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 given its high incidence, persistence, and detrimental effect on quality of life. 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. 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 using a biomarker of senescence in 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 and identify patients at high risk who may be candidates for preventive trials. Key Points: Question: Is cellular senescence an independent risk factor for chemotherapy-induced peripheral neuropathy? Findings: In a prospective observational cohort study of women with early-stage breast cancer undergoing treatment with taxane chemotherapy, a regression model containing a measure of cellular senescence and taxane type was a statistically significant predictor of grade 2+ CIPN incidence. Meaning: Cellular senescence is an independent risk factor for CIPN that, if validated, could guide treatment selection and identify high-risk patients for preventive strategies.