A Genetic Polymorphism in CTLA-4 Is Associated with Overall Survival in Sunitinib-Treated Patients with Clear Cell Metastatic Renal Cell Carcinoma.

Abstract

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.

• Authors: Xiaoyan Liu, Jesse J Swen, Meta H M Diekstra, Epie Boven, Daniel Castellano, Hans Gelderblom, Ron H J Mathijssen, Sita H Vermeulen, Egbert Oosterwijk, Kerstin Junker, Max Roessler, Kristin Alexiusdottir, Asgerdur Sverrisdottir, Marius T Radu, Valentin Ambert, Tim Eisen, Anne Warren, Cristina Rodríguez-Antona, Jesus García-Donas, Stefan Böhringer, Karel K M Koudijs, Lambertus A L M Kiemeney, Brian I Rini, Henk-Jan Guchelaar
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 10 Pg. 2350-2356 (05 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29490989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• CTLA-4 Antigen
• CTLA4 protein, human
• Protein Kinase Inhibitors
• Sunitinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor
• CTLA-4 Antigen (genetics)
• Carcinoma, Renal Cell (drug therapy, genetics, mortality, pathology)
• Female
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Prognosis
• Proportional Hazards Models
• Protein Kinase Inhibitors (therapeutic use)
• Sunitinib (therapeutic use)
• Survival Analysis
• Treatment Outcome