MET nucleotide variations and amplification in advanced ovarian cancer: characteristics and outcomes with c-Met inhibitors.

Abstract

PURPOSE:

MET alterations including amplifications and nucleotide variations have been associated with resistance to therapy and aggressive clinical behavior.

EXPERIMENTAL DESIGN:

The medical records of patients presenting to the University of Texas MD Anderson Cancer Center Phase I Clinic with relapsed or metastatic ovarian cancers and known MET nucleotide variation or amplification status were reviewed retrospectively (n=178). Categorical and continuous clinical and molecular characteristics were compared using Fisher's exact and Wilcoxon rank-sum tests, respectively. Univariate and multivariate survival were assessed via Kaplan-Meier and Cox regression analysis, respectively.

RESULTS:

MET amplification occurred in 4 (3.5%) of 113 patients, whereas nonsynonomous nucleotide variations were present in 9 (7.4%) of 122 patients. No patients exhibited concomitant amplification and variation. MET variations were observed only in white women with high-grade ovarian tumors, whereas amplifications were observed in both black and white women with high-grade serous ovarian primary tumors. No patients (n=4) exhibiting a MET alteration achieved an objective response when treated on a c-Met inhibitor phase I trial. In addition, ovarian cancer patients treated with a c-Met inhibitor with multikinase activity trended towards a longer time-to-failure compared with those treated with a c-Met-specific inhibitor (median: 1.5 vs. 4.5 months, p=0.07).

CONCLUSIONS:

MET alterations occur in a minority of patients with ovarian cancer. c-Met inhibitors with multikinase activity may exhibit less activity in ovarian cancer than c-Met specific drugs. These findings warrant further investigation.

• Authors: Chad Tang, Denis L Fontes Jardim, Gerald S Falchook, Kenneth Hess, Siqing Fu, Jennifer J Wheler, Ralph G Zinner, Aung Naing, Apostolia M Tsimberidou, Debora De Melo Galgiato, Shannon N Westin, Funda Meric-Bernstam, Razelle Kurzrock, David S Hong
• Journal: Oncoscience (Oncoscience) Vol. 1 Issue 1 Pg. 5-13 ( 2014) ISSN: 2331-4737 [Print] United States
• PMID: 25593979 (Publication Type: Journal Article)