The acute effects of adjuvant radiation and chemotherapy on peripheral blood epigenetic age in early stage breast cancer patients

Abstract

Survival has increased in early stage breast cancer (BC), and the late effects of treatment persist for decades. Molecular mechanisms underlying the acceleration of age-related diseases after chemotherapy and radiotherapy are poorly understood. We examined epigenetic changes in peripheral whole blood cells in early stage BC patients undergoing surgery followed by adjuvant radiotherapy, or surgery followed by adjuvant chemotherapy and radiotherapy. DNA methylation experiments were performed on whole blood samples collected before and after adjuvant therapy. Methylation profiles were used to estimate four measures of epigenetic age acceleration-intrinsic, extrinsic, phenotypic, and Grim-and cell counts. We found significant increases in extrinsic, phenotypic, and Grim epigenetic age acceleration and in estimated proportions of senescent T lymphocytes from pre-to posttreatment. When examining differential effects by treatment category, most of these increases were significant only in women undergoing radiation alone. Further studies are needed to examine whether these effects are related to the risk of cognitive and functional decline in BC survivors.

Effects of Breast Cancer Adjuvant Chemotherapy Regimens on Expression of the Aging Biomarker, p16INK4a

“…In addition, similar effects of chemotherapy and irradiation on telomere length have been reported ( 14-18 ). Also, measurement of additional biomarkers of aging that capture various molecular mechanisms of aging, such as an increase in inflammation (the measurement of the senescence-associated secretory phenotype) ( 10 ), epigenetic changes ( 19 , 20 ) (DNA methylation panels), and changes in metabolism, may deepen our understanding of processes affected by chemotherapy. Taken together, our results suggest that the choice of chemotherapy regimen, as well as the baseline “molecular age” of the patient, are important factors that determine the pro-aging capacity of chemotherapy regimens.…”

“…Finding biomarkers of aging that capture changes over the entire lifespan and reflect the clinical aspects of aging is a rich and expanding area of research ( 12 , 13 ). Potential biomarkers include inflammatory markers, telomere length ( 14-18 ), sarcopenia, DNA methylation ( 19 , 20 ), and maximal oxygen consumption (vO 2 max) ( 21 ). Expression of p16 INK4a , a biomarker of senescence, is considered a fundamental and dynamic measurement of molecular aging with a 10-fold increase in gene expression between ages 20 and 80 years ( 22 ).…”

Cancer Treatment-Induced Accelerated Aging in Cancer Survivors: Biology and Assessment

“…Not only has epigenetic clock been used to predict cancer risk, but also it has been tested in cancer survivors. For example, a recent study of 72 women with early-stage breast cancer (37 received radiation therapy alone and 35 received chemotherapy and radiotherapy) reported a statistically significantly increase in EEAA ( p = 0.0021), PEAA ( p = 0.015), and GEAA ( p = 3.2 × 10 −6 ) from pre-treatment to post-treatment, but not in IEAA [ 86 ]. Another study tested the Weidner’s clock in 19 patients with HCT [ 13 ].…”

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

“…When peripheral CD8 + T lymphocytes were assessed in metastatic breast cancer patients during the post-salvage taxane chemotherapy follow-up, it was found that CD8 + CD28 − populations were increased in breast cancer patients compared to the control cohort [ 23 ]. In another longitudinal study, radiotherapy and chemotherapy in early-stage breast cancer patients increased senescent cytotoxic T lymphocytes [ 59 ]. Shortened telomere length was observed in peripheral blood mononuclear cells in non-Hodgkin’s lymphoma patients undergoing chemotherapy [ 60 ].…”