Effects of Breast Cancer Adjuvant Chemotherapy Regimens on Expression of the Aging Biomarker, p16INK4a

Abstract

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.

Figure 1.

Chemotherapy-induced changes in p16^INK4a mRNA expression correlate with baseline p16^INK4a expression but not chronologic age. Correlation between chronologic age (A) or baseline p16^INK4a expression (B) and chemotherapy-induced change in p16^INK4a expression. AC = anthracycline; M = regression slope; non-AC = nonanthracycline-containing; NS = not statistically significant (P = .32).

Figure 2.

Patient’s expression levels of p16^INK4a prior to chemotherapy are a major predictor of chemotherapy-induced change in p16^INK4a mRNA expression. Correlation between baseline p16^INK4a expression and chemotherapy-induced change in p16^INK4a expression in patients receiving anthracycline (blue line) or nonanthracycline-containing regimens (orange line) (A) or patients who received (lavender line) or did not received (green line) postchemotherapy radiation (B). AC = anthracycline.

Figure 3.

Patients whose p16^INK4a expression levels are increased by chemotherapy are not restricted to any 1 treatment. Distribution of patients whose p16^INK4a levels increased above assay precision is similar among chemotherapy regimens commonly used to treat early stage breast cancer patients.