How Breast Cancer Chemotherapy May Impact Biological Aging and Loss of Healthy Life Years

Chemotherapy helps many women survive breast cancer, but the results of new research suggest that chemotherapy may also accelerate biological aging beyond chronological age and increase the risk of earlier death from other causes.  The study, by researchers at Georgetown University’s Lombardi Comprehensive Cancer Center and colleagues, is the first to estimate the lifetime balance of the benefits of curing breast cancer versus possible acceleration of biological aging using population-based simulation modeling. The findings point to a need to explore whether interventions to slow or reverse biological aging could improve long-term health for breast cancer survivors.

“Female breast cancer survivors comprise the single largest segment of the 18.6 million cancer survivors in the United States, said Jeanne Mandelblatt, MD, MPH, director of the Georgetown Lombardi’s Institute for Cancer and Aging Research (I-CARE). “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.” Mandelblatt notes that this accelerated biological aging can result in loss of healthy life years due to earlier onset of aging diseases and conditions like frailty and cognitive problems. “Chemotherapy-induced biologic aging can persist for years, and the effects of this acceleration are not visible for many years.”

Senior author Mandelblatt, together with first and corresponding author Swarnavo Sarkar, PhD, a member of I-CARE at Lombardi, and colleagues reported their findings in JAMA Open Network, titled “Chemotherapy-Induced Biological Age Acceleration and Lifetime Outcomes in Breast Cancer Survivors.” In their report the investigators concluded “These findings suggest that integrating knowledge about biological aging into survivorship care may help identify opportunities to deploy pharmaceutical and behavioral interventions that target aging-related processes.”

While breast cancer survival rates have been steadily increasing over time due to advances in screening and therapeutics, growing evidence also suggests that some breast cancer survivors may experience long-term toxic effects of chemotherapy, including accelerated aging (biological age in excess of chronological age), the authors wrote. This may be associated with the development of chronic aging-related diseases such as cardiovascular disease and diabetes.

“One mechanism by which chemotherapy accelerates aging is through increases in the accumulation of senescent cells, defined as cells that have stopped dividing but are resistant to cell death,” the team continued. “These cells promote further aging through changes in tissue modeling and inflammation, contributing to excess non–breast cancer morbidity and mortality.”

To investigate the potential long-term effect of cancer therapy on the biological aging of breast cancer survivors the team carried out a comparative effectiveness study that used an established population-level simulation model, and current data on chemotherapy’s effects on cellular senescence. “This comparative effectiveness study used an established Cancer Intervention and Surveillance Modeling Network breast cancer model integrating biological aging with breast cancer epidemiology,” they wrote.

The investigators used data about the relationships between chemotherapy and blood levels of the p16 protein, a common biomarker of senescence, to estimate the biological age of breast cancer survivors over their remaining lives. “Biological aging was modeled using data on distributions of post-chemotherapy senescence measured by p16^INK4a levels, and the model assumed chemotherapy-induced senescence only affected non–breast cancer mortality,” they explained. The p16 protein levels were used for this study because there is good data from published research and there is evidence from the lab that clearing p16-rich cells could increase their lifespan. There are also evolving studies of other biological aging markers that could be used in future studies.

The population simulation model the researchers developed was based on women who were 30 to 79 years of age; the model compared the effects of types of chemotherapy that caused more vs. less cellular damage (i.e., cytotoxic) and biological age acceleration. Breast cancer survivors who received the most cytotoxic anthracycline regimens were estimated to have lost 9.4 remaining life years on average due to earlier onset of aging-related diseases. “Survivors diagnosed at early ages and/or treated with the most cytotoxic regimens were projected to have the greatest biological age acceleration, with increased risk of death from non–breast cancer causes at earlier chronological ages than expected in general populations,” the researchers stated.

Sarkar added. “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. Senescent cells secrete biological molecules that cause several aging-related diseases through added tissue damage and inflammation.”

The data analysis was possible because both Mandelblatt and Sarkar are members of CISNET (Cancer Intervention and Surveillance Modeling Network), a 25-year-old consortium of National Cancer Institute-sponsored investigators who use simulation modeling to improve the understanding of cancer prevention, screening, and treatment and their effects on population trends in incidence and mortality.

While treatment choices will always be based on the potential to cure, Mandelblatt hopes that the model results can be used to guide future studies evaluating the benefits of testing biological age after treatment ends. “Since the goal of treatment is to improve breast cancer survival, oncologists should not modify treatment decisions based on potential for accelerated aging, but our results suggest the need for awareness of possible age acceleration,” the researchers pointed out.

The goal would be to provide personalized survivorship care to mitigate any aging effects of therapy and improve quality of life and health over a survivor’s lifetime. This is particularly salient now, Mandelblatt noted, since physical activity and medications being used for other purposes show promise in slowing accelerated aging in breast and other cancer survivors, which may recoup the loss of life years estimated in this study.

And as the authors also stated, more research is needed to test the impact of biological age assessment and management of biological age acceleration on survivorship outcomes. “Knowledge about the risks of accelerated aging among women exposed to chemotherapy may help motivate lifestyle changes,” they stated. “Further, as evidence on the safety and utility of senolytic and other anti-aging drugs evolves, modeling may help identify populations of survivors at risk for age acceleration who might benefit from pharmacologic intervention.”

Sarkar added, “There are two next steps we are planning, the first being expanding the scope of this methodology for other types of 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. We also plan to include information about survivor characteristics to help guide future conversations about individual outcomes.”

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