Abstract IA015: The tick-tock of epigenetic clocks in patients with cancer

Abstract

Abstract There is a growing need to understand how aging influences cancer outcomes in older adults. Prior work shows that older adults with cancer would elect to forgo life-prolonging therapies that would lead to cognitive or physical disability. Here, we hypothesized that aging biomarkers would define individuals at risk for impairment and identify therapeutic regimens associated with accelerated aging. We first tested whether published epigenetic clocks would maintain validity in isolated CD3+ T cells. Potential advantages of using this approach in cancer patients include reduced sample complexity, the ability to survey aging in the context of clonal B cell expansions, and the critical importance of this cell population in cancer control. The Hannum, Horvath, GrimAge, PhenoAge, and PACE clocks increased with chronologic age in CD3+ T cells from 185 healthy donors. However, accelerated epigenetic age varied in PBMCs and CD3+ T cells isolated from the same blood sample. Next, we conducted a longitudinal analysis of adults ≥60 years of age newly diagnosed with non-small cell lung cancer (n=41) or hematologic malignancy (n=94). Standard clinical tools were used to assess fitness (ECOG performance, IADLs, SPPB), comorbidities, cognition (BOMC), and potential for therapeutic toxicity (CARG chemo-toxicity calculator). Relationships between these metrics and baseline CD3+ T cell epigenetic age were investigated. These analyses revealed a direct correlation between epigenetic age and increasing ECOG performance score. Cancer therapies, including high-dose chemotherapy, immunotherapies, and hypomethylating agents, significantly impacted patient epigenetic age. No relationship between outcome and baseline epigenetic age was observed in either population. These data support the use of the Hannum, Horvath, GrimAge, PhenoAge, and PACE clocks to measure aging in CD3+ T cells, though differences in PBMC and CD3+ T cell measurements suggest that the rate of epigenetic aging may differ in each sample type. The inability of epigenetic clocks to consistently measure physical function and cognition or predict patient outcomes implies that new clocks may be required to circumvent the heterogeneity of disease, therapies, and comorbidities in older adults with cancer. Citation Format: Christin E. Burd. The tick-tock of epigenetic clocks in patients with cancer [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 IA015.