* for medical professionals to read only
With the release of the "China Expert Consensus on Clinical Testing of MET in Non-small Cell Lung Cancer", as the world's first clinical testing expert consensus on MET, it will greatly promote the standardization of clinical MET testing in my country and help MET accurately diagnose and treat MET to a new level.
Both the incidence and mortality rate of lung cancer rank first among malignant tumors in my country, and the disease burden is heavy. In recent years, targeted treatment of lung cancer has made rapid progress, and rare targets such as MET have received more and more attention, and various new drugs have been continuously developed. In 2021, my country's first highly selective MET inhibitor, Sevotinib, was approved for marketing to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) carrying the exon jump mutation No. 14 of the MET gene (hereinafter referred to as "MET 14 jump"). Since then, my country has begun the first year of MET, and targeted MET therapy has emerged from the previous dilemma of "no medicine available". In addition, data from multiple clinical trials show that patients with advanced NSCLC with MET gene amplification can benefit from the treatment of MET inhibitors, and MET protein overexpression has also shown important potential application value in many clinical trials.
Accurate treatment, testing is first. With the availability of MET inhibitors, precise MET detection becomes increasingly important. However, due to the diverse forms of MET abnormalities and many detection methods, there are still many problems and challenges in clinical testing, which need to be further sorted out and standardized.
Recently, the first "Chinese Expert Consensus on Clinical Testing of MET in Non-small Cell Lung Cancer" (hereinafter referred to as the "Consensus") was officially released in " Chinese Journal of Pathology ". This "Consensus" focuses on three main MET abnormal forms, namely MET 14 jumping, MET gene amplification and MET protein overexpression, and provides detailed explanations on clinical significance, applicable population, detection methods and pathways, and forms 7 consensuses. At the same time, the "Consensus" also introduces the types of common samples sent for testing, processing, and specifications for testing reports. The release of this "Consensus" will provide guidance for standardized MET testing in clinical practice, promote the clinical application of precise targeted treatment of MET inhibitors, and ultimately enable patients to benefit to the greatest extent.
Figure 1 Consensus title screenshot
01 MET gene and clinical significance
Consensus 1: MET 14 jump is one of the driver gene mutations in advanced NSCLC and is an important molecular marker for screening MET inhibitor-targeted therapy benefiting populations.
Consensus 2: MET gene amplification is the primary driver gene mutation of NSCLC and is also one of the important mechanisms of drug resistance of EGFR-TKI and ALK-TKI. It can be used as a potential molecular marker for combined targeted therapy after drug resistance in advanced patients. Clinical attention should be paid to MET gene amplification detection.
Consensus 3: MET protein overexpression has potential guiding value in the clinical treatment of NSCLC MET inhibitors, and the benefit thresholds of different patient populations need further research.
Figure 2 The incidence of MET abnormalities in non-small cell lung cancer and clinical significance
02 Applicable population for MET detection
02 Consensus 4: MET 14 jump test is highly recommended for patients with advanced NSCLC; MET gene amplification test is recommended for patients with advanced NSCLC after late treatment and after EGFR-TKI resistance.
03 Common sample types and processing
The sample types used for MET detection mainly include tumor tissue samples, cytology samples, and liquid samples. Among them, tumor tissue samples are preferred to use tumor tissue paraffin samples, including surgical and biopsy samples. Cytological samples include thoracic and abdominal effusion, bronchial brushing, intrabronchial ultrasound-guided fine needle aspiration biopsy samples, sputum, alveolar lavage fluid, etc. For patients with advanced NSCLC who cannot obtain tissue or cytology samples, blood tests may be considered for MET 14 jump. Some patients with advanced NSCLC who have meningeal metastasis have cerebrospinal fluid have an enrichment effect on circulating tumor DNA (ctDNA) of intracranial tumors, and cerebrospinal fluid can also be considered for related testing. It should be noted that the content of ctDNA in the blood and cerebrospinal fluid is very low, and the sensitivity is poor compared to tissue sample detection.
04 Common MET detection methods
Consensus 5: MET 14 jumps can be detected using reverse transcriptional instant fluorescence quantitative PCR (RT-qPCR), DNA second-generation sequencing or RNA second-generation sequencing. Different detection methods have their own advantages and disadvantages, and they can be verified or supplemented for detection if necessary.MET 14 jumping sites have diverse forms, and special attention should be paid in clinical testing and interpretation.
Table 1 Common detection methods for exon jump mutation of MET No. 14, non-small cell lung cancer,
Consensus 6: MET gene amplification can be detected by fluorescence in situ hybridization (FISH) and second-generation sequencing. FISH is the gold standard for detecting MET gene amplification. Second-generation sequencing detects MET gene amplification.
