Characterizing the Risk of Chemotherapy Side Effects Based on Epigenetic Age and Modification by Resistance Training Intervention

There is strong evidence that cancer treatment contributes to increased comorbidity, functional
decline, and accelerated biologic aging. Resistance training (RT) interventions may help to
minimize this functional decline by increasing lean mass. Patients diagnosed with colon cancer
are particularly likely to benefit from RT interventions given the high prevalence of involuntary loss
of skeletal muscle mass (sarcopenia) at diagnosis, which is associated with chemotherapy-
associated toxicities, and poor prognosis. Epigenetic clocks, which predict chronologic or
phenotypic age based on specific patterns of DNA methylation (DNAm), are easy to assay, well-
validated markers of biologic aging. Those with higher epigenetic age acceleration (AgeAccel;
DNAm-estimated age adjusting for chronologic age) are at an elevated risk for morbidity (early
onset of functional impairment, frailty and other aging syndromes) and mortality, independent of
other predictors of longevity. We hypothesize that colon cancer patients with higher blood
AgeAccel will be at greater risk for chemotherapy toxicities, dose reductions, and delays, that
AgeAccel will increase during colon cancer chemotherapy, and that a RT intervention can reduce
the rate of epigenetic aging. We further hypothesize that AgeAccel measured in blood and tumor
tissue will be related to colorectal cancer molecular subtypes and patient prognosis. We plan to
investigate these hypotheses in collaboration with the Resistance Training to Reduce
Chemotoxicity in Colon Cancer (FORCE) clinical trial. This clinical trial of RT in stage II and III
colon cancer patients includes detailed treatment and participant information, tumor specimens,
longitudinal collection of blood and multimodal measures of body composition. Our aims will
investigate whether several measures of blood AgeAccel at baseline relate to the incidence of
moderate/severe chemotoxicities, and relative dose intensity. We will assess the rate of blood
epigenetic aging over chemotherapy, and whether this rate is modified by RT. We will evaluate
whether AgeAccel estimated in blood and tumor tissue differs by colorectal cancer molecular
subtypes and associations with overall survival, recurrence, comorbidity accumulation, and
trajectories of muscle mass. Together, these analyses will provide novel insight into the biologic
processes of aging that predict tolerance for cancer treatment and patient prognosis to inform
appraisal of whether AgeAccel may serve as a useful tool to guide clinical care.

Grant Number: 5R37CA263064-05
NIH Institute/Center: NIH
Principal Investigator: Alexandra Binder