Anthracycline Chemo May Accelerate Biological Aging in Breast Cancer Survivors

Breast cancer survivors who receive anthracycline-based chemotherapy may lose a median of 9.4 life-years (IQR, 7.6–11.2) to biological age acceleration, according to findings from a simulation modeling study published in JAMA Network Open.¹

Across a simulated population of 400 million US women diagnosed with breast cancer between the ages of 30 and 79 years, more cytotoxic anthracycline-based regimens were associated with a median of 7.6 more life-years lost (IQR, 7.0-8.0) compared with less cytotoxic nonanthracycline regimens. Among anthracycline recipients, the point at which the risk of non–breast cancer mortality overtook the risk of breast cancer mortality arrived a median of 16 years (IQR, 12-19) earlier than chronological age alone would predict.

According to the investigators, more cytotoxic regimens were associated with higher breast cancer survival but carried a greater potential risk of earlier non–breast cancer mortality stemming from age acceleration. The authors suggested that integrating biological aging into survivorship care could help identify opportunities to use pharmaceutical and behavioral interventions that target aging processes.

“Female breast cancer survivors comprise the single largest segment of the 18.6 million cancer survivors in the US. However, some forms of chemotherapy that extend survival have triggered a secondary crisis: treatment-induced molecular damage to the body’s cells and organs, causing acceleration of biological age,” senior author Jeanne S. Mandelblatt, MD, MPH, director of Georgetown Lombardi’s Institute for Cancer and Aging Research (I-CARE), said in a press release.² “Chemotherapy-induced biologic aging can persist for years, and the effects of this acceleration are not visible for many years.”

To conduct the comparative effectiveness study, investigators led by Swarnavo Sarkar, PhD, of the Department of Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center, extended an established Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer model, known as Model GE, with a systems biology module for cellular senescence. Biological aging was modeled based on postchemotherapy senescence as measured by levels of p16^INK4a. The model assumed that chemotherapy-induced senescence affected only non–breast cancer mortality and that its effects persisted for life without recovery.

“The key to our methodology is accounting for the fact that while chemotherapy improves breast cancer survival, treatment can also increase damage to normal tissues. This affects many aging systems, including increasing the number of senescent cells, which are damaged cells that have stopped dividing and are also resistant to cell death.”

The simulated population included US women diagnosed between 1990 and 2030 who were followed until death. Investigators ran 2 simulations: one in which all women received an anthracycline-based regimen, and one in which all received a nonanthracycline regimen. Main outcomes included the age at which non–breast cancer mortality risk exceeded breast cancer mortality risk, posttreatment life-years, and all-cause mortality by age at diagnosis and senescence level.

Results were validated against the Anthracycline in Early Breast Cancer (ABC) trials. From 100 million simulated women, the model generated 40,166 survivors matching ABC trial characteristics (trial N = 4181). Consistent with the trials, the model showed higher breast cancer survival with anthracycline-based regimens but no difference in all-cause mortality over 8 years.

Women diagnosed at the youngest ages faced the largest potential losses. Among those diagnosed between ages 30 and 39 years, median life-years lost were 11.7 with an anthracycline vs 2.1 with a nonanthracycline regimen, a median difference of 9.6 years. For those diagnosed between ages 40 and 49 years, median losses were 13.9 vs 3.7 life-years, respectively, and the mortality crossover occurred a median of 19 years earlier (IQR, 16–23) with more cytotoxic chemotherapy. Median life-years lost were 11.8 years vs 3.2 for women aged 50 to 59 years, 10.0 vs 3.0 for those aged 60 to 69 years, and 7.0 vs 2.2 for those aged 70 to 79 years. Across all ages, median losses were 9.4 vs 1.8 life-years, translating to absolute posttreatment life-years of 25.0 and 29.7, respectively. Because older women have shorter life expectancy, age acceleration had less of an effect in those groups.

In the first 5 to 10 years after chemotherapy, all-cause survival differed by less than 5% between regimens. After 20 years, however, all-cause mortality was 10% to 25% higher with more cytotoxic regimens, which the investigators attributed to competing non–breast cancer mortality.

The authors described the analysis as the first to integrate a systems biology aging model with an established simulation model to study breast cancer survivorship. They noted that concerns about aging have largely centered on women diagnosed at 65 years or older, although younger women have more life-years at risk and often receive more chemotherapy because of aggressive tumor subtypes.

Importantly, the investigators stated that oncologists should not alter treatment based on aging risk, since the goal of therapy is to improve breast cancer survival; however, they wrote that awareness of possible age acceleration is warranted. They added that biological age acceleration could serve as an end point in correlative trial studies, and that the findings may help motivate survivors to adopt lifestyle interventions already recommended to slow aging, such as physical activity and improved sleep. Senolytic and other anti-aging agents may also have a future role, pending further evidence.

Limitations of the study included reliance on a single aging biomarker, hypothetical all-or-none treatment scenarios that did not reflect real-world treatment selection, and the use of only 2 exemplar regimens. Radiation, hormonal therapy, targeted therapy, and immunotherapy were not explicitly modeled due to limited data. The model also assumed baseline p16INK4a was independent of breast cancer risk, and senescence data were not stratified by social or environmental exposures. The authors characterized the results as illustrative.

Sarkar said the team plans to expand the methodology to other breast cancer treatments, “such as radiotherapy, immunotherapies, targeted therapies and hormonal treatments, which also appear to speed up aging, with effects potentially lasting for many years after treatment.” The investigators also intend to incorporate survivor characteristics to help guide future conversations about individual outcomes.

Looking ahead, the investigators concluded that future versions of the model could inform survivorship guidelines personalized to biological rather than chronological age. Because breast cancer is the most prevalent cancer among female survivors, they noted that strategies targeting aging mechanisms could improve both the quality and quantity of life for this population.

Reference

1. Sarkar S, Sedrak MS, Carroll JE, Schechter C, Muss HB, Mandelblatt JS. Chemotherapy-induced biological age acceleration and lifetime outcomes in breast cancer survivors. JAMA Netw Open. 2026;9(11):e2643008. doi:10.1001/jamanetworkopen.2026.43008
2. Chemotherapy for breast cancer linked to accelerated biological aging. News release. Georgetown Lombardi Comprehensive Cancer Center. November 10, 2026. Accessed November 12, 2026. https://tinyurl.com/4yj7chpx