Gene expression analysis of EAC in association with PET response.

Abstract

50 Background: Esophagectomy with preoperative chemotherapy or chemoradiotherapy are standard treatment regimens for localized esophageal adenocarcinoma (EAC). Early metabolic response to preoperative therapy (determined by FDG-PET scan) has been shown to predict histological response and survival. We present preliminary data from a randomized phase II trial of pre-operative cisplatin (C), 5-fluorouracil (F) and docetaxel ± radiotherapy based on early response to standard chemotherapy for resectable EAC. We present gene expression data for 22 patients with early FDG-PET response. Methods: Samples that were histologically proven invasive EAC and clinical stage T2/3 tumors were included in the analysis. All patients received C (day1) and F (days 1-4) chemotherapy. Early metabolic response was defined as >35% reduction in SUVmax on day 14 FDG-PET scan compared with baseline scan. Whole genome mRNA expression was obtained for pre-treatment biopsies using HumanHT-12v4 expression chips. Expression data was log2 transformed prior to robust spline normalization conducted with the lumi R package. Statistical analysis was performed in BRBarray. Results: There were 8 early PET responders and 14 early nonresponders to CF chemotherapy. Differentially expressed genes among PET responders and non-responders were identified using a random-variance t-test; 57 genes were identified as significantly differentially expressed between the two classes (p ≤ 0.001). A global test indicated significantly different expression profiles between the classes (p = 0.031). A gene classifier to predict PET response was explored and Support Vector Machines correctly classified 82% of samples with the prediction error estimated using leave-one-out cross-validation (p = 0.05). Epigenetic and apoptotic processes were significantly overrepresented in the gene list based on Gene Ontology analysis. Conclusions: This preliminary work supports a biological basis for the association between early metabolic PET response to preoperative therapy and survival in EAC patients. The list of differentially expressed genes may include potential biomarkers of treatment response and requires further investigation at the maturation of the phase II clinical trial for EAC.