MET nucleotide variations and amplification in advanced ovarian cancer: characteristics and outcomes with c-Met inhibitors
Chad Tang1, Denis L. Fontes Jardim2, Gerald S. Falchook2, Kenneth Hess4, Siqing Fu2, Jennifer J. Wheler2, Ralph G. Zinner2, Aung Naing2, Apostolia M. Tsimberidou2, Debora De Melo Galgiato2, Shannon N. Westin3, Funda Meric-Bernstam2, Razelle Kurzrock5, David S. Hong2
1 Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
2 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
3 Department of Gynecology Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
5 Moores Cancer Center, University of California San Diego Health System, San Diego, CA.
David S. Hong, email:
Keywords: MET nucleotide variations, MET amplification, ovarian cancer, c-Met inhibitor
Received: August 27, 2013 Accepted: December 9, 2013 Published: December 11, 2013
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.