Clinical and Experimental Pharmacology, "Centro di Riferimento Oncologico"- National Cancer Institute, via Franco Gallini 2, 33081, Aviano (PN), Italy.
Curr Med Chem. 2020;27(25):4249-4273. doi: 10.2174/0929867326666190712151417.
The introduction of anti-EGFR (cetuximab and panitumumab) and antiangiogenic (bevacizumab, regorafeninb, ramucirumab, and aflibercept) agents in the therapeutic armamentarium of the metastatic colorectal cancer (CRC) has significantly improved the therapeutic efficacy and patients survival. However, despite the great improvements achieved in the patients life expectation, the high inter-individual heterogeneity in the response to the targeted agents still represent an issue for the management of advanced CRC patients. Even if the role of tumor genetic mutations as predictive markers of drug efficacy has been well-established, the contribution of the host genetic markers is still controversial. Promising results regard the germ-line immune-profile, inflammation and tumor microenvironment. Inherent variations in KRAS 3'UTR region as well as EGF/ EGFR genes were investigated as markers of cetuximab effectiveness. More recently interesting data in the field of anti- EGFR agents were generated also for germ-line variants in genes involved in inflammation (e.g. COX-2, LIFR, IGF1 signaling), immune system (e.g., FCGRs, IL-1RA), and other players of the RAS signaling, including the Hippo pathway related genes (e.g. Rassf, YAP, TAZ). Host genetic variants in VEGF-dependent (i.e., EGF, IGF-1, HIF1α, eNOS, iNOS) and -independent (i.e., EMT cascade, EGFL7) pathways, with specific attention on inflammation and immune system-related factors (e.g., IL-8, CXCR-1/2, CXCR4-CXCL12 axis, TLRs, GADD34, PPP1R15A, ANXA11, MKNK1), were investigated as predictive markers of bevacizumab outcome, generating some promising results. In this review, we aimed to summarize the most recent literature data regarding the potential role of common and rare inhered variants in predicting which CRC patients will benefit more from a specifically targeted drug administration.
抗 EGFR（西妥昔单抗和帕尼单抗）和抗血管生成（贝伐珠单抗、瑞戈非尼、雷莫芦单抗和阿柏西普）药物在转移性结直肠癌（CRC）的治疗中引入，显著提高了治疗效果和患者的生存率。然而，尽管患者的预期寿命有了很大的提高，但靶向药物治疗的个体间异质性仍然是一个问题。尽管肿瘤基因突变作为药物疗效的预测标志物的作用已经得到很好的确立，但宿主遗传标志物的作用仍存在争议。种系免疫谱、炎症和肿瘤微环境的作用令人鼓舞。KRAS 3'UTR 区域以及 EGF/EGFR 基因的固有变异被作为西妥昔单抗疗效的标志物进行了研究。最近，在抗 EGFR 药物领域也有了一些有趣的发现，即炎症（如 COX-2、LIFR、IGF1 信号通路）、免疫系统（如 FCGRs、IL-1RA）以及 RAS 信号通路中的其他参与者（如 Hippo 通路相关基因，如 Rassf、YAP、TAZ）中的种系变体也与抗 EGFR 药物的疗效有关。宿主遗传变异与 VEGF 相关（即 EGF、IGF-1、HIF1α、eNOS、iNOS）和非相关（即 EMT 级联、EGFL7）途径有关，特别关注炎症和免疫系统相关因素（如 IL-8、CXCR-1/2、CXCR4-CXCL12 轴、TLRs、GADD34、PPP1R15A、ANXA11、MKNK1），被作为贝伐珠单抗疗效的预测标志物进行了研究，取得了一些有希望的结果。在这篇综述中，我们旨在总结关于常见和罕见遗传变异在预测哪些 CRC 患者将从特定靶向药物治疗中获益更多的最新文献数据。
