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岭南现代临床外科 ›› 2020, Vol. 20 ›› Issue (02): 243-253.DOI: 10.3969/j.issn.1009-976X.2020.02.023

• 综述 • 上一篇    下一篇

HER2阳性乳腺癌治疗及耐药性研究进展

  

  1. 中山大学孙逸仙纪念医院基础与转化医学研究中心,广州 510120
  • 通讯作者: 彭江云

Progress in the treatment and resistance of HER2-positive breast cancer

  1. Basic and Translational Medicine Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
  • Online:2020-04-20 Published:2020-04-20

摘要:

·综 述·

HER2阳性乳腺癌治疗及耐药性研究进展

彭江云, 姚伟城, 王永强, 邓伟溪

[摘要] 人表皮生长因子受体2(HER2)阳性并被定义为HER2蛋白过表达,通过免疫组织化学状态(IHC3+)或荧光原位杂交(FISH)测量的HER2基因拷贝数为六个及六个以上或HER2/CEP17比率为2.0及2.0以上。HER2阳性乳腺癌侵袭性高,预后差,约占乳腺癌的15%~20%。随着抗HER2药物的不断出现及广泛应用,HER2阳性乳腺癌患者的预后得到非常显著的改善,转移性HER2阳性乳腺癌女性患者的生存率接近5年,并且75%的患者实现了病理完全缓解。尽管取得这些成就,但是由于抗HER2治疗的耐药性和反应异质性,以及高达40%~50%的HER2阳性晚期乳腺癌患者发生脑转移等原因,HER2阳性乳腺癌导致的高死亡人数仍在持续增长,急需加强对新疗法和新组合的临床研究。

[关键词] HER2阳性乳腺癌;抗HER2治疗;耐药性

前言

乳腺癌是女性发病率最高的恶性肿瘤,占女性恶性肿瘤的四分之一。尽管乳腺癌的综合治疗水平在不断提高,但其死亡率仍然位居女性肿瘤的第2位。其中HER2阳性乳腺癌侵袭性高,预后差,约占乳腺癌的15%~20%。在标准疗法中加入曲妥珠单抗(trastuzumab)可显著改善HER2阳性乳腺癌患者的预后,并成为治疗HER2阳性乳腺癌患者的里程碑[1]。第二种抗HER2药物拉帕替尼(lapatinib),一种口服酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI),可逆性抑制HER1激酶或表皮生长因子受体(EGFR)激酶和HER2激酶,已被纳入HER2阳性晚期患者的常规治疗中。帕妥珠单抗(pertuzumab)是一种人源化单克隆抗体,可与HER2胞外域II结合(与曲妥珠单抗结合域不同),可防止同源二聚体和异源二聚体的形成。异源二聚体HER2/HER3激活多个细胞内信号传导级联反应,包括细胞增殖和生存,帕妥珠单抗可阻断异源二聚体HER2/HER3的形成。与紫杉烷(taxane)和曲妥珠单抗联合治疗相比,将帕妥珠单抗添加到紫杉烷和曲妥珠单抗联合治疗中作为晚期HER2阳性乳腺癌的一线治疗不仅使PFS得到改善,而且OS改善了近16个月,中位生存期达到将近5年的时间,因此该方案确立为一线治疗的首选方案[2]。最后,曲妥珠单抗-美坦新偶联物(trastuzumab emtansine,T-DM1)是一种抗体-药物偶联物(antibody-drug conjugate,ADC),与拉帕替尼加卡培他滨(capecitabine)相比,T-DM1作为二线治疗[3]以及先前接受曲妥珠单抗治疗的晚期HER2阳性乳腺癌患者的后续治疗[4],可显著改善PFS和OS。基于这些结果,T-DM1是目前唯一被批准用于治疗乳腺癌和晚期HER2阳性患者标准二线疗法的ADC。迄今为止,对于曲妥珠单抗、帕妥珠单抗和T-DM1治疗后的HER2阳性晚期肿瘤患者尚无标准的治疗方法。

尽管在晚期癌症的标准治疗中单独采用抗HER2疗法或双重阻断HER2疗法能显著改善生存,但大多数患者最终还是会疾病恶化并死亡。此外,高达40%~50%的HER2阳性晚期乳腺癌患者会在其病程中发生脑转移。显然需要开发更好的预防和治疗脑转移瘤的方法[5]。深入了解靶向HER2治疗、补偿途径、肿瘤异质性和肿瘤微环境的原发性和获得性耐药性潜在机制对于开发新的治疗策略至关重要。例如,一项研究揭示了可以通过特定的细胞表面标记物定义和分离功能性肿瘤相关成纤维细胞(Carcinoma-associated fibroblasts,CAFs),靶向 CD10+GPR77+CAF(CD10 和GPR77是两个细胞表面分子)可能是针对肿瘤干细胞驱动的实体瘤的有效治疗策略[6]。目前在临床前和临床环境中正广泛研究大量新型抗HER2治疗,以进一步改善患者预后。在这里,我们收集了针对不同状态下的HER2阳性乳腺癌患者的治疗方法和研究进展,并分析了抗HER2治疗的耐药性以及克服耐药性的新策略。

