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Supplementary Experimental Methods from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

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posted on 2023-04-03, 21:42 authored by Andrew J. Aguirre, Jonathan A. Nowak, Nicholas D. Camarda, Richard A. Moffitt, Arezou A. Ghazani, Mehlika Hazar-Rethinam, Srivatsan Raghavan, Jaegil Kim, Lauren K. Brais, Dorisanne Ragon, Marisa W. Welch, Emma Reilly, Devin McCabe, Lori Marini, Kristin Anderka, Karla Helvie, Nelly Oliver, Ana Babic, Annacarolina Da Silva, Brandon Nadres, Emily E. Van Seventer, Heather A. Shahzade, Joseph P. St. Pierre, Kelly P. Burke, Thomas Clancy, James M. Cleary, Leona A. Doyle, Kunal Jajoo, Nadine J. McCleary, Jeffrey A. Meyerhardt, Janet E. Murphy, Kimmie Ng, Anuj K. Patel, Kimberly Perez, Michael H. Rosenthal, Douglas A. Rubinson, Marvin Ryou, Geoffrey I. Shapiro, Ewa Sicinska, Stuart G. Silverman, Rebecca J. Nagy, Richard B. Lanman, Deborah Knoerzer, Dean J. Welsch, Matthew B. Yurgelun, Charles S. Fuchs, Levi A. Garraway, Gad Getz, Jason L. Hornick, Bruce E. Johnson, Matthew H. Kulke, Robert J. Mayer, Jeffrey W. Miller, Paul B. Shyn, David A. Tuveson, Nikhil Wagle, Jen Jen Yeh, William C. Hahn, Ryan B. Corcoran, Scott L. Carter, Brian M. Wolpin

Supplementary Experimental Methods

Funding

Lustgarten Foundation

Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Research

Hope Funds for Cancer Research

Doris Duke Charitable Foundation

Conquer Cancer Foundation of ASCO

Broman Fund for Pancreatic Cancer Research

National Institutes of Health National Cancer Institute

Harvard Clinical and Translational Science Center

National Center for Advancing Translational Sciences

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DFCI Medical Oncology Translational Research

Pancreatic Cancer Action Network

Noble Effort Fund

Peter R. Leavitt Family Fund

Wexler Family Fund

Promises for Purple

History

ARTICLE 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. 1062.This article is highlighted in the In This Issue feature, p. 1047

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    Cancer Discovery

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    Keywords

    Drug TargetsOncoprotein & tumor suppressor drug targetsGastrointestinal CancersPancreatic cancerGene TechnologiesMutation detection methodsGenome BiologyTranslational Research

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