported to be useful in patients with a BRCA mutation in Study 19 and SOLO-2 trials. It is important to establish a system for genetic counseling and to perform BRCA gene testing in patients with ovarian cancer. For patients with BRCA -mutated advanced cancer, if adequate response to chemotherapy has been achieved, olaparib is recommended as maintenance therapy for both advanced and recurrent cases. For patients without BRCA gene mutation, bevacizumab combined with chemotherapy or as maintenance therapy is also an option.

Ovarian cancer; BRCA mutation; PARP inhibitor

[1] Boussios S, Abson C, Moschetta M, Rassy E, Karathanasi A, Bhat T, et al. Poly (ADP-Ribose) polymerase inhibitors: talazoparib in ovarian cancer and beyond. Drugs in R&D. 2020; 20: 55-73.

[2] Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncology. 2016; 2: 482.

[3] Sakamoto I, Hirotsu Y, Nakagomi H, Ouchi H, Ikegami A, Teramoto K, et al. BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer. Cancer. 2016; 122: 84-90.

[4] Hirasawa A, Imoto I, Naruto T, Akahane T, Yamagami W, Nomura H, et al. Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer. Oncotarget. 2017; 8: 112258-112267.

[5] Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S, et al. NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017. Journal of the National Comprehensive Cancer Network. 2017; 15: 9-20.

[6] SGO Clinical Practice Statement. Genetic testing for ovarian cancer october (SGO 2014). Available at: https://www.sgo.org/reso urces/genetic-testing-for-ovarian-cancer/ (Accessed: 30 August 2020).

[7] Lambert M. ACOG guidelines for managing hereditary breast and ovarian cancer syndrome. American Family Physician. 2009; 15: 1505-1507.

[8] Balmaña J, Díez O, Rubio IT, Cardoso F. BRCA in breast cancer: ESMO Clinical Practice Guidelines. Annals of Oncology. 2011; 22: vi31-vi34.

[9] Gadzicki D, Evans DG, Harris H, Julian-Reynier C, Nippert I, Schmidtke J, et al. Genetic testing for familial/hereditary breast cancer-comparison of guidelines and recommendations from the UK, France, the Netherlands and Germany. Journal of Community Genetics. 2011; 2: 53-69.

[10] Graña B, Lastra E, Llort G, Brunet J, Isla D. SEOM clinical guide-lines for hereditary cancer. Clinical and Translational Oncology. 2011; 13: 580-586.

[11] NICE guideline. 2013. Available at: https://www.nice.org.uk/gu idance/cg164/chapter/Recommendations (Accessed: 30 August 2020).

[12] SIGN135. Management of epithelial ovarian cancer. 2013. Avail-able at: http://www.sign.ac.uk (Accessed: 30 August 2020).

[13] Miki Y, Swensen J, Shattuck-Eidens D, Futreal P, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994; 266: 66-71.

[14] Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995; 378: 789-792.

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

[16] Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. Journal of the American Medical Association. 2015; 313: 1347-1361.

[17] Genetic/Familial High-Risk Assessment. Breast and Ovarian Version3 2019 NCCN Clinical Practice Guidelines in Oncology Available at: https://www2.tri-kobe.org/nccn/guideline/gynecologic al/english/genetic_familial.pdf (Accessed: 30 August 2020).

[18] Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 Mutation carriers. Journal of the National Cancer Institute. 2009; 101: 80-87.

[19] Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. Journal of the American Medical Association. 2010; 304: 967-975.

[20] Marchetti C, De Felice F, Palaia I, Perniola G, Musella A, Musio D, et al. Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Women’S Health. 2015; 14: 150.

[21] Boussios S, Mikropoulos C, Samartzis E, Karihtala P, Moschetta M, Sheriff M, et al. Wise management of ovarian cancer: on the cutting edge. Journal of Personalized Medicine. 2020; 10: 41.

[22] De Vos M, Schreiber V, Dantzer F. The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochemical Pharmacology. 2012; 84: 137-146.

[23] Helleday T, Bryant HE, Schultz N. Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle (Georgetown, Tex.). 2006; 4: 1176-1178.

[24] Dantzer F, Schreiber V, Niedergang C, Trucco C, Flatter E, De La Rubia G, et al. Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie. 1999; 81: 69-75.

[25] Boussios S, Karihtala P, Moschetta M, Abson C, Karathanasi A, Zakynthinakis-Kyriakou N, et al. Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach. Investigational New Drugs. 2020; 38: 181-193.

[26] 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. The New England Journal of Medicine. 2019; 381: 2403-2415.

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

[28] 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. The Lancet Oncology. 2014; 15: 852-861.

[29] 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, placebo-controlled, double-blind, phase 2 trial. The Lancet Oncology. 2017; 17: 1579-1589.

