Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico - National Cancer Institute, 33081 Aviano, Italy.
Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico - National Cancer Institute, 33081 Aviano, Italy.
Drug Resist Updat. 2018 Jul;39:18-40. doi: 10.1016/j.drup.2018.07.001. Epub 2018 Jul 10.
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.
不良反应影响约 90%的结直肠癌（CRC）患者在疾病的任何阶段的药物治疗。包括氟嘧啶类、伊立替康和奥沙利铂的化疗是 CRC 药物治疗的基石。新型靶向药物的引入，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、瑞戈非尼、雷莫芦单抗）分子，已使晚期 CRC 患者的预期寿命显著提高，但毒性负担也大大增加。在这方面，药物基因组学在很大程度上被应用于 CRC 化疗的个体化，主要集中在研究编码 I 期和 II 期酶、三磷酸腺苷（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基因中固有多态性。这些研究努力导致了一些氟嘧啶类和伊立替康化疗毒性的已验证遗传标志物的确定。迄今为止，尚未确定奥沙利铂特异性毒性（如周围神经病变）的有效遗传决定因素。由于发表数据的异质性，宿主遗传标志物在预测新型靶向药物给药相关毒性中的作用仍存在争议。一些国际科学联盟，如临床药物基因组学实施联盟（CPIC）和荷兰药物遗传学工作组（DPWG），已发布药物基因组学指南，强烈建议根据 UGT1A1*28 基因型调整伊立替康的预处理剂量，并根据一些 DPYD 遗传变异调整氟嘧啶类药物的剂量，以提高治疗安全性。然而，这些建议在患者床边的应用仍然很差。美国和欧洲的几个正在进行的项目目前正在评估药物基因组学如何成功地应用于日常临床实践。大多数药物相关不良反应仍然无法解释，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的作用的认识。在这篇综述中，通过分析患者的遗传谱来确定有发生毒性风险的 CRC 患者的预处理方法的问题得到了解决。描述了现有的药物基因组学指南以及正在努力将其应用于临床实践的情况，并描述了新的探索性标志物以进行临床验证。
