M. Diekstra,1 J. J. Swen,1 E. Boven,2 D. Castellano,3 R. Ganapathi,4 H. Gelderblom,1 R. H. Mathijssen,5 C. Rodríguez-Antona,6 J. García-Donas,7 B. Rini,8 H. Guchelaar1; 1Leiden University Medical Center, Leiden, Netherlands, 2VU University Medical Center, Department of Medical Oncology, Amsterdam, Netherlands, 3Hospital Universitario 12 de Octubre, Oncology Department, Madrid, Spain, 4Cleveland Clinic Taussig Cancer Institute (CCF), Department of Solid Tumor Oncology, Cleveland, OH, 5Erasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, Netherlands, 6Spanish National Cancer Research Centre (CNIO), Hereditary Endocrine Cancer Group, Madrid, Spain, 7Clara Campal Comprehensive Cancer Center, Oncology Unit, Madrid, Netherlands, 8Cleveland Clinic Taussig Cancer Institute, Department of Solid Tumor Oncology, Cleveland, OH

BACKGROUND: Exploratory studies have associated single nucleotide polymorphisms (SNPs) in candidate genes with efficacy and toxicities of sunitinib in metastatic renal cell carcinoma (mRCC). The aim of the present study was to validate prior findings.
METHODS: mRCC patients treated with sunitinib and a DNA sample available were pooled from three exploratory studies conducted in the US, Spain and the Netherlands. A total of 22 SNPs and six haplotypes in 10 candidate genes related to pharmacokinetics and pharmacodynamics of sunitinib were tested for associations. Tested outcomes included toxicities, dose reductions, progression-free survival (PFS), overall survival (OS) and best objective response.
RESULTS: 333 patients were included. The presence of CYP3A5*1 was associated with dose reductions (OR=2.0, CI=1.0-4.0, p=0.039) and the presence of CGT in the ABCB1 haplotype (HR=1.9, CI=1.3-2.6, p=0.000275) was associated with an increased PFS, consistent with prior observations. Similar size and direction of effect were observed for the association of VEGFA rs1570360 with hypertension (OR=1.9, CI=0.8-4.5, p=0.173) and FLT3 rs1933437 with leukopenia (OR=3.6, CI=0.8-16.7, p=0.088). The present study also identified novel associations: CYP3A5*1 was associated with hypertension (OR=4.7, CI=1.4-15.0, p=0.009) and presence of the CGT haplotype in ABCB1 was associated with an improved OS (HR=1.6, CI=1.1-2.2, p=0.007) and a better response (OR=2.8, CI=1.0-7.8, p=0.044).
CONCLUSION: The validation of previously reported associations between polymorphisms in CYP3A5 and ABCB1 with sunitinib toxicity and efficacy confirm that these markers play a central role in guiding sunitinib treatment.