Genetic analysis of primary renal cell carcinoma to determine treatment approaches

ABSTRACT

Introduction

To date, there is no validated predictive biomarker available that guides treatment selection between an immune-based or an anti-VEGF-based regimen in patients with metastatic renal cell carcinoma (mRCC). Here, valid biomarkers could increase the benefit of therapy and thereby safe unnecessary toxicity. Recently, phase II and III clinical trials have shown a correlation between molecular clusters and responses to targeted therapy with tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) or as combination of both in patients with clear-cell mRCC.

Areas covered

This review discusses recent advances in the discovery of predictive biomarkers, highlighting the growing role of genetic analysis for treatment selection and its potential impact on precision medicine in mRCC. In this context, we extensively analyzed the available literature from Pubmed’s archives on this topic.

Expert opinion

Molecular subclassification which predicts responses to TKI, or ICI therapy is an exciting step toward personalized medicine in mRCC, but this still requires validation. However, intratumoral heterogeneity in relationship to the predictive power of molecular analysis of the primary tumor and circulating tumor DNA is challenging and requires further analysis.

KEYWORDS:

• Biomarker
• heterogeneity
• immune checkpoint inhibition
• individualized treatment
• renal cell carcinoma
• tyrosin kinase inhibitor

Article highlights

• Clear-cell RCCs are very heterogeneous tumors and express different gene signatures that allow a division into at least two main clusters (angiogenesis and immunology).

• Gene expression signatures from the IMmotion150 and JAVELIN Renal 101 studies pave the way to precision medicine in mRCC, but still requires prospective validation.

• The impact of intratumoral heterogeneity on the predictive power of molecular analysis in the primary tumor and circulating tumor DNA needs further research.

Declaration of interest

Dr. Bedke reports Consultancies and Speaker ́s Bureau: BMS; Eisai, EUSA, Ipsen, Novartis, MSD, Pfizer, Roche and study participation with institutional funding: Bayer, BMS; Eisai, Exelixis, Ipsen, Novartis, MSD, Pfizer, Roche. Dr. Stenzl reports Consultancies and Speaker ́s Bureau: Ipsen, Roche, Janssen, BMS, Alere, Stebabiotech, Synergo, Ferring, Astellas, Amgen, Sanofi Aventis, CureVac and study participation or research grants with institutional funding: Johnson & Johnson, Roche, Cepheid, Amgen, Bayer, CureVac, GemeDx biotechnologies GmbH, Novartis, Karl Storz, immatics biotechnologies GmbH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.