Prevalence of mutations in BRCA and homologous recombination repair genes and real-world standard of care of Asian patients with HER2-negative metastatic breast cancer starting first-line systemic cytotoxic chemotherapy: subgroup analysis of the global BREAKOUT study

Su-Jin Koh, Shozo Ohsumi, Masato Takahashi, Eisuke Fukuma, Kyung Hae Jung, Takanori Ishida, Ming-Shen Dai, Chuan-Hsun Chang, Tapashi Dalvi, Graham Walker, James Bennett, Joyce O'Shaughnessy, Judith Balmaña, Su-Jin Koh, Shozo Ohsumi, Masato Takahashi, Eisuke Fukuma, Kyung Hae Jung, Takanori Ishida, Ming-Shen Dai, Chuan-Hsun Chang, Tapashi Dalvi, Graham Walker, James Bennett, Joyce O'Shaughnessy, Judith Balmaña

Abstract

Background: The multinational BREAKOUT study (NCT03078036) sought to determine the prevalence of germline BRCA1/2 (gBRCA1/2) and somatic BRCA1/2 (sBRCA1/2) mutations and mutations in other homologous recombination repair (HRR) genes in women with HER2-negative metastatic breast cancer (MBC) starting first-line chemotherapy.

Methods: Genetic testing for gBRCA, sBRCA, and HRR gene mutations was performed in patients who started first-line chemotherapy for MBC in the last 90 days (341 patients across 14 countries) who were not selected based on risk factors for gBRCA mutations. We report data from the Asian cohort, which included patients in Japan (7 sites), South Korea (10 sites), and Taiwan (8 sites).

Results: Of 116 patients screened, 104 patients were enrolled in the Asian cohort. The median age was 53.0 (range 25-87) years. gBRCA1/2, gBRCA1, and gBRCA2 mutations were detected in 10.6% (11/104), 5.8% (6/104), and 4.8% (5/104) of patients, respectively; none had mutations in both gBRCA1 and gBRCA2. gBRCA1/2 mutations were detected in 10.0% (6/60) and 11.6% (5/43) of patients with hormone receptor-positive and triple-negative MBC, respectively. HRR gene mutations were tested in 48 patients without gBRCA mutations, and 5 (10.4%) had at least one HRR mutation in sBRCA, ATM, PALB2, and CHEK2.

Conclusion: We report for the first time the prevalence of gBRCA and HRR mutations in an Asian cohort of patients with HER2-negative MBC. Our results suggest that BRCA mutation testing is valuable to determine appropriate treatment options for patients with hormone receptor-positive or triple-negative MBC.

Study registration: NCT03078036.

Keywords: BRCA; Germline mutations; HER2-negative metastatic breast cancer; Homologous recombination repair; Somatic mutations.

Conflict of interest statement

Shozo Ohsumi and Takanori Ishida have received honoraria for lecture fees from AstraZeneca. Kyung Hae Jung has received consultancy fees from AstraZeneca, Celgene, Eisai, Novartis, and Roche. Masato Takahashi has received honoraria for lecture fees from AstraZeneca, Eisai, Eli Lilly, and Pfizer. Tapashi Dalvi, Graham Walker, and James Bennett are employees or contracted employees of AstraZeneca and may own stock. Joyce O’Shaughnessy has received honoraria for consulting and advisory boards from AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Eisai, Eli Lilly, Genentech, Genomic Health, GRAIL, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Roche, Seattle Genetics, and Syndax Pharmaceuticals. Judith Balmaña has received honoraria for consultancy from AstraZeneca, PharmaMar, and Pfizer, and research support from AstraZeneca and PharmaMar. Su-Jin Koh, Eisuke Fukuma, Ming-Shen Dai, and Chuan-Hsun Chang have nothing to declare.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design. Modified (restructured figure) from Fig. 1 in O’Shaughnessy et al. [12]. Prevalence of germline BRCA mutations in HER2-negative metastatic breast cancer: global results from the real-world, observational BREAKOUT study. Breast Cancer Research 2020;22:114. Available under a Creative Commons Attribution 4.0 International License. PFS and OS were not assessed due to the early termination of the study. *Blood sample: gBRCA1/2 mutation status was tested using the BRACAnalysis CDx® assay. †Tumor specimen: HRR gene mutations, including sBRCA1/2 and other genomic alterations, were tested using the FoundationOne CDx assay. HER2 human epidermal growth factor receptor 2, HRR homologous recombination repair, MBC metastatic breast cancer, OS overall survival, PFS progression-free survival
Fig. 2
Fig. 2
Patient disposition. Data for the global cohort are reprinted from Fig. 2 in O’Shaughnessy et al. [12]. Prevalence of germline BRCA mutations in HER2-negative metastatic breast cancer: global results from the real-world, observational BREAKOUT study. Breast Cancer Research 2020;22:114. Available under a Creative Commons Attribution 4.0 International License. FAS full analysis set

