Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer.

Academic Article

Abstract

  • BACKGROUND: Senescent cells, which express p16 (INK4a) , accumulate with aging and contribute to age-related pathology. To understand whether cytotoxic agents promote molecular aging, we measured expression of p16 (INK4a) and other senescence markers in breast cancer patients treated with adjuvant chemotherapy. METHODS: Blood and clinical information were prospectively obtained from 33 women with stage I to III breast cancer at four time points: before anthracycline-based chemotherapy, immediately after anthracycline-based chemotherapy, 3 months after anthracycline-based chemotherapy, and 12 months after anthracycline-based chemotherapy. Expression of senescence markers p16 (INK4a) and ARF mRNA was determined using TaqMan quantitative reverse-transcription polymerase chain reaction in CD3(+) T lymphocytes, telomere length was determined by Southern analysis, and senescence-associated cytokines were determined by enzyme-linked immunosorbent assay. Findings were independently assessed in a cross-sectional cohort of 176 breast cancer survivors enrolled a median of 3.4 years after treatment; 39% previously received chemotherapy. All statistical tests were two-sided. RESULTS: In prospectively analyzed patients, expression of p16 (INK4a) and ARF increased immediately after chemotherapy and remained elevated 12 months after treatment. Median increase in log2 p16 (INK4a) was 0.81 (interquartile range = 0.28-1.62; Wilcoxon signed-rank P < .001), or a 75% absolute increase in expression, equivalent to the increase observed over 14.7 years of chronological aging. ARF expression was comparably increased (P < .001). Increased expression of p16 (INK4a) and ARF was associated with dose-dense therapy and hematological toxicity. Expression of two senescence-associated cytokines (VEGFA and MCP1) was durably increased by adjuvant chemotherapy. Telomere length was not affected by chemotherapy. In a cross-sectional cohort, prior chemotherapy exposure was independently associated with a log2-increase in p16 (INK4a) expression of 0.57 (repeated measures model, P < .001), comparable with 10.4 years of chronological aging. CONCLUSIONS: Adjuvant chemotherapy for breast cancer is gerontogenic, inducing cellular senescence in vivo, thereby accelerating molecular aging of hematopoietic tissues.
  • Keywords

  • ADP-Ribosylation Factors, Adult, Aged, Animals, Anthracyclines, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Breast Neoplasms, Cellular Senescence, Cross-Sectional Studies, Cyclin-Dependent Kinase Inhibitor p16, Cytokines, Female, Humans, Mice, Middle Aged, Neoplasm Staging, Prospective Studies, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Telomere
  • Digital Object Identifier (doi)

    Author List

  • Sanoff HK; Deal AM; Krishnamurthy J; Torrice C; Dillon P; Sorrentino J; Ibrahim JG; Jolly TA; Williams G; Carey LA
  • Start Page

  • dju057
  • Volume

  • 106
  • Issue

  • 4