255 Summary ter 6. As it is recommended by the NCCN to use tumor DOI in making decisions on END, the results obtained for C-terminal MET uniform positivity were aligned with those for DOI > 4 mm. The cutoff value used within the Erasmus MC. The results of this study show that C-terminal MET uniform positivity is associated with RLNM (pN+ and occult) in early OSCC outperforming DOI and may be of value in clinical decision making on END. Knowing that MET ectodomain shedding occurs (chapters 3 – 5) and is associated with poor survival in OSCC (chapters 4 and 5), a perspective was written concerning the malignant potential of this process and its predictive value in OSCC (chapter 6). Here, it is proposed that MET ectodomain shedding, resulting from GPCR transactivation of EGFR signaling, and/or overexpression of ADAM10/17 and/or MET, stabilizes and possibly activates MET-EC- in OSCC. Therefore, it is concluded that MET-EC- should be incorporated in the design of CDx to improve patient stratification and ultimately prolonged survival. Initial steps were taken to design such a CD incorporating MET-EC- in chapters 4, 5, and 7. Herefore, it was assumed that only patients with cancers positive for the protein’s catalytic domain, are likely to be eligible for MET targeted therapies. As such it was assumed that cancers positive for transmembranous C-terminal MET (complete MET and/or MET-EC-) are likely to be eligible for MET targeted therapies. In short, it is recommended to use MET moAbs or TKIs for cancers positive for the full-length receptor, and TKIs or a combination of both for MET-EC- cancers. Finally, it was concluded that D1C2 uniform positivity and MET-EC- are associated with poor prognosis and might aid in the stratification of OSCC patients eligible for treatment with MET targeted therapies. It was also concluded that C-terminal MET (D1C2) uniform positivity is associated with RLNM (pN+ and occult) in early OSCC and could facilitate clinical decision making on performing an END. Furthermore, it was speculated that MET immunoreactivity might facilitate optimal treatment of the neck, and predict resistance/response to – systemic – therapy. Therefore, we foresee it taking a place in clinical decision making and patient counseling, ultimately improving shared decision making. Taking everything into consideration, we dare to state here that MET immunoreactivity is a valuable biomarker in the field of OSCC. 9
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