Abstract 563: A prospective biomarker study to demonstrate high MET expression and gene amplification in a subset of patients with advanced gastric cancer

Abstract

Abstract Aim: To characterize molecular features of HGF-MET axis in patients (pts) with advanced gastric cancer (GC). Methods: Pts with advanced GC undergoing routine surgery for tumor staging or resection were studied. Tumor specimens were fixed in 10% neutral buffered formalin immediately. Total (t)- and phosphorylated (p)-MET protein were assayed by IHC, and MET gene copy number by FISH. Circulating tumor cells were enumerated by CellSearch. Blood hepatocyte growth factor (HGF) and shedMET levels were measured at pre-, and post-operatively at 2 and 7 days, and 4 weeks. Biomarkers were correlated with disease stage, tumor size, histopathology, metastasis status, and overall-survival. Results: Forty pts were enrolled from East Asian. The median age was 67 years (range, 31-86 years); 78% were male; 37 and 3 pts had stage III or IV disease, respectively; tumor histopathology was poorly, moderately, or well differentiated in 18, 17, and 4 samples, respectively (1 sample with unknown status). Biomarker results were summarized in Table 1. Five out of 32 evaluable pts (15.6%) had MET gene amplification with amplified tumor cells ranged from 14-100%. Pts who were p-MET positive tended to have moderately differentiated tumors, larger tumor size (>5 cm), and distant metastasis compared with pts who were negative. Pts with MET gene amplification appeared to have distant metastasis, poor survival, and elevated blood CEA levels. Elevated circulating HGF levels were associated with larger tumor size (>5cm). Conclusions: In pts with advanced GC, positive p-MET and MET gene amplification was associated with larger tumor size, distant metastasis, and poor survival. These results support using a molecular basis to identify a subset of pts suitable for anti-MET therapy. This study is sponsored by Sanofi. Table 1: MET pathway alterationPts with MET pathway alteration/Total evaluable pts (%)Commentc-MET Amplification15/32 (15.6)High t-MET Expression218/31 (58.1)3/18 (16.7%) are MET-amplifiedPositive p-MET Expression37/20 (35.0)3/7 (42.9%) are MET-amplifiedCTC Count ≥ 18/30 (26.7)2/8 (25.0%) are MET-amplifiedElevated Baseline HGF412/32 (37.5)1/12 (8.3%) is MET-amplifiedHGF (n=40)Baseline: 765 pg/mL*Post Operation daysD2*: 1770 (CI#: 1.98 to 2.68)#Compared to baselineD7*: 1270 (CI#: 1.55 to 2.09)D28*: 903 (CI#: 1.02 to 1.45)shedMET (n=40)Baseline: 216 ng/mL*Post Operation daysD2*: 184 (CI#: 0.83 to 0.94)# Compared to baselineD7*: 219 CI#: 0.98 to 1.11)D28*: 244 (CI#: 1.09 to 1.26) 1Among 100 nuclei counted, >10% tumor cells with MET gene copy number>4 and MET/CEP7≥2; 2Pts having ≥50% tumor cells with membranous stain level ≥2; 3H-score ≥15 on membrane; 4HGF > 787 pg/mL. Citation Format: Yang Han-Kwang, Hiroya Takeuchi, Seong-Ho Kong, Hyuk-Joon Lee, Elias Shamiyeh, Nikki Daskalakis, Hélène Goulaouic, Christelle Castell, Marie-Laure Ozoux, Ju OK Lim, Kaida Wu. A prospective biomarker study to demonstrate high MET expression and gene amplification in a subset of patients with advanced gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 563. doi:10.1158/1538-7445.AM2014-563