59 MET immunoreactivity and poor prognosis Multivariable Cox regression analyses revealed an effect of MET staining pattern on survival that is dependent on the status of vasoinvasive growth (Supplementary tables S6 & S7). Where MET staining pattern significantly influences 5-year OS (HR = 3.019, p < 0.001; Figure 3C) and DFS (HR = 2.559, p < 0.001; Figure 3D) in patients lacking signs of vasoinvasive growth (n = 136), MET staining pattern has no effect on survival in patients with vasoinvasive growth (n = 39; Figures 3E & 3F). Based on these data, further multivariable Cox regression analyses were restricted to the subgroup of patients lacking histological signs of vasoinvasive growth. The best multivariable Cox regression model for 5-year OS includes: MET staining pattern, clinical N-stage and extranodal growth, while the final model for 5-year DFS includes: MET staining pattern and extranodal growth (Table 3). In short, these results demonstrate that MET uniform staining patterns, either negative or positive, remain independently associated with the poor prognosis of patients lacking histological signs of vasoinvasive growth after adjusting for other factors known to be associated with a poor outcome of HNSCC. Table 3: Explanatory variables significantly associated with 5-year OS and DFS. Outcome measure Variable HR 95% CI p-value 5-year OS MET uniform staining pattern 3.475 2.081 – 5.801 < 0.001 cN1-3 2.023 1.120 – 3.653 0.019 Extranodal growth 4.207 2.229 – 7.942 < 0.001 5-year DFS MET uniform staining pattern 2.923 1.797 – 4.756 < 0.001 Extranodal growth 5.624 3.306 – 9.566 < 0.001 Results of the optimal multivariate Cox proportional hazards regression models including only patients lacking histological signs of vasoinvasive growth. Abbreviations: OS, Overall Survival; DFS, Disease Free Survival; HR, Hazard Ratio; CI, Confidence Interval. Bold values highlight statistical significance. Discussion The receptor tyrosine kinase MET is expressed in the majority of HNSSC (20), making it an interesting target for therapy (19). Although several biologicals against MET have been developed, there are no guidelines concerning the stratification of patients eligible for treatment with MET inhibitors (19). Despite MET’s established role as a facilitator of invasive growth in HNSCC (20), its status as a prognostic factor remains unclear (21-30). A possible explanation might 3
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