Identifying the Appropriate FISH Criteria for Defining MET Copy Number–Driven Lung Adenocarcinoma through Oncogene Overlap Analysis

Abstract

Introduction MET gene copy number gain (CNG) may be a predictive biomarker for MET inhibition in lung cancer, but the most appropriate method and criteria for defining MET positivity are uncertain. Methods MET copy number was assessed by fluorescence in situ hybridization (FISH) in lung adenocarcinoma. Positivity criteria included mean MET/cell ≥5 (low ≥5 – <6, intermediate ≥6 –<7, high ≥7) and MET/CEP7 ratio ≥1.8 (low ≥1.8 – ≤2.2, intermediate >2.2 – < 5, high ≥5). Associated clinical and molecular characteristics were captured. Results 99/686 cases (14%) had mean MET/cell ≥ 5, 52/1164 (4.5%) had MET/CEP7 ≥1.8. Other oncogenic drivers (in EGFR, KRAS, ALK, ERBB2, BRAF, NRAS, ROS1 or RET) were detectable in 56% of the mean MET/cell ≥ 5 group and 47% of the MET/CEP 7 ratio ≥1.8 group, suggesting many MET ‘positive’ cases are not truly MET-addicted. Concomitant drivers in low, indeterminate and high categories of mean MET/cell were 32/52 (62%), 12/19 (63%) and 11/27 (41%) (p=0.2) and in MET/CEP7: 15/29 (52%), 9/18 (50%) and 0/4 (0%) respectively (p=0.04). MET/CEP7 ≥1.8, in the absence of other oncogenes, was associated with a higher rate of adrenal metastases (p=0.03), but not with never smoking status. Conclusions FISH MET/CEP7 ≥ 5 defined a MET ‘positive’ group with no oncogenic overlap. As this method and criteria are also associated with the highest response rate to MET inhibition it represents the clearest definition of a MET CNG-addicted state. However, a MET-associated phenotype may also exist across MET/CEP7 ≥ 1.8 cases when no other oncogene overlap occurs.

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance

“…One drawback with FISH was the question of what cutoff should be used to predict sensitivity to MET inhibitors. A recent study by Noonan et al sheds light on the matter as it showed that a FISH MET/CEP7 ratio of ≥5 was associated with the most sensitivity to MET inhibition (49). While circulatingtumor DNA (ctDNA) testing might be a good option for capturing MET point mutations, however it is less sensitive to detect copy number changes and gene rearrangements.…”

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer

“…Its role in the treatment naïve setting has also been investigated using copy number cutoffs (37). Patients with high copy number are reported to be an indicator of a more aggressive disease (38).…”

“…Patients with high copy number are reported to be an indicator of a more aggressive disease (38). Complicating the interpretation of these cutoffs, is the fact that MET copy number gain, can occur in the context of focal amplification, polysomy (likely a reflection of ploidy) and even with other genomic alterations e.g., EGFR, KRAS in up to 56% of cases using a 5 copy threshold (37). Thus while MET fluorescent in situ hybridization (FISH) has been largely adopted to pre-select patients for trials, it is important to note that concurrent screening with broader next generation sequencing to exclude other drivers or immunohistochemistry (IHC) to ascertain protein expression may be complementary and allow further enrichment for potential c-MET addicted tumors (39).…”

MET–GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors

“…One approach defined the cutoff for MET gene amplification by exploiting the mutually exclusive nature of more than one driver gene aberration (17). Here we present an alternative approach of characterizing tumor cells for MET signaling-associated protein complexes.…”