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Molecular Subtypes of Clear Cell Renal Cell Carcinoma Are Associated with Sunitinib Response in the Metastatic Setting

2015; American Association for Cancer Research; Volume: 21; Issue: 6 Linguagem: Inglês

10.1158/1078-0432.ccr-14-1128

1557-3265

Benoit Beuselinck, Sylvie Job, Étienne Becht, Alexandra Karadimou, Virginie Verkarre, Gabrielle Couchy, Nicolás A. Giraldo, Nathalie Rioux‐Leclercq, Vincent Molinié, Mathilde Sibony, Réza Elaidi, Corinne Teghom, Jean‐Jacques Patard, Arnaud Méjean, Wolf H. Fridman, Catherine Sautès‐Fridman, Aurélien de Reyniès, Stéphane Oudard, Jessica Zucman‐Rossi,

Cancer Genomics and Diagnostics

Abstract Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 21(6); 1329–39. ©2015 AACR.