Molecular Subtypes of Clear Cell Renal Cell Carcinoma Are Associated to Sunitinib Response in the Metastatic Setting
Menée initialement à l'aide d'échantillons tumoraux prélevés sur 53 patients atteints d'un carcinome métastatique rénal à cellules claires, puis validée sur 47 échantillons complémentaires, cette étude française identifie quatre sous-types moléculaires de la maladie en association avec la réponse au sunitinib
Purpose: Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKIs) is a challenge. Our aim was to identify molecular markers associated with outcome in m-ccRCC patients 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 VHL 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 ccRCCs 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.
Conclusion: 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.
Clinical Cancer Research , résumé, 2015