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492.
    1. Kurian AW, Gong GD, John EM, Miron A, Felberg A, Phipps AI, et al. Performance of prediction models for BRCA mutation carriage in three racial/ethnic groups: findings from the Northern California Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1084–1091. doi: 10.1158/1055-9965.Epi-08-1090.
    1. Malone KE, Daling JR, Doody DR, Hsu L, Bernstein L, Coates RJ, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res. 2006;66(16):8297–8308. doi: 10.1158/0008-5472.Can-06-0503.
    1. Valencia OM, Samuel SE, Viscusi RK, Riall TS, Neumayer LA, Aziz H. The role of genetic testing in patients with breast cancer: a review. JAMA Surg. 2017;152(6):589–594. doi: 10.1001/jamasurg.2017.0552.
    1. Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018;9(1):4083. doi: 10.1038/s41467-018-06581-8.
    1. Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269–275. doi: 10.1002/cncr.29041.
    1. Keung MYT, Wu Y, Vadgama JV. PARP inhibitors as a therapeutic agent for homologous recombination deficiency in breast cancers. J Clin Med. 2019;8(4):435. doi: 10.3390/jcm8040435.
    1. Chartron E, Theillet C, Guiu S, Jacot W. Targeting homologous repair deficiency in breast and ovarian cancers: Biological pathways, preclinical and clinical data. Crit Rev Oncol Hematol. 2019;133:58–73. doi: 10.1016/j.critrevonc.2018.10.012.
    1. Robson ME, Tung N, Conte P, Im SA, Senkus E, Xu B, et al. 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. 2019;30(4):558–566. doi: 10.1093/annonc/mdz012.
    1. 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(22):2091–2102. doi: 10.1056/NEJMoa1911440.
    1. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–327. doi: 10.1056/NEJMoa1903387.
    1. O’Shaughnessy J, Brezden-Masley C, Cazzaniga M, Dalvi T, Walker G, Bennett J, et al. Prevalence of germline BRCA mutations in HER2-negative metastatic breast cancer: global results from the real-world, observational BREAKOUT study. Breast Cancer Res. 2020;22:114. doi: 10.1186/s13058-020-01349-9.
    1. Foundation Medicine, Inc. FoundationOne CDxTM Technical Information (RAL-0003-02). Available at: . Accessed 12 Mar 2021.
    1. Griguolo G, Dieci MV, Guarneri V, Conte P. Olaparib for the treatment of breast cancer. Expert Rev Anticancer Ther. 2018;18(6):519–530. doi: 10.1080/14737140.2018.1458613.
    1. Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304–311. doi: 10.1200/jco.2014.57.1414.
    1. Robertson L, Hanson H, Seal S, Warren-Perry M, Hughes D, Howell I, et al. BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br J Cancer. 2012;106(6):1234–1238. doi: 10.1038/bjc.2012.31.
    1. Rosenberg SM, Ruddy KJ, Tamimi RM, Gelber S, Schapira L, Come S, et al. BRCA1 and BRCA2 mutation testing in young women with breast cancer. JAMA Oncol. 2016;2(6):730–736. doi: 10.1001/jamaoncol.2015.5941.
    1. Stevens KN, Vachon CM, Couch FJ. Genetic susceptibility to triple-negative breast cancer. Cancer Res. 2013;73(7):2025–2030. doi: 10.1158/0008-5472.Can-12-1699.
    1. Kwong A. Genetic testing for hereditary breast cancer in Asia—moving forward. Chin Clin Oncol. 2016;5(3):47. doi: 10.21037/cco.2016.05.11.
    1. Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) Cancer Epidemiol Biomarkers Prev. 2012;21(1):134–147. doi: 10.1158/1055-9965.Epi-11-0775.
