Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting

• Published in: Clinical cancer research 2015-03, Vol.21 (6), p.1329-1339
• Main Authors: Beuselinck, Benoit, Job, Sylvie, Becht, Etienne, Karadimou, Alexandra, Verkarre, Virginie, Couchy, Gabrielle, Giraldo, Nicolas, Rioux-Leclercq, Nathalie, Molinié, Vincent, Sibony, Mathilde, Elaidi, Reza, Teghom, Corinne, Patard, Jean-Jacques, Méjean, Arnaud, Fridman, Wolf Herman, Sautès-Fridman, Catherine, de Reyniès, Aurélien, Oudard, Stéphane, Zucman-Rossi, Jessica
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - therapeutic use; Antineoplastic Agents - therapeutic use; Carcinoma, Renal Cell - classification; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Humans; Indoles - therapeutic use; Kidney Neoplasms - classification; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Male; Mutation - genetics; Pyrroles - therapeutic use; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-1128

Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib. We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel-Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib. Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands. ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs.