「神药」又双叒翻车了?JAMA最新临床研究发现二甲双胍或对乳腺癌治疗结果并没有什么大用,但......

2022-05-27 LILYMED MedSci原创

JAMA:二甲双胍与安慰剂对乳腺癌患者侵袭性无病生存的影响——MA.32随机临床试验

二甲双胍,一种常用于治疗2型糖尿病的双胍类药物,在涉及糖尿病患者的观察性研究中发现与改善乳腺癌亚型的预后有关,尽管研究结果并不一致。二甲双胍还被证明可以降低空腹胰岛素水平,改善无糖尿病乳腺癌患者的肥胖相关生理机能。目前对二甲双胍在癌症中的作用的了解包括通过磷脂酰肌醇3-激酶(PI3K)和RAS途径减少胰岛素信号而产生的潜在间接作用,以及直接的抗肿瘤作用(特别是肝激酶B1 [LKB1]介导的amp活化蛋白激酶[AMPK],PI3K/蛋白激酶B的负调控因子[AKT]/雷帕霉素的哺乳动物靶点[mTOR]信号通路和蛋白合成)。

临床前研究提供了二甲双胍可能影响所有乳腺癌亚型的证据;然而,由于临床前研究中使用的体外和体内实验室系统中葡萄糖、胰岛素和二甲双胍的超生理浓度,将其转化为临床应用并不简单。

在临床干预研究中,在一些但不是所有的研究中,已报道在乳腺癌切除前给药二甲双胍可降低肿瘤内Ki67。在一项涉及人类表皮生长因子受体2 (ERBB2;HER2或HER2/neu)阳性乳腺癌,二甲双胍的新辅助化疗和ERBB2-targeted治疗导致更高的患者病理完全缓解率至少1份rs11212617 C等位基因的单核苷酸变异(SNV[原单核苷酸多态性{snp}),14个等位基因,也与增强的血糖糖尿病患者的反应和二甲双胍血药浓度升高。

基于以上数据,本研究假设使用二甲双胍(vs安慰剂)5年将改善可手术无糖尿病乳腺癌患者的侵袭性无病生存和其他结果,并旨在确定辅助用药二甲双胍(vs安慰剂)对无糖尿病的乳腺癌患者是否能改善预后。

MA.32是一项在加拿大、瑞士、美国和英国进行的3期随机、安慰剂对照、双盲试验,招募了3649名在2010年8月-2013年3月期间接受标准治疗的高风险非转移性乳腺癌患者,并随访到2020年10月。患者被随机分组(根据激素受体[雌激素受体和/或孕激素受体{ER/PgR}]状态分层,阳性vs阴性;体重指数≤30 vs >30;人表皮生长因子受体2 [HER2],阳性vs阴性;以及任何与没有化疗)到850mg口服二甲双胍,每天两次(n = 1824)或口服安慰剂,每天两次(n = 1825),持续5年。主要结果是激素受体阳性乳腺癌的侵袭性无病生存。分析了8个次要结果中的总生存期、无远处复发生存期和无乳腺癌间隔期。

3649例随机患者(平均年龄52.4岁;3643名女性[99.8%]),全部(100%)纳入分析。在第二次中期分析后,ER/PgR -患者宣告无效,因此对2533例ER/PgR+患者进行了初步分析。ER/PgR+组的中位随访时间为96.2个月(范围0.2-121个月)。465例ER/PgR+患者发生了侵袭性无病生存事件。二甲双胍组侵袭性无病生存事件发生率为2.78 / 100名患者年,安慰剂组为2.74 / 100名患者年(HR=1.01;95%CI,0.84-1.21;P =0.93),二甲双胍组的死亡率为1.46/100患者年,安慰剂组为1.32/100患者年(HR=1.10;95%CI,0.86-1.41;P=0.47)。在ER/PgR -的患者中,随访中位时间为94.1个月,侵袭性无病生存事件发生率分别为3.58 vs 3.60/100患者年(HR=1.01;95%CI,0.79 - -1.30;P = .92)。ER/PgR+组分析的3个次要结局均无统计学差异。

服用二甲双胍的患者发生3级非血液学毒性事件的频率高于服用安慰剂的患者(分别为21.5%和17.5%,P =0.003)。二甲双胍组与安慰剂组最常见的3级或以上不良事件是高血压(2.4% vs 1.9%)、月经不规则(1.5% vs 1.4%)和腹泻(1.9% vs 7.0%)。

虽然研究发现二甲双胍在治疗ER/PgR+ 和 ER/PgR-(不考虑 HER2 状态)乳腺癌方面无效,但该试验发现对于HER2 阳性乳腺癌,使用二甲双胍 5 年可能会降低死亡率,而 HER2 阳性癌症约占所有乳腺癌的 20%。

总的来说,在无糖尿病的高危可手术乳腺癌患者中,在标准乳腺癌治疗中加入二甲双胍与安慰剂并没有显著改善侵袭性无病生存。

 

原文来源:

Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Bliss JM, Rastogi P, Rabaglio-Poretti M, Mukherjee SD, Mackey JR, Abramson VG, Oja C, Wesolowski R, Thompson AM, Rea DW, Stos PM, Shepherd LE, Stambolic V, Parulekar WR. Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA. 2022 May 24;327(20):1963-1973. doi: 10.1001/jama.2022.6147. PMID: 35608580.

