Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands.
JCO Precis Oncol. 2022 Jul;6:e2200180. doi: 10.1200/PO.22.00180.
Around 20%-30% of patients treated with fluoropyrimidines develop severe treatment-related adverse events (AEs). These are mainly caused by deficiency of dihydropyrimidine dehydrogenase, its main metabolizing enzyme. The *7 variant allele contains a frameshift mutation that leads to absence of dihydropyrimidine dehydrogenase. Clinical studies on this variant in patients treated with fluoropyrimidines are lacking because of its low minor allelic frequency. However, the *7 minor allelic frequency is 56-times higher in the Dutch compared with the global population. This allowed us to evaluate fluoropyrimidine tolerability in *7 variant allele carriers.
Patients treated with standard-of-care fluoropyrimidine who were pretreatment genotyped for , , , and single-nucleotide polymorphisms were included for analyses. Patients were additionally screened for the *7 allele (rs72549309, 295-298delTCAT). AEs were graded if they worsened from baseline, according to Common Terminology Criteria for Adverse Events version 5.0. AEs ≥ grade 3 were considered severe.
From 3,748 patients, we found 13 patients carrying heterozygous . Relevant clinical data were available for 11 patients. All patients developed fluoropyrimidine-related AEs, of which five patients developed severe AEs (46%). From these five patients, three patients were started with 65% or 50% of standard dose, but apparently still developed severe toxicity. Because of severe AEs, three patients discontinued treatment prematurely (one patient already started with 50% of standard dose) and one patient who started with 50% of standard dose was further reduced to 35% of standard dose.
In this study, the clinical consequences of carrying the *7 variant allele were confirmed as 46% of the patients developed severe AEs, even in the presence of initial dose reductions. This underlines the need for prospective studies investigating the required fluoropyrimidine dose for *7 carriers.
约 20%-30%接受氟嘧啶治疗的患者出现严重的治疗相关不良反应 (AE)。这些不良反应主要是由于二氢嘧啶脱氢酶（其主要代谢酶）缺乏引起的。7 变体等位基因包含一个移码突变，导致二氢嘧啶脱氢酶缺失。由于其次要等位基因频率较低，因此缺乏接受氟嘧啶治疗的患者中该变体的临床研究。然而，与全球人群相比，荷兰人群中7 次要等位基因频率高 56 倍。这使我们能够评估*7 变体等位基因携带者对氟嘧啶的耐受性。
纳入了接受标准护理氟嘧啶治疗且在预处理时进行了 、 、 、 和单核苷酸多态性基因分型的患者进行分析。此外，还对患者进行了*7 等位基因（rs72549309，295-298delTCAT）的筛查。根据不良事件通用术语标准 5.0，如果 AE 从基线恶化，则对其进行分级。AE≥3 级被认为是严重的。
从 3748 例患者中，我们发现了 13 例携带杂合性的患者。对于 11 例患者，我们获得了相关的临床数据。所有患者均出现氟嘧啶相关 AE，其中 5 例患者出现严重 AE（46%）。这 5 例患者中，有 3 例患者起始剂量降低至标准剂量的 65%或 50%，但显然仍出现严重毒性。由于严重 AE，有 3 例患者提前停药（1 例患者已经开始使用标准剂量的 50%），还有 1 例开始使用标准剂量的 50%的患者进一步降低至标准剂量的 35%。
在这项研究中，携带7 变体等位基因的临床后果得到了证实，因为 46%的患者出现严重 AE，即使在初始剂量降低的情况下也是如此。这强调了需要进行前瞻性研究，以确定7 携带者所需的氟嘧啶剂量。