1 治疗原则

超过90%的乳腺癌都是非转移的,对于非转移的乳腺癌,治疗方法一般是切除和防止复发。非转移HER2阳性乳腺癌患者全身治疗,一般采用化疗和靶向HER2的抗体或者小分子抑制剂;非转移HER2阳性乳腺癌患者局部治疗一般采用手术切除和切除后放疗。越来越多的非转移性乳腺癌患者在手术前进行全身性治疗。HER2阳性转移性乳腺癌患者为了减缓症状延长生命,根据肿瘤和患者水平因素的不同而采取不同的治疗方案[7]

2 HER2阳性非转移性乳腺癌的全身性治疗

靶向HER2治疗方法的发展是乳腺癌治疗最大的进步。曲妥单抗,一个靶向HER2胞外区域的单克隆抗体,在20世纪90年代就第一次进入临床试验。随机辅助用药试验表明,标准辅助化疗添加一年曲妥单抗可以显著提高HER2阳性乳腺癌患者无病生存和总生存,无病生存率从0.48提高到0.75[8]。试验检测了长期使用曲妥珠单抗治疗(2年vs 1年)的效果,随访8年的数据显示,更长的治疗时间并没有给患者带来更多收益[9]。尽管随着曲妥珠单抗治疗时间的延长,出现心脏疾病的频率更高,但12个月的辅助曲妥珠单抗治疗仍是标准的治疗方式。在FinHER小样本(232例HER2阳性乳腺癌患者)试验中,接受多西他赛(docetaxel)或长春瑞滨(vinorelbine)化疗期间的HER2阳性乳腺癌女性患者被随机分配为仅接受或不接受9周曲妥珠单抗治疗。该试验表明,曲妥珠单抗用药9周降低了复发或死亡的风险,这促使开展更大的研究来测试是否有疗效相当于常规的12个月,且用时更短、更便宜的曲妥珠单抗疗程[10]

一项meta分析,分别评估了曲妥珠单抗在54例患者中位随访8年的疗效。分析结果表明,无论疾病的初始阶段如何,曲妥珠单抗的辅助治疗都是有益的,所以针对小肿瘤、非腋窝受累或两者兼而有之的患者都应进行靶向治疗[11]

由于曲妥单抗在防止HER2阳性乳腺癌复发和死亡方面有非常显著的作用,随后的研究主要集中在:①减少低风险病人辅助化疗用药数量;②高风险病人增加新型药物。

在一个单组试验中,406个瘤块小于2 cm的阴性肿瘤结节病人用紫杉醇(paclitaxel)12周和采用标准的一年曲妥单抗治疗,发现7年无复发率为97.5%,7年之后有5个患者局部复发和4个患者远距离复发[12]。考虑到长期的治疗效果和化疗药物毒性的减少,紫杉醇/曲妥单抗成为小瘤块阴性肿瘤结节HER2阳性乳腺癌患者标准治疗方式。一项试验首先使用阿霉素(adriamycin)加环磷酰胺(cyclophosphamide),然后每3周给予紫杉醇或每周给予紫杉醇,一组加用52周的曲妥珠单抗,另一组不加用曲妥珠单抗,其他治疗方法相同。3年的随访分析显示,加入曲妥珠单抗后,无病生存率得到改善,总体生存率显著提高,并在8.4年的中位随访中持续受益[13]。另外,同时给予曲妥珠单抗和紫杉醇对无病生存的影响在数值上优于连续给予曲妥珠单抗所观察到的效果,表明曲妥珠单抗与紫杉烷类药物的同时使用,可能比化疗后按顺序给药更有效[14]。在一项非随机的前瞻性研究中,患有HER2阳性小肿瘤的女性患者每周接受紫杉醇和曲妥珠单抗治疗12周,然后进行9个月的曲妥珠单抗单药治疗,中位4年随访侵入性的无病生存为98.7%,且耐受性良好[15]

以下几项试验测试了使用新药及其联合药物靶向HER2受体的方法。双重HER1和HER2络氨酸激酶抑制剂拉帕替尼具有临床活性,并且已被批准用于治疗曲妥珠单抗用药继续恶化的患者[16]。由于社会经济或后勤限制,在不能静脉注射曲妥珠单抗治疗的情况下,TEACH试验测试了拉帕替尼对比安慰剂作为替代疗法的疗效。该试验招募了3147名接受1年拉帕替尼或安慰剂治疗的女性患者,在将近4年的随访中,使用拉帕替尼的患者无病生存率微乎其微[17]。ALLTO研究比较了三种实验方案:拉帕替尼,拉帕替尼联合曲妥珠单抗,先接受曲妥珠单抗再接受拉帕替尼的序贯疗法。化疗结束后进行HER2靶向治疗,其中曲妥珠单抗和拉帕替尼双重靶向HER2虽然在数值上优于单药曲妥珠单抗和先曲妥珠单抗后拉帕替尼序贯用药,但不具有统计学意义。最终结果是,在曲妥珠单抗中添加拉帕替尼不能改善曲妥珠单抗辅助治疗的疗效,以及引起由拉帕替尼导致的其他毒性作用[18]

