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

aging

cancer

genetics

senescence

telomere length

Authors: Hanna K HK. Sanoff, Allison M AM. Deal, Janakiraman J. Krishnamurthy, Chad C. Torrice, Patrick P. Dillon, Jessica J. Sorrentino, Joseph G JG. Ibrahim, Trevor A TA. Jolly, Grant G. Williams, Lisa A LA. Carey, Amy A. Drobish, Brittaney-Belle BB. Gordon, Shani S. Alston, Arti A. Hurria, Karin K. Kleinhans, K Lenhard KL. Rudolph, Norman E NE. Sharpless, Hyman B HB. Muss
Published: 03/28/2014, Journal of the National Cancer Institute

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.

PubMed Full Text