Contraceptives and cancer risks in BRCA1/2 pathogenic variant carriers: a systematic review and meta-analysis

• Published in: Human reproduction update 2023-03, Vol.29 (2), p.197-217
• Main Authors: van Bommel, Majke H D, IntHout, Joanna, Veldmate, Guus, Kets, C Marleen, de Hullu, Joanne A, van Altena, Anne M, Harmsen, Marline G
• Format: Article
• Language: English
• Subjects: BRCA1 Protein - genetics; Breast Neoplasms - epidemiology; Breast Neoplasms - genetics; Contraceptive Agents; Female; Genetic Predisposition to Disease; Humans; Mutation; Ovarian Neoplasms; Reproducibility of Results; Review
• ISSN: 1355-4786; 1460-2369; 1460-2369
• DOI: 10.1093/humupd/dmac038

Abstract BACKGROUND Increasing numbers of BReast CAncer (BRCA) 1 or 2 pathogenic variant (PV) carriers, who have an inherited predisposition to breast and ovarian cancer, are being identified. Among these women, data regarding the effects of contraception on cancer risks are unclear and various guidelines provide various recommendations. OBJECTIVE AND RATIONALE We aim to optimize counselling regarding contraception for BRCA1/2-PV carriers. Therefore, we performed a systematic review and meta-analysis. We investigated the risk ratio for developing breast cancer or ovarian cancer in BRCA1/2-PV carriers who have used any form of contraception versus non-users. Second, we analysed breast and ovarian cancer risk among BRCA1/2-PV carriers as influenced by the duration of contraceptive use and by the time since last use. In addition, we provide an overview of all relevant international guidelines regarding contraceptive use for BRCA1/2-PV carriers. SEARCH METHODS A systematic search in the Medline database and Cochrane library identified studies describing breast and/or ovarian cancer risk in BRCA1/2-PV carriers as modified by contraception until June 2021. The search included medical subject headings, keywords and synonyms related to BRCA and contraceptives (any kind). PRISMA guidance was followed. Risk Of Bias In Non-randomized Studies of Interventions and Grading of Recommendations, Assessment, Development and Evaluations assessments were performed. Random-effects meta-analyses were used to estimate pooled effects for breast and ovarian cancer risk separately. Subgroup analyses were conducted for BRCA1 versus BRCA2 and for the various contraceptive methods. OUTCOMES Results of the breast cancer risk with oral contraceptive pill (OCP) analysis depended on the outcome measure. Meta-analyses of seven studies with 7525 women revealed a hazard ratio (HR) of 1.55 (95% CI: 1.36–1.76) and of four studies including 9106 women resulted in an odds ratio (OR) of 1.06 (95% CI: 0.90–1.25), heterogeneity (I2) 0% and 52%, respectively. Breast cancer risk was still increased in ever-users compared with never-users >10 years after last OCP use. In contrast, ovarian cancer risk was decreased among OCP users: HR 0.62 (95% CI: 0.52–0.74) based on two studies including 10 981 women (I2: 0%), and OR 0.49 (95% CI: 0.38–0.63) based on eight studies including 10 390 women (I2: 64%). The protective effect vanished after cessation of use. Tubal ligation also protects against ovarian canc