Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

TLDR

Pancreatic ductal adenocarcinoma has clinically relevant subtypes, yet molecular profiling is not yet routine, and this study demonstrates that real‑time genomic characterization is feasible and valuable. The study employed a rapid biopsy protocol to perform whole‑exome and RNA sequencing on patients with advanced PDAC. Among 71 patients, 48 % had therapeutically relevant somatic alterations, 18 % carried pathogenic germline variants, 30 % experienced a change in clinical management, and additional findings included DNA‑repair gene alterations, homologous recombination deficiency signatures, BRAF deletions responsive to MAPK inhibition, and clinically relevant tumor/stroma expression signatures. Published in *Cancer Discovery*, vol.

Abstract

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.