Chemotherapy-Induced Biological Age Acceleration and Lifetime Outcomes in Breast Cancer Survivors

Importance Growing evidence suggests some breast cancer survivors may experience accelerated aging (biological age in excess of chronological age) after receiving chemotherapy. Objective To quantify the range of lifetime changes in accelerated aging following chemotherapy. Design, Setting, and Participants This comparative effectiveness study used an established Cancer Intervention and Surveillance Modeling Network breast cancer model integrating biological aging with breast cancer epidemiology. Biological aging was modeled using data on distributions of postchemotherapy senescence measured by p16 INK4a levels, and the model assumed chemotherapy-induced senescence only affected non–breast cancer mortality. The simulated population included US women diagnosed with breast cancer at ages 30 to 79 years between 1990 and 2030, with follow-up until death. Two model simulations were run; the first assumed all women who developed breast cancer received anthracycline, and the second assumed all received nonanthracycline treatment. Modeling was conducted from November 2025 to April 2026. Results were validated by comparing model-predicted trends with findings from the Anthracycline for Early Breast Cancer (ABC) trials. Exposures More vs less cytotoxic chemotherapy, using exemplar anthracycline-based vs nonanthracycline regimens. Main Outcomes and Measures Lifetime outcomes included the age at which the risk of non–breast cancer mortality exceeded the risk of breast cancer mortality by chemotherapy regimen, posttreatment life-years, and all-cause mortality by age group at diagnosis and median senescence levels. Results The study included a simulated population of 400 million US women aged 30 to 79 years diagnosed with breast cancer. Breast cancer survivors who received anthracycline lost 9.4 (IQR, 7.6-11.2) years of remaining life years. Overall, among anthracycline recipients, the risk of non–breast cancer mortality was projected to exceed breast cancer mortality 16 (IQR, 12-19) years earlier than expected based on chronological age. There was heterogeneity in results, with greater variability for women diagnosed at younger vs older ages. Women receiving more vs less cytotoxic regimens were estimated to lose a median difference of 7.6 (IQR, 7.0-8.0) more years of life due to earlier ages at onset of aging-related diseases. The model closely replicated all-cause and 8-year breast cancer survival trends in the ABC trials. Conclusions and Relevance In this simulation model of chemotherapy-induced biological aging, increased breast cancer survival was seen with more (vs less) cytotoxic regimens, but this was paired with greater potential risk of earlier non–breast cancer mortality due to age acceleration. These results suggest the value of integrating knowledge about biological aging into survivorship care and could inform future research to address accelerated aging among breast cancer survivors.