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Nature：CDK4/6抑制剂--ER+乳腺癌治疗新选择!

2017-10-31 佚名 全球肿瘤医生网

周期蛋白依赖性激酶乳腺癌
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细胞周期的失调是肿瘤生长和转移的典型标志之一，通过CDK抑制剂重新建立细胞周期的调控在肿瘤靶向治疗的发展中已经成为有吸引力的方向。2015年美国FDA基于一项名为PALOMA-1的II期研究，批准了首创CDK4/6抑制剂-palbociclib用于ER+/HER2-晚期乳腺癌的一线治疗。雌激素受体阳性（ER+）的乳腺癌是最常见的乳腺癌亚型，在晚期乳腺癌中，超过70%的患者是ER+。如何合理选择治疗

细胞周期的失调是肿瘤生长和转移的典型标志之一，通过CDK抑制剂重新建立细胞周期的调控在肿瘤靶向治疗的发展中已经成为有吸引力的方向。2015年美国FDA基于一项名为PALOMA-1的II期研究，批准了首创CDK4/6抑制剂-palbociclib用于ER+/HER2-晚期乳腺癌的一线治疗。雌激素受体阳性（ER+）的乳腺癌是最常见的乳腺癌亚型，在晚期乳腺癌中，超过70%的患者是ER+。如何合理选择治疗手段延长患者的生存期，改善患者的生活至关重要。

认识CDK4/6抑制剂

作用机制

周期蛋白依赖性激酶（CDK）4/6 是细胞周期的关键调节因子，通过与cyclin D形成复合物，磷酸化Rb，释放E2F，从而能够触发细胞周期从DNA合成前期（G1期）进入到 DNA 复制期（S1期）。在ER+乳腺癌中，CDK4/6-cyclinD-Rb通路非常重要，且是ER信号的关键下游靶标。因此，阻断了CDK4/6激酶的活性，恢复细胞周期控制，阻断肿瘤细胞增殖，也就抑制了乳腺癌细胞的生长。

认识CDK4/6抑制剂优势

无论在ER+/HER2-绝经后不适合手术的转移或局部复发乳腺癌患者一线治疗中的作用，还是在内分泌耐药的二线及后线上，CDK4/6抑制剂都有不俗的表现，在几个临床数据中得到了非常好的结果。

PALOMA-1研究是一个临床2期研究，比较来曲唑联合或不联合CDK4/6抑制剂药物palbociclib在ER+/HER2-绝经后不适合手术的转移或局部复发乳腺癌患者一线治疗中的作用。结果显示，与来曲唑单药相比，palbociclib联合来曲唑治疗将PFS从10.2个月提高到20.2个月。2015年，III期PALOMA-2研究，同样显示了一致的疗效，结果显示联合组PFS从14.5个月提高到24.8个月。PALOMA-3研究是一个临床3期研究，比较palbociclib联合氟维司群对照氟维司群联合安慰剂治疗晚期HR+/HER2-乳腺癌患者的疗效，结果显示，palbociclib联合氟维司群同氟维司群联合安慰剂比较，PFS从4.6个月提高到11.2个月。

ER+晚期乳腺癌患者治疗策略的选择

ER+晚期乳腺癌患者治疗原则：内分泌治疗优先

对于ER+的患者，出现复发转移以后，如果这部分病人出现单纯的骨或软组织的转移或无症状的内脏转移，对于内分泌治疗敏感的这部分的患者都可以在一线、二线、甚至三线+，采用内分泌治疗优先的原则。

如何个体化、精准地制定ER+乳腺癌治疗策略

如何精准的制定ER+晚期乳腺癌治疗策略，没有一个肯定的答案。与所有的药物一样CDK4/6抑制剂不可能解决所有的问题。

基于PALOMA-1、PALOMA-2、PALOMA-3等临床数据，无论是在一线还是二线及后线，CDK4/6抑制剂的数据都是可以令人震撼，明显的延长PFS，即对于ER+/HER2-的患者联合CDK4/6抑制剂治疗是有好处的。因此，无论是在一线还是在二线，如果该患者经济情况允许，推荐内分泌治疗联CDK4/6抑制剂。

