br Subgroup OS analysis in
3.3. Subgroup OS analysis in lung adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB
Descriptive analysis for the whole study MCC950 showed that 20.4% of stage IA and 40.6% of stage IB patients received adjuvant chemotherapy, whereas the majority of patients with stage IIA-IIIB re-ceived adjuvant therapy (Suppl. Table 2). This discrepancy between existing evidence regarding adjuvant therapy and the real life data in our cohort resulted in the subgroup analysis of patients with stage IIA
–IIIB disease (n = 202). We included only patients with adenocarci-noma and squamous cell carcinoma in this analysis due to low/no re-presentation of the remaining histological subtypes in patients with stage IIA-IIIB disease (Suppl. Table 2).
Univariate OS analysis showed a significant OS impact of c-MET H-score ≥20 in this subgroup (HR = 0.60, 95% CI: 0.43−0.83, p-value = 0.002). Multivariate Cox regression OS analyses done as pre-viously described, showed that c-MET H-score ≥20 was a strong in-dependent positive prognostic factor (Suppl. Table 4) in all three mul-tivariate models. Univariate PFS analysis failed to show any significant eﬀect of c-MET H- score, but the multivariate PFS analyses in the whole study population (adjuvant treatment not included) and in the analysis with adjuvant treatment included as a co-variate, showed a positive correlation between H-score ≥20 and longer PFS (Suppl. Table 1).
Fig. 1. Overall Survival curves. 1a: Whole study population, 1b: Patients who received adjuvant treatment, 1c: Patients who did not receive any adjuvant treatment.
Univariate and multivariate Cox regression models (cMET < 20, ≥20 score).
Multivariate incl. Treatment
Multivariate, only treated patients
Adenocarcinoma 1.00 ref.
Performance status (PS)
Current smoker 1.00 ref.
No treatment 1.00 ref.
cMET: cellular Mesenchymal Epithelial Transition factor, ALK: Anaplastic Lymphoma Kinase, LCLC: Large-Cell Lung Cancer, NOS: Not Otherwise Specified, HR:
Hazard Ratio, Ref: Reference, CI: Confidence Interval.
The role of c-MET protein overexpression as a prognostic and pre-dictive biomarker in early stage NSCLC was the primary objective of our study. It is still unclear how c-MET protein expression, MET am-plification and MET exon 14 mutation correlate with each other. The Cancer Genome Atlas study of lung adenocarcinoma and a Japanese study, both done in surgically resected tumors (early stage disease), showed that MET exon 14 mutation and MET amplification are mu-tually exclusive [19,20]. A recently published study with 28 MET exon 14 mutated cases showed a statistically significant co-existence of MET exon 14 skipping mutation and both MET gene amplification/c-MET protein overexpression in stage IV NSCLC . In this study there was a significant association between MET amplification and stage IV disease, something which was not verified in a larger cohort with 298 MET exon 14 skipped patients . Dziadziuszko et al showed that MET gene copy number determined by silver in situ hybridization (SISH) and protein expression evaluated by IHC correlated significantly in a cohort of 189 patients with surgically resected NSCLC . This finding could not be confirmed in another surgical cohort (n = 222), where no sig-nificant association was observed between c-MET expression and gene copy number, but these two studies used diﬀerent IHC scoring systems . Bubendorf et al found a statistically significant correlation between MET gene amplification and c-MET protein overexpression in a large cohort of surgically resected NSCLC patients .