Purpose Earlier, the association of single nucleotide polymorphisms (SNPs) with toxicity and efficacy of sunitinib has been explored in patients with metastatic renal cell carcinoma (mRCC). Recently, additional SNPs have been suggested as potential biomarkers. We investigated these novel SNPs for association with sunitinib treatment outcome in mRCC patients. Methods In this exploratory study, we selected SNPs in genes CYP3A4, NR1I2, POR, IL8, IL13, IL4-R, HIF1A and MET that might possibly be associated with sunitinib treatment outcome. Each SNP was tested for association with progression-free survival (PFS) and overall survival (OS) by Cox-regression analysis and for clinical response and toxicity using logistic regression. Results We included 374 patients for toxicity analyses, of which 38 patients with non-clear cell renal cell cancer were excluded from efficacy analyses. The risk for hypertension was increased in the presence of the T allele in IL8 rs1126647 (OR = 1.69, 95 % CI = 1.07–2.67, P = 0.024). The T allele in IL13 rs1800925 was associated with an increase in the risk of leukopenia (OR = 6.76, 95 % CI = 1.35–33.9, P = 0.020) and increased prevalence of any toxicity > grade 2 (OR = 1.75, 95 % CI = 1.06–2.88, P = 0.028). No significant associations were found with PFS, OS or clinical response. Conclusions We show that polymorphisms in IL8 rs1126647 and IL13 rs1800925 are associated with sunitinib-induced toxicities. Validation in an independent cohort is required.

Objective: The individual response to targeted tyrosine kinase inhibitors (TKIs) in the treatment of metastatic renal cell cancer (mRCC) is highly variable. Outlined in this article are findings on potential biomarkers for TKI treatment outcome in mRCC and an evaluation of the status of clinical implementation.Methods: Articles were selected by two independent reviewers using a systematic search in five medical databases on renal cell carcinoma, TKIs, and pharmacogenetics.Results: Many researchers have focused on predictive biomarkers for treatment outcome of targeted therapies in mRCC patients. Attempts to explain differences in efficacy and toxicity of TKIs by use of genetic variants in genes related to the pharmacokinetics and pharmacodynamics of the drug have been successful.Conclusion: Most findings on potential biomarkers have not been validated and therefore biomarker testing to guide choice of therapy and dose in mRCC is not yet feasible.

Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI. Experimental Design: Twenty-seven single-nucleotide polymorphisms (SNP) in CD274 (PD-L1), PDCD1 (PD-1), and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (P < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis. Results: CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72–0.98; P = 0.028, and HR, 0.73; 95% CI, 0.54–0.99; P = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of P < 0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72–0.95; P = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found. Conclusions: The G-allele of rs231775 in the CTLA-4 gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. Clin Cancer Res; 24(10); 2350–6. ©2018 AACR.