ASCO GU 2022: Molecular Alterations Across Sites of Metastasis in Patients With RCC

( The 2022 GU ASCO Annual meeting included a session on emerging biomarkers and therapies in renal cell carcinoma (RCC) featuring a presentation by Dr. Rana McKay and colleagues reporting results of their study assessing molecular alterations across sites of metastasis in patients with RCC. RCC has a distinct pattern of metastatic spread with common sites of metastasis including the lung, bone, and liver, while less common sites include the brain, adrenal gland, and pancreas. While the pattern of metastatic spread has prognostic significance, the biology driving tropism to specific organ sites has not been fully characterized and is complex:

ASCOGU22_McKay_Molecular Alterations_0 

Dr. McKay and her co-investigators utilized a multi-institutional, real-world dataset to examine genomic alterations and transcriptional signatures across the spectrum of metastatic sites in patients with RCC.

RCC tissue specimens derived from the kidney and distant metastatic sites were sequenced utilizing a commercially available Clinical Laboratory Improvement Amendments (CLIA)-certified assay by Caris Life Sciences. Whole exome and transcriptome sequencing was performed. Molecular subgroups were defined according to the IMmotion151 metastatic RCC subtypes, with subgroups determined by a weighted average of gene expression levels. Molecular analysis and PD-L1 expression (SP142) were described by metastasis site.

There were 657 RCC samples from 653 patients that underwent molecular profiling. The median age was 62 years (range 14-90) and the majority were male (70.6%). The histological breakdown is as follows:

  • Clear cell: n = 508, 77.3%
  • Papillary: n = 63, 9.6%
  • Chromophobe: n = 30, 4.6%
  • Medullary: n = 8, 1.2%
  • MIT translocation: n = 8, 1.2%
  • Collecting duct: n = 6, 0.9%
  • Mixed: n = 34, 5.2%
The specimen source included:
  • Kidney: n = 340, 51.8%
  • Lung: n = 75, 11.4%
  • Bone: n = 45, 6.8%
  • Lymph nodes: n = 34, 5.2%
  • Liver: n = 28, 4.3%
  • Endocrine glands (adrenal, pancreas, and thyroid): n = 23, 3.5%
  • Brain/CNS: n = 16, 2.4%
  • Other metastatic sites: n = 96, 14.6%

Compared to the kidney, several genes were mutated at higher rates for select metastatic sites, including PBRM1 (59.5% bone, 59.1% endocrine, and 45.9% lung vs 33.8% kidney, p < 0.05) and KDM5C (27.8% endocrine, 29.2% lymph nodes, and 35.3% soft tissue vs 9.3% kidney, p < 0.05). When evaluating metastatic specimens versus kidney specimens, bone metastases had a significantly higher proportion of tumors classified as ‘Angio/stromal’ (n = 19, 42.2%; vs n = 52, 15.4%; p < 0.0001), while liver metastases had a higher proportion of the ‘complement/Ω-oxidation’ subgroup (n = 17, 60.7%; vs n = 48, 14.1%; p < 0.0001). PD-L1 expression in metastatic sites (range 6.8%-21.7%, with exception of 0% in GI; p = 0.09 to 0.99) was not significantly different from the kidney (16.6%). As follows is the distribution of molecular subtypes by site of metastasis:

ASCOGU22_McKay_Molecular Alterations_1 


Dr. McKay concluded her presentation assessing molecular alterations across sites of metastasis in patients with RCC with the following take-home messages:

  • Gene mutation profiles differ between distant metastatic sites and the primary renal tumor
  • Gene signatures and molecular subgroups differ between lung, bone, liver, skin and GI sites of metastasis when compared to the kidney
  • PD-L1 and PD-L2 gene expression is higher in lung, pleura, and bone metastasis
  • The frequency of immunotherapy related markers, including PD-L1 IHC, dMMR/MSI-high, and tumor mutational burden was similar between primary and distant sites of metastasis


Presented By: Rana R. McKay, MD, University of California San Diego, La Jolla, CA

Co-Authors: Pedro C. Barata, Andrew Elliott, Mehmet Asim Bilen, Earle F Burgess, Sourat Darabi, Nancy Ann Dawson, Benjamin Adam Gartrell, Hans J. Hammers, Elisabeth I. Heath, Daniel Magee, Arpit Rao, Charles J. Ryan, Przemyslaw Twardowski, Shuanzeng Wei, Tian Zhang, Matthew R. Zibelman, Chadi Nabhan, W. Michael Korn, Shuchi Gulati

Affiliations: Tulane School of Medicine, New Orleans, LA, CARIS Life Sciences, Irving, TX, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, Levine Cancer Institute, Charlotte, NC, Hoag Family Cancer Institute, Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, UT Southwestern Medical Center, Dallas, TX, Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, Caris Life Sciences, Phoenix, AZ, Baylor College of Medicine, Houston, TX, Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, City of Hope, Duarte, CA, Fox Chase Cancer Center, Department of Pathology, Philadelphia, PA, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, Fox Chase Cancer Center, Philadelphia, PA, Aptitude Health, Atlanta, GA, University of Cincinnati College of Medicine, Cincinnati, OH


Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022