研究表明,针对高风险HER2阳性乳腺癌患者,曲妥单抗化疗方案辅助增加帕妥珠单抗和诺拉替尼可以降低复发风险[16]。针对4804个Ⅰ~Ⅲ期HER2阳性乳腺癌病人的临床试验显示,帕妥珠单抗取得了统计学显著的3年无病生存率(帕妥珠单抗94.1%vs安慰剂93.2%,HR=0.81,95%CI:0.66-1.00,P=0.045)[19]。目前,高风险病人可以考虑包含帕妥珠单抗的治疗方案,但如果低风险病人要用的话需考虑药物毒性和费用的问题。奈拉替尼(Neratinib)是包括HER2在内的多个HER家族成员的口服小分子酪氨酸激酶抑制剂。一个针对2840个HER2阳性乳腺癌病人的随机Ⅲ期临床试验表明,采用曲妥单抗的新辅助/辅助化疗,每日辅助使用诺拉替尼与服用安慰剂相比,5年无病生存率有所提高(诺拉替尼90.2%vs安慰剂87.7%,HR=0.73;95%CI:0.57-0.92,P=0.008)。与帕妥珠单抗辅助试验相比,诺拉替尼的无病生存率只在HR+亚组提高,而对HR-病人无作用,具体原因还不清楚[20]。迄今为止,当作为辅助疗法施用时,两种药物均未显示出总生存益处。

3 非转移性乳腺癌的局部治疗

3.1 手术

在过去的几十年,乳腺癌的外科手术治疗取得了重大发展,主要体现在美容和减少后遗症方面。基于几十年的研究,在肿瘤边缘清晰的情况下,标准的方法或是全乳切除或者切除加辐射治疗[21]

腋窝淋巴结的手术必须与乳腺外科治疗分开考虑。淋巴结的去除是出于诊断的目的(确定乳腺癌解刨学范围)和治疗的目的(去除肿瘤细胞)。是否决定做外科手术是基于乳腺淋巴结的诊断结果和新辅助系统治疗的采用与否。腋窝淋巴结切除仍然是临床诊断出腋窝的首选治疗方法,也是临床结节阴性乳腺癌患者最普遍的治疗办法。采用全腋窝淋巴结切除的女性和采用哨位淋巴结活组织切片检查的女性在区域复发和生存率方面没有明显的差别,只有哨位淋巴结呈阳性的情况下才转换为腋窝淋巴结切除[22]。值得注意的是,假阴性的哨位淋巴结活组织切片在临床结节阴性疾病和手术中比例达到5%~10%,导致一些腋窝下的疾病治疗不能取得很好的长期效果[23]

随后的试验证明腋窝淋巴结切除并不是适用于所有阳性哨位淋巴结患者[24]。经历过保守手术治疗、肿瘤直径小于5 cm、同时拥有一到两个阳性哨位淋巴结的临床结节阴性乳腺癌患者,优先选择全身性治疗,单独进行哨位淋巴结活组织切片检查就可以满足大部分患者腋下治疗,然后选择性地对部分患者增加腋下放疗。

接受新辅助全身治疗患者的手术治疗正在快速发展。多个随机试验和meta分析证明,新辅助化疗可以增加病人保乳治疗的可能性,同时不会影响长期的治疗效果[25,26]。一些试验结果表明,在接受新辅助治疗由临床结节阳性转变为临床结节阴性的患者中,哨位淋巴结活组织切片检查的假阴性率和进行前面提到的外科手术治疗的假阴性率相似[27]。因此,目前临床实践和指导原则普遍支持由临床结节阳性转变为临床结节阴性的哨位淋巴结活组织切片检查,严格来讲忽略了哨位淋巴结阴性患者的腋窝淋巴结切除术[27]。然而,淋巴结患者新辅助治疗后的最佳治疗方法还有待研究者积极探索。

3.2 放射治疗

越来越多的研究证明低分次照射法(大概42.5 Gy超过16次)可以有效降低局部复发风险[28]。因此,用来全乳放疗的低分次照射法是目前首选的方法。乳腺切除术后对部分乳房而不是整个乳房进行放疗是主要针对50岁及以上低危患者的研究治疗方法。专门对肿瘤床进行辐射增强可改善局部控制,但不能提高整体存活率,因此在高危患者中可考虑使用[29]

