The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKIs). 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.
27 single nucleotide polymorphisms (SNPs) inCD274(PD-L1), PDCD1(PD-1) andCTLA-4were 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.
CTLA-4 rs231775 andCD274rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender and Heng prognostic risk group (HR=0.84, 95%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-4rs231775 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 to patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found.
The G-allele of rs231775 in theCTLA-4gene is associated with improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Feb 28 [Epub ahead of print]
Xiaoyan Liu, Jesse J Swen, Meta H M Diekstra, Epie Boven, Daniel Castellano, Hans Gelderblom, Ron Hj Mathijssen, Sita H Vermeulen, Egbert Oosterwijk, Kerstin Junker, Max Roessler, Kristin Alexiusdottir, Asgerdur Sverrisdottir, Marius T Radu, Valentin Ambert, Timothy Eisen, Anne Y Warren, Cristina Rodríguez-Antona, Jesus García-Donás, Karel K M Koudijs, Stefan Böhringer, Lambertus A Kiemeney, Brian Rini, Henk-Jan Guchelaar
Clinical Pharmacy & Toxicology, Leiden University Medical Center., Clinical Pharmacy and Toxicology, Leiden University Medical Center., Maastricht University Medical Centre., Medical Oncology, VU University Medical Center., Unidad de Uro-Oncología, Hospital Universitario 12 De Octubre., Department of Clinical Oncology, Leiden University Medical Center., Medical Oncology, Erasmus MC Cancer Institute., Radboud university medical center., Urology, Radboud university medical center., Dept of Urology, Saarland University., CESAR CENTRAL OFFICE, CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria., Dept. of Medicine, Landspitali-University Hospital., Department of Medical Oncology, Landspitali University Hospital., University of Medicine and Pharmacy Carol Davila., Addenbrooke's Hospital, Cambridge Biomedical Campus., Histopathology, Cambridge University Hospitals NHS Foundation Trust., Spanish National Cancer Research Centre., Gynecological and Genitourinary Tumors Programme, Centro Integral Oncologico Clara Campal., Department of Medical Statistics and Bioinformatics, Leiden University Medical Center., Department for Health Evidence, Radboud university medical center., Hematology/Oncology, Cleveland Clinic Taussig Cancer Institute., Clinical Pharmacy and Toxicology, Leiden University Medical Center .