Abstract 1808P
Background
MET is a receptor tyrosine kinase being involved in a plethora of physiologic and developmental processes. MET-inhibitors, e.g. crizotinib, capmatinib or lenvatinib, are effective in cancers with MET exon 14 skipping mutations or with top-level MET amplifications. Emerging evidence indicates that also MET fusions represent a predictive biomarker for potentially effective MET inhibition. However, data on frequencies and subtypes of MET fusions among solid tumors are limited so far.
Methods
545 solid cancers has been investigated with a targeted RNA sequencing approach (Archer® FusionPlex® CTL Panel) using anchored multiplex PCR and, thus, enabling the detection of novel MET translocation partners. MET amplification status was obtained from FISH and/or DNA-based NGS analyses in a subset of samples. Biologic and clinical relevance of MET fusions was determined by analysis of intragenic breakpoints, transcript and protein expression, gene amplification status and database research.
Results
Eight cases with MET -fusions were detected, representing 1.5% of the entire cohort. We found novel subtypes which have not been described so far: ETV6-MET, CAPZA2-MET, and EPS8-MET. Previously reported fusions include TRIM26-MET, PTPRZ1-MET. Affected entities were anaplastic- and papillary thyroid carcinomas, NSCLC and cholangiocarcinomas. Several cases showed concomitant MET amplification. Based on our ancillary evaluations, we regard the majority of fusions pathogenic, but found also rearrangements with low propensity to represent an oncogenic driver and a therapeutic target, i.e. CAPZA2-MET. Some of those passenger aberrations were associated with MET amplification. Pathogenic MET fusions were mutually exclusive with any common driver mutation in the respective tumor entities.
Conclusions
MET fusions represent an ultra-rare finding among solid cancers and were found in 1.5% of our series of 545 cancers mainly originating from lung, thyroid, pancreas and biliary tract. Careful bioinformatic evaluation is mandatory to select patients who may benefit from MET inhibitor treatment. Based on our findings we conclude that detection of MET fusions can be a useful enrichment of biomarker testing in solid tumors and MET inhibitors might be considered if standards of evaluation are considered.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.