Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma [Research Briefs]

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 tumor. 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. Multi-region sequencing showed significant discrepancy within the primary tumor and between the primary tumor and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, pilot analysis of cfDNA sequencing demonstrated the feasibility of detecting genomic amplifications not detected in primary tumor sampling. Lastly, we profiled paired primary, metastatic tumors and cfDNA from patients enrolled in the PANGEA trial of targeted therapies in GEA, and found that genomic biomarkers were recurrently discrepant between the primary tumor 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.

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