Lancet. Oncol:同一靶向治疗的不同预后:精准医疗仍在路上

2018-01-13 王强 肿瘤资讯

最近,耶鲁癌症中心肿瘤精准医疗专家组(Yale Cancer Center Precision Medicine Tumor Board)在著名的杂志《Lancet Oncology》发表了两个病例经同一靶向治疗而预后不同的文章,相信对我们的日常工作有一定提示意义。

最近,耶鲁癌症中心肿瘤精准医疗专家组(Yale Cancer Center Precision Medicine Tumor Board)在著名的杂志《Lancet Oncology》发表了两个病例经同一靶向治疗而预后不同的文章,相信对我们的日常工作有一定提示意义。

精准医疗(Precision Medicine)是以个体化医疗为基础、随着基因组测序技术快速进步以及生物信息与大数据科学的交叉应用而发展起来的新型医学概念与医疗模式。2015年1月20日,美国总统奥巴马在国情咨文中提出“精准医学计划”,希望精准医学可以引领一个医学新时代。精准医疗的概念已深入人心,但我们面对具体病例的时候,“精准”程度如何,对患者的治疗和预后会有什么影响,目前还缺乏充分认识。

【病例1】

71岁男性,确诊为局限型前列腺癌,Gleason评分10分,已进行过放疗及亮丙瑞林(leuprolide)治疗。2年后患者出现肩胛骨单发转移性,再次进行放疗,亮丙瑞林治疗持续进行中。此次治疗3年后,患者再次出现复发、多发淋巴结肿大,5年多的时间内历经多线治疗(如多西他赛、sipleucel-T、恩杂鲁胺、阿比特龙)。曾就诊于耶鲁癌症中心并连续参与两项临床试验,病变仍进展。肿瘤组织送分子检测。详见表1。

肿瘤精准医疗专家组意见:

鉴于该患者具有ATM的有害突变,建议患者进入临床试验接受奥拉帕尼(olaparib)治疗。

【病例2】

62岁男性,左肋部4.7cm高级别肉瘤,已切除,三枚淋巴结中一枚受累。辅助放疗后,辅助应用吉西他滨、多西他赛。由于化疗毒性,所以化疗方案改为阿霉素加异环磷酰胺。9个月后,PET-CT见肺部转移,进行阿霉素及olaratumab治疗,但两个周期后肿瘤仍进展。瘤组织送分子检测,详见表1。

肿瘤精准医疗专家组意见:

鉴于该患者具有ATM的有害突变,建议患者进入临床试验接受奥拉帕尼治疗。

表1.两例中二代测序检出的分子异常概述


临床随访

病例1中具有ATM突变的前列腺癌参加了临床试验(NCT0257644),开始接受奥拉帕尼300mg治疗、每日两次。此前出现进展的疾病已有6个月以上的稳定状态。

病例2中具有ATM突变的肉瘤也参加了临床试验,开始接受奥拉帕尼300mg治疗、每日两次。4周后出现恶性胸腔积液。8周后CT检查,明确病变进展,最终患者死于肿瘤进展。

讨论

很多肿瘤都有同源重组(homologous recombination,HR)缺陷,一般是DNA损伤应答(DNA damage response)网络中的关键基因失活所致。与PARP抑制剂敏感性相关的最常见DDR基因突变是影响BRCA1及BRCA2的突变,且大量数据表明该通路中许多其他基因(也包括ATM)出现的肿瘤相关突变具有相同性质。PARP是DNA单链断裂(single-stranded breaks,SSBs)修复的关键,且药物抑制该蛋白后可导致基因组中出现大量DNA单链断裂。DNA修复时,未修复的DNA单链断裂转变为双链断裂,这是修复过程中同源重组通路所需。因此PARP抑制剂对于同源重组缺陷细胞具有选择性毒性,且这两种有害性功能缺失(一种是突变所致,一种是药物所致)被认为具有协同致死作用。

上述两例中,ATM突变均为靶向治疗有效的最佳证据。临床前及临床研究均表明在多种肿瘤类型中(如神经母细胞瘤、肺癌、前列腺癌)ATM功能降低均可应用PARP抑制剂。某些家族中也曾有过显性负性乳腺癌相关突变的报道。前述进展期患者对系统治疗多线耐药,因此根据耶鲁肿瘤精准医疗专家组意见进行PARP抑制剂治疗。前列腺癌患者病情稳定已达6个月,且仍稳定中;而肉瘤患者病情进展,且很快去世。尽管两个患者的肿瘤均有ATM的有害突变,但其预后的不同仍引出了这样的问题:不同患者的相同基因有害性突变、实施相同靶向治疗,会产生不同的效果。当然,具体到本文的病例,原因可能有许多,比如:肿瘤类型不同、ATM中突变位置不同、同时伴随的其他突变间的差异、基因表达的表观遗传调控差异等。理解这些因素、以及其他因素对药物疗效的影响,在接下来的一段时间内仍将是精准医疗的主要任务!

