Abstract B018: Long-term epigenetic aging in older breast cancer survivors and non-cancer controls: Preliminary findings from the Thinking and Living with Cancer (TLC) Stud
Authors: Rentscher Kelly E. , Zhai Wanting , Small Brent J. , Ahn Jaeil , Ahles Tim A. , Bethea Traci N. , Breen Elizabeth C. , Cohen Harvey J. , Extermann Martine , Graham Deena M.A. , Jacobsen Paul B. , Jim Heather S.L. , McDonald Brenna C. , Nakamura Zev M. , Patel Sunita K. , Root James C. , Saykin Andrew J. , Tometich Danielle B. , Dyk Kathleen M. Van , Zhou Xingtao , Mandelblatt Jeanne S. , Carroll Judith E. 
Published: January 2023

Abstract
Cancer and its treatments are thought to increase risk for accelerated aging in survivors, and biological aging may be a key mechanism; however, no research to date has examined epigenetic markers of aging in long-term breast cancer survivors. We used data from the Thinking and Living with Cancer (TLC) study to examine whether older breast cancer survivors have accelerated epigenetic aging compared to non-cancer controls several years after treatment completion and whether epigenetic aging related to cognitive and physical function. Non-metastatic breast cancer survivors ages 62–84 years (n=89) and frequency-matched controls (n=101) provided two blood samples between 24- and 60-months post-diagnosis. DNA methylation profiling (Illumina Infinium EPIC array) derived epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging Methylation. Participants completed neuropsychological testing and questionnaires to assess cognitive and physical function at each visit. Mixed-effects models adjusted for chronological age and comorbidities and applied false discovery rate correction for multiple testing. Survivors were 1.04–2.22 years older biologically than controls at the first blood sample based on Horvath, Hannum, and GrimAge measures (corrected ps=.025, .025, and .058, respectively), with marginal differences for Dunedin Pace of Aging (corrected p=.096); however, survivors and controls showed similar changes in epigenetic aging over time. Exposure to prior chemotherapy (with or without hormonal therapy; n=29) was associated with an epigenetic age 1.97–2.71 years older than controls (corrected ps=.005 to .065). Among survivors who received chemotherapy, an older Hannum epigenetic age was associated with poorer self-reported cognition relative to controls (coeff=-0.64, uncorrected p=.047; n.s. after correction). Older breast cancer survivors, particularly those receiving chemotherapy, showed an accelerated epigenetic aging profile compared to their peers without cancer at 24 months or more post-diagnosis, following the completion of active therapy. This study also provides preliminary evidence that survivors who received chemotherapy may be at increased risk for poorer age-related survivorship outcomes.
Citation Format: Kelly E. Rentscher, Wanting Zhai, Brent J. Small, Jaeil Ahn, Tim A. Ahles, Traci N. Bethea, Elizabeth C. Breen, Harvey J. Cohen, Martine Extermann, Deena M.A. Graham, Paul B. Jacobsen, Heather S.L. Jim, Brenna C. McDonald, Zev M. Nakamura, Sunita K. Patel, James C. Root, Andrew J. Saykin, Danielle B. Tometich, Kathleen M. Van Dyk, Xingtao Zhou, Jeanne S. Mandelblatt, Judith E. Carroll. Long-term epigenetic aging in older breast cancer survivors and non-cancer controls: Preliminary findings from the Thinking and Living with Cancer (TLC) Stud [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B018.