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Meta-Analysis
. 2023 Mar 1;29(2):197-217.
doi: 10.1093/humupd/dmac038.

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

Majke H D van Bommel  1 , Joanna IntHout  2 , Guus Veldmate  3 , C Marleen Kets  4 , Joanne A de Hullu  1 , Anne M van Altena  1 , Marline G Harmsen  1
Affiliations
Meta-Analysis

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

Majke H D van Bommel et al. Hum Reprod Update. .

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 cancer: one study including 3319 women (I2: 0%): HR: 0.44 (95% CI: 0.26-0.74) and three studies with 7691 women (I2: 44%): OR: 0.74 (95% CI: 0.53-1.03). Data regarding other contraceptives were unavailable. No differences were observed between BRCA1 and BRCA2-PV carriers. The quality of evidence was either low or very low.

Wider implications: The OCP potentially increases breast cancer risk, while ovarian cancer risk decreases with either the OCP and tubal ligation in BRCA1/2-PV carriers. Counselling of BRCA1/2-PV carriers should be personalized; the genetic and non-genetic factors (like prior risk-reducing surgeries, prior breast cancer and age) and patients' preferences (reversibility, ease of use, reliability and effect on menstrual cycle) should be balanced. To further optimize counselling for high-risk women, future research should focus on other (commonly used) contraceptive methods and cancer risks in this specific population, and on the potential impact of changing formulations over time.

Keywords: BRCA1 gene; BRCA2 gene; breast cancer; contraception; oral contraceptive pill; ovarian cancer; tubal ligation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Graphical Abstract
Graphical Abstract
Contraceptives and cancer risks in BRCA1/2 pathogenic variant carriers: a systematic review and meta-analysis.
Figure 1.
Figure 1.
Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow chart of study selection.
Figure 2.
Figure 2.
Forest plots presenting meta-analysis of breast cancer risk as modified by ever use of the OCP. Analysis split on effect size, i.e. studies reporting a HR versus studies reporting an OR. HR: hazard ratio; N: number of participants; OCP: oral contraceptive pill; BRCA-PV: BRCA1/2 pathogenic variant; OR: odds ratio.
Figure 3.
Figure 3.
Forest plots visualizing the meta-analysis of the influence of ever OCP use on ovarian cancer risk. Analysis split on effect size, i.e. studies reporting a HR versus studies reporting an OR. HR: hazard ratio; N: number of participants; BRCA-PV: BRCA1/2 pathogenic variant; OCP: oral contraceptive pill.
Figure 4.
Figure 4.
Forest plots of the meta-analysis of the influence of TL on ovarian cancer risk. Analysis split on effect size, i.e. studies reporting a HR versus studies reporting an OR. HR: hazard ratio; N: number of participants; BRCA-PV: BRCA1/2 pathogenic variant; TL: tubal ligation.
See this image and copyright information in PMC

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