Up to approximately 20% of patients with gallbladder cancer had disease characterized by amplification of the MET gene, according to results of a retrospective study published in Cancer Research and Treatment.
Although primary gallbladder cancer is uncommon, it is considered to be the most aggressive cancer of the biliary tract. While combination therapy with gemcitabine and cisplatin is first-line therapy for patients with unresectable, advanced gallbladder cancer, this disease is associated with a poor prognosis. Hence, there is an unmet need to identify new therapeutic targets and approaches to improve outcomes in this patient group.
The MET gene encodes for the transmembrane MET receptor tyrosine kinase, which is involved in the activation of a number of downstream signaling pathways, including phosphatidylinositol kinase (PI3K) and Grb2-Ras–mitogen-activated protein kinase (MAPK), through binding of its ligand, hepatocyte growth factor (HGF).
Dysregulation of MET signaling has been identified as a driver of oncogenesis in certain cancers, including non-small cell lung cancer and hepatocellular carcinoma. However, neither the prevalence of overexpression of the MET protein or amplification of the MET gene nor the potential impact of these molecular features on the clinicopathological characteristics of gallbladder cancer have been well explored.
In this study, 116 tumor samples were obtained from 113 patients who underwent surgery for gallbladder cancer at a hospital in Korea between 1991 and 2016. At baseline, the median patient age was 63.5 years and 37.9% were men; over 50% of patients had stage III or stage IV disease, with N1/2 disease, lymphovascular invasion, and perineural invasion present in 42.8%, 35.7%, and 36.3% of patients, respectively. More than 90% the tumor samples were adenocarcinoma histology.
MET overexpression was evaluated by immunohistochemical (IHC) staining using scores of 0 (no expression) to 3+ (high expression). The degree of MET gene amplification was assessed using MET silver in situhybridization (SISH) followed by fluorescence in situhybridization (FISH) for samples classified as MET-amplified by SISH, and the results of ISH testing were scored using 4 separate systems.
Of the 80.2% of samples successfully evaluated by IHC, 39.8% were scored as 2+ or 3+, indicating MET overexpression. Of the 80.2% of samples successfully evaluated by SISH, MET gene amplification was found to be present in 9.7% to 18.3% of samples, depending on the scoring system used.
Notably, no significant correlation was found between level of MET expression and the number of MET gene copies.
However, MET gene amplification, irrespective of scoring system — but not MET overexpression — was significantly associated with adverse disease features, such as higher histological grade, more advanced primary tumor category, the presence of lymph node metastases, and more advanced disease stage.
In their concluding remarks, the study authors noted that “further studies are needed to elucidate the significance of MET amplification as a potential therapeutic target and predictive biomarker for anti-MET–targeted therapy in gallbladder cancer patients.”
Kim Y, Bang SS, Jee S, et al. Prevalence and clinicopathological significance of MET overexpression and gene amplification in patients with gallbladder carcinoma [published online October 24, 2019]. Cancer Res Treat. doi: 10.4143/crt.2019.370