According to researchers, some lung adenocarcinoma tumor specimens that are positive for a known oncogenic molecular alteration in MET are negative for MET overexpression by immunohistochemistry (IHC). The findings of this study were published online in the Journal of Thoracic Oncology.
Both MET amplification and a MET splice mutation in exon 14 (MET ex14) have previously been shown to drive lung cancer growth, survival, and metastasis through activation of the MET pathway. Furthermore, MET amplification has been identified as a mechanism of acquired resistance to small-molecule tyrosine kinase inhibitors of EGFR and ALK. Using fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) to detect de novo MET amplification, and NGS to identify MET ex14 mutations, it has been estimated that these molecular alterations occur in 1% to 5% of patients with lung cancer and 3% to 4% of patients with lung adenocarcinoma, respectively
Tissue staining of the MET protein using IHC has been suggested by some as a possible surrogate biomarker for the aforementioned MET alterations that could be used as an initial screen to identify specimens for subsequent molecular testing by FISH and/or NGS.
Nevertheless, increasing evidence suggests that overexpression of MET, as measured by IHC, is not predictive of benefit from MET inhibitors.
This study utilized clinicopathologic data collected from 3 institutions (Dana-Farber Cancer Institute, Boston, Massachusetts; University of Colorado, Aurora, Colorado, and Memorial Sloan Cancer Center, New York, New York) that participated in the Lung Cancer Mutation Consortium 2 (LCMC2). The study cohort included patients diagnosed with metastatic lung adenocarcinoma between May 2012 and January 2016 who were naive to treatment with targeted therapy, and had sufficient tumor tissue for biomarker testing.
The results of FISH testing were considered positive for MET amplification if the ratio of MET to the centromere of chromosome 7 (CEP7) was more than 2.2. Alternatively, a copy number-fold (log2 ratio) change of at least 1.8x was defined as MET amplification by NGS. An H-score (ie, 3 × percentage of strongly staining nuclei + 2 × percentage of moderately staining nuclei + percentage of weakly staining nuclei) of at least 200 was considered positive for overexpression of the MET protein by IHC.
Of the 181 patients included in the study, 39% had MET-positive tumors by IHC. Only 3 (2%) patients were determined to have disease characterized by MET amplification as determined by either FISH (2 individuals) or NGS (1 individual). Interestingly, only 1 of these cases was determined to be MET-positive by IHC. However, tumors from the 2 patients (1%) with disease characterized by a MET ex14 mutation were positive for MET by IHC. In addition, MET amplification and MET ex14 mutations were mutually exclusive in this patient cohort. These results were unchanged when MET positivity by IHC was defined by an H-score of 300.
Limitations of this study as identified by the authors included the low prevalence of MET molecular alterations in this patient cohort. They speculated that intratumoral heterogeneity with respect to MET amplification as measured by FISH, possible limitations of NGS in detecting MET amplification and covering targeted regions of exon 14, as well as uncertainties regarding the correlation of MET amplification status as determined by FISH with NGS, may have contributed to this low prevalence.
In their concluding remarks, the authors explained that “coupling the results of these trials with growing literature showing that MET IHC inadequately selects for MET amplification or MET ex14 mutations strongly challenges its use as a screen for MET dependency.”
“We recommend that tissue should be prioritized for NGS and FISH over IHC to test foractionable MET mutations or amplification in lung adenocarcinomas,” they further noted.
Guo R, Berry LD, Aisner DL, et al. MET IHC is a poor screen for MET amplification or MET exon 14 mutations in lung adenocarcinomas: Data from a tri-institutional cohort of the Lung Cancer Mutation Consortium [published online June 19, 2019]. J Thorac Oncol. Doi: 10.1016/j.jtho.2019.06.009