Circulatory and other-cause mortality after neoadjuvant versus adjuvant chemotherapy in women with stage II-III breast cancer.

Abstract

Most women with operable breast cancer increasingly survive long enough for non-cancer causes to become important contributors to mortality, particularly at older ages. We investigated whether the recorded sequence of systemic therapy relative to surgery among women receiving chemotherapy was associated with circulatory mortality and examined how causes of death evolve in long-term survivors. This retrospective population-based cohort study included 74,233 women with stage II-III non-metastatic invasive breast cancer diagnosed between 2010 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database who received chemotherapy and definitive surgery. A six-month landmark was used to reduce immortal-time bias, and treatment groups were balanced using stabilized inverse-probability-of-treatment weighting. Weighted cumulative incidence, cause-specific hazard, and Fine-Gray subdistribution models were used to evaluate circulatory mortality, while mortality patterns after a five-year landmark were examined descriptively by age. Median follow-up was 10.8 years. The weighted 10-year cumulative incidence of circulatory death was 2.06% after recorded preoperative systemic therapy and 2.10% after postoperative therapy, corresponding to a risk difference of -0.05 percentage points (95% confidence interval [CI], -0.31 to 0.18). The cause-specific hazard ratio was 1.092 (95% CI, 0.968-1.231), and the subdistribution hazard ratio was 1.024 (95% CI, 0.920-1.140). Among deaths occurring after the five-year landmark, the circulatory share increased with age, reaching 25.5% in women aged ≥75 years at diagnosis; however, other non-circulatory causes remained the largest category (49.9%). In women aged ≥75 years who survived five years, circulatory mortality approached and eventually exceeded breast-cancer mortality, but the difference was not significant at the prespecified seven-year time point. The recorded systemic-therapy/surgery sequence was not associated with long-term circulatory mortality. In older long-term breast-cancer survivors, late mortality is predominantly multimorbid rather than circulatory-dominant, supporting survivorship care that addresses cardiovascular risk within a broader framework of age-related competing health risks.