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

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 ¼ 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P ¼ 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P ¼ 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.

The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma

“…The tumor microenvironment and immune surveillance system are thought to play an important role for tumor growth and progression and also to be involved in the treatment responses to targeted therapy [20,21]. Beuselinck et al [10] demonstrated that the ccrcc4 molecular subtype was closely related to a poor response to sunitinib treatment. This tumor subtype also showed increased activity in the hypoxia pathway, a strong inflammatory immune environment, high levels of regulatory T-cell markers, such as Foxp3, increased numbers of myeloid-derived suppressor cells, and high PD-L1 expression.…”

“…A recent study analyzed the molecular subtype of primary CCRCC in patients who developed metastatic tumors and were treated with sunitinib. The study showed that ccrcc1/ccrcc4 tumors had a lower response rate, shorter overall survival (OS), and shorter progressionfree survival (PFS) than ccrcc2/ccrcc3 tumors [10]. Among the molecular subtypes analyzed, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented, but suppressive immune microenvironment, along with high expression of programmed death-1 (PD-1) and its ligand, PD-L1 [10].…”

“…The study showed that ccrcc1/ccrcc4 tumors had a lower response rate, shorter overall survival (OS), and shorter progressionfree survival (PFS) than ccrcc2/ccrcc3 tumors [10]. Among the molecular subtypes analyzed, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented, but suppressive immune microenvironment, along with high expression of programmed death-1 (PD-1) and its ligand, PD-L1 [10]. Meanwhile, PD-L1 expression in tumor cells and inflammatory cells was associated with aggressive pathologic features and poor prognosis in patients with CCRCC [11].…”

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs

“…Pathology slides were reviewed by expert genitourinary pathologists. All tumour samples were classified according to the molecular ccrcc1-4 classification (Beuselinck et al, 2015).…”

“…Recently, our team has described an expression profile-based classification of ccRCCs with four robust molecular subgroups (Beuselinck et al, 2015). These subtypes are associated with distinct RR, mPFS and mOS when treated with sunitinib in first-line metastatic setting.…”