ASCO GU 2021: Angiogenic and T-Effector Subgroups Identified by Gene Expression Profiling and Propensity for PBRM1 and BAP1 Alterations in Clear Cell Renal Cell Carcinoma

( With the emergence of multiple active treatment options in renal cell carcinoma (RCC), predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion1511 and Javelin Renal 1012 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. At the Poster Highlights: Renal Cell Cancer - Gene Signatures Session at the 2021 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, Dr. Pedro Barata and colleagues presented results of their study describing the genomic and gene expression profiles in a multi-institutional database of patients with clear cell RCC, and its association with other biomarkers of interest.

Whole transcriptome sequencing was performed for clear cell RCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, Arizona) from February 2019 to September 2020. Tumor gene expression profiling and hierarchical clustering based on the validated 66-gene signature were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included.

There was a total of 316 patients with clear cell RCC, with a median age of 62 (range 32-90) years, of which 71.8% were men that were included in this study. Tissue samples were obtained from the primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%), and other metastatic sites (27%). Gene expression analysis identified angiogenic subgroups in 24.1% of patients, mixed in 51.3%, and T-effector subgroups in 24.7%. As follows is the hierarchical clustering of gene expression signature:

hierarchical clustering of gene expression signature

Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009), and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), tumor mutational burden (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (ie. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup.

data from t effector subgroup

Dr. Barata concluded with the following summary points from his presentation:

  • These hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies
  • Angiogenic tumors were more likely to be found in patients who were older or female, and were more likely to harbor gastrointestinal metastases, stromal cell population, and PBRM1 mutations
  • BAP1 mutations and immunotherapy markers such as tumor mutational burden and dMMR/MSI-H, PD-L1, and immune cell population were more frequent in the “T-effector” signature
  • These findings have potential predictive value and require further validation in prospective clinical trials

Presented by: Pedro C. Barata, MD, MSc, Assistant Professor of Medicine Hematology & Medical Oncology, Tulane University School of Medicine, New Orleans, Louisiana

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


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2. Motzer, Robert J., Konstantin Penkov, John Haanen, Brian Rini, Laurence Albiges, Matthew T. Campbell, Balaji Venugopal et al. "Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma." New England Journal of Medicine 380, no. 12 (2019): 1103-1115.

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