De Mattia Elena, Milan Noemi, Assaraf Yehuda G, Toffoli Giuseppe, Cecchin Erika
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081 Aviano (PN), Italy.
The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
Int J Biol Sci. 2024 Jul 2;20(10):3742-3759. doi: 10.7150/ijbs.97686. eCollection 2024.
Fluoropyrimidines (FLs) [5-Fluorouracil, Capecitabine] are used in the treatment of several solid tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for FL detoxification, and its deficiency could lead to severe, life-threatening or fatal toxicity after FL administration. Testing with a pharmacogenetic panel of four deleterious variants in the dihydropyrimidine dehydrogenase gene (, c.2846A > T, c.1129-5923C > G) prior to FL treatment, is recommended by scientific consortia (e.g., CPIC, DPWG) and drug regulatory agencies (e.g., EMA). However, this panel identifies < 20% of patients at risk of severe FL-related toxicity. Cumulative recent evidence highlights the potential clinical value of rare (minor allele frequency < 1%) and novel genetic variants for identifying an additional fraction of DPD-deficient patients at increased risk of severe FL-related toxicity. In this review, we aimed to comprehensively describe the available evidence regarding the potential clinical predictive role of novel and rare variants as toxicity markers in FL-treated patients, and to discuss the challenges and opportunities in tailoring FL treatment based upon clinical application of such markers. Although we must overcome existing barriers to the clinical implementation, the available data support that comprehensive assessment of the sequence, including rare and novel genetic variants, may significantly enhance the pre-emptive identification of at-risk patients, compared to the current targeted approach.
氟嘧啶类药物（FLs）[5-氟尿嘧啶、卡培他滨]用于治疗多种实体瘤。二氢嘧啶脱氢酶（DPD）是FL解毒的限速酶，其缺乏可能导致FL给药后出现严重的、危及生命或致命的毒性。科学联盟（如CPIC、DPWG）和药品监管机构（如EMA）建议在进行FL治疗前，使用包含二氢嘧啶脱氢酶基因中四个有害变异（，c.2846A>T，c.1129-5923C>G）的药物遗传学检测板进行检测。然而，该检测板只能识别不到20%有严重FL相关毒性风险的患者。近期累积的证据凸显了罕见（次要等位基因频率<1%）和新型基因变异在识别另外一部分有严重FL相关毒性增加风险的DPD缺乏患者方面的潜在临床价值。在本综述中，我们旨在全面描述关于新型和罕见变异作为FL治疗患者毒性标志物的潜在临床预测作用的现有证据，并讨论基于此类标志物的临床应用来调整FL治疗方案时所面临的挑战和机遇。尽管我们必须克服临床实施中存在的障碍，但现有数据支持，与当前的靶向方法相比，对整个序列（包括罕见和新型基因变异）进行全面评估可能会显著提高对高危患者的预先识别能力。
