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

Mavaddat N1, Antoniou AC2, Mooij TM3, Hooning MJ4, Heemskerk-Gerritsen BA4; GENEPSO, Noguès C5, Gauthier-Villars M6, Caron O7, Gesta P8, Pujol P9, Lortholary A10; EMBRACE, Barrowdale D2, Frost D2, Evans DG11, Izatt L12, Adlard J13, Eeles R14, Brewer C15, Tischkowitz M16, Henderson A17, Cook J18, Eccles D19; HEBON, van Engelen K20, Mourits MJE21, Ausems MGEM22, Koppert LB23, Hopper JL24, John EM25, Chung WK26,27, Andrulis IL28,29, Daly MB30, Buys SS31; kConFab Investigators, Benitez J32, Caldes T33, Jakubowska A34,35, Simard J36, Singer CF37, Tan Y37, Olah E38, Navratilova M39, Foretova L39, Gerdes AM40, Roos-Blom MJ3, Van Leeuwen FE3, Arver B41,42, Olsson H42, Schmutzler RK43,44, Engel C45, Kast K46,47,48, Phillips KA24,49,50, Terry MB27,51, Milne RL24,52,53, Goldgar DE54, Rookus MA3, Andrieu N55,56,57,58, Easton DF2,59; IBCCS; kConFab; BCFR.

Breast Cancer Res. 2020 Jan 16;22(1):8. doi: 10.1186/s13058-020-1247-4.

Abstract
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.