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

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

doi:10.1038/s41523-022-00427-9

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

NPJ Breast Cancer. 2022 May 10;8(1):64. doi: 10.1038/s41523-022-00427-9.

Authors

Xuan Liu^#¹, Zhongqi Ge^#², Fei Yang³, Alejandro Contreras⁴, Sanghoon Lee⁵, Jason B White⁶, Yiling Lu⁷, Marilyne Labrie⁸, Banu K Arun⁶, Stacy L Moulder⁶, Gordon B Mills⁸, Helen Piwnica-Worms⁹, Jennifer K Litton⁶, Jeffrey T Chang^{10

11}

Affiliations

¹ Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.
² Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Genome Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
⁹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA. [email protected].
¹¹ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].

^# Contributed equally.

Abstract

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.