Esophageal adenocarcinomas are associated with a dismal prognosis. Deciphering the evolutionary history of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable esophageal adenocarcinomas, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of esophageal adenocarcinomas with the presence of heterogeneous driver mutations, parallel evolution, early genome-doubling events, and an association between high intratumor heterogeneity and poor response to NAC. Multiregion sequencing demonstrated a signifi cant reduction in thymine to guanine mutations within a CpTpT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of cytosine to adenine mutations within a CpC context following NAC. Esophageal adenocarcinomas are characterized by early chromosomal instability leading to amplifi cations containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches. SIGNIFICANCE:This work illustrates dynamic mutational processes occurring during esophageal adenocarcinoma evolution and following selective pressures of platinum exposure, emphasizing the iatrogenic impact of therapy on cancer evolution. Identifi cation of amplifi cations encoding targetable oncogenes maintained through NAC suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention. Cancer Discov; 5(8);

Distinct exhaled breath VOC profiles can distinguish patients with esophageal and gastric adenocarcinoma from noncancer controls.