BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.

Academic Department of Medical Genetics National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Cambridge UK

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Center for Familial Breast and Ovarian Cancer Center for Integrated Oncology Medical Faculty University Hospital Cologne Cologne Germany

Center for Molecular Medicine Cologne University of Cologne Cologne Germany

Centre Catherine de Sienne Service d'Oncologie Médicale Nantes France

Centre for Cancer Genetic Epidemiology Department of Oncology Strangeways Research Laboratory Worts Causeway University of Cambridge Cambridge CBI 8RN UK

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care Strangeways Research Laboratory Worts Causeway University of Cambridge Cambridge CBI 8RN UK

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne VIC 3010 Australia

Centre Hospitalier Service Régional d'Oncologie Génétique Poitou Charentes Niort France

Clinical Genetics Guy's and St Thomas' NHS Foundation Trust London UK

DASC Oncogénétique Clinique Institut Paoli Calmettes Marseille France

Département de Médecine Oncologique Gustave Roussy Hôpital Universitaire Villejuif France

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Zluty kopec 7 65653 Brno Czech Republic

Department of Clinical Genetics Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam Netherlands

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia PA USA

Department of Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Genetics Royal Devon and Exeter Hospital Exeter UK

Department of Dermatology University of Utah School of Medicine 30 North 1900 East SOM 4B454 Salt Lake City UT 841232 USA

Department of Epidemiology Columbia University New York NY USA

Department of Epidemiology Netherlands Cancer Institute P O Box 90203 1006 BE Amsterdam The Netherlands

Department of Genetics and Pathology Pomeranian Medical University Unii Lubelskiej 1 Szczecin Poland

Department of Genetics University Medical Center Utrecht Utrecht The Netherlands

Department of Gynaecological Oncology University Medical Center Groningen University of Groningen Groningen The Netherlands

Department of Gynecology and Obstetrics Medical Faculty and University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Medical Oncology Family Center Clinic Erasmus MC Cancer Institute Rotterdam The Netherlands

Department of Medical Oncology Peter MacCallum Cancer Centre Locked Bag 1 A'Beckett St East Melbourne Victoria 8006 Australia

Department of Medicine and Stanford Cancer Institute Stanford University School of Medicine Stanford CA USA

Department of Medicine Huntsman Cancer Institute University of Utah Health Sciences Center Salt Lake City UT USA

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Genetics University of Toronto Toronto Ontario Canada

Department of OB GYN and Comprehensive Cancer Center Medical University of Vienna Waehringer Guertel 18 20 A 1090 Vienna Austria

Department of Oncology Lund University Hospital Lund Sweden

Department of Surgical Oncology Erasmus MC Cancer Institute Rotterdam The Netherlands

Departments of Pediatrics and Medicine Columbia University Medical Center New York NY USA

Genomic Medicine Manchester Academic Health Sciences Centre Division of Evolution and Genomic Sciences Manchester University Central Manchester University Hospitals NHS Foundation Trust Manchester UK

Genomics Center Centre Hospitalier Universitaire de Québec Université Laval Research Center 2705 Laurier Boulevard Quebec City Quebec Canada

German Cancer Consortium Heidelberg Germany

Herbert Irving Comprehensive Cancer Center Columbia University Medical Center New York NY USA

Human Genetics Group and Genotyping Unit CEGEN Human Cancer Genetics Programme Spanish National Cancer Research Centre Madrid Spain

Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University Unii Lubelskiej 1 Szczecin Poland

INSERM U900 Paris France

Institut Curie Paris France

Institut Curie Service de Génétique Paris France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Institute of Genetic Medicine Centre for Life Newcastle Upon Tyne Hospitals NHS Trust Newcastle upon Tyne UK

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Ontario Canada

Mines Paris Tech Fontainebleau France

Molecular Oncology Laboratory Hospital Clinico San Carlos IdISSC CIBERONC Madrid Spain

National Center for Tumor Diseases Partner Site Dresden Dresden Germany

Oncogenetics Team The Institute of Cancer Research and Royal Marsden NHS Foundation Trust London UK

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia

PSL Research University Paris France

Sheffield Clinical Genetics Service Sheffield Children's Hospital Sheffield UK

The Department of Oncology and Pathology Karolinska Institute 171 76 Stockholm Sweden