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  1. [GetPortalCommentsPageByObjectIdResponse(id=1736438, encodeId=edfa1e3643874, content=<a href='/topic/show?id=a421604e721' target=_blank style='color:#2F92EE;'>#最新#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=60477, encryptionId=a421604e721, topicName=最新)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4bd534165494, createdName=贵阳, createdTime=Sat Feb 25 00:54:05 CST 2023, time=2023-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1234983, encodeId=e3a81234983da, content=神药也不是绝对的,不要指望任何一种超级物质一劳永逸,能有这样的殊效,二甲双胍也是傲视群雄了!, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://q.qlogo.cn/qqapp/1103841572/AF43A7988964C1346E091DE08822DCC1/100, createdBy=1b2b1959838, createdName=jiazhoudexue, createdTime=Wed Jul 27 04:51:01 CST 2022, time=2022-07-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1753646, encodeId=db981e536469d, content=<a href='/topic/show?id=6a57e33772b' target=_blank style='color:#2F92EE;'>#研究发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73377, encryptionId=6a57e33772b, topicName=研究发现)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7e1736602208, createdName=hanhaisha2020, createdTime=Fri Feb 10 05:54:05 CST 2023, time=2023-02-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1535959, encodeId=ec01153595902, content=<a href='/topic/show?id=ae716469300' target=_blank style='color:#2F92EE;'>#治疗结果#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64693, encryptionId=ae716469300, topicName=治疗结果)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=fa8e12645559, createdName=jiadan198786, createdTime=Sat May 28 01:54:05 CST 2022, time=2022-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1243524, encodeId=3a3a124352466, content=JAMA上文章都是顶级的,谢谢梅斯及时上新, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=肿瘤克星, createdTime=Thu May 26 13:54:05 CST 2022, time=2022-05-26, status=1, ipAttribution=)]
    2023-02-25 贵阳
  2. [GetPortalCommentsPageByObjectIdResponse(id=1736438, encodeId=edfa1e3643874, content=<a href='/topic/show?id=a421604e721' target=_blank style='color:#2F92EE;'>#最新#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=60477, encryptionId=a421604e721, topicName=最新)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4bd534165494, createdName=贵阳, createdTime=Sat Feb 25 00:54:05 CST 2023, time=2023-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1234983, encodeId=e3a81234983da, content=神药也不是绝对的,不要指望任何一种超级物质一劳永逸,能有这样的殊效,二甲双胍也是傲视群雄了!, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://q.qlogo.cn/qqapp/1103841572/AF43A7988964C1346E091DE08822DCC1/100, createdBy=1b2b1959838, createdName=jiazhoudexue, createdTime=Wed Jul 27 04:51:01 CST 2022, time=2022-07-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1753646, encodeId=db981e536469d, content=<a href='/topic/show?id=6a57e33772b' target=_blank style='color:#2F92EE;'>#研究发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73377, encryptionId=6a57e33772b, topicName=研究发现)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7e1736602208, createdName=hanhaisha2020, createdTime=Fri Feb 10 05:54:05 CST 2023, time=2023-02-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1535959, encodeId=ec01153595902, content=<a href='/topic/show?id=ae716469300' target=_blank style='color:#2F92EE;'>#治疗结果#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64693, encryptionId=ae716469300, topicName=治疗结果)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=fa8e12645559, createdName=jiadan198786, createdTime=Sat May 28 01:54:05 CST 2022, time=2022-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1243524, encodeId=3a3a124352466, content=JAMA上文章都是顶级的,谢谢梅斯及时上新, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=肿瘤克星, createdTime=Thu May 26 13:54:05 CST 2022, time=2022-05-26, status=1, ipAttribution=)]
    2022-07-27 jiazhoudexue

    神药也不是绝对的,不要指望任何一种超级物质一劳永逸,能有这样的殊效,二甲双胍也是傲视群雄了!

    0

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    2022-05-26 肿瘤克星

    JAMA上文章都是顶级的,谢谢梅斯及时上新

    0

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