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

Abstract

Importance: Identifying patients at higher risk of chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet need in oncology given its high incidence and persistence into survivorship. Objective: To determine if expression of p16, a biomarker of aging and cellular senescence, predicts CIPN. Design: Prospective observational cohort study including one hundred fifty-two participants enrolled between January 2014 and August 2018 and followed during the course of adjuvant chemotherapy. Expression of p16 was measured prior to and at the end of chemotherapy. Side effects, including peripheral neuropathy, were assessed prior to each chemotherapy cycle. Setting: A multi-center study including four major academic hospitals and five community oncology clinics. Participants: Women with newly diagnosed with stage I to III breast cancer to receive chemotherapy including a taxane. Main Outcomes and Measure: Development of grade 2+ (moderate or worse) CIPN during the course of chemotherapy treatment. CIPN symptoms were graded by participants oncology clinician using the NCI-CTCAE v5 system. Expression of p16 mRNA was measured by qPCR in T-lymphocytes isolated from fresh peripheral blood. Results: A multivariate model including taxane regimen type and p16Age Gap, a measure of discordance between chronological age and p16 expression, identified risk factors for CIPN. Participants with higher chronological age but lower p16 expression prior to chemotherapy (molecularly young) were at the highest risk. Incidence of CIPN positively correlated with chemotherapy-induced increase in p16 expression, with the largest increase seen in participants with the lowest p16 expression prior to treatment. Conclusions and Relevance: This is the first report describing a model to identify patients at risk for taxane-induced CIPN. Studies to confirm and validate our findings are ongoing. When validated, a p16Age Gap-based model can be used to guide chemotherapy selection in patients with early breast cancer, given that chemotherapy regimens for this indication usually employ one of two taxanes (paclitaxel or docetaxel) with similar efficacy but different risks of CIPN.

Senescence and cancer — role and therapeutic opportunities

“…Interestingly, chemotherapy promotes senescence not only in tumours but also, to a lesser extent and in a rather temporary way, in non-malignant tissues, with potential long-term implications for the recovery of non-malignant tissue after successful elimination of the malignant cell population. In this regard, the detection of an increased number of T cells overexpressing p16 INK4a in patients with breast cancer treated with different chemotherapeutic agents is a finding worth highlighting because it indicates that immunosenescence can occur as a bystander effect of treatment 99 , 100 . Neoadjuvant chemotherapy is also associated with elevated expression of p16 INK4a in the mammary duct, lobular and adipose tissues of patients with breast cancer 101 .…”