MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib

Abstract

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).

Fig 1.

Diagnostic features of MET-amplified gastroesophageal carcinoma. Hematoxylin and eosin staining of a representative (A) high-grade esophageal and (C) gastric adenocarcinoma with corresponding fluorescence in situ hybridization that demonstrate MET gene-to-chromosome ratios of (B) greater than five and (D) approximately four.

Fig 2.

Frequency of genetic subtypes by location and anatomic stage; Neg., no MET/EGFR/HER2 amplification.

Fig 3.

Overall survival (OS) of patients with stage III to IV MET-amplified tumors compared with patients who have EGFR-amplified, HER2-amplified, or no MET/EGFR/HER2 (negative [Neg]) amplification. Kaplan-Meier survival plots of OS in (A) esophageal + junctional cancer, (B) gastric cancer, and (C) the entire cohort. P values, log-rank test.

Fig 4.

Response of patient Cr3 with metastatic MET-amplified gastroesophageal cancer to the MET inhibitor crizotinib. (A) Pretreatment image and (B) partial response after two cycles of crizotinib (250 mg twice daily for a total of 8 weeks).