乳房切除术后的放疗是对胸壁的放疗,有时是对乳房切除术的瘢痕和/或局部淋巴结进行放疗。对腋窝淋巴结切除和全乳房切除术后放疗的随机试验的meta分析(N=8135)显示,淋巴结阴性的患者复发或生存结果与是否接受乳房切除术后放疗无关。但是,在淋巴结阳性的患者中,接受全乳房切除术后放疗与局部、总复发风险和乳腺癌死亡率的改善相关[30]。乳腺肿瘤块切除术或全乳房切除术后增加局部淋巴结放疗(覆盖腋窝、锁骨旁、和/或内部乳腺淋巴结)显著改善无病生存,与总生存无关,并增加放疗毒性例如导致肺炎和淋巴水肿,在接受腋窝淋巴结切除的女性中观察到了局部淋巴结转移的益处[31]。由于缺乏总生存益处,即使在淋巴结阳性的患者中也没有普遍采用淋巴结放射治疗,但对于淋巴结疾病较严重或生物学风险较高的患者,可以考虑采用此方法。

4 HER2阳性转移性乳腺癌的全身治疗

对于HER2阳性转移性乳腺癌患者,肿瘤和患者水平的因素对预后很重要:内脏转移、脑转移和多个部位转移均导致较差的预后,而更好的临床表现、更年轻的诊断年龄、仅骨转移以及从初始诊断到转移复发之间更长的无病间隔均可以改善预后。

对于转移性乳腺癌的全身治疗,一些通用原则至关重要。在HER2阳性转移性乳腺癌中,标准的一线治疗由紫杉烷加曲妥珠单抗和帕妥珠单抗组成,T-DM1通常用作二线治疗。后续治疗通常将新的化疗药物与靶向HER2治疗药物结合使用,因为在之前抗HER2药物治疗后继续进行HER2靶向治疗也可以改善预后[32]。最后,约10%至20%的转移性乳腺癌患者诊断出脑转移,其治疗仍然是一项挑战[33]。HER2阳性和三阴性乳腺癌女性患者发生脑转移的风险最高。由于血脑屏障、脑与非脑转移性病变的基因组差异,以及许多系统疗法的通透性差,导致治疗方案受到限制[34]

4.1 单一疗法与双重抗HER2疗法

多年来,Slamon等的一项关键性试验表明曲妥珠单抗加紫杉醇或多西紫杉醇(docetaxel)中位总生存期为25个月[35]。所以,曲妥珠单抗加紫杉醇或多西紫杉醇一直是HER2阳性转移性乳腺癌的标准一线治疗方案。HERNATA试验显示长春瑞滨加曲妥珠单抗在转移性乳腺癌的一线治疗中与多西他赛加曲妥珠单抗的疗效相同[36]。而MA.31试验显示,拉帕替尼加紫杉烷的疗效不如曲妥珠单抗加紫杉烷,而且前者还有更高的药物毒性和副作用[37]。NefERT-T试验显示,在HER2阳性转移性乳腺癌女性中,紫杉醇联合奈拉替尼与紫杉醇联合曲妥珠单抗的一线治疗无进展生存期相同(12.9个月)[38]

在HERITAGE3期临床研究中,第一个曲妥珠单抗生物仿制药显示出与曲妥珠单抗相同的总反应[39]。生物仿制药的开发周期缩短了,但仍应包括有关人体药代动力学的数据,并要求展现出与原始药物相似的安全性、功效和免疫原性。一般而言,生物仿制药的发展有可能使更多的患者获得原本无法接受的治疗方法。

在CLEOPATRA试验中,曲妥珠单抗和帕妥珠单抗的双重阻断HER2阳性乳腺癌中位总生存期为56.5个月,而接受曲妥珠单抗和安慰剂的对照组显示中位总生存期为40个月[40]。亚组分析表明,在曲妥珠单抗联合多西他赛方案中加入培妥珠单抗并不能使非内脏转移患者受益[非内脏疾病(HR=1.11)vs 内脏疾病(HR=0.59),P=0.03][40]。另外,持续阻断HER2信号传导是改善转移性乳腺癌生存结果的关键因素之一[37]

接受过前期治疗的转移性乳腺癌患者可以接着进行曲妥珠单抗加拉帕替尼治疗,而无需进行化疗[41]。曲妥珠单抗和拉帕替尼联合内分泌治疗作为HER2阳性和激素受体阳性乳腺癌的新辅助治疗,达到病理完全缓解的患者比例增加,尤其是在治疗24周后[42]

4.2 曲妥珠单抗-美坦新偶联物(T-DM1)

T-DM1是一种靶向HER2的抗ADCs,由曲妥珠单抗通过连接剂共价结接DM1,DM1是抗微管化学疗法美登素(maytansine)的衍生物。T-DM1使用曲妥珠单抗特异性定位HER2阳性肿瘤细胞,在与HER2结合后,T-DM1被内在化并蛋白水解,在过表达HER2的细胞内部释放美登素[43]。在EMILIA研究中,T-DM1在HER2阳性乳腺癌患者中作为二线和进一步治疗效果都优于卡培他滨加拉帕替尼[3]。因此,推荐T-DM1作为二线或进一步治疗。肝酶升高和血小板减少似乎是T-DM1治疗的主要毒性。

