“Adjuvant chemotherapy for breast cancer is gerontogenic,” accelerating the pace of physiologic aging, according to an analysis of blood and clinical data from 33 women with stage I to III breast cancer. “We have shown that cytotoxic chemotherapy potently induces the expression of markers of cellular senescence in the hematologic compartment in vivo, comparable with the effects of 10 to 15 years of chronologic aging in independent cohorts of healthy donors,” Hanna K. Sanoff, MD, of the University of North Carolina School of Medicine at Chapel Hill, and colleagues concluded in the study report published in the Journal of the National Cancer Institute.
“Cellular senescence is triggered by the activation of tumor-suppressor mechanisms in response to varied cellular stresses such as oncogene activation, tissue injury, telomere dysfunction, and persistent DNA damage,” the researchers explained. The authors previously showed p16INK4a is a marker of accelerated molecular age in peripheral blood T lymphocytes associated with smoking, physical inactivity, and chronic human immunodeficiency virus infection.
Blood and clinical data were prospectively obtained from women before, immediately after, 3 months after, and 12 months after neoadjuvant or adjuvant anthracycline-based chemotherapy. The median age of the women was 49. “The women had few comorbid conditions, although nearly half were obese,” the investigators noted. Most women received adjuvant doxorubicin and cyclophosphamide, usually in a dose-dense fashion, and a taxane.
Analyzing the blood for markers of cellular senescence, the researchers observed increased expression of the senescence markers p16INK4a and ARF in peripheral blood T lymphocytes immediately after chemotherapy, and these remained elevated for at least a year after treatment. The median increase in log2p16INK4a represented “a 75% increase equivalent to the increase observed over 14.7 years of chronological aging. ARF expression was comparably increased (P < .001). Increased expression of p16INK4a and ARF was associated with dose-dense therapy and hematological toxicity,” the authors stated.
“Expression of two senescence-associated cytokines (VEGFA and MCP1) was durably increased by adjuvant chemotherapy,” the authors continued. Telomere length, previously identified as a marker of cellular senescence, was not affected by chemotherapy.
An independent cross-sectional cohort of 176 long-term breast cancer survivors confirmed the effect of chemotherapy on p16INK4a expression comparable with 10.4 years of chronologic aging. “Because patients in this cohort were a median 3.4 years from the completion of chemotherapy (some up to 18 years from treatment), these results suggest that the sharp increase in p16INK4a expression observed after chemotherapy persists for at least several years, if not indefinitely, after chemotherapy exposure,” the authors stated.
The investigators noted:
Adjuvant anthracycline-based chemotherapy unequivocally saves lives, markedly decreasing the relative risk of breast cancer recurrence by 27% and death by 21%. Therefore, we believe the finding of durable, age-promoting effects of anthracyclines and alkylating agents must be weighed against these established benefits with regard to relapse risk. The ability to serially measure markers of molecular age in patients may provide a means to identify beneficial adjuvant approaches that are less ‘pro-aging.’
The researchers are currently enrolling in two prospective trials, “one evaluating whether changing PBTL p16INK4a expression is a biomarker of acute toxicity of various chemotherapy regimens (LCCC1027, NCT01305954); and a second focused exclusively on older patients evaluating the combination of a validated geriatric assessment and PBTL p16INK4a for prediction of treatment-related toxicity and change in function (NCT01472094).” ■
Sanoff HK, et al: J Natl Cancer Inst 106(4):dju057, 2014.