Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic

Abstract

Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications.Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status.Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P ¼ 0.007), high-grade tumors (P ¼ 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR ¼ 1.12; 95% confidence intervals, 0.83-1.85; P ¼ 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response.Conclusion: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336-45. Ó2014 AACR.

MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition inBRAF-Mutated Colorectal Cancer

“…The proportion of BRAF -mutant colorectal tumor samples coharboring MET molecular alterations is unknown, but a large series of 1,115 samples from any tumor types has previously reported that MET amplifi cation was associated with a higher prevalence of BRAF mutations compared with nonamplifi ed tumors ( 22 ). In our collection of 17 additional BRAF -mutant colorectal cancer samples from chemonaïve patients, we were able to fi nd MET -amplifi ed subclones in three cases.…”

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%.…”

“…Interestingly, a number of phase I trials of HGF/cMET targeting agents have included patients with ovarian cancer, [82,97,88,54,98,61] …”

Detection of MET amplification in gastroesophageal tumor specimens using IQFISH

“…Under normal circumstances HGF activation of Met is tightly controlled by mechanisms such as paracrine ligand delivery and ligand activated receptor internalization and degradation. Despite these controls, the HGF/Met signaling contributes to oncogenesis and tumor progression in several human cancers, including gastroesophageal, colorectal, lung, breast, renal and more (1,2).…”