在MARIANNEⅢ期试验中,与单独使用trastuzumab emtansine相比,T-DM1与培妥珠单抗联合使用没有额外提高生存期[44]。细胞系数据表明,T-DM1和帕妥珠单抗治疗的顺序很重要,首选顺序可能是T-DM1和pertuzumab联合治疗或TDM1治疗,然后添加帕妥珠单抗(pertuzumab)治疗[45]

治疗HER2阳性转移性乳腺癌的主要挑战之一是多达50%的患者发生脑转移[46]。CEREBEL试验研究了卡培他滨联合拉帕替尼在预防HER2阳性转移性乳腺癌患者脑转移方面是否比卡培他滨联合曲妥珠单抗更有效[47]。与中枢神经系统(Central Nervous System,CNS)转移预期发病率20%相比,用药后CNS转移作为第一复发部位的发生率低至4%,两组之间无显著差异(卡培他滨加拉帕替尼3%,卡培他滨加曲妥珠单抗5%,P=0.36)。总体而言,卡培他滨联合曲妥珠单抗组的无进展生存期优于卡培他滨联合拉帕替尼组(中位8.1个月vs 6.6个月,P=0.021)。在EMILIA试验中,卡培他滨联合拉帕替尼组和T-DM1组的CNS转移率相似[48]。在曲妥珠单抗组中,在基线无CNS转移的患者中CNS转移率为2.0%,在基线CNS转移的患者中CNS转移率为22.2%。卡培他滨加拉帕替尼组中,在基线无CNS转移的患者中有0.7%发生CNS转移,在基线CNS转移的患者中CNS转移率为16.0%。在基线CNS转移的患者中,与卡培他滨加拉帕替尼组相比,T-DM1组的总生存期有显著改善(中位26.8个月vs 12.9个月;P=0.008)。在NefERT-T试验中,与紫杉醇联合曲妥珠单抗相比,紫杉醇联合奈拉替尼治疗的脑转移患者的总生存期明显更长[38]

5 抗HER2治疗的耐药性和反应异质性机制

已经研究了解许多潜在的抗HER2治疗耐药机制,这些机制最终会通过信号通路冗余或刺激其他生存通路导致HER2信号通路或其下游信号的重新激活[49]。其中一些机制包括:①对HER2受体的不完全阻断从而激活HER家族(例如HER3)的补偿机制;②激活其他受体酪氨酸激酶(RTK)或HER家族外的其他膜受体(例如胰岛素样生长因子1受体IGF-1R[50]和MET12);③改变下游信号传导通路,例如通过降低肿瘤抑制基因(如PTEN和INPP4-B)或者通过激活PIK3CA(磷脂酰肌醇-4,5双磷酸3激酶催化亚基)突变来过度激活PI3K/AKT/mTOR通路[51]。其他一些生物学特征也与靶向HER2治疗的反应异质性有关,包括HER2 mRNA或蛋白质水平[52]、肿瘤固有亚型[53]、HER2受体(如p95HER2)的改变[54]、宿主肿瘤微环境成分(例如肿瘤浸润淋巴细胞)[55]和FCγR多态性[56]。例如,在CLEOPATRA试验中,高HER2蛋白水平以及高HER2和HER3 mRNA水平与明显更好的预后相关(P<0.05)。相比之下,尽管患者从培妥珠单抗和曲妥珠单抗治疗中获益,但PIK3CA突变仍被认为是强烈的阴性预后生物标记物[57]。在EMILIA试验中,经T-DM1治疗的高HER2 mRNA表达的患者也观察到更大的OS获益[58]。值得注意的是,在用卡培他滨加拉帕替尼治疗的患者中,PIK3CA突变与PFS、OS明显缩短有关,而在T-DM1治疗的患者中却不相关[58]。关于肿瘤浸润淋巴细胞,在CLEOPATRA试验中,用多西他赛、曲妥珠单抗和帕妥珠单抗(或安慰剂)治疗的晚期HER2阳性乳腺癌患者,基质肿瘤浸润淋巴细胞数量增加与OS改善显著相关[55]

在源自HER2乳腺癌患者体内的异种移植肿瘤中,已经证明细胞周期蛋白D1-CDK4信号通路可以在体内和体外介导对HER2靶向疗法的耐药性,并且以CDK4/6抑制剂靶向耐药性肿瘤细胞可使其对抗HER2疗法重新敏感并延缓肿瘤复发[59]

