Cardiovascular Risk in BRCA1/2 Mutation Carriers: A Matched Cohort Study of Breast Cancer Survivors

Introduction: Cardiovascular disease (CVD) is a leading non-cancer cause of morbidity among breast cancer (BC) survivors. Among them, women carrying germline BRCA1 or BRCA2 mutations (BRCA-BC) may be at particular risk of CVD, but evidence is inconsistent. The objective of this study is to determine whether BRCA-BC independently influences the risk for CVD after BC diagnosis in the Stockholm-Gotland region in Sweden (2008-2019). Methods: In this registry-based cohort study, we used exact matching on age at diagnosis, tumor stage, laterality, and pre-existing CVD or risk factors to construct 32 matched (1:1) subgroups. Multi-state Cox proportional hazards models estimated hazard ratios (HRs) for transitions from BC diagnosis to first cardiovascular event, while accounting for competing risks of distant metastasis or non-cardiovascular death. Results: In matched subgroups, BRCA-BC experienced fewer CVD (6.4% vs. 11.2% (IQR 9.4%-12.2%), but significantly more competing events (22.3% vs. 10.1% (IQR 8.9%-11.3%); p<0.05. Multi-state Cox models revealed an inverse association between BRCA-BC status and the first cardiovascular event (HR<1), but a higher hazard of the competing risk. Cardiovascular events clustered in the first year after BC diagnosis, especially among BRCA-BC, suggesting truncated time at risk. Conclusion: BRCA-BC did not demonstrate increased cardiovascular risk after BC diagnosis. The apparent inverse association with CVD likely reflects the high incidence of competing risks, which limit the window for CVD to manifest. A small subgroup of long-term BRCA-BC survivors may represent biologically distinct individuals with different cardiovascular susceptibility, warranting further investigation.