修回日期: 2016-01-27
接受日期: 2016-01-31
在线出版日期: 2016-03-08
相对传统化疗药物, 分子靶向药物具有特异性强、不良反应小的优点, 人类表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)是近年来研究的热点, 虽然HER2与胃癌预后的关系仍存在争议, 但随着曲妥珠单抗、拉帕替尼、帕妥珠单抗等抗HER2药物的相继问世, 越来越多的临床研究取得了较好的成果; 然而仍有部分患者因耐药的发生效果不尽如人意, 探索其中机制并寻找克服耐药增加疗效的方案, 才能使胃癌患者从个体化分子靶向治疗中得到最大程度的获益.
核心提示: 抗人类表皮生长因子受体2(human epidermal growth factor receptor 2)抗体联合化疗已被2012年美国国立综合癌症网络(National Comprehensive Cancer Network)指南推荐为标准治疗方案, 然而部分患者因为耐药并未获得临床获益, 曲妥珠单抗、帕妥珠单抗、拉帕替尼、T-DM1等靶向药物联合不同化疗方案, 及其之间的联合应用, 可通过阻断不同靶点的信号转导通路克服耐药, 实现胃癌的个体化靶向治疗.
引文著录: 段连香, 赵爱光, 郑坚. 人类表皮生长因子受体2基因检测下的胃癌个体化靶向治疗进展. 世界华人消化杂志 2016; 24(7): 1031-1039
Revised: January 27, 2016
Accepted: January 31, 2016
Published online: March 8, 2016
Compared with traditional chemotherapy drugs, molecular targeted drugs have the advantages of high specificity and fewer side effects. Human epidermal growth factor receptor 2 (HER2) has been a focus of research in recent years, although the relationship between HER2 and prognosis of gastric cancer remains controversial. With the advent of trastuzumab, lapatinib, pertuzumab and other anti-HER2 drugs, many clinical studies have achieved good results; however, there are still some patients with unsatisfactory results due to the occurrence of drug resistance. Finding solutions to overcome drug resistance can increase the efficacy, and individualized molecular targeted therapy can better benefit gastric cancer patients.
- Citation: Duan LX, Zhao AG, Zheng J. Individualized molecular targeted therapy for gastric cancer based on human epidermal growth factor receptor 2 gene detection. Shijie Huaren Xiaohua Zazhi 2016; 24(7): 1031-1039
- URL: https://www.wjgnet.com/1009-3079/full/v24/i7/1031.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i7.1031
胃癌是最常见的严重危害人类健康的消化系肿瘤之一, 在世界范围内发病率居第4位, 死亡率居于第3位[1,2], 约有2/3的患者初治时已是进展期, 即使是行根治术后大多数也会出现局部复发和/或远处转移[3]. 化疗是最有效的手段之一, 但预后仍不容乐观, 5年生存率约占20%[4]. 随着胃癌分子生物学、分子病理学研究的不断深入, 特别是继TOGA研究后, 肿瘤的治疗进入一个全新的时代, 以人类表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)为靶点的新型靶向治疗手段日益成为HER2阳性胃癌个体化治疗的主要研究方向.
HER2基因为原癌基因, 是酪氨酸激酶受体家族的重要成员, 对细胞增殖、胚胎发育、组织分化产生重要影响. 正常情况下HER2基因处于非激活状态, 受到某些内源或外源性因素的激活后可促进细胞分化和抑制凋亡[5]. HER2是人表皮生长因子受体(epidermal growth factor receptor, EGFR)家族成员中唯一没有直接配体的受体[6], 其通过与家族中的其他成员形成同源或异源二聚体而发挥作用[7]. 其中异源二聚体具有更高的信号活性和信号转导能力, 激活其下游的两个主要信号转导途径: 丝裂原活化蛋白激酶(mitogen-activated protein kinases, MAPK)通路和磷脂酰肌醇3-激酶/蛋白质丝氨酸苏氨酸激酶(phosphatidyli-nositol-3-kinases/protein-serine-threonine kinase, PI3K/AKT)通路[8], 影响肿瘤细胞的生长、增殖、分化和黏附等生物活动, 最终导致肿瘤的复发和转移.
HER2广泛表达于乳腺、胃肠、肾脏和心脏等多种组织器官中[9], 有报道每年胃癌新发病例存在HER2基因扩增或蛋白过表达比例约为6.0%-53.4%[10-13]. 这与全球多中心Ⅲ期随机临床研究TOGA[14]报道的22.1%阳性率存在巨大偏差, 考虑HER2的阳性表达可能与地域有一定的相关性.
筛选出HER2阳性的胃癌患者是治疗的关键, 而目前检测技术主要有免疫组织化学(immunohistochemistry, IHC)法、荧光原位杂交(fluorescence in situ hybridization, FISH)技术. 相比与IHC法, FISH技术能排除非癌细胞等物质的干扰, 更直接、准确地判断HER2基因是否存在扩增, 是目前胃癌HER2基因检测的金标准[15]. Rüschoff等[16]参照乳腺癌HER2的检测标准, 制订了用于胃、胃食管结合部HER2检测的指南, 从标本、材料的选择、到操作步骤、评判标准及质控等各个方面进行规范, 以确保结果的可重复性.