    1. Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran. 2016;30:369.
    1. Villarreal-Garza C, Weitzel JN, Llacuachaqui M, Sifuentes E, Magallanes-Hoyos MC, Gallardo L, et al. The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple-negative breast cancer. Breast Cancer Res Treat. 2015;150(2):389–394. doi: 10.1007/s10549-015-3312-8.
    1. Ryu JM, Choi HJ, Kim I, Nam SJ, Kim SW, Yu J, et al. Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea. Breast Cancer Res Treat. 2019;173(2):385–395. doi: 10.1007/s10549-018-5015-4.
    1. Owens DK, Davidson KW, Krist AH, Barry MJ, Cabana M, Caughey AB, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA. 2019;322(7):652–665. doi: 10.1001/jama.2019.10987.
    1. Baretta Z, Mocellin S, Goldin E, Olopade OI, Huo D. Effect of BRCA germline mutations on breast cancer prognosis: a systematic review and meta-analysis. Medicine (Baltimore) 2016;95(40):e4975. doi: 10.1097/md.0000000000004975.
    1. Mori H, Kubo M, Kai M, Velasquez VV, Kurata K, Yamada M, et al. BRCAness combined with a family history of cancer is associated with a poor prognosis for breast cancer patients with a high risk of BRCA mutations. Clin Breast Cancer. 2018;18(5):e1217–e1227. doi: 10.1016/j.clbc.2018.05.008.
    1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. 2019.
    1. Manchanda R, Patel S, Gordeev VS, Antoniou AC, Smith S, Lee A, et al. Cost-effectiveness of population-based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women. J Natl Cancer Inst. 2018;110(7):714–725. doi: 10.1093/jnci/djx265.
    1. Ficarazzi F, Vecchi M, Ferrari M, Pierotti MA. Towards population-based genetic screenings for breast and ovarian cancer: a comprehensive review from economic evaluations to patient perspectives. Breast. 2021;58:121–129. doi: 10.1016/j.breast.2021.04.011.
    1. Saito S, Nakazawa K, Nagahashi M, Ishikawa T, Akazawa K. Cost-effectiveness of BRCA1/2 mutation profiling to target olaparib use in patients with metastatic breast cancer. Per Med. 2019;16(6):439–448. doi: 10.2217/pme-2018-0141.
    1. Sun L, Brentnall A, Patel S, Buist DSM, Bowles EJA, Evans DGR, et al. A cost-effectiveness analysis of multigene testing for all patients with breast cancer. JAMA Oncol. 2019;5(12):1718–1730. doi: 10.1001/jamaoncol.2019.3323.
    1. Kemp Z, Turnbull A, Yost S, Seal S, Mahamdallie S, Poyastro-Pearson E, et al. Evaluation of cancer-based criteria for use in mainstream BRCA1 and BRCA2 genetic testing in patients with breast cancer. JAMA Netw Open. 2019;2(5):e194428. doi: 10.1001/jamanetworkopen.2019.4428.
    1. Nones K, Johnson J, Newell F, Patch AM, Thorne H, Kazakoff SH, et al. Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers. Ann Oncol. 2019;30(7):1071–1079. doi: 10.1093/annonc/mdz132.
    1. Ghiringhelli F, Richard C, Chevrier S, Vegran F, Boidot R. Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein. World J Gastroenterol. 2016;22(48):10680–10686. doi: 10.3748/wjg.v22.i48.10680.
    1. Horak P, Weischenfeldt J, von Amsberg G, Beyer B, Schutte A, Uhrig S, et al. Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance. Cold Spring Harb Mol Case Stud. 2019;5(2):a003657. doi: 10.1101/mcs.a003657.
    1. 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(18):1697–1708. doi: 10.1056/NEJMoa1506859.
