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BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1 , risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers. • Contralateral breast cancer (CBC) risk is high in BRCA1/2 mutation carriers. • Chemotherapy for primary breast cancer results in decreased CBC risk in BRCA1. • Anthracyclines with/without taxanes show the largest CBC risk reduction in BRCA1. • For BRCA2 similar trends are observed as in BRCA1 mutation carriers. • Chemotherapy must be considered in personalised CBC risk models. [ABSTRACT FROM AUTHOR]

Background: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure one to three years after a premenopausal oophorectomy. However, the long-term effects of a premenopausal oophorectomy on sexual functioning are unknown.Objective: Our aim was to study long-term sexual functioning in women at increased familial risk of breast/ovarian cancer who underwent a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group), or after the age of 54 years (postmenopausal group). We performed subgroup analyses in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy.Study Design: Between 2018 and 2021, we invited 817 women with a high familial risk of breast/ovarian cancer from an ongoing cohort study to participate in our study. Due to a large difference in age at study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual functioning between the groups to 368 women who were 60-70 years old at completion of the questionnaire (premenopausal group, n=226, postmenopausal group, n=142). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy we compared sexual functioning between women in the early premenopausal group (n=151) and the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes/no) and body image.Results: Mean time since risk-reducing salpingo-oophorectomy was 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (p-value <.001). In the premenopausal group, mean age at questionnaire completion was 62.7 years, versus 67.0 years in the postmenopausal group (p<.001). In the premenopausal group, 47.4% was still sexually active, compared to 48.9% of the postmenopausal group (p-value: .80). Current sexual pleasure scores were the same for women in the premenopausal group and the postmenopausal group (mean pleasure score 8.6, p-value .99). However, women in the premenopausal group more often reported substantial discomfort than women in the postmenopausal group (35.6% compared with 20.9%, p-value .04). After adjusting for confounders, premenopausal risk-reducing salpingo-oophorectomy was associated with substantially more discomfort during sexual intercourse, compared to postmenopausal risk-reducing salpingo-oophorectomy (odds ratio 3.1, 95% confidence interval 1.04; 9.4). Moreover, following premenopausal risk-reducing salpingo-oophorectomy, more severe complaints of vaginal dryness were observed (odds ratio 2.6, 95% confidence interval 1.4; 4.7). Women with a risk-reducing salpingo-oophorectomy before age 41 reported similar pleasure and discomfort scores as women with a risk-reducing salpingo-oophorectomy between ages 41 and 45.Conclusion: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was comparable to that among women with a postmenopausal risk-reducing salpingo-oophorectomy. However, after a premenopausal risk-reducing salpingo-oophorectomy, women experienced more vaginal dryness and more often had substantial sexual discomfort during sexual intercourse. This did not lead to less pleasure with sexual activity. [ABSTRACT FROM AUTHOR]