We examined whether 133 germline polymorphisms (SNPs) in 15 candidate genes (CSF1R, IL8RA, TLR4, IL10, IL10RA, CTLA4, IL2, IL2RA, TGFb1, ICOS, IL13, IL13RA2, IFNgR, IL15 and IL15RA) would predict clinical outcome in the ACCORD-12 phase III trial which randomly compared neoadjuvant radiotherapy (RT) plus capecitabine (CAP45) with dose-intensified RT plus capecitabine and oxaliplatin (CAPOX50) in T3-4 Nx M0 resectable rectal cancer.
A candidate-gene association study was conducted in 316 patients (n = 161 in the CAPOX50 and n = 155 in the CAP45 arm). The primary end-point was tumor response according to the Dworak score in each arm. Logistic regressions were used to assess uni/multivariate associations. The Storey and Tibshirani method based on the control of false discovery rate was used (q-value
In univariate analysis, two SNPs in IL2RA (rs11256456: OR = 5.1 [2.38; 11] and rs706781: OR = 4.2 [1.98; 8.74]) were significantly associated with the Dworak score in the CAP45 arm, and one in IL2RA the CAPOX50 arm (rs2104286: OR = 0.11 [0.01; 0.90]. All were confirmed in the multivariate analysis. Patients were categorized into 3 haplotype groups after the haplotype analysis of IL2RA rs11256456 and rs706781: one had a positive prognostic effect on tumor response in the CAP-45 arm (OR = 3.85 [1.97; 7.53], p = 0.0001) and in the overall population (OR = 1.76 [1.15; 2.68], p = 0.009). Interaction was also significant, suggesting a predictive positive effect of the same haplotype for response to CAP-45 (OR = 4.12 [1.71, 9.94], p = 0.002). None of the three IL2RA SNPs were correlated with survival in the multivariate analysis.
This pharmacogenetic analysis shows that SNPs in IL2RA are significantly associated with response to neoadjuvant chemoRT in patients with locally advanced rectal cancer. Their predictive effect may identify patients who benefit from CAP-45.
Clinical trial identification
Legal entity responsible for the study
B. Valerie: Consulting or/and advisory roles for Merck Serono, Amgen, Sanofi-Aventis, Prestizia and Bayer; honoraria from Amgen, Merck Serono, Roche, Novartis and Bayer; research funding from Merck Serono. J.F. Seitz: Grants for consultancy for Celgene, Lilly, Merck, Novartis Oncology, Pfizer, Sanofi, Roche; grants from Roche; payments for development of educational presentations for Amgen and Lilly. P. Laurent-Puig: Consulting or/and advisory boards for Sanofi, Merck KGaA, Amgen, Roche, Genomic Health, Myriad Genetics and Pfizer. All other authors have declared no conflicts of interest.