    1. Faraoni I, Graziani G. Role of BRCA mutations in cancer treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. Cancers (Basel) 2018;10(12):487. doi: 10.3390/cancers10120487.
    1. Ohmoto A, Yachida S. Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther. 2017;10:5195–5208. doi: 10.2147/ott.S139336.
    1. Kim SJ, Sota Y, Naoi Y, Honma K, Kagara N, Miyake T, et al. Determining homologous recombination deficiency scores with whole exome sequencing and their association with responses to neoadjuvant chemotherapy in breast cancer. Transl Oncol. 2021;14(2):100986. doi: 10.1016/j.tranon.2020.100986.
    1. Kwong A, Cheuk IW, Shin VY, Ho CY, Au CH, Ho DN, et al. Somatic mutation profiling in BRCA-negative breast and ovarian cancer patients by multigene panel sequencing. Am J Cancer Res. 2020;10(9):2919–2932.
    1. Vidula N, Dubash T, Lawrence MS, Simoneau A, Niemierko A, Blouch E, et al. Identification of somatically acquired BRCA1/2 mutations by cfDNA analysis in patients with metastatic breast cancer. Clin Cancer Res. 2020;26(18):4852–4862. doi: 10.1158/1078-0432.CCR-20-0638.
    1. Meric-Bernstam F, Brusco L, Daniels M, Wathoo C, Bailey AM, Strong L, et al. Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann Oncol. 2016;27(5):795–800. doi: 10.1093/annonc/mdw018.
    1. Dalvi T, Maclachlan S, Briceno J, Bennett J, McLaurin K, Hettle R, et al. Demographic, clinical/disease characteristics, and treatment of patients with germline breast cancer susceptibility gene mutated (gBRCAm) metastatic breast cancer: a CancerLinQ study. San Antionio Breast Cancer Symposium, December 4–8, 2018, San Antonio, TX, USA.
    1. Dalvi T, McLaurin K, Briceno J, Nordstrom B, Bennett J, Hettle R, et al. A real-world evidence study of germline BRCA mutations and survival in HER2-negative breast cancer. San Antionio Breast Cancer Symposium, December 4–8, 2018, San Antonio, TX, USA.
    1. Boussios S, Karihtala P, Moschetta M, Karathanasi A, Sadauskaite A, Rassy E, et al. Combined strategies with poly (ADP-Ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer: a literature review. Diagnostics (Basel) 2019;9(3):87. doi: 10.3390/diagnostics9030087.
    1. Kim H, George E, Ragland R, Rafail S, Zhang R, Krepler C, et al. Targeting the ATR/CHK1 axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian cancer models. Clin Cancer Res. 2017;23(12):3097–3108. doi: 10.1158/1078-0432.Ccr-16-2273.
    1. Lux MP, Nabieva N, Hartkopf AD, Huober J, Volz B, Taran FA, et al. Therapy landscape in patients with metastatic HER2-positive breast cancer: data from the PRAEGNANT real-world breast cancer registry. Cancers (Basel) 2018;11(1):10. doi: 10.3390/cancers11010010.
    1. Fasching PA, Hu C, Hart S, Hartkopf AD, Taran FA, Janni W, et al. Germline BRCA1 and BRCA2 mutations in patients with HER2-negative metastatic breast cancer (mBC) treated with first-line chemotherapy: data from the German PRAEGNANT registry. J Clin Oncol. 2019;37(15 suppl):1048. doi: 10.1200/JCO.2019.37.15_suppl.1048.
    1. Zardavas D, Maetens M, Irrthum A, Goulioti T, Engelen K, Fumagalli D, et al. The AURORA initiative for metastatic breast cancer. Br J Cancer. 2014;111(10):1881–1887. doi: 10.1038/bjc.2014.341.

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