Abstract 4424: Analysis of 1115 patients tested for MET amplification and therapy response in the MD Anderson phase I clinic
Authors: Tang Chad , Jardim Denis , Gagliato Debora , Falchook Gerald , Hess Kenneth , Fu Siqing , Wheler Jennifer , Zinner Ralph , Naing Aung , Tsimberidou Apostolia , Meric-Bernstam Funda , Hong David 
Published: May 2015

Background: Increased c-Met activity has been implicated in numerous oncologic processes. However, its prevalence among different cancers, association with demographics and genetic aberrations, and implication in therapy resistance has not been fully described.

Patients and Methods: Between May 2010 to November 2012, 3607 patients were referred to the investigational cancer therapeutics department at MD Anderson Cancer Center for consideration of a phase I protocol. Among these patients, 1115 underwent MET amplification testing via fluorescence in-situ hybridization and were included in this analysis. Copy numbers are expressed as a ratio to the centromeric gene CEP7 with amplification defined as MET/CEP7 ≥2 or &gt;20 gene copies in &gt;10% of nuclei. Patient demographic, histologic, and molecular characteristics were stratified based on MET amplification status. Among patients with MET amplification, 20 were treated on a phase I protocol and evaluated for therapy response. Responses were categorized by RECIST criteria with objective responses defined as stable disease lasting ≥6 months or any observed partial responses. Categorical variables were compared via Chi-Squared and Fisher Exact Tests, while continuous variables were compared via Student's T-Test. Overall survival from the date of first consultation at our phase I clinic were compared via the Log-Rank test.

Results: Twenty-nine (2.6%) patients exhibited MET amplification (median 3.48; range 2.05-16.14). Of these, 2 exhibited MET/CEP7 ratios 20 MET copies among &gt;10% of nuclei. The highest prevalence was in tumors of adrenal (2 of 13; 15%) and renal (4 of 28; 14%) origins. Stratifying by MET amplification status, no differences were observed in demographic characteristics including age, ethnicity, or gender (all P&gt;0.10). Amplified patients exhibited more organ systems involved with metastatic disease (median 3 vs. 4, P=0.0005). MET amplification was correlated with higher incidence of BRAF mutation, high-grade histology, and PTEN loss (all P&lt;0.01). There were no differences in overall survival when stratifying by amplification status. Of the 20 patients with MET amplification treated and evaluated on a phase I protocol, 6 (30%) achieved objective responses on any phase I protocol. No patients treated with a c-Met inhibitor (0 of 6) achieved an objective response. Considering only the best response on a phase I protocol, the highest response rate was observed with agents targeting VEGFR (4 of 7, 57%).

Conclusions: Although caution must be stressed when interpreting these results, MET amplification exhibits an association with higher metastatic burden, specific molecular characteristics (BRAF mutation, PTEN loss), and high grade histology. Patients with MET amplification in this cohort exhibited a high response rate to VEGFR inhibitors while c-Met targeted agents showed little activity.

Citation Format: Chad Tang, Denis Jardim, Debora Gagliato, Gerald Falchook, Kenneth Hess, Siqing Fu, Jennifer Wheler, Ralph Zinner, Aung Naing, Apostolia Tsimberidou, Funda Meric-Bernstam, David Hong. Analysis of 1115 patients tested for MET amplification and therapy response in the MD Anderson phase I clinic. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4424. doi:10.1158/1538-7445.AM2014-4424