Predictive biomarkers in renal cell cancer: Insights in drug resistance mechanisms

• Published in: Drug resistance updates Vol. 17; no. 4; pp. 77 - 88
• Main Authors: van der Mijn, Johannes C, Mier, James W, Broxterman, Henk J, Verheul, Henk M
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.10.2014
• Subjects: Angiogenesis Inhibitors - pharmacology; Biomarkers, Tumor - metabolism; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Disease-Free Survival; Drug Resistance, Neoplasm; Hematology, Oncology and Palliative Medicine; Humans; Infectious Disease; Kidney Neoplasms - blood supply; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Molecular Targeted Therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Predictive biomarker; Renal cell carcinoma; Treatment Outcome; Vascular Endothelial Growth Factor A - metabolism; VEGF targeted therapy; VEGF targeted therapy; Renal cell carcinoma; Predictive biomarker
• ISSN: 1368-7646; 1532-2084
• DOI: 10.1016/j.drup.2014.10.003

Abstract Introduction VEGF-targeted therapy is currently the first line treatment for patients with metastatic clear cell renal cell carcinoma (ccRCC), but most patients either display primary (intrinsic) resistance or acquire drug resistance. In recent years multiple mechanisms of resistance to VEGF-targeted therapy emerged from preclinical research, but it is currently unknown to what extent these drug resistance modalities play a role in the clinic. Here we reviewed the current literature on biomarkers that predict treatment outcome in patients with ccRCC to gain insight in clinical drug resistance mechanisms. Methods A search syntax was compiled by combining different synonyms of “biomarker” AND “renal” AND “cancer”. MEDLINE was accessed through PubMed, where this syntax was entered and used to search titles and abstracts of publications. Articles were selected based on three criteria: (1) description of patients with clear cell RCC, (2) treatment with VEGF targeted therapy and (3) discussion of biomarkers that were studied for potential association with treatment response. Results The literature search was performed on March 4th 2014 and yielded 1882 articles. After carefully reading the titles and abstracts based on the three previously mentioned criteria, 103 publications were evaluated. Backward citation screening was performed on all eligible studies and revealed another 24 articles. This search revealed that (1) High glucose uptake and low contrast enhancement on PET- and CT-imaging before start of treatment may correlate with poor response to therapy, (2) Low dose intensity due to treatment intolerance is related to shorter progression free survival. (3) Acquired resistance appears to be associated with rebound vascularization based on both longitudinal monitoring of contrast enhancement by CT and blood vessel counts in tumor tissue, and (4) Based on plasma cytokine and single nucleotide polymorphism (SNP) studies, interleukin-8, VEGFR-3, FGFR2 and HGF/MET emerged as potential clinical markers for chemoresistance. Conclusion Low dose intensity, specific tumor-imaging techniques and potential biological biomarkers may be predictive for response to VEGF-targeted therapy in ccRCC. Some of these plausible biomarkers may also provide more insight into the underlying mechanisms of resistance such as altered glucose metabolism and rapid rebound vascularization.