Genomic analysis offers clinical insight into VHL-positive vs -negative ccRCC tumors

Results of a comprehensive analysis shared at the 2021 ESMO Congress offers additional clues into the genomic makeup and characteristics of clear cell renal cell carcinoma (ccRCC) tumors based on their VHL mutation status.¹

Gennady Bratslavsky, MD

The analysis identified differences and even some similarities between these tumor subtypes that may provide additional insight regarding treatment selection in patients with ccRCC.

“Further study of ccRCC based on VHL mutations status in the clinical trial setting appears warranted,” Gennady Bratslavsky, MD, of SUNY Upstate University Hospital in Syracuse, New York, and colleagues wrote in the poster.

Researchers performed comprehensive genetic profiling in 948 patients with clinically advanced ccRCC to assess all classes of genomic alternation. Of these patients, 75% had VHL-mutated disease (median age, 62 years; 71% men) and 25% had VHL wild type ccRCC (median age, 63 years; 71% men).

Some of the significant differences in currently “untargetable” genomic alterations included higher TERT genomic alterations in patients with VHL wild type ccRCC (P = .007) and higher frequencies of SETD2 in those with VHL mutated ccRCC (P = .04). Patients with VHL mutated or VHL wild type ccRCC had similar frequencies of genomic alterations that could potentially be targeted except for MTAP deletions; these deletions were observed more frequently in patients with VHL wild type ccRCC (P = .03).

Researchers also assessed patients with genomic alterations associated with immune checkpoint inhibitor efficacy. In these patients, PBRM1 genomic alterations were significantly more frequent in those with VHL wild type disease compared with VHL mutated disease (P < .0001). Patients with ccRCC had low tumor mutational burden levels, with 1% to 2% of patients having levels above 10 mut/Mb.

Patients with VHL mutated ccRCC and those with VHL wild type disease often had low positive PD-L1 expression (1%-49% tumor cell staining). In addition, both groups rarely had high positive staining (≥ 50% tumor cell staining).

VHL mutation status has become an area of clinical interest in the RCC paradigm. The FDA recently approved belzutifan (Welireg) for adult patients with VHL disease who require therapy for associated RCC.

Reference

Bratslavsky G, Necchi A, Grivas P, et al. Comprehensive Genomic Profiling of VHL Mutated and VHL Wild Type Clear Cell Renal Cell Carcinoma. Presented at 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 690P.