Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial

• Main Authors: Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Chiara Cremolini, Sabina Murgioni, Sara Lonardi, Yan Ning, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Afsaneh Barzi, Fotios Loupakis, Alfredo Falcone, Heinz-Josef Lenz
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Cancers
• Subjects: NER; oxaliplatin; metastatic colorectal cancer; RPA2
• Online Access: https://www.mdpi.com/2072-6694/12/7/1742

Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes <i>RPA2</i> and <i>GTF2H1</i> are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether <i>RPA2</i> and <i>GTF2H1</i> SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. Patients and methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (<i>n</i> = 230, discovery cohort) and first-line FOLFIRI plus BEV (<i>n</i> = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. Results: In the FOLFOXIRI + BEV-treated cohort expressing wild-type <i>KRAS</i>, progression-free survival (PFS) was shorter for the <i>RPA2</i> rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07–5.03, <i>p </i>= 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27–6.94, <i>p </i>= 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant <i>RAS</i> and <i>RPA2</i> rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09–0.62, <i>p </i>= 0.002) but no superiority of FOLFOXIRI + BEV was observed for the<i> RAS</i> mutant, <i>RPA2</i> rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56–1.07, <i>p </i>= 0.12) or the <i>RAS</i> wild-type, <i>RPA2</i> rs7356 C/C variant subgroup. Conclusion: <i>RPA2</i> SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a <i>RAS</i> status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV.