Correlation of c-MET Expression with PD-L1 Expression in Metastatic Clear Cell Renal Cell Carcinoma Treated by Sunitinib First-Line Therapy

Solène-Florence Kammerer-Jacquet (1, 2) , Sarah Médane (3, 2) , Karim Bensalah (4) , Jean-Christophe Bernhard (5) , Mokrane Yacoub (6, 7) , Frantz Dupuis (8) , Alain Ravaud (9) , Grégory Verhoest (4) , Romain Mathieu (10, 3) , Benoit Peyronnet (4) , Angélique Brunot (11, 12) , Brigitte Laguerre (13) , Alexandra Lespagnol (3, 2) , Jean Mosser (2, 3) , Frédéric Dugay (2, 14) , Marc-Antoine Belaud-Rotureau (2, 14) , Nathalie Rioux-Leclercq (2)

1 Service de Pathologie [Rennes] = Pathology [Rennes]
2 IGDR - Institut de Génétique et Développement de Rennes
3 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
4 Service d'urologie [Rennes] = Urology [Rennes]
5 Service d'urologie, andrologie et transplantation rénale
6 Service d'Oncologie Médicale [Bordeaux]
7 UroCCR - French Network for Research on Kidney Cancer
8 CHU de Bordeaux Pellegrin [Bordeaux]
9 Hôpital Saint-André
10 ISC - Institut des Sciences Cognitives
11 UR - Université de Rennes
12 CRLCC - CRLCC Eugène Marquis
13 Département d'oncologie médicale [Rennes]
14 Service de Cytogénétique et de Biologie Cellulaire

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.

Domaines: Cancer; Urologie et Néphrologie; Médicaments

Solène-Florence Kammerer-Jacquet, Sarah Médane, Karim Bensalah, Jean-Christophe Bernhard, Mokrane Yacoub, et al.. Correlation of c-MET Expression with PD-L1 Expression in Metastatic Clear Cell Renal Cell Carcinoma Treated by Sunitinib First-Line Therapy. Targeted Oncology, 2017, 12 (4), pp.487-494. ⟨10.1007/s11523-017-0498-1⟩. ⟨hal-01578072⟩