By Associate Professor Mirette Saad
Introduction
NSCLC comprises approximately 85%-90% of all lung cancers. The MET exon 14 skipping mutation (METΔex14), also known as METex14sk, is present in ~ 3% to 5% of non-small cell lung cancer (NSCLC) cases across all histologic subtypes (incidence varies by histology). Some studies have reported the detection of METΔex14 in squamous cell carcinoma (~2%) and large cell carcinoma (0.8%).
The MET gene is a proto-oncogene that encodes for a receptor tyrosine kinase protein. MET abnormalities have been associated with rapid tumour growth, aggressively invasive disease, and a poor prognosis. Today, approved targeted therapies are available for patients with NSCLC who are positive for oncogenic drivers, such as EGFR, ALK, BRAF V600E, ROS1, NTRK1/2/3, RET, and METΔex14.
METΔex14 are characterised by an average age of over 70 years at diagnosis, a smoking history, and a higher frequency in pleomorphic carcinoma and adenosquamous cell carcinoma than in adenocarcinoma. The correlation between the frequency of METΔex14 and race, sex, stage, and histological grade has not yet been reported or is still controversial.
Recommended by guidelines
METΔex14 skipping mutations now are incorporated into professional guidelines for the clinical management of NSCLC. This category of mutations is considered clinically actionable in NSCLC because clinical trial data showed the association of METΔex14 alterations with therapeutic responsiveness to oral MET tyrosine kinase inhibitors (TKIs).
MET exon 14 skipping mutation and molecular targeted therapies
In 2020 and 2021, the approval of two MET-TKIs, capmatinib and tepotinib, for NSCLCs carrying METΔex14 dawned a new era for MET-targeted therapy. Both MET-TKIs are potent and highly selective ATP competitors for MET in in vitro or in vivo models carrying METΔex14. These drugs yielded progression-free survival of 5.4−12.4 months in clinical trials.
Studies reported on-target and off-target mechanisms of acquired resistance to MET-TKIs. NSCLCs with this mutation may harbour highly heterogeneous co-driver mutations. Therefore, it is understandable that some patients show inherent resistance to MET-TKIs.
In contrast with EGFR/ALK-positive NSCLC having zero or low PD-L1 expression, METΔex14 NSCLC tumours were found to express high levels of PD-L1. Currently, there are conflicting data regarding the impact of METΔex14 skipping mutations on immunotherapy, and this consideration is under active investigation. In addition to immunotherapy, novel treatments, including novel MET-TKIs, MET antibodies, and novel combination therapies, are now being evaluated in clinical trials.
When to test?
Surgical resection is unfeasible for patients that present with advanced disease. NSCLC specimens typically are small, yet requirements for molecular biomarker analysis are ever-expanding. Single-gene testing for multiple biomarkers sequentially may result in longer turnaround times, increase the risk of tissue exhaustion, and may reduce the sensitivity to identify molecular biomarkers.
Broad molecular profiling is strongly advised by the NCCN guidelines in NSCLC given the other oncogenic biomarkers recommended for routine analysis in this tumour type using tissue biopsy specimens that often are composed of limited tissue.
Laboratory methods
There are several methods to detect METΔex14 in NSCLCs. These include next-generation sequencing (NGS)-based panel tests, with RNA-based or DNA-based techniques that employ some degree of target enrichment. Although DNA-based assays may be used for successful detection of the underlying molecular biology of METΔex14 skipping mutations, it has its limitations. It has been reported that the sensitivity of RNA-based tests is better than DNA-based tests. RNA-based assays, by directly detecting omission of exon 14 from the transcript, overcome many of the limitations of DNA-based analyses. However, RNA-based testing may be hampered by a higher rate of poor-quality RNA in clinical tumour samples.
Immunohistochemistry (IHC), although applicable for some biomarker analyses, has been shown to be of limited clinical utility in NSCLC for the detection of METΔex14 skipping mutations. It is important for clinicians to recognise that assays including MET in their list of covered genes may not detect all alterations that lead to METΔex14 skipping. Careful consideration of the limitations of the sequencing assays to guide treatment decisions is recommended.
Conclusion
METΔex14 skipping mutations are clinically relevant because they are predictive for approved targeted therapies and are deemed a part of routine biomarker analysis in professional guidelines for the clinical and laboratory management of NSCLC. Molecular profiling is strongly advised in NSCLC. Data will continue to emerge with ongoing assessment of the most recently approved targeted agents.
How to order
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MET exon 14 skipping test MBS Eligibility Criteria (Item 73436)
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References
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About the author:
Assoc. Prof. Mirette Saad
MBBS (HONS) MD (HONS) MAACB FRCPA PHD
National Director of Molecular Genetics Australian Clinical Labs
Lab: Clayton
Speciality: Chemical Pathology
Areas of Interest: Molecular genetics, precision medicine, cancer genetics, antenatal screening, NIPT, endocrine, fertility testing and research, medical teaching
Phone: (03) 9538 6777
Email: mirette.saad@clinicallabs.com.au
Associate Professor Mirette Saad is a Consultant Chemical Pathologist and the National Director of Molecular Genetics at Australian Clinical Labs. She has a Fellowship with honours in Chemical and Molecular Pathology, with a Microbiology subspeciality, from Suez Canal University, Egypt. A/P Saad received her NHMRC-sponsored PhD degree in Cancer Genetics from Melbourne University and Peter MacCallum Cancer Institute. Along with her teaching and research roles, A/P Saad is a registered medical practitioner with AHPRA, a Chemical Pathology Fellow (FRCPA) at the Royal College of Pathologists of Australasia, and a Member of the Australasian Association of Clinical Biochemists (MAACB). She is a Chair of the RCPA Chemical Pathology Advisory Committee, a Member of the RCPA Genetic Advisory Committee, AACB, and a Chair of the Precision Medicine Services at Australian Clinical Labs. At Clinical Labs, A/Prof Mirette Saad leads the Molecular Genetic testing for non-invasive prenatal testing (NIPT), antenatal screening, personalised drug therapy, and cancer.
