Journal
BRITISH JOURNAL OF CANCER
Volume 113, Issue 9, Pages 1313-1322Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2015.352
Keywords
Renal cell carcinoma; bone metastases; outcome; RANK/RANKL/OPG pathway; anti-VEGFR-TKIs; prognosis
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Funding
- INCa (Institut du Cancer)
- Ligue Nationale Contre le Cancer (Paris-France)
- Fondation Martine Midy (Paris, France)
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen (Belgium)
- GlaxoSmithKline
- ARC (Paris, France)
- ARTUR (Association pour la recherche des tumeurs du rein, Paris, France)
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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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