中国开展CDK4/6抑制剂研究基本与世界同步

亚洲人群参加了全球的临床试验，亚洲人的数据和全球的数据去比较，总体来说疗效差不多。而在毒副反应方面，亚洲人的骨髓抑制可能更厉害，但是这方面有待于进一步的临床研究。因此，对于中国数据与欧美的差距，不需要有顾虑。目前，CDK4/6抑制剂与其他靶向药物等联合治疗的众多临床研究也正在进行，许多国内研究也正在进行、计划开展中。

CDK4/6抑制剂的未来

目前，关于CDK4/6抑制剂的研究主要针对ER+/HER2-的患者，采用CDK4/6抑制剂联合芳香化酶抑制剂（AI）或是联合氟维司群，是否可以联合三苯氧胺或是其他化疗药物有待进一步认识和研究。同时，对于ER+/HER2+患者，在采用CDK4/6抑制剂联合AI的基础上加上抗HER2治疗，其治疗效果有待研究。

《Nature》最新研究显示，CDK4/6抑制剂不单是阻断了实体瘤的细胞周期，同时在免疫增强方面有一些效应。对于三阴性乳腺癌采用免疫治疗联合CDK4/6抑制剂，其结果拭目以待。CDK4/6抑制剂是很有前景的药物，未来有更多利用空间。

在过去的四十年里，乳腺癌的内分泌治疗经过了，他莫昔芬、孕激素、芳香化酶抑制剂等，患者的生存期都不断的延长，通常是3~4个月的一个无进展生存期延长。自从CDK4/6抑制剂上市以后，一系列的研究显示，CDK4/6抑制剂明显的延长了晚期乳腺癌病人的生存期，取得了巨大的进步。

ER+乳腺癌的治疗方法包括内分泌治疗、化疗和其他的一些治疗手段，合理选择治疗方案，个体化、精准的制定ER+晚期乳腺癌治疗策略，最终使患者获益。

原始出处：

Goel， S.， et al.， CDK4/6 inhibition triggers anti-tumour immunity. Nature， 2017. 548(7668)： p. 471-475.

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    2017-11-02 jklm09

    #抑制剂#

    0

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    2018-01-06 liye789132251

    #Nat#

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    2018-10-10 soongzhihua

    #CDK4#

    0

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    2017-11-02 zhouqu_8

    #CDK#

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1851562, encodeId=09fe1851562f6, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=24, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Thu Nov 02 03:32:00 CST 2017, time=2017-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1882588, encodeId=025f18825881c, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sat Jan 06 21:32:00 CST 2018, time=2018-01-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703079, encodeId=9cf01e03079d4, content=<a href='/topic/show?id=98b24402bb' target=_blank style='color:#2F92EE;'>#CDK4#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4402, encryptionId=98b24402bb, topicName=CDK4)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=166330479856, createdName=soongzhihua, createdTime=Wed Oct 10 07:32:00 CST 2018, time=2018-10-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1435501, encodeId=a6ca143550182, content=<a href='/topic/show?id=09dc439915' target=_blank style='color:#2F92EE;'>#CDK#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4399, encryptionId=09dc439915, topicName=CDK)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Thu Nov 02 13:32:00 CST 2017, time=2017-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1490682, encodeId=38a8149068228, content=<a href='/topic/show?id=2765440372' target=_blank style='color:#2F92EE;'>#CDK4/6#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=24, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4403, encryptionId=2765440372, topicName=CDK4/6)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=c7068807080, createdName=zhangj7111, createdTime=Thu Nov 02 13:32:00 CST 2017, time=2017-11-02, status=1, ipAttribution=)]
    2017-11-02 zhangj7111

    #CDK4/6#

    0