Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma

Our plain-English summary of Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma, by E. Santoni-Rugiu, M.J.S. Lü, J.N. Jakobsen, et al (International Journal of Molecular Sciences, 2021).

The study

• Authors: E. Santoni-Rugiu, M.J.S. Lü, J.N. Jakobsen, L.C. Melchior, J. Ravn, J.B. Sørensen
• Journal: International Journal of Molecular Sciences
• Published: 2021;22(23)
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Thanks to clinically newly introduced inhibitors of the mesenchymal-epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated.

In plain English

This laboratory study, from the Danish National Mesothelioma Center in Copenhagen, examined tumor tissue from 155 consecutive malignant mesothelioma cases treated in 2015 to 2017. The cases were pleural and peritoneal, and epithelioid, biphasic and sarcomatoid. It also examined 33 benign reactive mesothelial proliferations as controls. The authors looked for raised levels of a cell-surface protein called MET and for extra copies of the MET gene. Asbestos exposure was recorded only as yes or no, and no fiber types were studied. Raised MET protein was found in 35% of the 155 mesotheliomas (27 strong, 27 moderate). These were mostly epithelioid tumors. None of the 10 sarcomatoid tumors and none of the 33 controls showed it. No case had high-level MET gene gain: 3 had intermediate-level gain and 9 had low-level gain. In two matched groups of 30 patients given platinum-pemetrexed chemotherapy, 37% of MET-positive patients responded, compared with 70% of MET-negative patients (p = 0.04). Progression-free and overall survival did not differ significantly between the groups. The authors concluded that MET overexpression may lower response to standard chemotherapy, and that larger cohorts are needed to judge survival.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of archived tumor tissue (immunohistochemistry, fluorescence in situ hybridization and RNA next-generation sequencing), plus a comparison of outcomes in two matched groups of treated patients
• Who was studied: 155 consecutive malignant mesothelioma cases treated at the authors' institution (Rigshospitalet, Copenhagen, Denmark) between 2015 and 2017. These were 110 diagnostic biopsies of untreated mesothelioma (97 pleural, 13 peritoneal) and 45 pleurectomy/decortication specimens taken after 3 courses of cisplatin-pemetrexed. By type, 77 were epithelioid, 68 biphasic and 10 sarcomatoid. Controls were 33 benign reactive mesothelial proliferations from patients operated for non-malignant disease. The outcome comparison used 60 previously untreated patients with epithelioid or biphasic mesothelioma, 30 MET-positive and 30 MET-negative.
• Exposure: The factor studied was MET protein overexpression and MET gene copy number gain or amplification in tumor tissue, not asbestos. Asbestos exposure was recorded only as yes or no, with no fiber types, products, jobs or doses given. Exposure was recorded as yes in 34 of 45 (76%) pleurectomy patients, 77 of 110 (70%) biopsy patients, and 0 of 33 controls. The two outcome groups were matched for asbestos exposure, among other factors.
• Main results:
  • Moderately or strongly increased MET protein (2+ or 3+) was found in 35% of the mesothelioma patients, while none of the reactive mesothelial proliferations showed MET overexpression.
  • Among the 155 mesothelioma specimens, 27 (17.4%) had strong (3+) MET staining and 27 (17.4%) moderate (2+) staining. The remaining 101 (65.2%) scored 1+ or 0.
  • Of the 27 mesotheliomas with 3+ staining, 23 (85%) were epithelioid and 4 were biphasic. In biphasic tumors, only the epithelioid component showed raised MET. None of the 10 sarcomatoid mesotheliomas scored 2+ or 3+.
  • None of the 33 benign reactive mesothelial proliferations showed raised MET (2+ or 3+). Ten (30.3%) scored 1+ and 23 (69.7%) scored 0.
  • None of the 155 mesothelioma cases had high-level MET gene copy gain or amplification.
  • Three of the 155 mesothelioma cases (2%) had intermediate-level MET gene gain, all pleural epithelioid tumors with 3+ staining. Nine (6%) had low-level gain. No case with 1+ or 0 staining had any gene gain.
  • RNA sequencing of 20 samples with 3+ MET staining (15 without and 5 with MET gene gain) found no MET exon 14 skipping mutations. No variants or fusions were found in the other genes on the panel.
  • In the matched groups of 30 patients each given first-line platinum-pemetrexed chemotherapy, 37% of MET-positive patients responded, compared with 70% of MET-negative patients (p = 0.04).
  • Progression-free survival did not differ significantly between the two matched groups. Median progression-free survival was 8 months vs. 10 months, with the MET-positive group listed first (log-rank p = 0.430).
  • Overall survival did not differ significantly between the groups. Median overall survival was 20 months in the MET-positive group and 27 months in the MET-negative group (log-rank p = 0.934).
  • Fewer patients were alive in the MET-positive group (17%) than in the MET-negative group (27%), but the difference was not statistically significant (p = 0.532).
  • In multivariate analysis, female gender and stage IV had an independent negative impact on survival. MET status, mesothelioma subtype, asbestos exposure, smoking status, performance status and age did not have a statistically significant independent effect. For overall survival, the hazard ratio for MET status was 1.051 (95% CI 0.563 to 1.962, p = 0.877), and for asbestos exposure it was 1.923 (95% CI 0.825 to 4.478, p = 0.130).
  • In a pilot comparison of 30 paired samples, neoadjuvant chemotherapy did not change MET staining between the diagnostic biopsy and the later surgical specimen.
• The authors' conclusion: The authors concluded that MET overexpression occurs in a substantial fraction of mainly epithelioid mesotheliomas, and that it correlates poorly with MET gene amplification. They concluded it may lower response to standard chemotherapy. They stated that larger cohorts are needed to reach conclusions about survival, and that the value of MET testing for possible MET-targeted therapy remains to be clarified.
• Limitations the authors state:
  • The two matched patient groups were small, which affected statistical power.
  • The authors did not carry out extensive genomic analysis for other mutations in tumors with low or intermediate MET gene gain.
  • The authors suggested that the survival effect of female gender may reflect the low number of women in the groups.
  • The authors suggested that the apparent survival benefit of pleurectomy, which was not statistically significant, may reflect the low number of pleurectomized patients analysed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Lung Cancer, Immunohistochemistry, Fluorescence In Situ Hybridization (FISH), Epithelioid, MET exon 14 skipping, Next-Generation Sequencing (NGS), Chemotherapy.

Related studies

• Epidermal growth factor receptor overexpression in malignant pleural mesothelioma: prognostic correlations — O. Rena, L.R. Boldorini, et al. (2011)
• Amplification of MET in a Patient with Malignant Pleural Mesothelioma — S. Varesano, S. Salvi, et al. (2015)
• Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma — W.B. Ou, C. Hubert, et al. (2011)
• Absence of amplification of the FGFR1-gene in human malignant mesothelioma of the pleura: a pilot study — T. Plönes, F. Beckers, et al. (2014)
• Hepatocyte growth factor/scatter factor and its receptor c-Met are overexpressed and associated with an increased microvessel density in malignant pleural mesothelioma — E. Tolnay, C. Kuhnen, et al. (1998)
• MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma — R. Kanteti, I. Dhanasingh, et al. (2014)

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