Trials with adjuvant vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) failed to demonstrate meaningful benefit in clinically high-risk, fully resected clear cell renal cell carcinoma (ccRCC). We evaluated whether the ccrcc1-4 molecular subtypes and gene expression signatures (GES) are associated with outcomes in this setting.
We determined molecular subtypes as well as angiogenesis- and immune-related GES through RNA sequencing of 75 fresh frozen (FF) and 62 formalin-fixed, paraffin-embedded (FFPE) tumor samples. We studied disease-free (DFS) and overall survival (OS) and determined correlations among GES and Leibovich score.
Angiogenesis-related GES and molecular subtypes were associated with longer DFS and OS across both cohorts, whereas immune-related GES were not. In the FF cohort, molecular subtypes (ccrcc2 & 3 vs. ccrcc1 & 4) were associated with DFS and OS, on bivariable analysis with Leibovich score (HR 0.62, 95%CI 0.39-0.98, P = .04 and HR 0.35, 95%CI 0.19-0.64, P < .001). In the FFPE cohort, molecular subtypes (ccrcc2 & 3 vs. ccrcc1&4) were also associated with DFS (HR 0.53, 95%CI 0.31-0.93, P = .03), but not OS (HR 0.59, 95%CI 0.31-1.13, P = .11) on bivariable analysis with Leibovich score. Leibovich score was significantly inversely correlated with all angiogenesis-related GES (all P < .01), but not correlated with immune-related GES.
Molecular subtypes and angiogenesis-related GES are prognostic for DFS and OS in fully resected, localized ccRCC. Favorable ccrcc2 & 3 molecular subtypes with high angiogenesis-related GES, which respond best to VEGFR-TKIs, are at lower risk of relapse but were probably underrepresented in the adjuvant VEGFR-TKI trials since they inversely correlate with Leibovich score. Conversely, immune-related GES are not correlated with Leibovich score and clinically high-risk tumors can display both high and low immune-related GES. Therefore, molecular characterization could guide patient selection for adjuvant treatment.
Clinical genitourinary cancer. 2021 Jul 10 [Epub ahead of print]
Eduard Roussel, Annelies Verbiest, Lisa Kinget, Bram Boeckx, Jessica Zucman-Rossi, Gabrielle Couchy, Stefano Caruso, Sylvie Job, Aurélien de Reyniès, Liesbeth De Wever, Marcella Baldewijns, Hendrik Van Poppel, Steven Joniau, Diether Lambrechts, Maarten Albersen, Benoit Beuselinck
Department of Urology, University Hospitals Leuven, Leuven, Belgium., Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium., Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium., Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris. Paris, France., Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France., Department of Radiology, University Hospitals Leuven, Leuven, Belgium., Department of Pathology, University Hospitals Leuven, Leuven, Belgium., Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. Electronic address: .