ASCO GU 2021: Sarcomatoid Versus Clear Cell RCC: A Comparative Comprehensive Genomic Profiling Study

( Sarcomatoid renal cell carcinoma (RCC) is a well-described histologic entity often featuring rapid progression and aggressive clinical course when compared with classic clear cell RCC. However, there is a paucity of data assessing the genetic alteration landscape of sarcomatoid RCC. At the 2021 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, Dr. Gennady Bratslavsky and colleagues presented results of their study assessing whether comprehensive genomic profiling may uncover opportunities for targeting and immunotherapy for sarcomatoid RCC patients that could individualize their treatment and entry into clinical trials.

Using a hybrid capture-based comprehensive genomic profiling assay to evaluate all classes of genomic alterations, this study included 160 cases of sarcomatoid RCC and 1,664 cases of clear cell RCC that were sequenced from formalin-fixed paraffin-embedded (FFPE) tissue samples. Sequencing was performed on 324 cancer-related genes and introns from 28 genes commonly rearranged in cancer. Tumor mutational burden was determined from 0.83-1.1 Mbp of sequenced DNA and microsatellite instability 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.

Gender and age distributions for both tumor types were similar. Sarcomatoid RCC featured significantly higher genetic alterations/tumor than clear cell RCC (p < 0.0001). Comprehensive genomic profiling revealed major differences with clear cell RCC associated more frequently with tumor suppressor gene losses in VHLPBRM1TSC2 and SETD2 (all p < 0.0001). In contrast, sarcomatoid RCC is associated with cell proliferation with increased inactivation of cell cycle regulatory genes including TP53CDKN2A/BMDM2 and TERT (all p < 0.0001). RB1 genetic alterations in sarcomatoid RCC may reflect neuroendocrine differentiation occasionally found in these tumors. Finally, NF2 genetic alterations were more frequently seen in sarcomatoid RCC (p < 0.0001). As follows are the long tail plots of genomic alterations in cases of clear cell and sarcomatoid RCC:

tail plots of genomic alterations in cases of clear cell and sarcomatoid RCC

Dr. Bratslavsky provided the following concluding remarks for his presentation comparing comprehensive genomic profiling among clear cell and sarcomatoid RCC:

  • Comprehensive genomic profiling reveals striking differences between sarcomatoid RCC and clear cell RCC which may in part explain the differing histologic appearances and typical clinical course of these two aggressive malignancies
  • Clear cell RCC is driven more by tumor suppressor gene (TSG) loss and sarcomatoid RCC 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 clear cell RCC and NF2 in sarcomatoid RCC)
  • Although the higher PBRM1GA frequency in clear cell RCC may explain the immunotherapy benefit well-known for this tumor type, the sarcomatoid RCC group features significantly increased tumor mutational burden, CD274 amplification, and PD-L1 staining which may also create immunotherapy opportunities for sarcomatoid RCC patients

Presented by: Gennady Bratslavsky, MD, Professor and Chair of Urology, Professor of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York

Written by: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021