Analysis of MET genetic aberrations in patients with breast cancer at MD Anderson Phase I unit.

BACKGROUND: c-MET is a receptor tyrosine kinase whose phosphorylation activates important proliferation pathways. MET amplification and mutation have been described in various malignancies, including breast cancer (BC), and c-MET overexpression is associated with worse survival outcomes in patients with BC. We describe MET mutation and amplification rates in a BC cohort of patients referred to a Phase I Unit. METHODS: We reviewed the electronic medical records of all patients with advanced BC tested for MET amplification, mutation, or both who were referred to the Department of Investigational Cancer Therapeutics at MD Anderson. RESULTS: A total of 107 patients with advanced BC were analyzed for MET mutation/variant (88 patients) or amplification (63 patients). Of these, 49 were tested for both genetic abnormalities. Three of 63 patients (4.7%) demonstrated MET gene amplification by fluorescence in situ hybridization (2 in primary tissue; 1 in metastatic site). MET mutation/variant was detected in 8 of 88 patients (9%). High-grade tumors were characteristic of all patients harboring MET amplification and were present in 7 of 8 (87.5%) of those with MET mutation. Metastatic sites were greater in MET-amplified compared with wild-type patients (median of 7 vs. 3 sites). Five of 8 patients (62.5%) with MET mutations had triple negative BC compared with 46% in controls. In addition, patients with positive test results for MET aberrations (n = 11) had inferior overall survival (OS) from Phase I consult compared with wild-type patients (n = 37), although this was not statistically significant (median OS = 9 vs. 15 months, P = .43). CONCLUSIONS: In this cohort of patients with BC who were referred to our Phase I Department, MET aberrations were associated with higher metastatic burden and high-grade histology. We could not demonstrate differences in survival outcomes because of a small sample size.

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

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.

MET aberrations and c-MET inhibitors in patients with gastric and esophageal cancers in a phase I unit.

We sought to investigate the demographics and tumor-associated features in patients with gastroesophageal (GE) malignancies referred to our Phase I Program who had formalin-fixed, paraffin-embedded tissue from archival or new biopsies tested for MET mutation and/or amplification. MET amplification was found in 5 of 76 (6.6%) patients (3/34 [8.8%] esophageal, 2/26 [7.7%] gastric and none in 22 gastroesophageal junction cancers). The only MET mutation detected in 3 of 41 (7.3%) patients was N375S. No demographic and histologic characteristics were associated with specific MET abnormalities. Median overall survival was 3 and 5 months for patients with and without a MET alteration, respectively (hazard ratio [HR] = 2.1; 95% CI, 0.8 to 5.5; P=.14). Sixteen of 81 (20%) patients were enrolled in a c-MET inhibitor trial. Best responses were stable disease in 3 patients (19%), including a patient with esophageal adenocarcinoma that remained on the trial for 9.9 months (wild-type for MET abnormality). All tumors with MET abnormality (n=3) progressed on a c-MET inhibitor in fewer than 2 months. In conclusion, MET abnormalities can be found in a small group of patients with GE adenocarcinoma and further studies are necessary to better characterize the prognostic and predictive impact of MET alterations.

Comprehensive characterization of malignant phyllodes tumor by whole genomic and proteomic analysis: biological implications for targeted therapy opportunities.

BACKGROUND: Phyllodes tumors are uncommon breast tumors that account for less than 0.5% of all breast malignancies. After metastases develop, the prognosis is poor, with very few patients living more than 1 year. The biology of this unusual cancer is not understood and, consequently, no potential targets for treatments are currently available. There has been an exponential increase in the number of commercially available tumor profiling services. Herein, we report a case of metastatic malignant phyllodes tumor for which a comprehensive molecular analysis was performed by using Clinical Laboratory Improvement Amendments (CLIA)-certified labs, providing new insights into the potential opportunities for molecularly targeted therapies for this extremely rare disease. METHODS: Next-generation sequencing was performed by using the FoundationOne™ platform (Foundation Medicine, Cambridge, MA). Whole-genome array-based comparative genomic hybridization (array CGH) was performed by using the DNAarray™ (CombiMatrix Diagnostics, Irvine, CA). Immunohistochemical and morphoproteomics analysis were performed at Consultative proteomics®, The University of Texas, UT Health Medical School, Houston,TX (Robert E Brown Lab); Clarient Diagnostics, Aliso Viejo, CA; and Caris Life Sciences Target one, Irving, TX, USA. RESULTS: Next-generation sequencing showed 3 aberrant genes: activating mutation Q61L on NRAS; inactivating mutations Q504* and K740* on RB1; and TP53 loss. Whole-genome array-based comparative genomic hybridization (array CGH) revealed amplifications of chromosome (chr.) 1 (CKS1B gene), chr. 8 (MYC gene), and chr. 9 (CDKN2A gene) Deletions of chr. 17 (TP53), chr. 10 (GATA3), chr. 11 (FGF4 and CCND1 genes), and chr.22 (PDGFß). Immunohistochemical analysis for relevant markers showed a positive staining for transducing-like enhancer of split (TLE) 3; secreted protein acidic and rich in cysteine (SPARC) was expressed at 2-3+ in the cytoplasm of the tumors cells, whereas mammalian target of rapamycin (mTOR) was expressed up to 2+ in the nuclei of the tumor cells. CONCLUSIONS: We describe for the first time an NRAS mutation with concomitant activation of PI3K/Akt/mTOR in phyllodes tumor. We also found markers for sensitivity to taxane-based therapies, especially albumin-bound paclitaxel. Exploring the biology of rare malignancies by CLIA certified labs may be reasonable strategy for the development of targeted treatments.