Gene expression profile (GEP) for the prediction of pathologic complete response (pCR): Preliminary data from a neoadjuvant study of capecitabine (C), oxaliplatin (OXP), and radiation (RT) for esophageal cancer (EC).

Background: A pCR following chemoradiation (CRT) is associated with improved survival in EC patients (pts). Our prior study noted the safety of combination C, OXP and RT. The present phase II neoadjuvant (NA) EC trial was designed to examine the pCR rate using C, OXP and RT, correlate GEP with pCR, and assess toxicity. Method(s): EC pts with stages II-IVa, adequate organ function and performance status were eligible. Treatment (Rx) consisted of OXP, 85 mg/m2 iv on days 1, 15 and 29, C (oral or enteral tube) 625 mg/m2 bid with RT, and 50.4 Gy RT (3D conformal), followed by surgery (S) 4-6 wks later. 2 cycles of OXP + C were given post-operatively. GEP using Agilent microarrays was conducted on primary tumor tissue pre-Rx, day (D) 17 of CRT and at S.More than 50% viable tumor cells were required. Result(s): 32 pts enrolled (27 M); median age 58.5 yrs; 25 adenocarcinomas and 7 squamous. Stage: II (9), III (19) and IVa (4). 30 pts completed NA Rx; 4 pts did not undergo S (2 disease progression, 2 declined). 21 pts have undergone S with 7 pCR (33%). 10/13 pts starting adjuvant therapy completed 2 cycles. No G4 nonhematologic toxicity during NA Rx; G3 toxicity: anorexia (1), esophagitis (1), fatigue (1), hyperbilirubinemia (2), elevated AST (6), OXP hypersensitivity (2), neutropenia (1). Post-op complications: pneumonia (2), infection (4), leak (2), esophageal fistula (1) and bowel obstruction (2). 1 pt developed acute leukemia, likely OXP-related 17 months post-Rx. Analysis on pre-Rx GEP on 22 pts via gene set analysis revealed several enriched genetic pathways comparing pCR with non-pCR pts. Specifically, the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways glutathione metabolism and base excision repair, 2 pathways that may be important for chemotherapy resistance, were found to be enriched. Conclusion(s): C, OXP and RT is effective and well tolerated in resectable EC. Ongoing work will further validate the noted pathways in determining chemotherapy resistance.