A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination-deficient Pancreatic Cancer.
作者： Yifan Wang , Jin Yong Patrick Park , Alain Pacis , Robert E Denroche , Gun Ho Jang
DOI: 10.1158/1078-0432.CCR-20-1439
关键词:
摘要: Purpose: Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated heterogeneous responses. Experimental Design: We performed seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, which nine were mutated. From 179 whose was whole-genome transcriptome sequenced, we identified 21 cases homologous recombination deficiency (HRD), investigated prognostic biomarkers. Results: found that biallelic inactivation BRCA1/BRCA2 genomic hallmarks HRD required for cisplatin talazoparib (PARPi) sensitivity. persisted xenografts despite the emergence therapy resistance, indicating presence scar. tumor polyploidy low Ki67 index as predictors poor response. In PDAC, basal-like transcriptomic subtype independent shorter survival. To facilitate clinical assignment subtype, developed novel pragmatic two-marker assay (GATA6:KRT17). Conclusions: summary, propose predictive model gBRCA-mutated basis hallmarks, index, ploidy, subtype.
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