大量的临床前和临床研究支持HER2和雌激素受体(ER)信号之间的双向交互作用(bidirectional cross-talk)[60]。同时表达ER和HER2的肿瘤对内分泌治疗的敏感性低于ER阳性HER2阴性的肿瘤[61]。针对早期和晚期HER2阳性乳腺癌,抑制ER和双重靶向HER2治疗同时进行可以改善预后[62]

在确定ADCs的耐药机制时,需要考虑多个因素,例如与抗体、连接子或有效载荷有关的机制。临床前研究表明,T-DM1作用需要CDK1/cyclin B1活性。沉默细胞cyclin B1可以诱导对T-DM1的耐药性,同时增加耐药细胞中cyclin B1的水平可以部分恢复敏感性[63]。T-DM1耐药性的其他潜在机制包括:多药抗性蛋白的上调引起的细胞内DM1负载(DM1 payload)的减少[64]、溶酶体蛋白水解活性受损[65]、溶酶体转运蛋白损失(例如SLC46A3)[64]

在某些乳腺癌患者中观察到HER2和雌激素受体基因ESR1的体细胞激活突变,并且不断有临床证据表明这两种突变均可以预测对标准疗法的反应和耐药性:HER2激活突变对奈拉替尼有耐药性,ESR1突变似乎对芳香化酶抑制剂有耐药性,并很大程度上保留了对氟维司群(fulvestrant)的敏感性[66]

尽管进行了广泛的翻译研究,但大多数HER2耐药性机制以及潜在的应答或耐药性生物标志物尚未得到临床验证,或者结果相矛盾[67]。迄今为止,在HER2阳性乳腺癌患者中,尚无HER2以外的生物标记物可供靶向HER2治疗的患者选择。值得注意的是,由于肿瘤异质性、耐药性和补偿信号通路的复杂性,以及使用不同的肿瘤细胞系,仅基于临床前模型对耐药机制的解释可能具有挑战性。此外,在同一细胞中可能存在多种耐药性机制。

6 克服针对抗HER2治疗耐药性的新策略

6.1 替代当前的抗HER2疗法以改善抗HER2药物

6.1.1 抗体-药物偶联物 ADCs是一种治疗药物类,通过更有效和更具体的药物传递提供更广泛的治疗窗。ADCs利用单克隆抗体(monoclonal antibodies,MAbs)的靶标选择性将细胞毒性药物递送至表达抗原的细胞,以提高肿瘤选择性并减少对正常细胞的损害[68]。T-DM1的成功引领新型ADCs快速、广泛的开发。包括rastuzumab deruxtecan(DS-8201,Daiichi Sankyo,Inc.)[69]、SYD985(Synthon Biopharmaceuticals BV)[70] 、MEDI4276(Medimmune)、ADCT-502(ADC Therapeutics)[71]。MEDI4276(Medimmune)和 ADCT-502(ADC Therapeutics)出于疗效和安全性方面的考虑,目前已经停止临床试验。

与T-DM1相比,大多数新型ADCs具有可裂解的药物连接子,介导旁杀死效应(bystander killing activity)。通过游离细胞毒素从靶标阳性癌细胞被动扩散到肿瘤微环境中,杀死由于缺乏或只有有限的靶标表达而对ADC不敏感的邻近癌细胞。鉴于在HER2阳性乳腺癌中常见的异质性,靶向HER2的ADCs这一理想特性可能是一把双刃剑,因为其具有更高的毒性。

6.1.2 新型抗HER2抗体 马格妥昔单抗(Margetuximab,MGAH 22)是Fc优化的嵌合单克隆抗体,与曲妥珠单抗结合相同的表位。马格妥昔单抗具有增强的Fcγ受体结合特性,对CD16A多态性的亲和力增加,对抑制性受体FcγRIIB(CD16B)的亲和力降低,这使其可以更紧密地结合效应细胞并增加抗体依赖性细胞介导的细胞毒性(antibody-dependent cell-mediated cytotoxicity,ADCC);同时它也保留了曲妥珠单抗的抗增殖特性[72]。一项人体的Ⅰ期研究表明,在经过大量预处理的HER2阳性实体瘤患者中,马格妥昔单抗具有单药活性的前景。在24例转移性乳腺癌患者中,ORR(overall response rate)为17%[73]

6.1.3 双特异性抗体 双特异性抗体(Bispecific antibodies,BsAbs)结合了两个单克隆抗体的功能,在相同或不同的受体中靶向两个不同的靶标或表位。BsAbs可通过使RTK或其配体失活而干扰两个或多个RTK信号通路。包括MCLA-128(Merus)[74]、ZW25(Zymeworks Inc.)[75]等。

6.1.4 T细胞双特异性抗体 T细胞双特异性抗体(T-cell bispecific antibodies,TCBs)是经过改造的分子,在单个实体中包含与T细胞受体(T cell receptor,TCR)不变CD3链以及与肿瘤相关或肿瘤特异性抗原的结合位点。与肿瘤抗原的结合导致TCR的交联、淋巴细胞活化和杀死肿瘤细胞。但是,由重定向的淋巴细胞引起的靶上非肿瘤效应(on-target off-tumor)可能导致严重的毒性。目前有几种药物正在临床开发中,包括GBR1302(Glenmark Inc.)[76]、PRS-343(Pieris Pharmaceuticals,Inc.)等。

