Introduction:

Sarcomatoid dedifferentiation of RCC(srcRCC) has historically carried a poor prognosis due to propensity to present as advanced or metastatic disease and have a poor response to traditional ccRCC therapies. Through recent studies, metastatic srcRCC has been found to exhibit a strong response to immune-oncology (IO) agents. Two emerging targets of immunotherapy in srcRCC are programmed death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) as these are biomarkers that have been found to be expressed by srcRCC. PD-L1 blocking therapies like nivolumab and atezolizumab allow the body’s own immune system to destroy malignant cells. We aimed to evaluate the mutational landscape that may contribute to demonstrated IO effectiveness in srcRCC and potentially help guide future treatment selection.

Methods:

Using a hybrid capture-based comprehensive genomic profiling (CGP) assay to evaluate all classes of genomic alterations, 160 cases of srcRCC were sequenced from FFPE tissue samples. We evaluated known factors associated with IO response, such as tumor mutational burden (TMB), microsatellite instability (MSI), frequency of PBRM1 mutations, and PD-L1 expression. 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 immunohistochemistry (IHC; Dako 22C3) with low tumor cell positive staining set at 1-49% and high staining >50% expression.

Results:

Of the study participants, 33% were female (53/160) and median age was 60 years old (15-90). Median TMB was found to be 3.5 mutations per megabase, MSI high status was present in 1% of samples, PBRM1 alterations were found in 10% of tumors, and PD-L1 high expression was seen in 38% of cases by IHC.

Conclusion:

Previous studies have noted high expression of PD-L1 in srcRCC and this study supports these findings. While we have not performed a direct comparison of PD-L1 status to other histologies, the known PD-L1 status in the literature has been shown to be much lower than the one reported in our data. With the observed high expression of PD-L1, this study further supports the use of immune checkpoint inhibitors, such as PD-L1 inhibitors, in the treatment of srcRCC and provides additional evidence for high response of metastatic srcRCC to IO therapy. While the role of PBRM1 mutations is still controversial as a marker of IO response, this study denotes the need for CGP in patients with metastatic srcRCC as way of selecting future therapies that target specific aspects of srcRCC’s pathogenesis.

Funding: N/A