Solène-Florence Kammerer-Jacquet1, Sarah Medane2, Karim Bensalah3, Jean-Christophe Bernhard4, Mokrane Yacoub5, Frantz Dupuis5, Alain Ravaud6, Grégory Verhoest3, Romain Mathieu3, Benoit Peyronnet3, Angélique Brunot7, Brigitte Laguerre7, Alexandra Lespagnol8, Jean Mosser8, Frédéric Dugay9, Marc-Antoine Belaud-Rotureau9, Nathalie Rioux-Leclercq2. 1. Université 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. 2. Université de Rennes 1, UMR 6290-IGDR, Univ Bretagne Loire, CHU de Rennes, Service d'Anatomie et Cytologie Pathologiques, F-35042, Rennes, France. 3. Université de Rennes 1, CHU de Rennes, Service d'Urologie, F-35042, Rennes, France. 4. Service d'Urologie, CHU Pellegrin, Bordeaux, France. 5. Service d'Anatomie et Cytologie Pathologiques, CHU Pellegrin, Bordeaux, France. 6. Service d'Oncologie Médicale, CHU Saint-André, Bordeaux, France. 7. Centre Eugène Marquis, Service d'Oncologie Médicale, Université de Rennes 1, Rennes, France. 8. Université de Rennes 1, UMR 6290-IGDR, Univ Bretagne Loire, CHU de Rennes, Service de Génétique Somatique des Cancers, F-35042, Rennes, France. 9. Université de Rennes 1, UMR 6290-IGDR, Univ Bretagne Loire, CHU de Rennes, Service de Cytogénétique et Biologie cellulaire, F-35042, Rennes, France.
Abstract
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.
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.
Authors: Toni K Choueiri; Bernard Escudier; Thomas Powles; Paul N Mainwaring; Brian I Rini; Frede Donskov; Hans Hammers; Thomas E Hutson; Jae-Lyun Lee; Katriina Peltola; Bruce J Roth; Georg A Bjarnason; Lajos Géczi; Bhumsuk Keam; Pablo Maroto; Daniel Y C Heng; Manuela Schmidinger; Philip W Kantoff; Anne Borgman-Hagey; Colin Hessel; Christian Scheffold; Gisela M Schwab; Nizar M Tannir; Robert J Motzer Journal: N Engl J Med Date: 2015-09-25 Impact factor: 91.245
Authors: Nathalie Rioux-Leclercq; Pierre I Karakiewicz; Quoc-Dien Trinh; Vincenzo Ficarra; Luca Cindolo; Alexandre de la Taille; Jacques Tostain; Richard Zigeuner; Arnaud Mejean; Jean-Jacques Patard Journal: Cancer Date: 2007-03-01 Impact factor: 6.860
Authors: Philipp Jurmeister; Dido Lenze; Erika Berg; Stefanie Mende; Frank Schäper; Udo Kellner; Hermann Herbst; Christine Sers; Jan Budczies; Manfred Dietel; Michael Hummel; Maximilian von Laffert Journal: Lung Cancer Date: 2014-12-06 Impact factor: 5.705
Authors: Selma Pennacchietti; Paolo Michieli; Maria Galluzzo; Massimiliano Mazzone; Silvia Giordano; Paolo M Comoglio Journal: Cancer Cell Date: 2003-04 Impact factor: 31.743
Authors: L Zhou; X-D Liu; M Sun; X Zhang; P German; S Bai; Z Ding; N Tannir; C G Wood; S F Matin; J A Karam; P Tamboli; K Sircar; P Rao; E B Rankin; D A Laird; A G Hoang; C L Walker; A J Giaccia; E Jonasch Journal: Oncogene Date: 2015-09-14 Impact factor: 9.867
Authors: Jean-Jacques Patard; Patricia Fergelot; Pierre I Karakiewicz; Tobias Klatte; Quoc-Dien Trinh; Nathalie Rioux-Leclercq; Jonathan W Said; Arie S Belldegrun; Allan J Pantuck Journal: Int J Cancer Date: 2008-07-15 Impact factor: 7.396
Authors: J-J Patard; N Rioux-Leclercq; D Masson; S Zerrouki; F Jouan; N Collet; C Dubourg; B Lobel; M Denis; P Fergelot Journal: Br J Cancer Date: 2009-09-15 Impact factor: 7.640
Authors: Aly-Khan A Lalani; Kathryn P Gray; Laurence Albiges; Marcella Callea; Jean-Christophe Pignon; Soumitro Pal; Mamta Gupta; Rupal S Bhatt; David F McDermott; Michael B Atkins; G F Vande Woude; Lauren C Harshman; Toni K Choueiri; Sabina Signoretti Journal: Oncotarget Date: 2017-10-23