Prognostic value of c-MET in head and neck cancer: A systematic review and meta-analysis of aggregate data

Objectives: The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) ligand/receptor axis has been implicated in pathogenesis of malignant diseases including squamous cell carcinoma of the head and neck (SCCHN). Overexpression of c-MET has been reported as a common molecular abnormality in SCCHN, although its prognostic and predictive value remains to be validated. Methods: We systematically searched literature for studies evaluating c-MET expression on immunohistochemistry in newly diagnosed, non-metastatic SCCHN. The c-MET expressing cases were classified into three categories according to predefined cut-off values for positivity. Our aim was to assess the prevalence of c-MET expression and its relationship with selected clinicopathological variables. Results: Twenty-eight studies with 2019 cases were included. Relative frequencies of c-MET expression above cut-off levels I, II, and III were 81.8%, 63.8%, and 46.2%, respectively. Differences between these three values were statistically significant (p < 1.0 x 10(-6)). Above cut-off level II, c-MET positivity was associated with worse overall survival (p = 4.0 x 10(-6)), positive nodal status (p = 1.0 x 10(-4)), higher disease stage (p = 7.0 x 10(-4)), older age (p = 2.1 x 10(-3)), disease recurrence (p = 2.0 x 10(-2)), and primary tumour localization in the oral cavity (p = 2.3 x 10(-2)). Above cut-off level III, c-MET positivity was associated with worse disease-free or progression-free survival (p = 9.0 x 10(-6)), p16 negativity ( p = 2.4 x 10(-4)), worse overall survival (p = 4.0 x 10(-4)), positive epidermal growth factor receptor (EGFR) status (p = 7.2 x 10(-4)), and larger primary tumours (p = 4.6 x 10(-3)). Conclusion: In SCCHN, immunohistochemical overexpression of c-MET above cut-off levels III and particularly II was associated with inferior survival outcomes and advanced disease. Moreover, it represents a promising predictive biomarker for c-MET targeting, yet the optimal scoring method remains to be defined.