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Lancet oncol：根据DPYD基因型适当降低尿嘧啶剂量可减少其毒副作用

2018-10-29 MedSci MedSci原创

尿嘧啶DPYD
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尿嘧啶治疗可造成严重的毒副作用，发生率高达30%，通常是由于二氢嘧啶脱氢酶(DPD)编码基因（DPYD）突变导致DPD活性降低所引起的。现研究人员前瞻性筛查四种最常见的DPYD突变（DPYD*2A [rs3918290，c.1905+1G>A， IVS14+1G>A]，c.2846A>T[rs67376798，D949V]，c.1679T>G [rs55886062，DPY

尿嘧啶治疗可造成严重的毒副作用，发生率高达30%，通常是由于二氢嘧啶脱氢酶(DPD)编码基因（DPYD）突变导致DPD活性降低所引起的。现研究人员前瞻性筛查四种最常见的DPYD突变（DPYD*2A [rs3918290，c.1905+1G>A， IVS14+1G>A]，c.2846A>T[rs67376798，D949V]，c.1679T>G [rs55886062，DPYD*13，I560S]和c.1236G>A[rs56038477，E412E]），探究根据DPYD基因型调整尿嘧啶用药剂量对患者安全性的影响。

本研究是在新西兰的17家医院开展的前瞻性、多中心的安全性分析，招募年满18岁的打算进行以氟嘧啶为基础的抗癌治疗（单用卡培他滨或氟尿嘧啶，或结合其他化疗药物或放疗）的癌症患者，不限肿瘤类型。研究人员对DPYD*2A、c.2846A>T、c.1679T>G和c.1236G>A进行基因分型。DPYD杂合突变携带者初始治疗剂量减少25%（c.2846A>T和c.1236G>A）或50%（DPYD*2A和c.1679T>G），DPYD野生型（即无突变的）患者按标准疗法治疗。主要结点：氟嘧啶相关的严重毒副作用的发生率。

2015年4月30日-2017年12月21日，共招募了1103位符合要求的患者，其中85位（8%）为杂DPYD杂合突变携带者，1018位（92%）为DPYD野生型患者。总体上，尿嘧啶相关的严重毒性在DPYD突变携带者中的发生率要高于野生型患者（33/85[39%] vs 231/1018[23%]；p=0.0013）。基因型导向给药 vs DPYD*2A、c.1679T>G、c.2846A>T和c.1236G>A携带者的既往队列的尿嘧啶相关的严重毒性的相对风险[RR]分别是1.31（95% CI 0.63-2.73）vs 2.87（2.14-3.86）、无毒性 vs 4.30 (2.10–8.80)、2.00（1.19-3.34）vs 3.11（2.25-4.28）和1.69（1.18-2.42）vs 1.72（1.22-2.42）。

综上所述，前瞻性DPYD分型可用于日常临床实践，DPYD分型导向的剂量缩减可提高尿嘧啶治疗的安全性。对于DPYD*2A和c.1679T>G携带者，尿嘧啶初始剂量可降低50%。对于c.2846A>T和c.1236G>A携带者，初始治疗剂量是否可降低50%（取代25%）仍需要进一步研究。鉴于尿嘧啶是最常见的抗癌药，该研究提示DPYD基因型导向的个体化给药或可成为一种新的标准疗法。


原始出处：

Linda M Henricks，et al. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer： a prospective safety analysis. The Lancet Oncology.October 19，2018.https：//doi.org/10.1016/S1470-2045(18)30686-7

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    2018-12-15 ms5187542471278033

    #DPYD#

    0

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    2019-09-01 showtest

    #副作用#

    0

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    2019-03-24 liuyong2980

    #毒副作用#

    0

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    2019-06-05 kzlchina

    #基因型#

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1993224, encodeId=636919932244f, content=<a href='/topic/show?id=8771622ee7' target=_blank style='color:#2F92EE;'>#DPYD#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6227, encryptionId=8771622ee7, topicName=DPYD)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKUdkK5dVTue7YQDvwqM1ugOuEpDZEzvXhoGClFiavehcrNAYDuPbks3MkKLPpyAEicgic80KguxwicYQ/132, createdBy=ec952500165, createdName=ms5187542471278033, createdTime=Sat Dec 15 07:18:00 CST 2018, time=2018-12-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1824303, encodeId=79bb182430367, content=<a href='/topic/show?id=56a932e7800' target=_blank style='color:#2F92EE;'>#副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32778, encryptionId=56a932e7800, topicName=副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8f0715, createdName=showtest, createdTime=Sun Sep 01 18:18:00 CST 2019, time=2019-09-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2078793, encodeId=61ce20e8793e1, content=<a href='/topic/show?id=6dbc635680d' target=_blank style='color:#2F92EE;'>#毒副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63568, encryptionId=6dbc635680d, topicName=毒副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=de89102, createdName=liuyong2980, createdTime=Sun Mar 24 08:18:00 CST 2019, time=2019-03-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1890848, encodeId=3e3f1890848cf, content=<a href='/topic/show?id=742341e1782' target=_blank style='color:#2F92EE;'>#基因型#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=41717, encryptionId=742341e1782, topicName=基因型)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f984116, createdName=kzlchina, createdTime=Wed Jun 05 08:18:00 CST 2019, time=2019-06-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1865575, encodeId=2dfd18655e5b8, content=<a href='/topic/show?id=16ce133504e' target=_blank style='color:#2F92EE;'>#Oncol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13350, encryptionId=16ce133504e, topicName=Oncol)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b63894, createdName=minlingfeng, createdTime=Tue Jun 04 19:18:00 CST 2019, time=2019-06-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1829861, encodeId=18451829861a1, content=<a href='/topic/show?id=1b6210686b2' target=_blank style='color:#2F92EE;'>#Lancet#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=15, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10686, encryptionId=1b6210686b2, topicName=Lancet)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3f0227, createdName=howi, createdTime=Sun Aug 25 18:18:00 CST 2019, time=2019-08-25, status=1, ipAttribution=)]
    2019-06-04 minlingfeng

    #Oncol#

    0

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    2019-08-25 howi

    #Lancet#

    0

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