关键词: Capecitabine DPD deficiency DPYD polymorphism Fluoropyrimidines HapB3 Personalized medicine c.2194G>A

Mesh : Male Humans Middle Aged Capecitabine Fluorouracil Antimetabolites, Antineoplastic / therapeutic use Dihydrouracil Dehydrogenase (NADP) / genetics metabolism Antimetabolites

来  源:   DOI:10.1007/s00280-023-04515-w

Abstract:
Fluoropyrimidines (FPs) form still nowadays the backbone of chemotherapic schemes in colorectal cancer (CRC). Inter-patient variability of the toxicity profile of FPs may be partially accounted for by variable expression of dihydropyrimidine dehydrogenase (DPD). DPD rate activity is genetically determined by its extremely polymorphic coding gene DPYD. In spite of pharmacogenetic guideline-directed-dosing of FPs based regimens treating carrier of multiple variants of DPYD gene remains still challenging.
We present a case of a 48-year-old Caucasian man, compound heterozygous variant carrier of the DPYD gene (HapB3 and c.2194G>A) who had a diagnosis of adenocarcinoma of the left colon and was safely treated with a pharmacogenetic-guided 25% dose reduction of the standard CAP adjuvant treatment. Compound heterozygosis may have been responsible for an earlier over exposure to CAP resulting into low-grade toxicity with an anticipated median time to toxicity of the c.2194G>A variant to the 4th vs. 6th cycles. Some haplotypes of DPYD variants may have an advantage in terms of survival compared to wild-type patients. Our patient may also have benefitted from compound heterozygosis, as shown by no evidence of disease (NED) at 6-month follow-up.
Pharmacogenetic-guided dosing of DPYD intermediate metabolizer compound heterozygous HapB3 and c.2194G>A variant carries should be managed by a multidisciplinary team with a dose reduction ranging from 25 to 50% to maintain effectiveness and close clinical monitoring for early detection of ADRs.
摘要:
背景:如今,氟嘧啶(FPs)仍然是结直肠癌(CRC)化疗方案的支柱。FPs毒性谱的患者间变异性可能部分由二氢嘧啶脱氢酶(DPD)的可变表达来解释。DPD率活性由其极端多态的编码基因DPYD遗传决定。尽管基于药物遗传学指导的FP给药方案治疗DPYD基因多种变体的携带者仍然具有挑战性。
方法:我们介绍了一个48岁的白种人,DPYD基因的复合杂合变体携带者(HapB3和c.2194G>A),诊断为左结肠腺癌,并通过药物遗传学指导的剂量减少25%的标准CAP辅助治疗安全治疗。复合杂合可能是导致早期过度暴露于CAP的原因,导致低度毒性,预期的中位毒性时间为c.2194G>A变体至第4与第六周期与野生型患者相比,DPYD变体的一些单倍型可能在存活方面具有优势。我们的病人也可能从复合杂合中受益,如6个月随访时无疾病证据(NED)所示。
结论:药物遗传学指导剂量的DPYD中间代谢物复合杂合子HapB3和c.2194G>变种携带者应由多学科团队管理,剂量减少25%至50%,以保持有效性并密切临床监测,以早期发现ADR。
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