Risks of Second Non-Breast Primaries Following Breast Cancer in Women: A Systematic Review and Meta-Analysis

Background: Second primary cancer incidence is rising among breast cancer survivors. We examined the risks of non-breast second primaries, in combination and at specific cancer sites, through a systematic review and meta-analysis. Methods: We conducted a systematic search of PubMed, Embase, and Web of Science, seeking studies published by March 2022. We included studies that reported standardized incidence ratios (SIRs), with associated standard errors, assessing the combined risk of second non-breast primaries following breast cancer. We performed meta-analyses of combined second primary risks, stratifying by age, follow-up duration, and geographic region. We also assessed second primary risks at several specific sites, stratifying by age. The inverse-variance method with DerSimonian-Laird estimators was used in all meta-analyses, assuming a random-effects model. Associated biases and study quality were evaluated using the Newcastle-Ottawa scale. Results: One prospective and twenty-seven retrospective cohort studies were identified. SIRs for second non-breast primaries combined ranged from 0.84 to 1.84. The summary SIR estimate was 1.24 (95%CI: 1.14-1.36, I 2 99%). This varied by age: the estimate was 1.59 (95%CI: 1.36-1.85) when breast cancer was diagnosed before age 50, which was significantly higher than in women first diagnosed at 50 or over (SIR: 1.13, 95%CI: 1.01-1.36, p for difference: < 0.001). SPC risks were also significantly higher when based on Asian, rather than European, registries (Asia - SIR: 1.47, 95%CI: 1.29-1.67. Europe - SIR: 1.16, 95%CI: 1.04-1.28). There were significantly increased risks of second thyroid (SIR: 1.89, 95%CI: 1.49-2.38), uterus (SIR: 1.84, 95%CI: 1.53-2.23), ovary (SIR: 1.53, 95%CI: 1.35-1.73), kidney (SIR: 1.43, 95%CI: 1.17-1.73), oesophagus (SIR: 1.39, 95%CI: 1.26-1.55), skin (melanoma) (SIR: 1.34, 95%CI: 1.18-1.52), blood (leukaemia) (SIR: 1.30, 95%CI: 1.17-1.45), lung (SIR: 1.25, 95%CI: 1.03-1.51), stomach (SIR: 1.23, 95%CI: 1.12-1.36) and bladder (SIR: 1.15, 95%CI: 1.05-1.26) primaries. Conclusions: Breast cancer survivors are at significantly increased risk of second primaries at many sites. Risks are higher for those diagnosed with breast cancer before age 50 and in Asian breast cancer survivors compared to European breast cancer survivors. This study is limited by a lack of data on potentially confounding variables. The conclusions could inform clinical management decisions following breast cancer.