[30] 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.

[31] 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. The Lancet Oncology. 2017; 18: 1274-1284.

[32] 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. The New England Journal of Medicine. 2019; 381: 2416-2428.

[33] Liu JF, Barry WT, Birrer M, Lee J, Buckanovich RJ, Fleming GF, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. The Lancet Oncology. 2014; 15: 1207-1214.

[34] Liu JF, Barry WT, Birrer M, Lee J-, Buckanovich RJ, Fleming GF, et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Annals of Oncology. 2019; 30: 551-557.

[35] National Cancer Institute (NCI). Olaparib or cediranib maleate and olaparib compared with standard platinum-based chemotherapy in treating patients with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT02446600 (Accessed: 30 August 2020).

[36] University College, London. Study evaluating the efficacy of maintenance olaparib and cediranib or olaparib alone in ovarian cancer patients (ICON9). 2020. Available at: https://clinicaltrials.gov/c t2/show/NCT03278717 (Accessed: 30 August 2020).

[37] National Cancer Institute (NCI). Cediranib maleate and olaparib or standard chemotherapy in treating patients with recurrent platinum-resistant or -refractory ovarian, fallopian tube, or primary peritoneal cancer. 2015. Available at: https://clinicaltrials.g ov/ct2/show/NCT02502266 (Accessed: 30 August 2020).

[38] University of Oxford. Cediranib maleate and olaparib or standard chemotherapy in treating patients with recurrent platinum-resistant or -refractory ovarian, fallopian tube, or primary peritoneal cancer. 2020. Available at: https://clinicaltrials.gov/ct2/sh ow/NCT03117933 (Accessed: 30 August 2020).

[39] AstraZeneca. Efficacy and safety study of cediranib in combination with olaparib in patients with recurrent platinum-resistant ovarian cancer (CONCERTO). 2020. Available at: https://clinicaltria ls.gov/ct2/show/NCT02889900 (Accessed: 30 August 2020).

[40] Drew Y, de Jonge M, Hong SH, Park YH, Wolfer A, Brown J, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA -mutated ( gBRCA m) platinum-sensitive relapsed (PSR) ovarian cancer (OC) Gynecologic Oncology. 2018; 149: 246-247.

[41] Drew Y, Kaufman B, Banerjee S, Lortholary A, Hong SH, Park YH, et al. Phase II study of olaparib + durvalumab (MEDIOLA): updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC) Annals of Oncology. 2019; 30: v485-v486.

[42] Konstantinopoulos PA, Waggoner SE, Vidal GA, Mita MM, Fleming GF, Holloway RW, et al. TOPACIO/Keynote-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)-Results from ROC cohort. Journal of Clinical Oncology. 2018; 36: 106-106.

[43] Konstantinopoulos PA, Munster P, Forero-Torez A, Holloway RW, Schwartzberg L, Matulonis UA, et al. Preliminary activity and safety in patients (pts) with platinum-resistant ovarian cancer (PROC) in a phase 1/2 study of niraparib in combination with pembrolizumab. Gynecologic Oncology. 2018; 149: 246.

[44] Antolín AA, Mestres J. Linking off-target kinase pharmacology to the differential cellular effects observed among PARP inhibitors. Oncotarget. 2015; 5: 3023-3028.

[45] Francica P, Rottenberg S. Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response. Genome Medicine. 2018; 10: 101.

[46] Blazek D, Kohoutek J, Bartholomeeusen K, Johansen E, Hulinkova P, Luo Z, et al. The cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes & Development. 2011; 25: 2158-2172.

[47] Johnson SF, Cruz C, Greifenberg AK, Dust S, Stover DG, Chi D, et al. CDK12 inhibition reverses De Novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Reports. 2017; 17: 2367-2381.

[48] Garcia TB, Snedeker JC, Baturin D, Gardner L, Fosmire SP, Zhou C, et al. A Small-molecule inhibitor of WEE1, AZD1775, syner-gizes with olaparib by impairing homologous recombination and enhancing DNA damage and apoptosis in acute leukemia. Molecular Cancer Therapeutics. 2018; 16: 2058-2068.

[49] Boussios S, Karathanasi A, Cooke D, Neille C, Sadauskaite A, Moschetta M, et al. PARP inhibitors in ovarian cancer: the route to “Ithaca”. Diagnostics. 2019; 9: 55.

[50] Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. The New England Journal of Medicine. 2012; 365: 2473-2483.

[51] Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. The New England Journal of Medicine. 2012; 365: 2484-2496.

[52] Coleman RL, Brady MF, Herzog TJ, Sabbatini P, Armstrong DK, Walker JL, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology. 2017; 18: 779- 791.

[53] Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS : a randomized, double-blind, placebo-controlled 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.