SAVANNAH results show that osimertinib combined with sevotinib showed good clinical efficacy in patients with high MET amplification (FISH GCN ≥10) after osimertinib resistance.
Table 2 Common detection methods for MET gene amplification of non-small cell lung cancer
MET protein overexpression is immunohistochemistry (IHC). It is worth noting that there are currently diversity in the antibodies for detecting MET at home and abroad, and there are differences in the staining performance of different antibodies, and there is no unified judgment standard.
The current interpretation criteria of clinical studies combine the expression intensity and percentage of relevant antibodies in tumor cells. For example, patients with MET IHC ≥50% tumor cells were enrolled in the TATTON and SAVANNAH studies, and the antibody clone number used was SP44; patients with ≥50% tumor cells were enrolled in the INSIGHT study, and patients with ≥50% tumor cells were enrolled in the INSIGHT study, and patients with ≥50% tumor cells were enrolled in the INSIGHT study, and patients with ≥50% tumor cells were enrolled in the NCT01610336 study, and the antibody clone number used was 3077. Given that the current diversity of antibodies and interpretation standards have not yet been unified, it is necessary to conduct consistency comparison studies on different antibodies, and more clinical studies are needed to confirm the clinical value of MET protein overexpression, and further clarify the interpretation standards and benefit thresholds. SAVANNAH study shows that patients with MET IHC ≥90% of tumor cells 3+ after osimertinib resistance can benefit from osimertinib combined with sevotinib treatment. The consensus suggests that the IHC test results should include at least the antibody information used, the percentage of positive in tumor cells and the staining intensity.
05 MET detection path
Consensus 7: The tumor tissue/cytological sample is preferred for advanced NSCLC MET detection, and the MET 14 jump sequence is detected using a multigene joint detection platform including MET (RT-qPCR or second-generation sequencing). When the DNA second-generation sequencing test results are negative, RNA sample supplementary detection can be considered; FISH is recommended for patients with advanced NSCLC, especially patients after EGFR-TKI resistance. When the tissue/cytological sample is not in time, liquid biopsy sample can be selected for detection of MET 14 jump.
Figure 3 MET detection pathway for non-small cell lung cancer
In addition, the "Consensus" suggests that for patients with advanced NSCLC, especially patients with EGFR-TKI resistant, MET protein overexpression has potential guiding value in the clinical treatment of NSCLC MET inhibitors, IHC can be considered for testing MET protein overexpression when tumor tissue is sufficient.
06 MET detection report specifications and other precautions
MET 14 jump report specifications: DNA second-generation sequencing report should include clear variant name description (MET 14 jump), mutation site information, mutation site proportion (variant allele frequency), and reference transcript information (common transcripts used in MET genes include NM_000245 and NM_001127500, and special attention should be paid to the sequence number of the two).
MET gene amplification reporting specification: is recommended in the FISH test report to include at least the number of tumor cells evaluated, average MET copy number/cell, average CEP7 copy number/cell, the ratio of average MET copy number to average CEP7 copy number, and the proportion of tumor cells that have amplified. The second-generation sequencing test report should include clear description of the variation information, gene copy number information, and the detection platform itself to determine the positive judgment threshold for MET gene copy number variation. For second-generation sequencing reports using liquid samples for MET gene amplification detection, considering that the current sensitivity of liquid detection is low, the report should indicate relevant information such as high false negative rates.
In addition, laboratories that perform MET testing should do a good job in indoor quality control and inter-room quality evaluation to optimize standardized testing procedures to ensure the accuracy of experimental operations and the effectiveness of test results.At the same time, due to the complexity of MET abnormality, there are certain challenges in clinical interpretation of MET test results. It is recommended to establish a clinical pathological communication mechanism to ensure timely communication between clinical pathology.
Although MET is a rare driver gene in NSCLC, due to the large base of lung cancer patients in my country, there are many patients with MET abnormalities. With the approval of my country's first highly selective MET inhibitor, sevotinib, to market, it has brought hope for long-term survival for patients with MET abnormalities. The release of this "Consensus" will promote the standardization of clinical MET testing and improve the accuracy of MET testing, thereby providing guidance for precise MET treatment and benefiting more patients.
Appendix 1: Common reports listed in the "Consensus" MET 14 jump site
References:
[1] Pathology Branch of the Chinese Medical Association, National Center for Pathology Quality Control, Lung Cancer Group of the Oncology Branch of the Chinese Medical Association, et al. Consensus on Chinese Experts on Clinical Testing of MET for MET in Clinical Testing [J]. Chinese Journal of Pathology, 2022, 51(11): 1094-1103. DOI: 10.3760/cma.j.cn112151-20220606-00491.
*This article is only used to provide scientific information to medical personnel and does not represent the views of this platform
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