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MET Amplification: Causes, Diagnosis & Treatment

MET amplification is a genetic alteration in which the MET gene is duplicated in excess, promoting uncontrolled tumor growth. It plays a key role in cancer diagnostics and targeted therapy.

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Things worth knowing about "MET Amplification"

MET amplification is a genetic alteration in which the MET gene is duplicated in excess, promoting uncontrolled tumor growth. It plays a key role in cancer diagnostics and targeted therapy.

What is MET Amplification?

MET amplification is a genetic alteration characterized by an abnormally high number of copies of the MET gene (Mesenchymal-Epithelial Transition gene) within a cell. Under normal conditions, the MET gene encodes the MET receptor, a receptor tyrosine kinase that regulates controlled cell growth, proliferation, and tissue repair. When this gene is amplified, the MET signaling pathway becomes overactivated, promoting uncontrolled cell growth and tumor development.

Causes and Development

MET amplification arises from somatic (non-hereditary) mutations in the DNA of body cells. Contributing factors include:

Errors during DNA replication in cell division
Genomic instability, commonly observed in cancer
Exposure to carcinogenic substances
Development as a resistance mechanism against existing cancer therapies, particularly EGFR inhibitors in non-small cell lung cancer (NSCLC)

MET amplification can occur both as a primary genetic alteration driving tumor growth and as a secondary acquired resistance mechanism in response to targeted therapies.

Affected Cancer Types

MET amplification has been identified in several cancer types, including:

Non-small cell lung cancer (NSCLC) – the most clinically relevant context
Gastric cancer (stomach cancer)
Esophageal cancer
Hepatocellular carcinoma (liver cancer)
Renal cell carcinoma (kidney cancer)
Head and neck cancers

Symptoms

MET amplification itself does not cause specific symptoms. Clinical manifestations depend on the tumor type and disease stage. General cancer-related symptoms may include:

Unexplained weight loss
Persistent fatigue and weakness
Pain depending on tumor location
Cough or shortness of breath (in lung cancer)
Difficulty swallowing (in esophageal cancer)

Diagnosis

MET amplification is diagnosed through molecular pathology testing of tumor tissue or blood samples (liquid biopsy). The following methods are used:

FISH (Fluorescence In Situ Hybridization): Gold standard for detecting gene amplifications; enables visualization of gene copy numbers
NGS (Next-Generation Sequencing): Comprehensive genomic analysis capable of detecting multiple genetic alterations simultaneously
IHC (Immunohistochemistry): Detects overexpression of the MET protein in tumor tissue
PCR-based methods: Faster but less comprehensive analysis

Clinically relevant MET amplification is generally defined by a MET/CEP7 ratio of ≥2.0 or an absolute MET gene copy number of ≥6 per cell.

Treatment and Targeted Therapy

The presence of MET amplification enables the use of specific MET inhibitors as targeted therapies. Clinically relevant agents include:

Capmatinib (Tabrecta®): Approved for adults with NSCLC harboring MET exon 14 skipping mutations and MET amplification
Tepotinib (Tepmetko®): Another selective MET inhibitor approved for NSCLC
Crizotinib: A multikinase inhibitor with activity against MET
Savolitinib: Under clinical investigation for MET-dependent tumors

When MET amplification occurs as a resistance mechanism to EGFR inhibitors, a combination of a MET inhibitor and an EGFR inhibitor is often used. Treatment decisions are always made within an interdisciplinary tumor board.

Prognosis

The prognosis for tumors with MET amplification depends on several factors, including tumor type, disease stage, and response to targeted therapy. Patients with confirmed MET amplification treated with an appropriate MET inhibitor have shown significant response rates in clinical trials. However, resistance can develop during the course of therapy, requiring further treatment adjustments.

References

Drilon A. et al. - MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated with Advanced Age and Stage-Dependent MET Genomic Amplification. Journal of Clinical Oncology, 2018.
Cappuzzo F. et al. - Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. Journal of Clinical Oncology, 2009.
European Medicines Agency (EMA) - Product Information: Tabrecta (Capmatinib). EMA, 2022. Available at: www.ema.europa.eu

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