Correlation of c-MET Expression with PD-L1 Expression in Metastatic Clear Cell Renal Cell Carcinoma Treated by Sunitinib First-Line Therapy
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Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Solène-Florence Kammerer-Jacquet1, Sarah Medane2, Karim Bensalah3
1Université de Rennes 1, UMR 6290-IGDR, Univ Bretagne Loire, CHU de Rennes, Service d'Anatomie et Cytologie Pathologiques, F-35042, Rennes, France. jacquet.sf@gmail.com.
Background:
Clear cell renal cell carcinoma (ccRCC) is highly metastatic. Cabozantinib, an anti-angiogenic tyrosine kinase inhibitor that targets c-MET, provided interesting results in metastatic ccRCC treatment.
Objective:
To understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC.
Patients And Methods:
For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib. The expression of c-MET was correlated with pathological, immunohistochemical (VEGFA, CAIX, PD-L1), clinical, and molecular criteria (VHL status) by univariate and multivariate analyses and to clinical outcome using Kaplan-Meier curves compared by log-rank test.
Results:
Of ccRCC, 31.1% had low c-MET expression (absent to weak intensity by IHC) versus 68.9% with high expression (moderate to strong intensity). High expression of c-MET was associated with a gain in FISH analysis (p=0.0284) without amplification. No mutations were detected in NGS. Moreover, high c-MET expression was associated with lymph node metastases (p=0.004), sarcomatoid component (p=0.029), VEGFA (p=0.037), and PD-L1 (p=0.001) overexpression, the only factor that remained independently associated (p<0.001) after logistic regression. No difference was observed in clinical outcomes.
Conclusion:
This study is the first to analyse c-MET status in metastatic ccRCC. The high expression of c-MET in the majority of ccRCC and its independent association with PD-L1 expression, may suggest a potential benefit from combining c-MET inhibitors and targeted immunotherapy.
Insights
High c-MET expression is common in metastatic clear cell renal cell carcinoma (ccRCC) and linked to PD-L1. This suggests combining c-MET inhibitors with immunotherapy may benefit ccRCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Clear cell renal cell carcinoma (ccRCC) is a highly metastatic cancer.
- Cabozantinib, a c-MET targeting tyrosine kinase inhibitor, shows promise in metastatic ccRCC treatment.
Purpose of the Study:
- To investigate the role and status of c-MET in metastatic ccRCC.
- To correlate c-MET expression with clinical and molecular features and patient outcomes.
Main Methods:
- Retrospective analysis of 90 primary ccRCC tumor samples from patients with metastases.
- Assessed c-MET expression via immunohistochemistry (IHC), copy number alterations by fluorescence in situ hybridization (FISH), and mutations by next-generation sequencing (NGS).
- Correlated c-MET status with pathological, immunohistochemical (VEGFA, CAIX, PD-L1), clinical, and molecular (VHL) criteria and clinical outcomes.
Main Results:
- High c-MET expression (moderate to strong intensity) was observed in 68.9% of ccRCC cases.
- High c-MET expression correlated with lymph node metastases, sarcomatoid component, VEGFA, and PD-L1 overexpression.
- PD-L1 overexpression was the only factor independently associated with high c-MET expression after logistic regression (p<0.001).
- No c-MET mutations were detected; high expression was associated with a gain in FISH analysis without amplification.
Conclusions:
- This study is the first to analyze c-MET status in metastatic ccRCC.
- The frequent high expression of c-MET and its independent association with PD-L1 suggest potential therapeutic benefits from combining c-MET inhibitors with targeted immunotherapy in ccRCC.
