Cancer Discov. 2018 Jun 14. pii: CD-18-0275. doi: 10.1158/2159-8290.CD-18-0275. [Epub ahead of print]
Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine.
Aguirre AJ1, Nowak JA2, Camarda ND3, Moffitt RA4, Ghazani AA5, Hazar-Rethinam M6, Raghavan S3, Kim J7, Brais LK8, Ragon D8, Welch MW8, Reilly E8, McCabe D9, Marini L3, Anderka K10, Helvie K11, Oliver N3, Babic A3, Da Silva A12, Nadres B13, Van Seventer EE13, Shahzade HA13, St Pierre JP8, Burke KP3, Clancy TE14, Cleary JM3, Doyle LA2, Jajoo K15, McCleary NJ16, Meyerhardt JA3, Murphy JE13, Ng K3, Patel AK17, Perez K3, Rosenthal MH18, Rubinson DA3, Ryou M15, Shapiro GI3, Sicinska E19, Silverman SG11, Nagy RJ20, Lanman RB20, Knoerzer D21, Welsch DJ22, Yurgelun MB11, Fuchs CS23, Garraway LA3, Getz G24, Hornick JL25, Johnson BE26, Kulke MH3, Mayer RJ3, Miller JW27, Shyn PB28, Tuveson DA29, Wagle N3, Yeh JJ30, Hahn WC3, Corcoran RB13, Carter SL31, Wolpin BM8.
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 MAP-kinase 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.