Abstract 2374: Tumoral MET expression and plasma HGF level in patients with ALK 2p23 fusion driven lung cancer.
Authors: Feng Yan , Minca Eugen , Zhang Wei , Yin Lihong , Pennell Nathan , Farver Carol , Tubbs Raymond , Liu Angen , Ma Patrick 
Published: August 2014

Background. MET is the tyrosine kinase receptor for the ligand hepatocyte growth factor (HGF). MET kinase has been identified as a novel promising target in non-small cell lung lung cancer (NSCLC). Crizotinib, a recently FDA-approved ALK inhibitor for NSCLC harboring ALK 2p23 fusion (ALK+), was initially developed as a MET inhibitor. MET expression level is a potential biomarker for response to MET inhibitors. The role of MET/HGF pathway in ALK+ NSCLC is unknown.

Methods. A cohort of 51 NSCLC patients tested for ALK fusion at Cleveland Clinic (2000 to 2012), including 15 ALK(+) and 36 ALK(-) subjects, were included in the study. Immunohistochemistry (IHC) stain against MET was performed using a monoclonal CONFIRM anti-Total c-MET antibody (SP44, Ventana). Staining was performed on a Ventana Benchmark XT automated immunostainer (Ventana Medical Systems). A four-tier (0, 1+, 2+, 3+) scoring system and H-score (the sum of each intensity score x %) were used. Thirteen ALK(+) patients treated on crizotinib therapy were prospectively followed and a total of 32 blood plasma samples were collected (1) prior to crizotinib initiation, (2) during responding period and (3) at disease progression, for HGF level measurement using HGF ELISA kit (R&D). Statistical analysis was performed using Fisher exact test and Wilcoxon rank sum test in JMP.

Results. Of the 51 tumor tested for MET IHC, 39 were adenocarcinoma (15 ALK+ and 24 ALK-), 6 squamous cell, 4 large cell carcinoma and 2 other NSCLC. None received any MET inhibitor when tissue was collected. The percentage of negative MET IHC (score 0 or 1+ in 50% tumor cells) was not statistically significant between ALK(+) and ALK(-) groups (40% vs 30%, p=0.5). The plasma HGF levels in ALK(+) patients varies from undetectable to 14000pg/ml. The median (25th-75th quantiles) level in patients prior to crizotinib therapy (n=5), during responding period (CR/PR/SD, n=12) and at disease progression (n=5) were 2137(767-12100)pg/ml, 1629(785-3430)pg/ml and 4064(1108-7308)pg/ml. The plasma HGF level showed a trend of decreasing during clinical response to crizotinib and elevation upon disease progression, albeit not reaching statistical significance in this small study cohort (p&gt;0.05).

Conclusions. MET expression is commonly seen in NSCLC, and no significant difference were observed between fusion ALK(+) and ALK(-) NSCLC. The baseline plasma HGF concentration varied significantly among ALK(+) NSCLC patients, but showed a trend correlating with therapeutic response and resistant progression, to crizotinib therapy. Prospective study with larger cohorts is warranted to further evaluate the role of MET/HGF as biomarker in ALK targeted therapy.

Citation Format: Yan Feng, Eugen Minca, Wei Zhang, Lihong Yin, Nathan Pennell, Carol Farver, Raymond Tubbs, Angen Liu, Patrick Ma. Tumoral MET expression and plasma HGF level in patients with ALK 2p23 fusion driven lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2374. doi:10.1158/1538-7445.AM2013-2374