SUO 2019: The Therapeutic Landscape for Predictive Biomarkers in Renal Cell Carcinoma

Washington, DC ( The therapeutic landscape for metastatic renal cell carcinoma (mRCC) is rapidly evolving with the incorporation of single- and more recently dual-agent targeted therapies, and biomarkers may provide an opportunity to further classify tumors prior to treatment. There are several categories of biomarkers including diagnostic, prognostic, predictive, pharmacodynamic, discovery, and surrogate.
Dr. Joshua Lang discusses that predictive markers, or those that categorize patients by their likelihood for response to treatment (e.g. EGFR mutation in NSCLC and sensitivity to erlotinib/gefitinib), pharmacodynamic markers such as tumor dynamics as determined by serial radiographic imaging, and discovery markers, or those that are intended to identify previously unknown alterations that promote tumorigenesis/metastasis/resistance (e.g. genomic analysis for ALK rearrangements), are the most informative in his practice. 

There is a clear need for prognostication tools in RCC. Presently, nomograms and risk stratification scores (e.g. IMDC) provide some guidance while limited prognostic utility has been demonstrated with cytokine and angiogenic factors. Tissue biopsy has its advantages but also has its own associated risks and limitations—for example, PD-L1 expression from archived biopsy specimens has been shown to have limited predictive capacity (Pal et al 2017, Motzer et al 2018)—particularly with heterogeneous cancers. Circulating tumor cells and biomarkers may help provide much needed clarity in these situations. 

Dr. Lang showed an example of the seemingly simple VERSA (Versatile Exclusion-based Rare Sample Analysis) assay. A sample of blood is used to capture RCC cells of interest through a process of cell-sorting. Once RCC cells of interest are isolated, specific biomarkers can be identified in the form of protein, RNA and DNA. Subsequent use of renal markers such as carbonic anhydrase (CA) can improve the isolation and identification of circulating tumor cells (CTCs). In turn, a higher burden of RCC CTCs has been correlated with radiographic disease progression, representing additional prognostic value. Furthermore, PD-L1 and HLA expression can be reliably detected on CTCs, and higher expression of these markers has been associated with improved response to immune checkpoint inhibitor (ICI) therapies. Additionally, tumor clones with potential immune escape mechanisms can be identified with single-cell analyses, and their response to ICI may be expected to be attenuated. 

In summary, there is a clear need for clinical predictive biomarkers for patients with RCC as tissue biopsies may not adequately represent heterogeneous tumors and clinical nomograms have limited predictive potential. Liquid biopsies may better represent heterogeneous tumors and potentially help identify the tumor subclones that are most aggressively proliferating so that therapies can be more effectively targeted. Furthermore, single-cell phenotypic analyses have shown early clinical correlations for ICI and tyrosine kinase inhibitor (TKI) therapies and may help to further tailor patient management.

Presented by: Joshua M. Lang, MD, Assistant Professor, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Written By: Selma Masic, MD, Urologic Oncology Fellow (SUO), Fox Chase Cancer Center, @selmasic at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC