Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer
| Autor: | Jingyuan Wang, Shivani Soni, Bodour Salhia, Shannon M. Mumenthaler, Christoph Mancao, Natsuko Kawanishi, Yi Xiao, Hiroyuki Arai, Wu Zhang, Heinz-Josef Lenz, Joshua Millstein, Priya Jayachandran, Aparna Raj Parikh, Francesca Battaglin |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Oncology
DNA Replication Male Cancer Research medicine.medical_specialty Bevacizumab Organoplatinum Compounds Colorectal cancer Leucovorin Single-nucleotide polymorphism Cell Cycle Proteins Polymorphism Single Nucleotide Article FOLFOX Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Biomarkers Tumor Humans Allele Neoplasm Metastasis Germ-Line Mutation Aged business.industry Intracellular Signaling Peptides and Proteins medicine.disease digestive system diseases Oxaliplatin Irinotecan DNA-Binding Proteins Survival Rate Colonic Neoplasms FOLFIRI Camptothecin Female Fluorouracil business medicine.drug |
| Zdroj: | Br J Cancer |
| Popis: | BACKGROUND: The TIMELESS–TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS–TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). METHODS: We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. RESULTS: In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49–6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. CONCLUSIONS: TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC. |
| Databáze: | OpenAIRE |
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