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

Germline mutations in BRCA1 or BRCA2 exist in approximately 7% of patients diagnosed with breast cancer and are associated with defects in homologous recombination repair, which has led to the approval of PARP inhibitors for treatment of these cancers 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%. However, nearly half of the patients treated did not have pCR, thus better strategies are needed to overcome treatment resistance, as well as to identify tumors likely to respond to therapy. 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 underlying biology of pre-treatment tumors contain activities that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for the better selection of patients for treatment, as well as a roadmap for the development of novel therapies to overcome resistance. Treatment naïve tumors from early breast cancer patients with germline mutations in BRCA1 or BRCA2 were subjected to RNA-Seq profiling. Response to single agent talazoparib was assessed after six months of treatment. -------------------------------------------------------- Submitter states the following: Due to IRB requirements, we are not allowed to upload the raw data, except to a controlled access database. We will be submitting the raw data to a controlled access database. However, we would like to make the processed data available here without controlled access to maximize data accessibility.