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World J Gastroenterol. Aug 14, 2014; 20(30): 10316-10330
Published online Aug 14, 2014. doi: 10.3748/wjg.v20.i30.10316
FOLFOX/FOLFIRI pharmacogenetics: The call for a personalized approach in colorectal cancer therapy
Beatrice Mohelnikova-Duchonova, Bohuslav Melichar, Pavel Soucek
Beatrice Mohelnikova-Duchonova, Pavel Soucek, Department of Toxicogenomics, National Institute of Public Health, 10042 Prague, Czech Republic
Beatrice Mohelnikova-Duchonova, Bohuslav Melichar, Department of Oncology, Palacky University Medical School and Teaching Hospital, 77525 Olomouc, Czech Republic
Author contributions: Mohelnikova-Duchonova B and Soucek P conceived the review; Mohelnikova-Duchonova B, Melichar B and Soucek P drafted the manuscript and performed its revisions.
Supported by Internal Grant Agency of the Czech Ministry of Health, No. NT14329-3; Research project Biomedreg, No. CZ.1.05/2.1.00/01.0030; Project from European Regional Development Fund, No. CZ.1.05/2.1.00/03.0076; and the project of the Palacky University, No. LF_2013_010
Correspondence to: Beatrice Mohelnikova-Duchonova, MD, PhD, Department of Oncology, Palacky University Medical School and Teaching Hospital, IP Pavlova 6, 77525 Olomouc, Czech Republic. d.beatrice@seznam.cz
Telephone: +420-775-270283
Received: October 29, 2013
Revised: March 5, 2014
Accepted: April 15, 2014
Published online: August 14, 2014
Abstract

While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%, the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival. However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.

Keywords: Colorectal cancer, Chemotherapy, 5-Fluorouracil, Oxaliplatin, Irinotecan

Core tip: 5-fluorouracil/leucovorin combined with oxaliplatin (FOLFOX) and irinotecan (FOLFIRI) represent the most effective chemotherapy regimens for colorectal carcinoma patients with distant metastases. Pharmacogenetics represents a promising strategy for the individualization of therapy, including identification of patients at increased risk of toxicity. This review summarizes contemporary knowledge about associations of gene and protein expression and genetic variability of putative biomarkers for the response of colorectal cancer to FOLFOX/FOLFIRI regimens. From the published data reviewed it is obvious that the problem is highly complex and the ultimate profile of the drug-sensitive or resistant patient will most probably be jointly defined by genetic, epigenetic, intracellular, extracellular, and extrinsic factors.