Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma

Eirini Pectasides, Matthew D. Stachler, Sarah Derks, Yang Liu, Steven Maron, Mirazul Islam, Lindsay Alpert, Heewon Kwak, Hedy Kindler, Blase Polite, Manish R. Sharma, Kenisha Allen, Emily O’Day, Samantha Lomnicki, Melissa Maranto, Rajani Kanteti, Carrie Fitzpatrick, Christopher Weber, Namrata Setia, Shu-Yuan XiaoJohn Hart, Rebecca J. Nagy, Kyoung-Mee Kim, Min-Gew Choi, Byung-Hoon Min, Katie S. Nason, Lea O’Keefe, Masayuki Watanabe, Hideo Baba, Rick Lanman, Agoston T. Agoston, David J. Oh, Andrew Dunford, Aaron R. Thorner, Matthew D. Ducar, Bruce M. Wollison, Haley A. Coleman, Yuan Ji, Mitchell C. Posner, Kevin Roggin, Kiran Turaga, Paul Chang, Kyle Hogarth, Uzma D. Siddiqui, Andres Gelrud, Gavin Ha, Samuel S. Freeman, Justin Rhoades, Sarah Reed, Greg Gydush, Denisse Rotem, Jon Davison, Yu Imamura, Viktor Adalsteinsson, Jeeyun Lee, Adam J. Bass, Daniel V. Catenacci

Research output: Contribution to journalArticleAcademicpeer-review


Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential rea-son for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy. SIGNIFICANCE: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated.
Original languageEnglish
Pages (from-to)37-48
JournalCancer discovery
Issue number1
Publication statusPublished - 2018

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