Effect of Cytotoxic Chemotherapy on Markers of Molecular Age in Patients With Breast Cancer
A partir d'échantillons sanguins prélevés de façon séquentielle sur 33 patientes atteintes d'un cancer du sein de stade I à III (avant une chimiothérapie à base d'anthracycline, immédiatement après, 3 et 12 mois plus tard), cette étude analyse les effets d'une chimiothérapie adjuvante sur des biomarqueurs de la sénescence cellulaire
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.
Journal of the National Cancer Institute , résumé, 2014