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

Nasim Mavaddat (1) , Antonis C. Antoniou (1) , Thea Mooij (2) , Maartje Hooning (3) , Bernadette Heemskerk-Gerritsen (3) , Catherine Noguès (4) , Marion Gauthier-Villars (5) , Olivier Caron (6, 7) , Paul Gesta (8) , Pascal Pujol (9) , Alain Lortholary (10) , Daniel Barrowdale (1) , Debra Frost (1) , D. Gareth Evans (11) , Louise Izatt (12) , Julian Adlard (13, 14) , Ros Eeles (15) , Carole Brewer (16) , Marc Tischkowitz (1) , Alex Henderson (17) , Jackie Cook (18) , Diana Eccles (19) , Klaartje van Engelen (20) , Marian Mourits (21) , Margreet Ausems (22) , Linetta Koppert (3) , John Hopper (23) , Esther John (24) , Wendy Chung (25) , Irene Andrulis (26) , Mary Daly (27) , Saundra Buys (28) , Javier Benitez (29) , Trinidad Caldés (30) , Anna Jakubowska (31) , Jacques Simard (32) , Christian Singer (33) , Yen Tan (34) , Edith Olah (35) , Marie Navratilova (36) , Lenka Foretova (37) , Anne-Marie Gerdes (38) , Marie-José Roos-Blom (39) , Flora E. van Leeuwen (39) , Brita Arver (40) , Håkan Olsson (41) , Rita Schmutzler (42) , Christoph Engel (43) , Karin Kast (44) , Kelly-Anne Phillips (45) , Mary Beth Terry (46) , Roger L Milne (47) , David E. Goldgar (48) , Matti A. Rookus (49) , Nadine Andrieu (50, 51) , Douglas F. Easton (52)

1 CAM - University of Cambridge [UK]
2 NKI - Netherlands Cancer Institute
3 Erasmus MC Cancer Institute, Rotterdam
4 IPC - Institut Paoli-Calmettes
5 Institut Curie [Paris]
6 IGR - Institut Gustave Roussy
7 Département de médecine oncologique [Gustave Roussy]
8 CH Georges Renon Niort - Centre Hospitalier Georges Renon [Niort]
9 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
10 CCS - Centre Catherine-de-Sienne [Nantes]
11 MFT - Manchester University NHS Foundation Trust
12 Guy's & St Thomas' NHS Foundation Trust
13 Chapel Allerton Hospital
14 University of Leeds
15 Royal Marsden NHS Foundation Trust
16 Royal Devon & Exeter Hospital
17 Newcastle Upon Tyne Hospitals NHS Foundation Trust
18 Sheffield Children's NHS Foundation Trust
19 Wessex clinical genetics service
20 VU - Vrije Universiteit Amsterdam [Amsterdam]
21 UMCG - University Medical Center Groningen [Groningen]
22 Department of Medical Genetics
23 Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia
24 Department of Epidemiology
25 Columbia University [New York]
26 Departments of Molecular Genetics and Laboratory Medicine and Pathobiology
27 Division of Population Science
28 Department of Internal Medicine
29 Departemento Genetica Humana
30 IdISSC - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain]
31 Department of Genetics and Pathology
32 Cancer Genomics Laboratory
33 Division of Special Gynecology
34 Medizinische Universität Wien = Medical University of Vienna
35 National Institute of Oncology
36 MMCI - Masaryk Memorial Cancer Institute
37 MUNI - Masaryk University [Brno]
38 Department of Clinical Genetics [Copenhagen]
39 The Netherlands Cancer Institute [Amsterdam, The Netherlands]
40 Radiumhemmet
41 Department of Oncology
42 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un
43 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]
44 Department of Gynaecology and Obstetrics
45 Dept of Haematology and Medical Oncology
46 Department of Epidemiology [Columbia University]
47 Cancer Epidemiology Centre
48 IACR - International Agency for Cancer Research
49 Department of Epidemiology
50 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
51 PSL - Université Paris sciences et lettres
52 Cancer Research U.K. Genetic Epidemiology Unit

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.

Mots clés: Mutation; Risk-reducing salpingo-oophorectomy; BRCA2; BRCA1; Breast cancer

Domaines: Sciences du Vivant [q-bio]; Cancer; Santé publique et épidémiologie; Génétique; Génétique humaine

Nasim Mavaddat, Antonis C. Antoniou, Thea Mooij, Maartje Hooning, Bernadette Heemskerk-Gerritsen, et al.. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers. Breast Cancer Research, 2020, 22 (1), pp.8. ⟨10.1186/s13058-020-1247-4⟩. ⟨inserm-02445596⟩