De Mattia Elena, Polesel Jerry, Scarabel Lucia, Cecchin Erika
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Province of Pordenone, Italy.
Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Province of Pordenone, Italy.
Front Pharmacol. 2024 Dec 5;15:1516375. doi: 10.3389/fphar.2024.1516375. eCollection 2024.
Dihydropyrimidine dehydrogenase (DPD, encoded by the gene) is the rate-limiting enzyme for the detoxification of fluoropyrimidines (FLs). Rs4294451 is a regulatory polymorphism that has recently been functionally characterized and associated with increased DPD expression in the liver. The aim of the present study was to test the clinical implications of being a carrier of rs4294451 in a cohort of 645 FL-treated colorectal cancer patients. Carriers of at least one rs4294451-T variant allele had a lower risk of developing NCI-CTC grade 4-5 hematological [odds ratio (OR) = 0.39; 95% confidence interval (CI): 0.15-0.98; additive model] and hematological/non-hematological (OR = 0.44; 95% CI: 0.22-0.88; dominant model) FL-related toxicity. Patients with the rs4294451-T allele also had a longer time to severe toxicity development after starting FL treatment [hematological, Hazard ratio (HR) = 0.27; 95% CI: 0.09-0.79; Fine-Gray test = 0.1569; hematological/non-hematological: HR = 0.38, 95% CI: 0.17-0.85; Fine-Gray test = 0.0444]. It is worth noting that while being at lower risk of toxicity, rs4294451-T allele carriers also tend to present a shorter overall survival (HR = 1.41; 95% CI: 1.05-1.90; log-rank = 0.0406). These findings demonstrate a clinical effect of -rs4294451 polymorphism coherent with the recently described functional effect. Further investigation is warranted to elucidate the potential clinical value to the rs4294451 polymorphism as toxicity and especially as an efficacy marker in colorectal cancer.
二氢嘧啶脱氢酶（DPD，由该基因编码）是氟嘧啶（FLs）解毒的限速酶。Rs4294451是一种调节性多态性，最近已在功能上得到表征，并与肝脏中DPD表达增加相关。本研究的目的是在一组645例接受FL治疗的结直肠癌患者中测试作为rs4294451携带者的临床意义。至少携带一个rs4294451-T变异等位基因的携带者发生NCI-CTC 4-5级血液学毒性[优势比（OR）=0.39；95%置信区间（CI）：0.15-0.98；相加模型]以及血液学/非血液学毒性（OR=0.44；95%CI：0.22-0.88；显性模型）的风险较低。携带rs4294451-T等位基因的患者在开始FL治疗后发生严重毒性的时间也更长[血液学毒性，风险比（HR）=0.27；95%CI：0.09-0.79；Fine-Gray检验=0.1569；血液学/非血液学毒性：HR=0.38，95%CI：0.17-0.85；Fine-Gray检验=0.0444]。值得注意的是，虽然rs4294451-T等位基因携带者发生毒性的风险较低，但他们的总生存期也往往较短（HR=1.41；95%CI：1.05-1.90；对数秩检验=0.0406）。这些发现证明了rs4294451多态性的临床效应与最近描述的功能效应一致。有必要进一步研究以阐明rs4294451多态性作为毒性尤其是作为结直肠癌疗效标志物的潜在临床价值。
