Abstract
MET alterations including amplifications and nucleotide variations have been associated with resistance to therapy and aggressive clinical behavior. 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. 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). 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.
Highlights
The c-Met tyrosine kinase receptor (TKR), upon activation by its cognate antigen, hepatocyte growth factor (HGF), generates proliferation, migration, and survival signals in numerous cancers[1, 2]
MET alterations occur in a minority of patients with ovarian cancer. c-Met inhibitors with multikinase activity may exhibit greater activity in ovarian cancer than c-Met specific drugs
The c-Met pathway has emerged as a resistance pathway in therapies targeting the epidermal growth factor receptor (EGFR)[3, 4], B-Raf[5], and vascular endothelial growth factor receptor (VEGFR)
Summary
The c-Met tyrosine kinase receptor (TKR), upon activation by its cognate antigen, hepatocyte growth factor (HGF), generates proliferation, migration, and survival signals in numerous cancers[1, 2] This signaling cascade parallels, and at times can supplement, the activity of other oncogenic TKRs. As a result, the c-Met pathway has emerged as a resistance pathway in therapies targeting the epidermal growth factor receptor (EGFR)[3, 4], B-Raf[5], and vascular endothelial growth factor receptor (VEGFR). Primary peritoneal, and fallopian tube cancers have similar ontological origins and clinical presentations Their aggressive metastatic behavior and generally poor prognosis has prompted interest in developing therapies with TKR inhibitors, including those targeting EGFR and c-Met[8, 9]. We investigated the clinical and molecular characteristics of patients with ovarian cancers referred to our Phase I Clinical Trials Program and their response to treatment on a phase I c-Met inhibitor trial
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