Jon M. Davison

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. 14. See related article by Janjigian et al., p. 49. This article is highlighted in the In This Issue feature, p. 1

As a result of injury caused by chronic gastroesophageal reflux, Barrett's esophagus with high-grade dysplasia and esophageal adenocarcinoma are rapidly increasing problems in the United States. The current standard of care involves esophagectomy, a procedure associated with a high morbidity, a negative impact on long term quality of life, and a mortality rate of 1-6 percent. An entirely endoscopic technique for circumferential, long segment en bloc removal of the mucosa and submucosa with subsequent placement of a biologic scaffold material that promotes a constructive remodeling response and minimizes stricture is described herein. The results of this approach are reported for five patients with 4-24-month follow-up. Restoration of normal mature, K4+/K14+, squamous epithelium, and return to a normal diet without significant dysphagia is reported for all patients. Two of five patients show a small focus of recurrent Barrett's esophagus at the gastroesophageal junction, but the entire length and circumference of the reconstituted esophageal mucosa remains free of disease. This experience provides evidence that a regenerative medicine approach may, for the first time, enable aggressive endoscopic resection of early stage neoplasia without the need for esophagectomy and its associated complications.