Clear-cell Renal Cell Carcinoma: Molecular Characterization of IMDC Risk Groups and Sarcomatoid Tumors.

Recent trials have suggested predictive biomarkers in advanced clear-cell renal cell carcinoma (accRCC): International Metastatic RCC Database Consortium (IMDC) good risk or angiogenic gene signature for sunitinib and IMDC intermediate/poor risk for ipilimumab-nivolumab and T-effector cell signature or sarcomatoid dedifferentiation for atezolizumab-bevacizumab. We hypothesized that earlier described molecular subtypes, ccrcc1 to ccrcc4, could provide similar information as a single generic biomarker and molecularly characterize the heterogeneous intermediate-risk group.

Patients with accRCC treated with systemic therapies were included. We assessed associations between the 5 biomarkers and their impact on progression-free survival (PFS) and response rate (RR) on first-line sunitinib or pazopanib. The cutoff percentage of sarcomatoid dedifferentiation with optimal discriminative value was determined.

In total, 430 patients were included (163 with molecular data). The molecular ccrcc2 subtype identified tumors with higher angiogenic gene expression across IMDC risk groups: prevalence was high in IMDC good risk and low in IMDC poor risk (P < .001). Molecular subtype, IMDC, and angiogenic gene expression had comparable C-indices to predict PFS and RR (range, 60%-66%). The ccrcc2 subtype and angiogenic gene expression were positive predictors of PFS in IMDC intermediate-risk patients (P = .006; P = .04). Immune signature did not differ between IMDC groups, but was strongly correlated with molecular subtype (P = .8 and P = .0007). A cutoff value of 25% sarcomatoid differentiation discriminated tumors with distinct molecular characteristics and therapeutic sensitivity.

In accRCC, molecular subtypes can explain differences in IMDC risk group, expression of angiogenesis and immune response genes, and sarcomatoid dedifferentiation. They can identify molecularly different patient populations within the heterogeneous IMDC intermediate group and select patients for systemic therapies.

Clinical genitourinary cancer. 2019 May 25 [Epub ahead of print]

Annelies Verbiest, Inne Renders, Stefano Caruso, Gabrielle Couchy, Sylvie Job, Annouschka Laenen, Virginie Verkarre, Nathalie Rioux-Leclercq, Patrick Schöffski, Yann Vano, Reza-Thierry Elaidi, Evelyne Lerut, Maarten Albersen, Stéphane Oudard, Wolf-Hervé Fridman, Catherine Sautès-Fridman, Laurence Albigès, Agnieszka Wozniak, Jessica Zucman-Rossi, Benoit Beuselinck

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium., Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium., Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France., Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France., Biostatistics and Statistical Bioinformatics Center, KU Leuven, Leuven, Belgium., Department of Pathology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France., Department of Pathology, CHU de Rennes, Rennes, France., Department of Medical Oncology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France., Department of Imaging and Pathology, KU Leuven, Leuven, Belgium., Department of Urology, University Hospitals Leuven, Leuven, Belgium., Inserm, UMR-S1138, Centre de Recherche des Cordeliers, Sorbonne University, Paris, France., Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France., Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium., Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium; Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France. Electronic address: .

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