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

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.
Clin Cancer Res; 21(6): 1329-39, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25583177

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.
Selo DaSilva