HER2‐positive gastric cancer with concomitant MET and/or EGFR overexpression: A distinct subset of patients for dual inhibition therapy

Growth factor receptors, often carrying tyrosine kinase activities in their cytoplasmic domains, are overexpressed in many cancers. Coactivation of receptor tyrosine kinases (RTKs) plays a critical role in tumor response to targeted therapeutics. We examined concomitant overexpression of EGFR and MET in patients with HER2(+) and HER2(-) gastric cancers (GCs). Tissue microarray samples obtained from 1,589 GC patients who received R0 gastrectomy with extensive node dissection and adjuvant chemoradiationtherapy were analyzed by immunohistochemistry and fluorescence in situ hybridization. HER2(+) was observed in 169 patients (11%). Out of 169 HER2(+) patients, 15 (9%) were EGFR(+) and MET(+) , 29 (17%) were EGFR(+) , 37 (22%) were MET(+) and the remaining 88 patients (52%) were HER2(+) only, without concomitant EGFR or MET overexpression. Greater number of overexpressed RTKs correlated with younger age (p < 0.001), larger tumor size (p = 0.027), intestinal histology (p < 0.001) and shorter overall survival (p = 0.002). The mean overall survival was 113 months for HER2(-) /EGFR(-) /MET(-) and 63 months for HER2(+) /EGFR(+) /MET(+) subgroups. Patients with HER2(+) /EGFR(+) /MET(+) GCs had a substantial risk of death with a hazard ratio of 3.01 (95% CI: 1.54-5.90), compared with HER2(-) /EGFR(-) /MET(-) GC patients. Using patient-derived tumor cell models isolated from pericardial effusion of HER2(+) and MET(+) GC cases, we demonstrated that the combination of HER2-inhibitor (lapatinib) and MET-inhibitor offered a more profound inhibition in the ERK/AKT pathway and cell proliferation than lapatinib alone. Co-overexpression of RTKs was demonstrated in small subsets of GC associated with aggressive behavior and in these cases, combination therapy may be considered as potential treatment options.