Impact of biological aging due to chemotherapy on breast cancer survivorship

Background: Chemotherapy improves breast cancer survival, but also increases the accumulation of senescent cells in breast cancer survivors. Excess accumulation of senescent cells increases inflammation and tissue damage, which leads to premature onset of age-related diseases (biological age acceleration) in breast cancer survivors. Objective : We integrate a systems biology model of accumulation of senescent cells with chronological age and a well-established Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation model to estimate the impact of biological age acceleration on survivorship outcomes. Methods: We used published data on senescence biomarker expression level (p16 INK4a mRNA expression) in chemotherapy recipient breast cancer survivors to simulate the elevated senescence expression level in the remaining lifetime of breast cancer survivors. The difference in the senescence expression level in the chemotherapy group was evaluated against the expression level in the general female population to quantify the biological age acceleration after chemotherapy. The biological age, instead of chronological age, was used to determine the hazard of non-breast cancer mortality in chemotherapy recipient breast cancer survivors. We used CISNET breast cancer simulation model to simulate multi-birth cohorts of US females diagnosed with breast cancer to estimate survivorship outcomes after chemotherapy. Outcomes included remaining life years after breast cancer diagnosis, absolute number of non-breast cancer deaths, and time-point of transition to dominant risk of non-breast cancer mortality. Results: Biological age acceleration after anthracycline-based regimens caused a greater loss of life years than anthracycline-free regimens for women diagnosed at ages 30-39 years (median of 17.7 years vs. 2.8 years lost). Within the anthracycline group, life years lost varies from 10.4 years to 23.3 years, depending on the level of biological age acceleration. The loss in life years diminished with increasing age at diagnosis (median of 7.5 years vs. 2.2 years lost for 70-79 year old women). The risk of non-breast cancer mortality exceeded breast cancer mortality up to 10-15 years earlier than expected based on chronological age, especially after anthracycline-based regimens. Conclusions: Including biological age acceleration as a factor in breast cancer life history simulation models can help to identify subgroups of breast cancer survivors who need targeted survivorship care for non-breast cancer mortality. Biological age acceleration is a crucial factor especially for the long-term care of younger chemotherapy recipient breast cancer survivors.