Abstract
BackgroundPatients with metastatic renal cell cancer (mRCC) are commonly treated with the tyrosine kinase inhibitor sunitinib, which blocks signalling from vascular endothelial growth factor (VEGF) - and platelet-derived growth factor-receptors, inhibiting development of new blood vessels. There are currently no predictive markers available to select patients who will gain from this treatment. Epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is up-regulated in tumor endothelial cells in many types of cancer and may be a putative predictive biomarker due to its association with ongoing angiogenesis.MethodsELTD1, CD34 and VEGF receptor 2 (VEGFR2) expressions were analysed in tumor vessels of renal cancer tissues from 139 patients with mRCC using immunohistochemistry. Ninety-nine patients were treated with sunitinib as the first or second-line therapy. Early toxicity, leading to the termination of the treatment, eliminated 22 patients from the analyses. The remaining (n = 77) patients were included in the current study. In an additional analysis, 53 sorafenib treated patients were evaluated.ResultsPatients with high ELTD1 expression in the tumor vasculature experienced a significantly better progression free survival (PFS) with sunitinib treatment as compared to patients with low ELTD1 expression (8 versus 5.5 months, respectively). The expression level of CD34 and VEGFR2 showed no correlation to sunitinib response. In sorafenib treated patients, no association with ELTD1 expression and PFS/OS was found.ConclusionsOur results identify tumor vessel ELTD1 expression as a positive predictive marker for sunitinib-treatment in patients suffering from mRCC. The negative results in the sorafenib treated group supports ELTD1 being a pure predictive and not a prognostic marker for sunitinib therapy.
Highlights
Patients with metastatic renal cell cancer are commonly treated with the tyrosine kinase inhibitor sunitinib, which blocks signalling from vascular endothelial growth factor (VEGF) - and platelet-derived growth factor-receptors, inhibiting development of new blood vessels
We have previously reported Tissue microarray (TMA)-studies indicating that cubilin (CUBN) and annexin A1 (ANXA1) expressed in the tumor cells are predictive markers in metastatic renal cell cancer (mRCC) patients treated with sunitinib and sorafenib [11, 12]
To determine if tumor vessel expression of ELTD1 generally predicted response to Tyrosine kinase inhibitor (TKI)-therapy, we analysed TMA cores from patients treated with sorafenib in the first or second line setting (n = 53)
Summary
Patients with metastatic renal cell cancer (mRCC) are commonly treated with the tyrosine kinase inhibitor sunitinib, which blocks signalling from vascular endothelial growth factor (VEGF) - and platelet-derived growth factor-receptors, inhibiting development of new blood vessels. For hypoxiainducible factor 1α (HIF-1α), CD31, vascular endothelial growth factor (VEGF) receptors, CA9, Ki67 and plateletderived growth factor receptor α (pPDGFRα) associations with response to sunitinib therapy have been demonstrated [8, 9] In another and larger TMA-based study, tumoral expression of programmed death ligand 1 (PD-L1) or PD-L1 plus tumor infiltrating CD8+ T-cells were correlated to significantly shorter PFS and overall survival (OS) in patients treated with sunitinib or pazopanib [10]. We have previously reported TMA-studies indicating that cubilin (CUBN) and annexin A1 (ANXA1) expressed in the tumor cells are predictive markers in mRCC patients treated with sunitinib and sorafenib [11, 12]
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