Tumoral cubilin is a predictive marker for treatment of renal cancer patients with sunitinib and sorafenib

Marjut Niinivirta,Gustav J Ullenhag,Fredrik Pontén,Per-Henrik Edqvist,Anca Dragomir,Gunilla Enblad

doi:10.1007/s00432-017-2365-y

Abstract

PurposeTyrosine kinase inhibitors like sunitinib and sorafenib are commonly used to treat metastatic renal cell cancer patients. Cubilin is a membrane protein expressed in the proximal renal tubule. Cubilin and megalin function together as endocytic receptors mediating uptake of many proteins. There is no established predictive marker for metastatic renal cell cancer patients and the purpose of the present study was to assess if cubilin can predict response to treatment with tyrosine kinase inhibitors.MethodsCubilin protein expression was analyzsed in tumor tissue from a cohort of patients with metastatic renal cell cancer (n = 139) using immunohistochemistry. One hundred and thirty six of the patients were treated with sunitinib or sorafenib in the first- or second-line setting. Thirty of these were censored because of toxicity leading to the termination of treatment and the remaining (n = 106) were selected for the current study.ResultsFifty-three (50%) of the tumors expressed cubilin in the membrane. The median progression-free survival was 8 months in patients with cubilin expressing tumors and 4 months in the cubilin negative group. In addition, the overall survival was better for patients with cubilin positive tumors. We also found that the fraction of cubilin negative patients was significantly higher in the non-responding group (PFS ≤3 months) compared to responding patients (PFS >3 months).ConclusionsWe show for the first time that tumoral expression of cubilin is a positive predictive marker for treatment of metastatic renal cell cancer patients with sunitinib and sorafenib.

Highlights

Renal cell carcinoma (RCC) is highly resistant to chemotherapy and radiotherapy (Motzer et al 1996)
We show for the first time that tumoral expression of cubilin is a positive predictive marker for treatment of metastatic renal cell cancer patients with sunitinib and sorafenib
Two common used Tyrosine kinase inhibitors (TKI), are the focus for this study. Both these agents target the receptors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) (Escudier et al 2012)

Summary

Introduction

Renal cell carcinoma (RCC) is highly resistant to chemotherapy and radiotherapy (Motzer et al 1996). Cytokine therapy (high-dose interleukin 2 (IL-2) and interferon-alpha (IFN-α) has been approved for the treatment of metastatic renal cell carcinoma (mRCC). IFN-α is the most frequently used cytokine and it achieves an objective response rate of 7.5% and a median overall survival (OS) time of 13 months (Negrier et al 1998). Tyrosine kinase inhibitors (TKI); sunitinib, sorafenib, pazopanib and axitinib, act by blocking essential biochemical pathways or proteins that are required for tumor cell growth and survival (Cho and Chung 2012). Two common used TKIs, are the focus for this study. Both these agents target the receptors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) (Escudier et al 2012).

Objectives

Methods

Results

Conclusion