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. 2015 Nov 3;113(9):1313-22.
doi: 10.1038/bjc.2015.352. Epub 2015 Oct 13.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs

B Beuselinck  1   2   3 , J Jean-Baptiste  1   2 , G Couchy  1   2 , S Job  4 , A De Reynies  4 , P Wolter  3 , C Théodore  5 , G Gravis  6 , B Rousseau  7 , L Albiges  8 , S Joniau  9 , V Verkarre  10 , E Lerut  11 , J J Patard  12 , P Schöffski  3 , A Méjean  13 , R Elaidi  14 , S Oudard  2   14 , J Zucman-Rossi  1   2   14
Affiliations
Free PMC article

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs

B Beuselinck et al. Br J Cancer. .
Free PMC article

Abstract

Background: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs.

Methods: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression.

Results: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001).

Conclusions: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.

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Conflict of interest statement

SO received honoraria from Takeda, Novartis, Sanofi, Astellas Roche and Bayer. PJJ received honoraria for advisory, consultant and/or educational activities from GlaxoSmithKline, Bayer, Novartis and Amgen. BB and WP are investigators of the EudraCT: 2011-006085-40/MetaSun trial supported by Pfizer. BB received honoraria for educational activities from GlaxoSmithKline and Amgen. Z-RJ received honorarium from Pfizer, Astellas, Lilly and Bayer. AL received consulting fees from Pfizer, Sanofi, Novartis and Amgen and research funding from Novartis and Pfizer. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kaplan–Meier analysis. (A) Association between RANK/OPG ratio and time to metastasis (in 56 patients). (B) Association between RANK/OPG- ratio and time to BM (in 117 patients). (C) Association between RANK/OPG ratio and overall survival since diagnosis (in 129 patients). (D) Association between RANK/OPG ratio and progression-free survival since start of anti-VEGFR-TKIs (in 127 patients). (E) Association between RANK/OPG ratio and overall survival since start of anti-VEGFR-TKI (in 129 patients).
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