MET Amplification Identifies a Small and Aggressive Subgroup of Esophagogastric Adenocarcinoma With Evidence of Responsiveness to Crizotinib
Author(s) -
Jochen K. Lennerz,
Eunice L. Kwak,
A. B. Ackerman,
Michael Michael,
Stephen B. Fox,
Kristin Bergethon,
Gregory Y. Lauwers,
James G. Christensen,
Keith D. Wilner,
Daniel A. Haber,
Ravi Salgia,
YungJue Bang,
Jeffrey W. Clark,
Benjamin Solomon,
A. John Iafrate
Publication year - 2011
Publication title -
journal of clinical oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.482
H-Index - 548
eISSN - 1527-7755
pISSN - 0732-183X
DOI - 10.1200/jco.2011.35.4928
Subject(s) - medicine , crizotinib , adenocarcinoma , polysomy , fluorescence in situ hybridization , gene duplication , cohort , gastroenterology , oncology , carcinoma , cancer , lung cancer , pathology , gene , biology , biochemistry , malignant pleural effusion , chromosome
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 = .16) less than HER2 (16.9 months; P = .89) when compared with the negative group (16.2 months). Two of four patients with MET-amplified tumors treated with crizotinib experienced tumor shrinkage (−30% and −16%) and experienced progression after 3.7 and 3.5 months.Conclusion MET amplification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066).
Accelerating Research
Robert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom
Address
John Eccles HouseRobert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom