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

Abstract

A B S T R A C T PurposeAmplification 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 MethodsFrom 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 ϭ 222 esophageal, including n ϭ 21 squamous carcinomas). MET, EGFR, and HER2 amplification status was assessed by using fluorescence in situ hybridization. ResultsTen (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 ϭ 4 of 80). EGFR-amplified tumors showed the highest fraction of squamous cell carcinoma (17%; n ϭ 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 Ͻ .001) less than EGFR (11.2 months; P ϭ .16) less than HER2 (16.9 months; P ϭ .89) when compared with the negative group (16.2 months). Two of four patients with MET-amplified tumors treated with crizotinib experienced tumor shrinkage (Ϫ30% and Ϫ16%) and experienced progression after 3.7 and 3.5 months. ConclusionMET amplification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066).

Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

“…Furthermore, 26% (24 of 93) of the amplifications were amplification of one of four genes (ERBB2, FGFR2, MET, and EGFR) that encode a RTK. The frequencies of these gene amplifications were not significantly different from those previously reported for ERBB2, FGFR2, 9,10,12,14 MET, 6,7,14,15 and EGFR. 6,20 It is intriguing that, except for case 7, RTK gene amplification occurred in a mutually exclusive manner.…”

“…However, there is an urgent need for other inhibitors to be investigated for the therapy of many of the unique molecular subtypes of gastric cancer. 5 In particular, FGFR2 and MET, which encode RTKs similar to ERBB2, are considered as strong candidate targets because their amplification is associated with advanced stages, 6,7 and furthermore, the amplification of FGFR2 was preferentially found in a poorly differentiated subtype. 8,9 In preclinical studies, cells with amplified FGFR2 or MET showed overexpression of their respective proteins, and inhibitors to these receptors were shown to effectively block their downstream signal transduction and induce apoptosis.…”

“…However, the prevalence of amplification of each of these genes, as assessed by oligonucleotide array comparative genetic hybridization, real-time PCR, fluorescence in situ hybridization (FISH), or silver in situ hybridization is low, ie, from 2 to 5% for FGFR2, 9,10,12,14 and from 2 to 8% for MET, respectively. 6,7,14,15 Intriguingly, a recent comprehensive genome-wide analysis of copy number alterations using an single nucleotide polymorphism array 13 showed that amplification of FGFR2, EGFR, ERBB2, and MET occurred mutually exclusively and that other genes such as MYC and CCND1 were also amplified in gastric cancer. When considering promising targets of molecular therapy, the apparently low prevalence of these gene amplifications in gastric cancer makes selection of the right set of patients that can benefit from targeted therapy a difficult challenge.…”

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

“…5,7,11,14,[16][17][18][19][20][21][22][23]33 Although MET expression showed poor prognostic effects on gastric carcinomas, 7,18,20,21,23 most studies were performed 410 years ago 5,7,17,[19][20][21][22] and interpreted either cytoplasmic or membranous positivity only 5,17-21 without considering intensity. In a recent large cohort study with gastric cancers with the same MET monoclonal antibody as ours, interpretation of membranous staining, which was used for HER2, failed to find any clinical significance and not all MET 3 þ cases exhibited amplification of MET gene.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…As yet, there is no clinically validated method for defining cMET amplification, and thus the actual rate of amplification in tumour samples varies significantly between studies. The correlation between sensitivity to cMET-inhibitory agents and cMET amplification remains unclear, with various studies reporting correlation [48][49][50][51], transient sensitivity [52], or no correlation [53][54][55], and as such it will be important to define a method by which copy number can be accurately determined and clinically validated. In high grade serous ovarian cancer, the TCGA cBioPortal [56,57] reveals mutations in the Met gene to be present in 1.3% of cases, and amplifications in 1.6%.…”