Germline Polymorphisms in Genes Involved in the Antioxidant System Predict the Efficacy of Cetuximab in Metastatic Colorectal Cancer Patients Enrolled in FIRE-3 Trial

Arai, Hiroyuki; Millstein, Joshua; Yang, Yan; Stintzing, Sebastian; Wang, Jingyuan; Battaglin, Francesca; Kawanishi, Natsuko; Jayachandran, Priya; Soni, Shivani; Zhang, Wu; Heinemann, Volker und Lenz, Heinz-Josef (2022): Germline Polymorphisms in Genes Involved in the Antioxidant System Predict the Efficacy of Cetuximab in Metastatic Colorectal Cancer Patients Enrolled in FIRE-3 Trial. In: Clinical Colorectal Cancer, Bd. 21, Nr. 3: S. 259-266

Abstract

Although reactive oxygen species are tightly linked to the EGFR/RAS/MAPK signaling pathway, the clinical implications of aberrance in molecules regulating redox balance in metastatic colorectal cancer are unclear. We present the first evidence from a phase III study that an antioxidant-related single-nucleotide polymorphism (TXN2 rs4921494) is associated with the efficacy of cetuximab in metastatic colorectal cancer patients. Background: Reactive oxygen species activate EGFR/RAS/MAPK signaling either through the inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in antioxidant genes link to the efficacy of cetuximab in patients with metastatic colorectal cancer (mCRC). Patients and Methods: We analyzed genomic and clinical data from FIRE-3, a phase Ill trial comparing cetuximab and bevacizumab along with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped. Thirteen functional SNPs in antioxidant genes were tested for associations with clinical outcomes. Results: In total, 236 patients were included (FOLFIRI/cetuximab arm, n = 129;FOLFIRI/bevacizumab arm, n = 107). In univariate analysis, two SNPs (TXN2 rs4821494 and GPX4 rs4807542) were significantly associated with overall survival (OS) in the FOLFIRI/cetuximab arm. Multivariate analysis confirmed the significant association of TXN2 rs4821494 (T/T vs. any G allele, hazard ratio = 2.47, 95% confidence interval = 1.06-5.72, P = .03). In the FOLFIRI/bevacizumab arm, no SNPs were significantly associated with clinical outcomes. Treatment-by-SNP interaction test confirmed the predictive value of TXN2 rs4821494 (OS: P = .03). Conclusion: TXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab-based first-line chemotherapy in mCRC, warranting further validation studies. (C) 2022 Elsevier Inc. All rights reserved.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1533-0028
• Sprache: Englisch