||5R37CA263064-03 Interpret this number
||University Of Hawaii At Manoa
||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 co-morbidity, functional
decline, and accelerated biologic aging. Resistance training (RT) interventions may help to
minimize this functional decline by increasing lean mass and strength. 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. Geriatric assessment, which measures
facets of functional aging, can improve the prediction of chemotoxicity risk to guide treatment
decisions. However, application of this tool is frequently limited by the resources required for
assessment. 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.
Epigenetic age acceleration (AgeAccel; DNAm-estimated age adjusting for chronologic age) has
been associated with indicators of decreased muscle mass and function. We hypothesize that
colon cancer patients with increased 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 plan to address this scientific
premise 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
DNA and multi-modal measures of body composition collected at the beginning and end of
chemotherapy. Our first primary aim will evaluate the relationship between several measures of
AgeAccel at baseline and incidence of grade 3 and 4 chemotoxicities, dose reductions, and delays
among FORCE participants. We anticipate that increased baseline AgeAccel will be associated
with an increased incidence of these outcomes, and that RT can reduce the strength of these
associations. Our second primary aim will assess the rate of epigenetic aging during treatment,
and whether this rate is modified by RT. We expect that AgeAccel will be higher at the end of
chemotherapy relative to the beginning, and that the rate of epigenetic aging will be attenuated in
the RT group. Together, these analyses will provide novel insight into the biologic processes of
aging that predict tolerance of cancer treatment, and inform appraisal of whether AgeAccel may
serve as a useful tool to guide treatment decisions.
D3-creatine dilution, computed tomography and dual-energy X-ray absorptiometry for assessing myopenia and physical function in colon cancer: A cross-sectional study.
, Caan B.J.
, Cawthon P.M.
, Evans W.J.
, Hellerstein M.K.
, Shankaran M.
, Campbell K.L.
, Binder A.M.
, Sternfeld B.
, Meyerhardt J.A.
, et al.
Journal of cachexia, sarcopenia and muscle, 2023-10-30; , .