6.1.5 新型络氨酸激酶抑制剂 酪氨酸激酶抑制剂(tyrosinekinaseinhibitors,TKIs)是口服有生物药效应的小分子,可进一步阻断HER受体家族,作用于细胞内结构域。与MAb相比,那些靶向HER的TKIs具有更低的分子量,从而使其更有效地穿透血脑屏障,因此从理论上讲可能更有效地治疗HER2脑转移。拉帕替尼是第一个获批用于HER2阳性晚期乳腺癌的TKI(迄今为止,仍是唯一的)。目前有几种新型TKIs正在进行临床研究,包括奈拉替尼[77]、Tucatinib(ONT-380)[78]、吡咯替尼(Pyrotinib)[79]、Poziotinib[80]

6.2 抗HER2药物与其他药物联合

6.2.1 免疫疗法 临床前和临床数据表明,HER2阳性乳腺癌具有免疫原性[81]。与腔瘤相比,HER2阳性肿瘤具有更高的突变率,并且具有更高的TILs阳性和程序性细胞死亡蛋白1配体(programmed cell death protein 1 ligand,PD-L1)阳性[82]。此外,抗HER2 MAb的作用机制不仅包括ADCC,还包括适应性免疫的产生[83]。这些数据共同支持将抗HER2治疗与免疫检查点阻断(抗PD-1剂或抗PD-L1剂)结合。PANACEA研究是第一项在HER2阳性乳腺癌患者中向曲妥珠单抗中添加派姆单抗以评估曲妥珠单抗耐药性的研究。这项Ib/II期研究表明,该组合治疗PD-L1阳性患者的ORR为15.2%,中位PFS和OS分别为2.7个月和16个月[84]。但是,因为在PD-L1阴性组和大多数耐药性的PD-L1阳性患者组中均未见反应,这些数据也凸显了这种组合的局限性。因为在PD-L1阴性组和大多数最初反应最终导致耐药性的PD-L1阳性患者中均未见反应。目前靶向HER2的疫苗的免疫疗法还在临床试验研究中。

6.2.2 CDK4/6抑制剂 CDK4/6的活性受到多种机制的调控,这些机制包括通过增加CCND1表达或增加细胞周期蛋白D1蛋白稳定性来促成有丝分裂信号通路[59,85]。此外,小鼠模型表明细胞周期蛋白D1/CDK4在HER2驱动的乳腺癌的形成和增长中发挥着重要作用[86]。临床前研究表明,抗HER2治疗与CDK4/6抑制剂之间具有明显的协同作用[87],并且CDK4/6抑制作用可以特异性克服获得性抗HER2治疗耐药性[59]。此外,在小鼠模型中,CDK4/6抑制作用可延迟HER2驱动的乳腺癌的复发[59]。早期的临床数据也支持CDK4/6抑制剂在HER2驱动的乳腺癌中的应用,尤其是在ER阳性HER2阳性疾病的患者亚群中[88]。SOLTI1303 PATRICIAⅡ期临床试验评估了哌柏西利(palbociclib)、曲妥珠单抗 ±来曲唑(letrozole)联合治疗的、接受过大量预处理的(在转移情况下多达2-4线治疗)HER2阳性乳腺癌患者,该试验显示哌柏西利、曲妥珠单抗和来曲唑联合在PAM50的管腔亚型中尤其有效,与非管腔相比,PFS更好(12.4 vs 4.1 months,HR=0.30,95%CI:0.11-0.86,P=0.025)[89]。因此,无论其 HR 状态如何,通过PAM50识别非管腔亚型可能有助于判别那些在此治疗策略中获益尚浅的患者。

6.2.3 PI3K/Akt/mTOR抑制剂 PI3K/AKT/mTOR通路的失调似乎在曲妥珠单抗耐药中起重要作用。PI3K抑制导致过表达HER2的乳腺癌中HER2信号增强,特别是导致HER2和HER3的表达增加[90]。靶向此通路可以阻止耐药性的发展。但是,一项Ⅲ期临床试验评估了mTOR抑制剂依维莫司(everolimus)与曲妥珠单抗加紫杉醇联合作为一线治疗的疗效(BOLERO-1)[91],另一项Ⅲ期临床试验评估了mTOR抑制剂依维莫司与曲妥珠单抗加长春瑞滨在曲妥珠单抗耐药晚期HER2阳性乳腺癌的疗效(BOLERO-3)[92],结果都相当令人失望,药物毒性显著增加。BOLERO-1和BOLERO-3试验的联合生物标记物分析表明使用依维莫司治疗时,PIK3CA突变或PTEN缺失的患者PFS得到改善[93]。目前的工作集中在评估α特异性PI3K抑制剂,即PIK3CA基因编码的异构体,如alpelisib(BYL719)与抗HER2治疗的联合。在经过大量预处理的HER2阳性患者中进行的alpelisib和T-DM1的Ⅰ期研究显示出药物具有显著活性,ORR为43%,中位 PFS 为 8.1 个月(95%CI:3.9-10.8)[94]。此外,在具有ORR且临床获益率分别为30%和60%、中位PFS为6.3个月(95%CI:1.6-10.5)的T-DM1耐药患者中观察到活性。目前正在临床评估的药物还包括Taselisib(GDC-0032)、Copanlisib、MEN1611等。

