Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma.

Pectasides E1,2, Stachler MD1,3, Derks S1,4, Liu Y1,5, Maron S6, Islam M1,5, Alpert L7, Kwak H7, Kindler H6, Polite B6, Sharma MR6, Allen K6, O'Day E6, Lomnicki S6, Maranto M6, Kanteti R6, Fitzpatrick C7, Weber C7, Setia N7, Xiao SY7, Hart J7, Nagy RJ8, Kim KM9, Choi MG10, Min BH11, Nason KS12, O'Keefe L12, Watanabe M13, Baba H14, Lanman R8, Agoston AT3, Oh DJ15, Dunford A5, Thorner AR16, Ducar MD16, Wollison BM16, Coleman HA16, Ji Y17, Posner MC18, Roggin K18, Turaga K18, Chang P19, Hogarth K20, Siddiqui UD21, Gelrud A21, Ha G5, Freeman SS5, Rhoades J5, Reed S5, Gydush G5, Rotem D5, Davison J12, Imamura Y13,14, Adalsteinsson V5, Lee J22, Bass AJ23,5, Catenacci DV24.

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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); 1-12. ©2017 AACR.