点评

精准医疗的基础,是大量、或者说海量数据;仅就分子遗传学改变相关数据来说,就会受到多种因素影响。比如DNA分析样变的制备过程,会受所取样本的类型影响-粗针穿刺、细针抽吸、手术标本之间的制备方案不尽相同;获取样本的时间(疾病的早期或晚期)、是否经过治疗等也很关键。分析所用的平台、所分析的项目多少、分析深度等样本之外的因素也不容忽视。本文中不同病例、相同突变,经过相同的靶向治疗后,预后显着不同,也为目前的“精准医疗”提出了新的问题:精准医疗,仍在路上!

原始出处

Cecchini M,Walther Z,Sklar JL,et al.Yale Cancer Center Precision Medicine Tumor Board: two patients, one targeted therapy, different outcomes[J].The Lancet. Oncology,2018,19(1):23-24.

Cecchini M,Walther Z,Sklar JL,et al.Introduction to the Yale Precision Medicine Tumor Board[J].The Lancet. Oncology,2018,19(1):19-20.

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    2018-12-07 minlingfeng
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    2018-07-30 howi
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createdBy=3f0227, createdName=howi, createdTime=Mon Jul 30 20:05:00 CST 2018, time=2018-07-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=317112, encodeId=a7d031e112ae, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=cdfc1646964, createdName=1ddbadeam12(暂无匿称), createdTime=Mon May 21 06:27:21 CST 2018, time=2018-05-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=280152, encodeId=41d8280152d3, content=精准医疗绝不是简单先进检查方法罗列后的治疗***境界应该与真正中医异曲同工:因人而异的治疗, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/Q3auHgzwzM6lQViaiaazgKwu3ASkx2y57ib6ISo2VFcU2BYlssBOpcOQcjB5rSVpl36mTeQD5lzAvY9wwxyOuebVA/0, 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createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/DYAIOgq83eqM5Us62Ftfq8p2yibwa3jhic5XN6OqqUA1ibvzfWQrumpRkzzF8blLlriaI7xhwibxy1rlhbhvf8hOLCg/0, createdBy=21782224515, createdName=zhangxiaoxi, createdTime=Mon Jan 15 22:32:35 CST 2018, time=2018-01-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1403283, encodeId=ad921403283aa, content=<a href='/topic/show?id=ebbde6353be' target=_blank style='color:#2F92EE;'>#精准#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76353, encryptionId=ebbde6353be, topicName=精准)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83epQX9hfEIBiaPg0e9KvLYVBCSGYydH6K6OQxBh3RaOC0TYP9HYy2v0XdHib1LFnZNU5Siak0P8oh8Aqw/132, createdBy=acd92440184, createdName=shijzhiewnjhch, createdTime=Mon Jan 15 14:05:00 CST 2018, time=2018-01-15, status=1, ipAttribution=), 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time=2018-01-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278438, encodeId=0c7a2e8438bf, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Sun Jan 14 13:00:49 CST 2018, time=2018-01-14, status=1, ipAttribution=)]
    2018-05-21 1ddbadeam12(暂无匿称)

    学习

    0

  4. 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time=2018-01-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278438, encodeId=0c7a2e8438bf, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Sun Jan 14 13:00:49 CST 2018, time=2018-01-14, status=1, ipAttribution=)]
    2018-01-19 wl1122050

    精准医疗绝不是简单先进检查方法罗列后的治疗***境界应该与真正中医异曲同工:因人而异的治疗

    0

  5. 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time=2018-01-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278438, encodeId=0c7a2e8438bf, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Sun Jan 14 13:00:49 CST 2018, time=2018-01-14, status=1, ipAttribution=)]
    2018-01-16 1ddf0692m34(暂无匿称)

    学习了.涨知识

    0

  6. 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time=2018-01-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278438, encodeId=0c7a2e8438bf, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Sun Jan 14 13:00:49 CST 2018, time=2018-01-14, status=1, ipAttribution=)]
    2018-01-15 zhangxiaoxi

    学习了.谢谢

    0

  7. 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    2018-01-15 sunfeifeiyang

    0

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    2018-01-15 神功盖世

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    2018-01-14 神功盖世

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