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

Abstract

Background While chemotherapy saves lives, increasing evidence shows that chemotherapy accelerates aging. We previously demonstrated that mRNA expression of p16INK4a, 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 p16INK4a 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. p16INK4a expression was analyzed pre-chemotherapy and post-chemotherapy (median 6.2 months after the last chemotherapy) in peripheral blood T-lymphocytes. Chemotherapy-induced change in p16INK4a expression was compared among regimens. All statistical tests were two-sided. Results In 146 women, chemotherapy was associated with a statistically significant increase in p16INK4a 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). Non-anthracycline-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 p16INK4a levels, but not chronologic age or race, were also associated with the magnitude of increases in p16INK4a. Patients with lower p16INK4a 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 p16INK4a level. Measurement of p16INK4a expression is not currently available in the clinic, but non-anthracycline regimens offering similar efficacy as anthracycline regimens might be favored.

A biomarker of aging, p16, predicts peripheral neuropathy in women receiving adjuvant taxanes for breast cancer

“…Surprisingly, we found that patients with the greatest risk were chronologically older but molecularly younger (lower p16 expression). Although our findings of higher CIPN risk for those with age-inappropriately low p16 (low p16Age Gap) initially seemed counterintuitive, this paradoxical result can be understood in the context of data demonstrating that patients with lower baseline p16 expression are more likely to have a larger chemotherapy-induced increase in p16 49 (Figure 3A). And larger chemotherapy-induced change in p16 expression (pre-treatment to post-treatment) is associated with higher CIPN risk (Figure 3B).…”

“…Finally, we asked why patients with lower baseline p16 expression may be at higher risk of CIPN. We previously showed that p16 expression prior to chemotherapy is inversely correlated with the magnitude of chemotherapy-induced p16 increase 49 (also Figure 3A). Patients who experienced a post-chemotherapy increase in p16 were twice as likely to develop CIPN (37.5% vs 18.3%, p=0.02) as patients whose p16 did not change (Figure 3B).…”

“…Peripheral blood samples were collected prior to starting chemotherapy and again at the end of chemotherapy, T cells were isolated, and p16 mRNA expression was analyzed by real-time qPCR as described [45][46][47] . Positive and negative controls were included in each run; overall precision of p16 measurement (biological and technical) was 0.8 Ct.…”

The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence

“…In stage 0-IIIa breast cancer patients analyzed a median of 6.2 months after their last round of chemotherapy, anthracycline-based regimens significantly upregulated p16 INK4 comparably to 23-26 years chronologic aging. In contrast, non-anthracycline regimens nonsignificantly increased p16 INK4 levels by a magnitude equivalent to 9-11 years of chronologic aging (155).…”

The Interplay Between Autophagy and Senescence in Anthracycline Cardiotoxicity

“…The above-mentioned mechanism may explain the accumulation of senescent cells observed in cancer patients undergoing radiotherapy/chemotherapy regimen and associated with high risk of premature age-related cardiovascular complications [49••]. Clinical studies reported that patients receiving chemotherapy treatment have accumulation of p16 INK4a -positive cells in different tissues, including the heart [50][51][52][53], which is detected within 1 year from treatment interruption [52][53][54].…”