Aguirre, A. J., Nowak, J. A., Camarda, N. D., Moffitt, R. A., Ghazani, A. A., Hazar-Rethinam, M., Raghavan, S., Kim, J., Brais, L. K., Ragon, D., Welch, M. W., Reilly, E., McCabe, D., Marini, L., Anderka, K., Helvie, K., Oliver, N., Babic, A., Da Silva, A., Nadres, B., Van Seventer, E. E., Shahzade, H. A., St Pierre, J. P., Burke, K. P., Clancy, T. E., Cleary, J. M., Doyle, L. A., Jajoo, K., McCleary, N. J., Meyerhardt, J. A., Murphy, J. E., Ng, K., Patel, A. K., Perez, K., Rosenthal, M. H., Rubinson, D. A., Ryou, M., Shapiro, G. I., Sicinska, E., Silverman, S. G., Nagy, R. J., Lanman, R. B., Knoerzer, D., Welsch, D. J., Yurgelun, M. B., Fuchs, C. S., Garraway, L. A., Getz, G., Hornick, J. L., Johnson, B. E., Kulke, M. H., Mayer, R. J., Miller, J. W., Shyn, P. B., Tuveson, D. A., Wagle, N., Yeh, J. J., Hahn, W. C., Corcoran, R. B., Carter, S. L., Wolpin, B. M. (June 2018) Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov, 8 (9). pp. 1096-1111. ISSN 2159-8274
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 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.
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