Germline Genetic Biomarkers of Sunitinib Efficacy in Advanced Renal Cell Carcinoma: Results From the RENAL EFFECT Trial.
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.
Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: motzerr@mskcc.org.
Robert J
RJ
Motzer
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Robert A
RA
Figlin
Pfizer Inc, La Jolla, CA.
Jean-François
JF
Martini
Pfizer Inc, New York, NY.
Subramanian
S
Hariharan
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Neeraj
N
Agarwal
Pfizer Inc, La Jolla, CA.
Chun Xiao
CX
Li
Pfizer Inc, La Jolla, CA.
J Andrew
JA
Williams
Baylor Sammons Cancer Center-Texas Oncology, Dallas, TX.
Thomas E
TE
Hutson
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D009362:Neoplasm Metastasis; D000071184:Pharmacogenomic Variants; D011758:Pyrroles / Q000008:administration & dosage* / Q000627:therapeutic use; D012189:Retrospective Studies; D000077210:Sunitinib; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D005819:Genetic Markers; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
Angiogenesis inhibition; Genetic analysis; Kidney cancer; Single nucleotide polymorphism; Tyrosine kinase inhibitor