We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC).
A query of our institutional clinical sequencing database (MSK-IMPACT) was performed which included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB) and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort was used to assess the clonality of somatic mutations.
Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% (95%CI 12.7 - 17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95%CI 6.9-11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the MET gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared to those with localized disease (OR 2.50, 95%CI 1.16 - 6.16, Fisher's p=0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be ~5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR 1.35 [95%CI 0.46, 5.40], p=0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors.
RCC harbors a low prevalence of clinically actionable alterations compared to other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Jul 14 [Epub ahead of print]
Kyrollis Attalla, Renzo G DiNatale, Phillip M Rappold, Christoper J Fong, Francisco Sanchez-Vega, Andrew W Silagy, Stanley Weng, Jonathan Coleman, Chung-Han Lee, Maria I Carlo, Jeremy C Durack, Stephen B Solomon, Victor Reuter, Paul Russo, Timothy A Chan, Robert J Motzer, Nikolaus Schultz, Ed Reznik, Martin H Voss, A Ari Hakimi
Surgery - Urology Service, Memorial Sloan Kettering Cancer Center., Marie-Josee & Henry R. Kravis Center for Molecular Oncology; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Surgery, Urology Service, Memorial Sloan Kettering Cancer Center., Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center., Medicine, Memorial Sloan Kettering Cancer Center., Radiology, Memorial Sloan Kettering Cancer Center., Interventional Radiology, Memorial Sloan Kettering Cancer Center., Pathology, Memorial Sloan Kettering Cancer Center., Surgery- Urology service, Memorial Sloan Kettering., Center for Immunotherapy, Cleveland Clinic., Department of Medicine, Memorial Sloan Kettering Cancer Center., Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center., Computational Oncology, Memorial Sloan Kettering Cancer Center., GU oncology, Memorial Sloan Kettering Cancer Center., Surgery - Urology Service, Memorial Sloan Kettering Cancer Center .