Molecular Subtypes of Clear Cell Renal Cell Carcinoma are Associated with Outcome During Pazopanib Therapy in the Metastatic Setting - Beyond the Abstract

Over the past decade, systemic treatment for advanced clear-cell renal cell carcinoma (ccRCC) has evolved from hardly any efficacious therapy available to an abundance of options: several angiogenesis inhibitors, immune checkpoint inhibitors and, to a lesser extent, mTOR inhibitors. 1 While these drugs have improved the prognosis of advanced ccRCC, patient responses to different drug categories are very variable and no molecular biomarkers for patient selection have entered the clinic so far. Response to immune checkpoint inhibitors has been linked to high PD-L1 expression, to a T-effector cell gene signature and to IMDC intermediate/poor risk category in the Checkmate025, IMmotion150 and Checkmate214 trials respectively.2-4 Response to the angiogenesis inhibitor sunitinib has been linked to a pro-angiogenic gene signature and to IMDC good risk category in the IMmotion150 trial and our own patient series and in the Checkmate214 trial respectively.3-5 

We have proposed four molecular subtypes of advanced ccRCC, named ccrcc1 to -4, which differ in terms of gene expression, immune infiltrate, cytogenetic anomalies, mutation and methylation profile.6 Ccrcc2 and the rare ccrcc3 tumors have a more indolent disease course, as shown by their longer overall survival after diagnosis of metastatic disease and after metastasectomy, as well as their enrichment for IMDC good risk patients.6,7  The ccrcc2 subtype is characterized by a pro-angiogenic gene signature and has indeed the highest response rate to sunitinib or pazopanib.6,8 This probably explains the link between IMDC good risk and sunitinib response in the Checkmate214 trial. On the other hand, ccrcc1 and -4 tumors have an intermediate and poor prognosis respectively, as shown by their shorter overall survival after diagnosis of metastatic disease, early relapse after metastasectomy and enrichment for IMDC intermediate/poor risk patients.6,7 They are characterized by upregulation of c-MYC targets, marking them as aggressive tumors, and have lower response rates to sunitinib or pazopanib.6,8 Ccrcc4 tumors, which have the poorest prognosis and lowest response rates, are characterized by an immune inflamed phenotype with high expression of immune checkpoints and CD8+ lymphocyte infiltration.6 This suggests them as good candidates for treatment with immune checkpoint inhibitors and probably explains the link between IMDC intermediate/poor risk and response to nivolumab-ipilimumab in the Checkmate214 trial.

In the future, a combination of clinical and molecular markers will probably guide individualized treatment decisions. The advantage of the ccrcc1-4 classification as a prognostic and predictive biomarker, is the fact that it is based on intrinsic tumor biology and not designed for a specific therapy. Therefore, it has the potential to retain its value in the rapidly shifting landscape of ccRCC treatment. Although the current work was done on fresh frozen material, we are validating the classifier on paraffin embedded tissue, using a Nanostring nCounter panel, which will allow for its wider use.

Written by:

Annelies Verbiest, MD, PhD, Fellow, Department of General Medical Oncology, University Hospitals Leuven, Belgium, Laboratory of Experimental Oncology, Belgium

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  6. Beuselinck B, Job S, Becht E, et al. Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting. Clin Cancer Res. 2015;21(6):1329-39.
  7. Verbiest A, Couchy G, Job S, et al. Molecular subtypes of metastatic clear-cell renal cell carcinoma are associated with outcome after metastasectomy with curative intent. Eur Urol Supplements 16.10 (2017): e2625-e2627. Abstract O1. 2017 EMUC Annual Meeting.
  8. Verbiest A, Couchy G, Job S, et al. Molecular Subtypes of Clear Cell Renal Cell Carcinoma Are Associated With Outcome During Pazopanib Therapy in the Metastatic Setting. Clinical Genitourinary Cancer. 2017 (epub ahead of print).