Adverse events affect the pharmacological treatment of approximately 90% of colorectal cancer (CRC) patients at any stage of the disease. Chemotherapy including fluoropyrimidines, irinotecan, and oxaliplatin is the cornerstone of the pharmacological treatment of CRC. The introduction of novel targeted agents, as anti-EGFR (i.e. cetuximab, panitumumab) and antiangiogenic (i.e. bevacizumab, ziv-aflibercept, regorafenib, and ramucirumab) molecules, into the oncologist’s toolbox has led to significant improvements in the life expectancy of advanced CRC patients, but with a substantial increase in toxicity burden. In this respect, pharmacogenomics has largely been applied to the personalization of CRC chemotherapy, focusing mainly on the study of inhered polymorphisms in genes encoding phase I and II enzymes, ATP-binding cassette (ABC)/solute carrier (SLC) membrane transporters, proteins involved in DNA repair, folate pathway and immune response. These research efforts have led to the identification of some validated genetic markers of chemotherapy toxicity, for fluoropyrimidines and irinotecan. No validated genetic determinants of oxaliplatin-specific toxicity, as peripheral neuropathy, has thus far been established. The contribution of host genetic markers in predicting the toxicity associated with novel targeted agents’ administration is still controversial due to the heterogeneity of published data. Pharmacogenomics guidelines have been published by some international scientific consortia such as the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) strongly suggesting a pre-treatment dose adjustment of irinotecan based on UGT1A1*28 genotype and of fluoropyrimidines based on some DPYD genetic variants, to increase treatment safety. However, these recommendations are still poorly applied at the patient’s bedside. Several ongoing projects in the U.S. and Europe are currently evaluating how pharmacogenomics can be implemented successfully in daily clinical practice. The majority of drug-related adverse events are still unexplained, and a great deal of ongoing research is aimed at improving knowledge of the role of pharmacogenomics in increasing treatment safety. In this review, the issue of pre-treatment identification of CRC patients at risk of toxicity via the analysis of patients’ genetic profiles is addressed. Available pharmacogenomics guidelines with ongoing efforts to implement them in clinical practice and new exploratory markers for clinical validation are described.

在疾病的任何阶段，不良事件都会影响大约90％的大肠癌（CRC）患者的药物治疗。包括氟嘧啶，伊立替康和奥沙利铂在内的化学疗法是CRC药物治疗的基石。在肿瘤学家的工具箱中引入了新的靶向药物，例如抗EGFR（即西妥昔单抗，帕尼单抗）和抗血管生成（即贝伐单抗，ziv-aflibercept，雷戈非尼和雷莫昔单抗）分子，从而显着改善了晚期CRC的预期寿命病人，但毒性负担大大增加。在这方面，药物基因组学已广泛应用于CRC化疗的个性化，主要侧重于研究编码I和II期酶的基因的固有多态性，ATP结合盒（ABC）/溶质载体（SLC）膜转运蛋白，参与DNA修复，叶酸途径和免疫反应的蛋白质。这些研究工作已导致针对氟嘧啶和伊立替康确定了一些经过验证的化学疗法毒性的遗传标记。迄今为止，尚未确定作为外周神经病变的已证实的奥沙利铂特异性毒性的遗传决定因素。由于已发表数据的异质性，宿主遗传标志物在预测与新型靶向药物给药相关的毒性方面的贡献仍然存在争议。基于某些DPYD的UGT1A1 * 28基因型和氟嘧啶基因变异，以增加治疗安全性。但是，这些建议在患者的床边仍然应用不佳。美国和欧洲的几个正在进行的项目目前正在评估如何在日常临床实践中成功实施药物基因组学。大多数与药物相关的不良事件仍无法解释，并且大量正在进行的研究旨在提高对药物基因组学在提高治疗安全性中作用的认识。在这篇综述中，通过对患者的遗传谱进行分析，探讨了对有毒性风险的CRC患者进行治疗前鉴定的问题。描述了可用的药物基因组学指南，以及正在努力在临床实践中实施它们的努力以及用于临床验证的新探索性标志物。