Effects of Breast Cancer Adjuvant Chemotherapy Regimens on Expression of the Aging Biomarker, p16(INK4a)

BACKGROUND: Although chemotherapy saves lives, increasing evidence shows that chemotherapy accelerates aging. We previously demonstrated that mRNA expression of p16(INK4a), a biomarker of senescence and molecular aging, increased early and dramatically after beginning adjuvant anthracycline-based regimens in early stage breast cancer patients. Here, we determined if changes in p16(INK4a) expression vary by chemotherapy regimen among early stage breast cancer patients. METHODS: We conducted a study of stage I-III breast cancer patients receiving adjuvant or neoadjuvant chemotherapy. p16(INK4a) expression was analyzed prechemotherapy and postchemotherapy (median 6.2 months after the last chemotherapy) in peripheral blood T lymphocytes. Chemotherapy-induced change in p16(INK4a) expression was compared among regimens. All statistical tests were 2-sided. RESULTS: In 146 women, chemotherapy was associated with a statistically significant increase in p16(INK4a) expression (accelerated aging of 17 years; P < .001). Anthracycline-based regimens were associated with the largest increases (accelerated aging of 23 to 26 years; P ≤ .008). Nonanthracycline-based regimens demonstrated a much smaller increase (accelerated aging of 9 to 11 years; P ≤ .15). In addition to the type of chemotherapy regimen, baseline p16(INK4a) levels, but not chronologic age or race, were also associated with the magnitude of increases in p16(INK4a). Patients with lower p16(INK4a) levels at baseline were more likely to experience larger increases. CONCLUSIONS: Our findings suggest that the aging effects of chemotherapy may be influenced by both chemotherapy type and the patient’s baseline p16(INK4a) level. Measurement of p16(INK4a) expression is not currently available in the clinic, but nonanthracycline regimens offering similar efficacy as anthracycline regimens might be favored.