Abstract 4696: Identification of driver mutations and gene amplifications in resected asophageal adenocarcinoma: Impact on clinical care

Abstract

Abstract BACKGROUND: Adenocarcinoma of the distal esophagus and esophagogastric junction (EGJ) have received much attention because of increasing frequency and poor outcome despite multimodality therapy. Driver mutations and gene amplifications in resected esophageal adenocarcinoma are not widely investigated. Opportunity exists to discover actionable mutations in resected esophageal adenocarcinoma. METHODS: We analyzed driver mutations harbored in coding regions of 25 selected genes (∼95 point mutations) using a multiplex PCR-based assay. EGFR, HER2, MET, and PI3K amplifications were tested using fluorescent in situ hybridization in patients who underwent esophagectomy for distal esophagus and EGJ adenocarcinoma from 2009 to 2013. Disease free survival (DFS) and overall survival (OS) were compared between patients with TP53, KRAS, PI3K, BRAF, APC mutant and wild-type tumors using Kaplan-Meier methods and Cox regression models. The impact of HER2 expression and outcomes were also analyzed. RESULTS: Of 54 distal esophagus and EGJ adenocarcinoma patients, 5 different driver mutations were observed in 39 patients, including TP53 (11/39, 28.2%), KRAS (6/39,15.4%), PI3K (2/11,5.1%), BRAF(1/39, 2.6%) and APC (2/39,5.1%). Double driver mutations (3/39, 7.9%) were shared in 3 patients with TP53 and KRAS (1/39, 2.6%), TP53 and PI3K (1/39, 2.6%), KRAS and PI3K (1/39, 2.6%), respectively. Amplifications in HER2 (10/45, 22.2%), MET (1/34, 2.9%) and EGFR (2/17, 11.8%) were observed where directed therapy was altered in 5 patients (1 patient received induction herceptin and 4 patients received adjuvant herceptin). In the targeted patients with HER2 amplification who received herceptin, mean progression-free survival was 18.8 (range 7-41 months) vs. 8.9 (1-28 months) [p=0.089] and OS was 35.7 (range 26-46 months) vs. 24.2 (range 20-29 months) [p=0.053], compared to herceptin naive patients. We did not identify any significant difference in DFS and OS (inclusive of all stages) between TP53, KRAS or any mutation compared to wild type patients. DISCUSSION: Oncogenic driver mutations are under-investigated in resected distal esophageal and EGJ adenocarcinoma. Different therapeutic opportunities may become available if routine tumor genotyping is employed in the treatment of esophageal adenocarcinoma. We recommend the routine use of driver mutation and gene amplification analysis for esophageal cancer. Citation Format: Haiyu Zhou, Luis Tapias Vargas, Justin Elliot, Douglas J. Mathisen, Michael Lanuti. Identification of driver mutations and gene amplifications in resected asophageal adenocarcinoma: Impact on clinical care. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4696. doi:10.1158/1538-7445.AM2014-4696