112 Chapter 4 Table 13). Therefore, it was excluded that MET ectodomain shedding showed an interaction with vasoinvasive growth. Consequently, all cancers defined as positive for transmembranous C-terminal MET were included for multivariable survival analyses. In view of power, multivariable correction was restricted to six variables known to be associated with poor survival (24, 35-37). More specifically, ectodomain shedding, age at diagnosis, pT, pN, extranodal growth, and degree of differentiation. The fact that ectodomain shedding has a significant contribution for disease-free survival, makes it a promising predictive marker for oral squamous cell carcinoma patients. Moreover, this result can be explained on biological grounds, namely by the finding that deletion of the ectodomain unleashes the aggressive potential of cancer cells (21, 27). There is no association between MET protein status and stage, nor between shedding and stage for C-terminal MET positive cancers (Supplementary Tables 14, 15). This implies that patients with both early and late stage oral squamous cell carcinoma might be eligible for treatment with biologicals directed against MET. Although shedding has no predictive value (only associated with disease-free survival), abundant C-terminal MET immunoreactivity has a predictive value (associated with disease-free survival) and overall survival (18). Since 57.1% (n = 8) of patients showing abundant C-terminal MET immunoreactivity are subjective to ectodomain shedding, it might have an impact on the choice of therapy. In the future, it might be of interest to validate the occurrence of ectodomain shedding in oral squamous cell carcinoma using e.g., the expression of ADAMs as an alternative read-out. However, we find this beyond the scope of this paper. In summary, we conclude that monitoring MET protein status by comparing C- and N-terminal immunohistochemistry might be of added value in the stratification of cancers eligible for treatment with targeted therapies directed against this receptor tyrosine kinase (Fig. 10). It is hypothesized that patients having cancers classified as MET negative or positive for the decoy receptor—lacking the protein’s kinase domain—are not eligible for treatment with targeted therapies directed against MET. It is hypothesized that patients showing abundant immunoreactivity for the entire receptor might be eligible for treatment with either MET monoclonal antibodies or tyrosine kinase inhibitors. Finally, it is proposed that patients having cancers showing immunoreactivity for transmembranous C-terminal MET lacking the ectodomain—in more than 35% of the cancer cells—might benefit from MET tyrosine kinase inhibitors, treatment strategies directed against proteins that orchestrate ectodomain shedding—such as ADAMs (23, 38)—or MET monoclonal antibodies
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