Department of Pathology, Vasa Central Hospital, Hietalahdenkatu 2-4, 65130, Vaasa, Finland.
Department of Oncology, Vasa Central Hospital, Vaasa, Finland.
Cancer Chemother Pharmacol. 2021 May;87(5):657-663. doi: 10.1007/s00280-021-04236-y. Epub 2021 Feb 5.
Capecitabine is a fluoropyrimidine that is widely used as a cancer drug for the treatment of patients with a variety of cancers. Unfortunately, early onset, severe or life-threatening toxicity is observed in 19-32% of patients treated with capecitabine and 5FU. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of 5FU and a DPD deficiency has been shown to be a major determinant of severe fluoropyrimidine-associated toxicity. DPD is encoded by the DPYD gene and some of the identified variants have been described to cause DPD deficiency. Preemptive screening for DPYD gene alterations enables the identification of DPD-deficient patients before administering fluoropyrimidines. In this article, we describe the application of upfront DPD screening in Finnish patients, as a part of daily clinical practice, which was based on a comprehensive DPYD gene analysis, measurements of enzyme activity and plasma uracil concentrations. Almost 8% of the patients (13 of 167 patients) presented with pathogenic DPYD variants causing DPD deficiency. The DPD deficiency in these patients was further confirmed via analysis of the DPD activity and plasma uracil levels. Interestingly, we identified a novel intragenic deletion in DPYD which includes exon 4 in four patients (31% of patients carrying a pathogenic variant). The high prevalence of the exon 4 deletion among Finnish patients highlights the importance of full-scale DPYD gene analysis. Based on the literature and our own experience, genotype preemptive screening should always be used to detect DPD-deficient patients before fluoropyrimidine therapy.
卡培他滨是一种氟嘧啶类药物，广泛用于治疗多种癌症患者的癌症药物。不幸的是，在接受卡培他滨和 5FU 治疗的患者中，有 19-32%观察到早期发病、严重或危及生命的毒性。二氢嘧啶脱氢酶（DPD）是 5FU 降解的限速酶，DPD 缺乏已被证明是严重氟嘧啶相关毒性的主要决定因素。DPD 由 DPYD 基因编码，一些已鉴定的变体已被描述为导致 DPD 缺乏。在给予氟嘧啶类药物之前，对 DPYD 基因改变进行抢先筛查可以识别 DPD 缺乏的患者。本文描述了在芬兰患者中作为日常临床实践的一部分，基于全面的 DPYD 基因分析、酶活性和血浆尿嘧啶浓度测量，进行抢先 DPD 筛查的应用。近 8%的患者（167 例患者中的 13 例）表现出导致 DPD 缺乏的致病性 DPYD 变体。通过分析 DPD 活性和血浆尿嘧啶水平进一步证实了这些患者的 DPD 缺乏。有趣的是，我们在四个患者（携带致病性变异的患者的 31%）中鉴定出 DPYD 基因内的新型内含子缺失，包括外显子 4。芬兰患者中外显子 4 缺失的高发生率突出了全面 DPYD 基因分析的重要性。基于文献和我们自己的经验，在氟嘧啶治疗前，应始终使用基因型抢先筛查来检测 DPD 缺乏的患者。
