ASCO 2018: Alterations in Key Clear Cell Renal Cell Carcinoma Genes to Refine Patient Prognosis

Chicago, IL ( Currently, the IMDC classification, based on clinical factors, helps guide clinicians on prognosis in patients with metastatic RCC (mRCC). However, genetics can play an important role in clinical outcomes and treatment response. Certain genomic alterations have a well defined association with developing RCC, including (but not limited to): VHL, PBRM1, BAP1, SETD2, TP53 and KDM5C. Indeed, they are often found mutated on genomic analysis of mRCC patients. Yet, the prognostic value of these mutations above and beyond the IMDC classification is not clearly known.

Dr. Vaishampayan, Dr. Heng and Dr. Brugarolas gave excellent talks that touched on the impact of the PBRM1, BAP1 and SETD2 mutations on RCC management – full talks are found online at!

In this study, the authors from 7 US centers and 1 annotated cohort (33 patients) from TCGA (The Cancer Genome Atlas) were analyzed. All patients had clear cell RCC (ccRCC), were treated with a 1st line VEGF tyrosine kinase inhibitor and had tumor genomics available – in general, it is presumed tumor genomics were taken prior to therapy, though is not clearly mentioned.

Tumors were sequenced using next generation sequencing (NGS), utilizing either institutional and commercial platforms at the 7 centers or whole exome sequencing in the TCGA dataset. Specifically, with regards to the genes of interest, there was identification of loss of function (LOF) - defined as presence of pathogenic gene variant or 2 copy deletion. The question the authors wished to address was whether LOF of any of these genes went above and beyond the current IMDC classification in predicting clinical outcomes (overall survival in particular).

• They identified 308 patients, of which 21% had favorable risk disease, 54% intermediate, and 17% poor risk. In terms of LOF of genomic alterations, 77% had VHL, 43% PBRM1, 29% SETD2, 19% BAP1, 11% TP53, and 11% KDM5C.
• Median age 61
• 72% male
• 78% had prior nephrectomy
• 84% had KPS >= 80%
• Most had been pretreated with prior sunitinib (58.8%) or pazopanib (37.3%)

Specific association of individual genomic alterations with survival and risk category:

1. BAP1 - associated with worse IMDC risk group (favorable 8%, intermediate 23% and poor 20%, p = 0.023) and worse OS (aHR 1.7; 95%CI 1.1-2.5, p = 0.01)
2. PBRM1 – associated with better OS (aHR = 0.6; 95%CI 0.4-0.8, p = 0.001)
3. KDM5C – associated with better OS (aHR = 0.4; 95%CI 0.2-0.8, p = 0.007)
4. SETD2 – not associated with prognosis
5. TP53 – not associated with prognosis
6. VHL - not associated with prognosis

In a small subset of patients (3.8%), there was a co-occurrence of BAP1 and PBRM1 mutations – and in patients with PBRM1 wild type and GA in BAP1, they had significantly worse OS [37 vs 50 months, aHR 1.9 (95%CI 1.2-2.8 p = 0.004]. In particular, this was prognostic for patients with intermediate risk disease only (HR 1.77, p = 0.032).

Genomic alterations do appear to have some effect on clinical outcomes in patients treated with TKI systemic therapy – however, it is unclear if this would impact systemic therapy of another agent. Hence, further studies are required in the era of immunotherapy.

Additionally, only a small subset of patients had genomic alterations that affected clinical outcomes beyond the IMDC classification system – hence, at this time, genomic evaluation likely will not impact clinical management; except in a small subset of IMDC intermediate risk patients with wild type PBRM1 and concurrent BAP1 mutations.

Presented by: Dominick Bossé, MD

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA