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Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma
Authors
Viktor Adalsteinsson
Agoston T Agoston
+55 more
Kenisha Allen
Lindsay Alpert
Hideo Baba
Adam J Bass
Daniel V Catenacci
Paul Chang
Min-Gew Choi
Haley A Coleman
Jon Davison
Sarah Derks
Matthew D Ducar
Andrew Dunford
Carrie Fitzpatrick
Samuel S Freeman
Andres Gelrud
Greg Gydush
Gavin Ha
John Hart
Kyle Hogarth
Yu Imamura
Mirazul Islam
Yuan Ji
Rajani Kanteti
Kyoung-Mee Kim
Hedy Kindler
Heewon Kwak
Rick Lanman
Jeeyun Lee
Yang Liu
Samantha Lomnicki
Melissa Maranto
Steven Maron
Byung-Hoon Min
Rebecca J Nagy
Katie S Nason
Emily O'Day
Lea O'Keefe
David J Oh
Eirini Pectasides
Blase Polite
Mitchell C Posner
Sarah Reed
Justin Rhoades
Kevin Roggin
Denisse Rotem
Namrata Setia
Manish R Sharma
Uzma Siddiqui
Matthew D Stachler
Aaron R Thorner
Kiran Turaga
Masayuki Watanabe
Christopher Weber
Bruce M Wollison
Shu-Yuan Xiao
Publication date
1 January 2018
Publisher
eScholarship, University of California
Abstract
Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason 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. Cancer Discov; 8(1); 37-48. ©2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Janjigian et al., p. 49This article is highlighted in the In This Issue feature, p. 1
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Last time updated on 25/07/2023