Abstract B021: Breast cancer survivors and expression of p16INK4a, DNA damage, and the SASP prior to and following treatment

Abstract

Abstract Purpose: To examine whether breast cancer therapy accelerates aging via increasing expression of cellular senescence (p16INK4a), the DNA damage response (DDR), or the proinflammatory senescence associated secretory phenotype (SASP), we measured gene expression of these pathways in a cohort of women recruited following a diagnosis of breast cancer (Stage 0-III). Methods: The RISE study is a Los Angeles-based longitudinal, observational study of biological and behavioral processes following surgery, radiation (RT) and/or chemotherapy (CT); and more persistent changes in these processes in the months after adjuvant treatment completion and initiation of endocrine therapy (6, 12, 18 month post-treatment follow-ups). Of the 270 women enrolled in the study, gene expression data was available for 184 women (aged average of 55.5 years, SD 11.2). Peripheral blood mononuclear cells (PBMC) gene expression was determined using RNA sequencing on quality-verified RNA. We determined transcript abundance for cellular senescence marker p16INK4a, genes that express proteins of the SASP, and genes responsive to DNA damage. Longitudinal data for p16INK4a, DDR and SASP were modeled using mixed models, including a quadratic term for time and its interaction with four treatment groups (1: Surgery alone [no RT or CT], RT alone, CT alone, and CT+RT), and a zero-inflated two-part model with p16INK4a. Covariates included age, BMI, race, initial surgery type, receipt of interim surgery, and endocrine therapy. Results: Analyses testing whether there was a change in p16INK4a over time by treatment group revealed that all groups experienced increases in p16INK4a expression over time. At baseline 53% of women had no detectable p16INK4a transcripts in their PBMC samples, and this proportion changed over time across all groups indicating significant increases in women expressing the marker for cellular senescence, p<0.0001. Women receiving CT or CT+RT had a 40% and 36% increase in percentage expressing p16INK4a (26% increase among those with surgery alone and 31% for RT alone) by 18 months post treatment compared to their pretreatment values. Analyses found a significant initial increase in DDR over time in all groups (p's<0.002) followed by a deceleration in all three groups except CT+RT, which continued an upward trajectory. There were also significant increases in SASP across all groups (p’s<0.05), with a significant quadratic effect in the RT group only (p<0.001). Conclusions: These results indicate that there was activation of genes associated with acceleration of biological aging across all groups after breast cancer diagnosis. Survivors had increases in p16INK4a, DNA damage response genes, and SASP from pre to 18 months post treatment for breast cancer. (NCI R01 CA237535) Citation Format: Judith E. Carroll, Catherine M. Crespi, Laura Petersen, Julie E. Bower. Breast cancer survivors and expression of p16INK4a, DNA damage, and the SASP prior to and following treatment [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 B021.