Tumoral MET/HGF expression and MET gene amplification in patients with ALK 2p23 fusion driven lung cancer.
http://meetinglibrary.asco.org/content/116773-132
Background: MET receptor and its ligand HGF are both promising targets in non-small cell lung cancer (NSCLC) therapy. Crizotinib, a recently approved ALK inhibitor for NSCLC harboring oncogenic ALK 2p23 fusion (ALK+), was initially developed as a bona fide MET inhibitor. The role of MET/HGF pathway in ALK+ NSCLC is still unknown. Methods: The study included 73 NSCLC patients tested for ALK rearrangements at Cleveland Clinic (2000-2012), including 21 ALK+ and 52 ALK-. Immunohistochemistry (IHC) on FFPE tumor tissue was performed for c-MET using a monoclonal CONFIRM antibody (SP44, Ventana) with Ventana Benchmark XT automated immunostainer and for HGF using a polyclonal antibody (R&D) following a manual protocol. IHC scoring was interpreted on a 4-tier system (0, 1+, 2+, 3+). MET gene amplification by MET/Chromosome 7 dual probe in-situ hybridiazation (DISH) (Ventana) was also performed. Statistical analysis was performed using Fisher exact test in JMP. Results: Of the tested tumors, 61 were adenocarcinoma (21 ALK+ and 40 ALK-), 6 squamous cell, 4 large cell and 2 NSCLC-NOS. None received any MET inhibitor prior to tissue collection. MET expression by IHC score 0-3 was: 35%, 33%, 15% and 17% in ALK-, and 5%, 37%, 42% and 16% in ALK+ tumor group, respectively. HGF IHC score 0-3 was 34%, 55%, 11% and 0% in ALK-, and 0%, 63%, 32% and 5% in ALK+ tumor group, respectively. The percentages of high MET or HGF expression (2+ or 3+) were higher in ALK+ group compared to ALK- (58% vs 32%, p=0.06, and 37% vs 11%, p=0.03). The correlation coefficient between MET and HGF expression was 0.48. MET gene amplification by DISH was detected in 15% (7/47) ALK- tumors but 0% (0/15) ALK+ tumors (difference not statistically significant, p=0.18). The correlation coefficient between MET IHC and MET gene amplification was 0.33. Conclusions: MET and HGF expression is commonly seen in NSCLC, with more frequent high expression levels in ALK+ than ALK- tumors. Using a newly developed DISH method, we show that MET gene amplification tend to be less frequent in ALK+ tumor. A prospective study with larger sample size is warranted to further define the role of MET/HGF as biomarkers in the biology of NSCLC with ALK rearrangements and their targeted therapy. |
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