Memorial Sloan Kettering Cancer Center, New York, NY.
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Clin Genitourin Cancer. 2017 Oct;15(5):526-533. doi: 10.1016/j.clgc.2017.02.006. Epub 2017 Feb 27.
Sunitinib, the vascular endothelial growth factor pathway inhibitor, is an established standard-of-care for advanced renal cell carcinoma (RCC). This study aimed to assess correlations between candidate germline single nucleotide polymorphisms (SNPs) and sunitinib efficacy in patients from the RENAL EFFECT trial (NCT00267748), a randomized phase II study in patients with metastatic RCC comparing the 4-weeks-on/2-weeks-off schedule and a continuous daily dosing schedule.
Informed consent for pharmacogenetics research was obtained from 202 out of 289 treated patients in the trial. Associations between 9 SNP variants (CXCL8, LOXL2, CCDC26, SH3GL2, CLLU1, IL2RA, AURKB, and 2 SNPs on Chromosomes 7 and 12) and progression-free survival (PFS), objective response rate, and overall survival were assessed using Kaplan-Meier analysis, Cox proportional hazard model, and the Fisher exact test.
CXCL8 rs1126647 A/A versus A/T (P = .004) or T/T (P < .0001) and SH3GL2 rs10963287 C/C versus C/T (P = .005) or T/T (P = .018) were associated with improved overall survival in all patients. CLLU1 rs525810 A/A genotype versus A/G (P = .014) or G/G (P = .048) was associated with improved PFS in the continuous daily dosing arm. IL2RA rs7893467 T/G versus T/T was associated with improved PFS (P = .034) in the 4-weeks-on/2-weeks-off arm and objective response rate (P = .034) in all patients. No significant associations between improved efficacy and genotype were found for other SNPs.
Germline variants in CLLU1, IL2RA, CXCL8, and SH3GL2 warrant further retrospective study in independent cohorts of patients with metastatic RCC treated with vascular endothelial growth factor-class inhibitors, to test their biological significance and potential clinical fitness as biomarkers to guide treatment.
舒尼替尼是一种血管内皮生长因子通路抑制剂，已被确立为晚期肾细胞癌（RCC）的标准治疗方法。本研究旨在评估候选种系单核苷酸多态性（SNP）与 RENAL EFFECT 试验（NCT00267748）中接受舒尼替尼治疗的患者疗效之间的相关性，该试验是一项比较转移性 RCC 患者 4 周/2 周方案和连续每日剂量方案的随机 II 期研究。
从该试验的 289 名治疗患者中获得了 202 名患者的遗传药理学研究知情同意书。使用 Kaplan-Meier 分析、Cox 比例风险模型和 Fisher 确切检验评估 9 个 SNP 变体（CXCL8、LOXL2、CCDC26、SH3GL2、CLLU1、IL2RA、AURKB 和染色体 7 和 12 上的 2 个 SNP）与无进展生存期（PFS）、客观缓解率和总生存期之间的相关性。
在所有患者中，CXCL8 rs1126647 A/A 与 A/T（P=0.004）或 T/T（P<0.0001）和 SH3GL2 rs10963287 C/C 与 C/T（P=0.005）或 T/T（P=0.018）与总生存期改善相关。在连续每日剂量组中，CLLU1 rs525810 A/A 基因型与 A/G（P=0.014）或 G/G（P=0.048）与 PFS 改善相关。在 4 周/2 周方案组中，IL2RA rs7893467 T/G 与 T/T 与 PFS 改善相关（P=0.034），在所有患者中与客观缓解率相关（P=0.034）。其他 SNP 与疗效改善之间未发现显著相关性。
CLLU1、IL2RA、CXCL8 和 SH3GL2 的种系变异需要在接受血管内皮生长因子类抑制剂治疗的转移性 RCC 患者的独立队列中进行进一步的回顾性研究，以检验其生物学意义和作为指导治疗的潜在临床适用性生物标志物。
