Sarcomatoid (srcRCC) versus clear cell (ccRCC) renal cell carcinoma: A comparative comprehensive genomic profiling (CGP) study.

Abstract

349 Background: srcRCC is a well-described histologic entity often featuring rapid progression and aggressive clinical course when compared with classic ccRCC. We queried whether CGP would uncover opportunities for targeted and immunotherapy (IO) for srcRCC patients that could individualize their treatment and entry into clinical trials. Methods: Using a hybrid capture-based CGP assay to evaluate all classes of genomic alterations (GA), 160 cases of srcRCC and 1,664 cases of ccRCC were sequenced from FFPE tissue samples. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining set at 1-49% and high staining >50% expression. Results: Gender and age distributions for both tumor types were similar. srcRCC featured significantly higher GA/tumor than ccRCC (P < .0001). CGP revealed major differences with ccRCC associated more frequently with tumor suppressor gene (TSG) losses in VHL, PBRM1, TSC2 and SETD2 (all P < .0001). In contrast, srcRCC is associated with cell proliferation with increased inactivation of cell cycle regulatory genes including TP53, CDKN2A/B, MDM2 and TERT (all P < .0001). RB1 GA in srcRCC may reflect neuroendocrine differentiation occasionally found in these tumors. NF2 GA were more frequent in srcRCC (P < .0001). Conclusions: CGP reveals striking differences between srcRCC and ccRCC which may in part explain the differing histologic appearances and typical clinical course of these 2 aggressive malignancies. ccRCC is driven more by TSG loss and srcRCC is driven more by cell cycle dysregulation. Targeted therapy opportunities were uncommon for both tumor types although each featured biomarkers potentially predictive of mTOR inhibitor responses ( TSC2 in ccRCC and NF2 in srcRCC). Although the higher PBRM1 GA frequency in ccRCC may explain the IO benefit well-known for this tumor type, the srcRCC group features significantly increased TMB, CD274 amplification and PD-L1 staining which may also create IO opportunities for srcRCC patients. [Table: see text]