背景:二氢嘧啶脱氢酶(DPD)缺乏症是危及生命的氟嘧啶(FP)诱导毒性的主要已知原因。我们对个体患者数据进行了荟萃分析,以评估有害DPYD变异*2A/D949V/*13/HapB3(由EMA推荐)和临床因素的贡献。预测G4-5毒性。
方法:研究合格标准包括招募没有基于DPD的FP剂量调整的白种人患者。主要终点是12周的血液或消化性G4-5毒性。DPYD变体的值*2A/p。D949V/*13合并,使用多变量逻辑模型(AUC)评估HapB3和MIR27Ars895819。
结果:在25项符合条件的研究中,15项研究(8733例患者)获得了完整的临床变量和主要终点.12周G4-5毒性患病率为7.3%(641起事件)。临床模型包括年龄,性别,身体质量指数,FP管理时间表,伴随的抗癌药物。添加*2A/p。D949V/*13变体(至少一个等位基因,患病率2.2%,OR9.5[95CI6.7-13.5])显著改善了模型(p<0.0001)。添加HapB3(患病率4.0%,98.6%杂合),尽管与毒性显著相关(OR1.8[95CI1.2-2.7]),没有改进模型。MIR27Ars895819与毒性无关,与DPYD变体无关。
结论:FUSAFE荟萃分析强调了DPYD*2A/p的主要相关性。D949V/*13结合临床变量,以确定有非常严重的FP相关毒性风险的患者。
BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity.
METHODS: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC).
RESULTS: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants.
CONCLUSIONS: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.