The Sir Peter MacCallum Department of Oncology University of Melbourne Parkville Australia

Unité d'Oncogénétique CHU Arnaud de Villeneuve Montpellier France

University of Southampton Faculty of Medicine Southampton University Hospitals NHS Trust Southampton UK

Yorkshire Regional Genetics Service Chapel Allerton Hospital and University of Leeds Leeds UK

Erratum v

Breast Cancer Res. 2020 Feb 26;22(1):25. doi: 10.1186/s13058-020-01259-w. PubMed

Zobrazit více v PubMed

Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105(11):812–822. doi: 10.1093/jnci/djt095. PubMed DOI

Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402–2416. doi: 10.1001/jama.2017.7112. PubMed DOI

Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26(8):1331–1337. doi: 10.1200/JCO.2007.13.9626. PubMed DOI PMC

Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101(2):80–87. doi: 10.1093/jnci/djn442. PubMed DOI PMC

Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, Offit K, et al. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case-control study. J Clin Oncol. 2005;23(30):7491–7496. doi: 10.1200/JCO.2004.00.7138. PubMed DOI

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. JAMA. 2010;304(9):967–975. doi: 10.1001/jama.2010.1237. PubMed DOI PMC

Klaren HM, van’t Veer LJ, van Leeuwen FE, Rookus MA. Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst. 2003;95(13):941–947. doi: 10.1093/jnci/95.13.941. PubMed DOI

Fakkert IE, Mourits MJ, Jansen L, van der Kolk DM, Meijer K, Oosterwijk JC, et al. Breast cancer incidence after risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers. Cancer Prev Res. 2012;5(11):1291–1297. doi: 10.1158/1940-6207.CAPR-12-0190. PubMed DOI

Heemskerk-Gerritsen BA, Seynaeve C, van Asperen CJ, Ausems MG, Collee JM, van Doorn HC, et al. Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst. 2015;107(5). PubMed

Heemskerk-Gerritsen BA, Hooning MJ, Rookus MA. Response. J Natl Cancer Inst. 2015;107(9). PubMed PMC

Phillips KA, Butow PN, Stewart AE, Chang JH, Weideman PC, Price MA, et al. Predictors of participation in clinical and psychosocial follow-up of the kConFab breast cancer family cohort. Familial Cancer. 2005;4(2):105–113. doi: 10.1007/s10689-004-6129-x. PubMed DOI

Thorne H, Mitchell G, Fox S. kConFab: a familial breast cancer consortium facilitating research and translational oncology. J Natl Cancer Inst Monogr. 2011;43:79–81. doi: 10.1093/jncimonographs/lgr042. PubMed DOI

Goldgar D, Bonnardel C, Renard H. The international BRCA1/2 carrier cohort study: purpose, rationale, and study design. Breast Cancer Res. 2000;2E10. 10.1186/bcr93.

John EM, Hopper JL, Beck JC, Knight JA, Neuhausen SL, Senie RT, et al. The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer. Breast Cancer Res. 2004;6(4):R375–R389. doi: 10.1186/bcr801. PubMed DOI PMC

Terry MB, Phillips KA, Daly MB, John EM, Andrulis IL, Buys SS, et al. Cohort profile: The Breast Cancer Prospective Family Study Cohort (ProF-SC) Int J Epidemiol. 2016;45(3):683–692. doi: 10.1093/ije/dyv118. PubMed DOI PMC

Kotsopoulos J, Huzarski T, Gronwald J, Kim-Sing C, Neuhausen S, Demsky R, et al. Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2017;109(1). PubMed PMC

Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE study group. J Clin Oncol. 2005;23(31):7804–7810. doi: 10.1200/JCO.2004.00.8151. PubMed DOI

Kotsopoulos Joanne, Gronwald Jacek, Karlan Beth Y., Huzarski Tomasz, Tung Nadine, Moller Pal, Armel Susan, Lynch Henry T., Senter Leigha, Eisen Andrea, Singer Christian F., Foulkes William D., Jacobson Michelle R., Sun Ping, Lubinski Jan, Narod Steven A. Hormone Replacement Therapy After Oophorectomy and Breast Cancer Risk Among BRCA1 Mutation Carriers. JAMA Oncology. 2018;4(8):1059. doi: 10.1001/jamaoncol.2018.0211. PubMed DOI PMC