7 小结与展望

自曲妥珠单抗开发以来,陆续有一些其他药物、抗体、酪氨酸激酶抑制剂和抗体-药物偶联物可用于治疗HER2阳性乳腺癌。在十多年的时间里,HER2靶向治疗方案的数量和质量已深刻改变了HER2阳性乳腺癌。尽管取得这些进展,但是,许多患者仍然死于HER2阳性乳腺癌,我们需要鉴定和研究更新、更好的疗法。测试抗HER2药物的组合,以及与PI3K抑制剂、mTOR靶向剂、CDK4/6抑制剂或免疫疗法(例如抗PD-L1抗体)的组合,这将增加开发有效治疗方法的可能性,尤其是转移性乳腺癌的治疗方法。

结合HER2靶向疗法的优化策略可能会改善HER2阳性乳腺癌患者的预后,也可使某些选择性患者降级治疗,从而有可能避免不必要的治疗及其相关毒性。因此,潜在的反应或耐药性生物标记物(例如内在亚型)可能有助于患者更好地选择适合其治疗的策略。此外,还需要开发针对HR阳性HER2阳性乳腺癌的特定策略。

抗HER2治疗和补偿途径的潜在耐药机制确实很复杂,并且在同一细胞中可能同时存在多种耐药机制。因此,需要结合临床策略并在转化环境中加强国际合作,以验证HER2以外的预测性生物标记物,这将有助于我们更好地选择患者并改善其结果。

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Progress in the treatment and resistance of HER2-positive breast cancer

PENG Jiang-yun,YAO Wei-cheng,WANG Yong-qiang,DENG Wei-xi
Basic and Translational Medicine Research Center,Sun Yat-sen Memorial Hospital,Sun Yat-Sen University,Guangzhou,Guangdong 510120,China

[Abstract] HER2 positivity is defined as evidence of HER2 protein overexpression as HER2 gene copy number of six or more or a HER2/CEP17 ratio of2.0 or greater,which is measured by immunohistochemistry status(IHC3+)or by fluorescence in-situ hybridization(FISH)measurement.HER2-positive breast cancer with high invasiveness and poor prognosis accounts for 15%~20%of breast cancer.With survival rates of almost five years in women with metastatic HER2-positive breast cancer and 75%of patients achieving a complete pathological response,the emergence and widespread application of new anti-HER2 treatments have improved the prognosis of HER2-positive breast cancer.Despite these achievements,however,the persisting high death toll of HER2-positive breast cancer remains due to resistance and heterogeneity in anti-HER2 therapy,as well as brain metastases in up to 40%~50%of HER2-positive advanced breast cancer patients.So it calls for continued,intensive clinical research of newer therapies and combinations.

[Key words] HER2-positive breast cancer;Anti-HER2 treatment;Resistance

doi: 10.3969/j.issn.1009-976X.2020.02.023

中图分类号:R737.9

文献标识码:A

作者单位:中山大学孙逸仙纪念医院基础与转化医学研究中心,广州510120

通讯作者:彭江云,Email:15914528388@163.com

(收稿日期:2019-11-21)

关键词: HER2阳性乳腺癌, 抗HER2治疗, 耐药性

Abstract: [Abstract] HER2 positivity is defined as evidence of HER2 protein overexpression as HER2 gene copy number of six or more or a HER2/CEP17 ratio of 2.0 or greater, which is measured by immunohistochemistry status (IHC3+) or by fluorescence in-situ hybridization (FISH) measurement. HER2-positive breast cancer with high invasiveness and poor prognosis accounts for 15%~20% of breast cancer. With survival rates of almost five years in women with metastatic HER2-positive breast cancer and 75% of patients achieving a complete pathological response, the emergence and widespread application of new anti-HER2 treatments have improved the prognosis of HER2-positive breast cancer. Despite these achievements, however, the persisting high death toll of HER2-positive breast cancer remains due to resistance and heterogeneity in anti-HER2 therapy, as well as brain metastases in up to 40%~50% of HER2-positive advanced breast cancer patients. So it calls for continued, intensive clinical research of newer therapies and combinations.

Key words: HER2-positive breast cancer, Anti-HER2 treatment, Resistance

中图分类号: