Aim: Germline variants could modify survival of metastatic colorectal cancer patients (mCRC). Patients & methods: The association of 285 haplotype-tagging SNPs in 11 candidate genes and overall survival (OS) was tested in two cohorts totalizing 417 FOLFIRI-treated mCRC. Gene expression was investigated in vitro and in public datasets. Results: In the combined cohort, CES1 rs9921399T>C was associated with prolonged OS (hazard ratio [HR] = 0.40) whereas ABCC1 rs17501011G>A (HR = 2.08) and UGT1 rs1113193G>A (HR = 2.12) were associated with shorter OS (p ≤ 0.005). A combined effect of these polymorphisms was observed with HR of 1.98-2.97 (p < 0.05). The ABCC1 rs17501011A variant reduced reporter-gene activity (p < 0.05) whereas ABCC1 tumor expression was associated with shorter survival (p ≤ 0.013). Conclusion: We identified a combination of genetic determinants that could predict mCRC survival.
Keywords: biomarkers; irinotecan; metastatic colorectal cancer; pharmacogenomics; polymorphisms.
Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression.Ann Oncol. 2016 Nov;27(11):2082-2090. doi: 10.1093/annonc/mdw402. Epub 2016 Aug 29. Ann Oncol. 2016. PMID: 27573561 Free PMC article. Clinical Trial.
Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer.Pharmacogenomics J. 2018 Sep;18(5):623-632. doi: 10.1038/s41397-018-0030-8. Epub 2018 Jun 21. Pharmacogenomics J. 2018. PMID: 29925895 Free PMC article.
An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients.Ann Oncol. 2012 May;23(5):1207-13. doi: 10.1093/annonc/mdr387. Epub 2011 Sep 16. Ann Oncol. 2012. PMID: 21926398
Chemotherapy of metastatic colorectal cancer.Prescrire Int. 2010 Oct;19(109):219-24. Prescrire Int. 2010. PMID: 21180382 Review.
Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patients with metastatic colorectal cancer. a meta-analysis.Int J Colorectal Dis. 2015 Oct;30(10):1305-10. doi: 10.1007/s00384-015-2296-5. Epub 2015 Jun 23. Int J Colorectal Dis. 2015. PMID: 26099322 Review.