MET Amplification Identifies a Small and Aggressive Subgroup of Esophagogastric Adenocarcinoma With Evidence of Responsiveness to Crizotinib

作者：Jochen K. Lennerz, Eunice Lee Kwak, A. B. Ackerman, Michael Michael, Stephen B. Fox, Kristin E. Bergethon, Gregory Yves Lauwers, James G. Christensen, Keith D. Wilner, Daniel A. Haber, Ravi Salgia, Yung‐Jue Bang, Jeffrey William Clark, Benjamin J. Solomon, Anthony John Iafrate · 发表于：Journal of Clinical Oncology · 年份：2011 · DOI：10.1200/jco.2011.35.4928 · 被引用次数：434 · 研究领域：Liver physiology and pathology、Lung Cancer Treatments and Mutations、Esophageal Cancer Research and Treatment

PURPOSE: Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET-amplified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study. PATIENTS AND METHODS: From 2007 to 2009, patients with GEC were genetically screened as a consecutive series of 489 tumors (stages 0, I, and II, 39%; III, 25%; IV, 36%; n = 222 esophageal, including n = 21 squamous carcinomas). MET, EGFR, and HER2 amplification status was assessed by using fluorescence in situ hybridization. RESULTS: Ten (2%) of 489 patients screened harbored MET amplification; 23 (4.7%) harbored EGFR amplification; 45 (8.9%) harbored HER2 amplification; and 411 (84%) were wild type for all three genes (ie, negative). MET-amplified tumors were typically high-grade adenocarcinomas that presented at advanced stages (5%; n = 4 of 80). EGFR-amplified tumors showed the highest fraction of squamous cell carcinoma (17%; n = 4 of 23). HER2, MET, and EGFR amplification were, with one exception (MET and EGFR positive), mutually exclusive events. Survival analysis in patients with stages III and IV disease showed substantially shorter median survival in MET/EGFR-amplified groups, with a rank order for all groups by median survival (from most to least aggressive): MET (7.1 months; P < .001) less than EGFR (11.2 months; P =...