A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination-deficient Pancreatic Cancer.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline <i>BRCA1</i> or <i>BRCA2</i> (g<i>BRCA</i>) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on g<i>BRCA</i> mutational status alone is associated with heterogeneous responses. We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were g<i>BRCA</i> mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers. We found that biallelic inactivation of <i>BRCA1</i>/<i>BRCA2</i> is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17). In summary, we propose a predictive and prognostic model of g<i>BRCA</i>-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.