MET in gastric cancer – discarding a 10% cutoff rule

AIMS: We aimed to develop a putative predictive biomarker score for future hepatocyte growth factor receptor (MET)‐targeted therapy of gastric cancer (GC). METHODS AND RESULTS: MET expression and MET amplification were analysed by immunohistochemistry (IHC) and chromogenic in‐situ hybridization (CISH) in 470 GC patients. Immunostaining was documented with the HistoScore. The percentage area of MET‐amplified tumour cell clones was assessed by virtual microscopy. The expression of MET was heterogeneous in primary and metastatic GC. Immunostaining intensity (MET‐IHC 2+/3+) correlated with MET amplification and a positive MET status was defined by a combination of MET‐IHC 2+ or 3+ with MET amplification, or MET‐IHC 3+ without MET amplification. The prognostic significance of the MET status was independent from the percentage area of positive tumour cells (e.g. <10 versus ≥10%). MET‐positive GCs were microsatellite stable and of KRAS/PIK3CA wild‐type. MET‐positive GCs had a very poor prognosis, with a median survival of 5.4 months and a hazard ratio of 2.126. CONCLUSIONS: A combination of immunohistochemistry and CISH is suitable to assess MET status. If MET status is used as a predictive biomarker, prospective studies should pay specific attention to adequate tissue sampling, should ignore cutoff values for tumour areas, may consider the KRAS and PIK3CA genotype as negative predictive markers and should carry out the analysis expeditiously.