Terry Mary Beth, Daly Mary B, Phillips Kelly Anne, Ma Xinran, Zeinomar Nur, Leoce Nicole, Dite Gillian S, MacInnis Robert J, Chung Wendy K, Knight Julia A, Southey Melissa C, Milne Roger L, Goldgar David, Giles Graham G, Weideman Prue C, Glendon Gord, Buchsbaum Richard, Andrulis Irene L, John Esther M, Buys Saundra S, Hopper John L. Risk-Reducing Oophorectomy and Breast Cancer Risk Across the Spectrum of Familial Risk. JNCI: Journal of the National Cancer Institute. 2018;111(3):331–334. doi: 10.1093/jnci/djy182. PubMed DOI PMC

Day FR, Ruth KS, Thompson DJ, Lunetta KL, Pervjakova N, Chasman DI, et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet. 2015;47(11):1294–1303. doi: 10.1038/ng.3412. PubMed DOI PMC

Collins IM, Milne RL, McLachlan SA, Friedlander M, Hickey M, Weideman PC, et al. Do BRCA1 and BRCA2 mutation carriers have earlier natural menopause than their noncarrier relatives? Results from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. J Clin Oncol. 2013;31(31):3920–3925. doi: 10.1200/JCO.2013.49.3007. PubMed DOI

Oktay K, Kim JY, Barad D, Babayev SN. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol. 2010;28(2):240–244. doi: 10.1200/JCO.2009.24.2057. PubMed DOI PMC

Finch A, Valentini A, Greenblatt E, Lynch HT, Ghadirian P, Armel S, et al. Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation. Fertil Steril. 2013;99(6):1724–1728. doi: 10.1016/j.fertnstert.2013.01.109. PubMed DOI

van Tilborg TC, Broekmans FJ, Pijpe A, Schrijver LH, Mooij TM, Oosterwijk JC, et al. Do BRCA1/2 mutation carriers have an earlier onset of natural menopause? Menopause. 2016;23(8):903–910. doi: 10.1097/GME.0000000000000633. PubMed DOI

Phillips KA, Collins IM, Milne RL, McLachlan SA, Friedlander M, Hickey M, et al. Anti-Mullerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations. Hum Reprod. 2016;31(5):1126–1132. doi: 10.1093/humrep/dew044. PubMed DOI PMC

Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13(11):1141–1151. PubMed PMC

National Comprehensive Cancer Network (NCCN) clinical practice guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf Accessed 25 Oct 2019

Cancer Australia clinical recommendations for management of women at high risk of ovarian cancer. https://guidelines.canceraustralia.gov.au/guidelines/high_risk_ovarian/ch01s03.php Accessed Oct 25 2019.

Domchek SM, Friebel TM, Neuhausen SL, Wagner T, Evans G, Isaacs C, et al. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Lancet Oncol. 2006;7(3):223–229. doi: 10.1016/S1470-2045(06)70585-X. PubMed DOI

Metcalfe K, Lynch HT, Foulkes WD, Tung N, Kim-Sing C, Olopade OI, et al. Effect of oophorectomy on survival after breast cancer in BRCA1 and BRCA2 mutation carriers. JAMA Oncol. 2015;1(3):306–313. doi: 10.1001/jamaoncol.2015.0658. PubMed DOI

Huzarski T, Byrski T, Gronwald J, Cybulski C, Oszurek O, Szwiec M, et al. The impact of oophorectomy on survival after breast cancer in BRCA1-positive breast cancer patients. Breast Cancer Res Treat. 2016;156(2):371–378. doi: 10.1007/s10549-016-3749-4. PubMed DOI

van Verschuer VM, Heemskerk-Gerritsen BA, van Deurzen CH, Obdeijn IM, Tilanus-Linthorst MM, Verhoef C, et al. Lower mitotic activity in BRCA1/2-associated primary breast cancers occurring after risk-reducing salpingo-oophorectomy. Cancer Biol Ther. 2014;15(4):371–379. doi: 10.4161/cbt.27628. PubMed DOI PMC

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers