Journal Article

Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers

Moulder, Stacy L, Lu, Yiling, Ge Zhongqi, Contreras, Alejandro, Chang, Jeffrey T, Liu, Xuan, Labrie Marilyne, Piwnica-Worms Helen, White, Jason B, Litton, Jennifer K, Mills, Gordon B, Yang, Fei, Lee, Sanghoon, Arun, Banu K

2022

Overview

Germline mutations in BRCA1 or BRCA2 exist in ~2–7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked for biomarkers that were predictive of response (assessed by residual cancer burden) after 6 months of therapy. We found that all resistant tumors exhibited either the loss of SHLD2, expression of a hypoxia signature, or expression of a stem cell signature. These results indicate that the deep analysis of pre-treatment tumors can identify biomarkers that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for better selection of patients for treatment, as well as a roadmap for the development of novel combination therapies to prevent emergence of resistance.

• Publisher: Nature Publishing Group
• Subject: Biomarkers / Breast cancer / Treatment resistance / Tumors