Predicting treatment response to chemo-radiotherapy (CRT) in esophageal cancer remains an unrealized goal despite studies linking constellations of genes to prognosis. We aimed to determine if specific expression profiles are associated with pathologic complete response (pCR) after neoadjuvant CRT.

Eleven genes previously associated with esophageal cancer prognosis were identified. Esophageal adenocarcinoma (EAC) patients treated with neoadjuvant CRT and esophagectomy were included. Patients were classified into two groups: pCR and no-or-incomplete response (NR). Polymerase chain reaction was used to evaluate gene expression. Omnibus testing was applied to overall gene expression differences between groups, and log-rank tests compared individual genes.

Eleven pCR and eighteen NR patients were analyzed. Combined expression profiles were significantly different between pCR and NR groups (p < 0.01). The gene CCL28 was over-expressed in pCR patients (Log-HR: 1.53, 95%CI: 0.46–2.59, p = 0.005), and DKK3 was under-expressed in pCR (Log-HR: −1.03 95%CI: −1.97, −0.10, p = 0.031).

EAC tumors that demonstrated a pCR have genetic profiles that are significantly different from typical NR profiles. The genes CCL28 and DKK3 are potential predictors of treatment response.