231 General discussion, conclusion, and future perspective General discussion Despite the fact that MET is widely expressed in HNSCC and acts as an orchestrator of invasive growth (1-3), its association with survival remains unclear (4-19). Furthermore, use of MET targeted therapies, in the form of moAbs and TKIs, have not yet resulted in major survival benefits (20-22). A possible explanation might be found in the lack of reliable antibodies, suboptimal scoring methods, biology, and the absence of CDx (17, 20, 21). Therefore, the primary aim of this thesis was to stratify those patients likely to benefit from MET targeted therapies and design a relevant patient stratification scheme. Since both moAbs and TKIs can target MET when its located at the cell membrane (20), the assumption was made to restrict scoring of C- and N-terminal MET immunoreactivity to the membrane throughout the entire thesis. First, it was established that out of five C-terminal MET antibodies, moAb clone D1C2 was most reliable in the detection of membranous MET immunoreactivity in FFPE OSCC (chapter 3). Additionally, using a TMA, it was observed that membranous D1C2 immunoreactivity is either uniform (negative or positive), or variable across a cancer cross section (chapter 3). Next, use of reliable C- and N-terminal MET moAbs (D1C2 and A2H2-3) revealed that ectodomain shedding occurs in OSCC, resulting in a transmembranous C-terminal MET fragment lacking the ectodomain (MET-EC-) (chapter 4). Subsequently, using WTSs, a scoring system was designed that describes membranous MET immunoreactivity across cancer fields in the form of four staining patterns (uniform negative, gradient toward the periphery, uniform positive, and gradient toward the center) and accounts for MET ectodomain shedding (chapter 5). Eventually, this work led to the stratification of OSCC into three categories based on MET protein status: MET negative (no immunoreactivity), decoy MET (more positivity for the N-terminal moAb), and transmembranous C-terminal MET (equal positivity for both moAbs (complete MET), or more positivity for the C-terminal moAb (complete MET and/or MET-EC-) (chapters 4 and 5). Furthermore, it was shown that within the latter category, C-terminal MET (D1C2) uniform positivity and ectodomain shedding are associated with poor survival (chapters 4 and 5). Ultimately, a CD was designed that accounts for MET ectodomain shedding, seen its potential impact on the use of targeted therapies in the form of moAbs and/or TKIs (chapters 4 and 5). Furthermore, seen MET’s role as an orchestrator of invasive growth, it was investigated and confirmed that D1C2 uniform positivity is associated with the presence of RLNM in early OSCC, outperforming DOI. Therefore, the added value of D1C2 uniform positivity potentially lies in the preoperative setting during 8
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