Transcriptomic markers of biological aging in breast cancer survivors: a longitudinal study

Abstract

Background The purpose of this study was to examine the impact of breast cancer therapy on biological aging as measured by expression of genes for cellular senescence (p16INK4a, SenMayo), DNA damage response, and proinflammatory senescence-associated secretory phenotype. Methods This longitudinal, observational study evaluated women diagnosed with breast cancer (stage 0-III) prior to radiation therapy (RT) and/or chemotherapy (CT) and at repeated visits out to 2 years. Peripheral blood mononuclear cell gene expression was assessed using RNA sequencing on quality-verified RNA. Longitudinal data were analyzed using mixed linear models and a zero-inflated 2-part model. Results Women (mean age = 55.5 years) receiving CT with or without RT (n = 73) had higher odds (odds ratio = 2.97, 95% confidence interval = 1.52 to 5.8) of having detectable p16INK4a following treatment compared with RT (n = 76) or surgery alone (n = 37). The proportion of women expressing 16INK4a over the follow-up period increased in all treatment groups (P < .001), with no interaction by treatment. All groups also increased over time in DNA damage response (P < .001), SenMayo (P < .001), and senescence-associated secretory phenotype (P < .001). Groups differed in the pattern of increase over time with statistically significant quadratic time by group differences for CT with or without RT compared with RT alone for DNA damage response (P = .05), SenMayo (P = .006), and the senescence-associated secretory phenotype (P = .02). Conclusions Results revealed activation of genes associated with biological aging in women with breast cancer from diagnosis through early survivorship, including DNA damage response, cell senescence, and the inflammatory secretome. Increases were evident across cancer treatments, although women receiving CT showed sustained increases, whereas RT exhibited slowing at later time points. Overall, findings suggest that women treated for breast cancer are aging within their immune cells.