A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors.

摘要: Background: Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is pressing need for novel targets and models preclinical testing. Here we report characterization of breast patient-derived xenografts (PDX) largely generated from residual tumors following chemotherapy.Experimental Design: PDXs were derived surgical samples primary or locally recurrent tumors. Normal tumor DNA sequencing, RNASeq, reverse phase protein arrays (RPPA) performed. Phenotypic profiling was performed by determining efficacy panel standard investigational agents.Results: Twenty-six developed 25 patients. Twenty-two disease chemotherapy, 24 triple-negative (TNBC). These harbored heterogeneous set genomic alterations represented all TNBC molecular subtypes. On RPPA, varied in extent PI3K MAPK activation. also their sensitivity chemotherapeutic agents. PI3K, mTOR, MEK inhibitors repressed growth but did cause regression. The PARP inhibitor talazoparib caused dramatic regression five 12 PDXs. Notably, four talazoparib-sensitive harbor germline BRCA1/2 mutations, several had somatic homologous repair pathways, including ATM deletion BRCA2 alterations.Conclusions: capture the phenotypic heterogeneity TNBC. show that inhibition can activity beyond altered tumors, causing variety represent an opportunity discovery rational combinations with targeted therapies predictive biomarkers. Clin Cancer Res; 23(21); 6468-77. ©2017 AACR.