HER2检测是抗HER2靶向治疗的前提, 但是胃癌异质性较高, 不同检测方法、不同试剂等因素都可能导致检测结果的误差, 使HER2阳性的判定缺乏一个统一和公认的标准, 这也是HER2在胃癌的应用研究中一个较为重要的问题.
一项Meta分析[17]显示, HER2的过表达与胃癌的肿瘤的分化程度、淋巴结转移、Bormann分型、Lauren分型等有关, 而与肿瘤的大小、浸润的层次及肿瘤的分期无关. 大量临床试验均证实HER2过表达和/或基因扩增主要与胃癌的原发部位和组织学类型有密切相关性[14,18]. 然而也有报道HER2蛋白的表达与患者的性别﹑年龄﹑肿瘤的大小﹑部位﹑分化程度等均无相关性[19]. 王双双等[20]应用IHC及FISH法检测了208例内镜活检胃癌组织中HER2蛋白的表达, 结果显示HER2蛋白过表达与患者性别、年龄均无关(P>0.05), 而与发生部位(P = 0.011)及Lauren分型(P = 0.029)密切相关. 此外也有研究表明HER2的表达与发病年龄有关, 年龄<45岁者HER2阳性表达率为3%, 基因扩增率为5%[21].
相对于年龄、性别等相关因素与HER2阳性表达关系的备受争议, 肿瘤的部位, 分型等因素意见则具有高度一致性, 胃食管结合部癌和近端胃癌明显高于远端胃癌[22], 肠型胃癌HER2阳性率明显高于弥漫型和混合型胃癌[23-25].
HER2阳性是乳腺癌患者独立的预后不良因素, HER2在胃癌、乳腺癌、食管癌、卵巢癌等多种恶性肿瘤存在不同程度的蛋白过表达和/或基因扩增[26]. 然而在胃癌患者其预后指导意义仍存在争议.
Kim等[27]应用IHC的方法分析了1414例胃癌肿瘤组织中HER2表达与胃癌预后的关系, 结果显示HER2阳性胃癌患者的预后较HER2阴性者差(P = 0.014). 胡晓莉等[28]对108例术后复发晚期胃癌患者进行HER2表达的检测, 结果显示HER2阴性患者的肿瘤进展时间(time to progression, TTP)较阳性患者有所延长, 差异有统计学意义(P = 0.003), 表明HER2可能是胃癌预后不良的标志之一.
然而也有研究表明HER2与胃癌患者的预后并无关联[29]. 一项对726例胃癌根治术后患者进行的回顾性分析得出HER2阳性不是胃癌预后的独立因素, 只有肿瘤分期是生存期的独立危险因素(P<0.001)[30].
虽然现阶段HER2阳性表达情况与胃癌预后的相关性并无统一定论, 但大多数临床研究仍倾向于认为HER2阳性是胃癌预后的高危因素. Chen等[31]通过荟萃分析得出HER2对胃癌患者的总生存期(overall survival, OS)有显著的预测能力, 可用于评估胃癌患者的预后. HER2是影响胃癌复发转移治疗的关键靶点, 目前HER2基因检测为筛出HER2阳性/过表达患者, HER2与预后的关系为靶向药物的研发与应用提供了依据.
曲妥珠单抗(Trastuzumab)通过与HER2结合阻止同源二聚体的形成, 从而抑制下游MAPK和PI3K途径, 最终抑制肿瘤细胞的生长. TOGA研究[14]是第一个在分子检测基础上进行的胃癌靶向治疗Ⅲ期临床试验, 结果显示曲妥珠单抗组的中位生存时间(median survival time, MST)明显高于对照组(13.8 mo vs 11.1 mo, P = 0.0048), 证实了曲妥珠单抗联合卡培他滨/氟尿嘧啶+顺铂能改善晚期胃癌患者的预后, 在3/4级不良反应方面无统计学差异.
一项Ⅱ期临床研究NeoHx[32]通过曲妥珠单抗联合卡培他滨+奥沙利铂治疗进展期HER2阳性胃癌患者, 结果显示术前接受曲妥珠单抗联合化疗的患者临床缓解率较高, 且耐受性较好.
Kim等[33]筛选了年龄>75岁的HER2过度表达的进展期胃癌患者, 采用低剂量卡培他滨加曲妥珠单抗治疗, 结果显示MST为9.3 mo, 疾病控制率(disease control rate, DCR)为80%, 且没有出现与治疗相关的死亡或明显不良反应. 与此同时, 曲妥珠单抗联合S-1/顺铂可延长HER2阳性的晚期胃癌患者的OS, 且耐受良好, 可联合作为晚期胃癌的一线治疗[34].
基于大量临床试验结果, 曲妥珠单抗是唯一取得Ⅱ、Ⅲ期临床疗效的抗HER2靶向药物, 其联合化疗被2012年NCCN指南推荐为HER2过表达晚期胃癌患者的标准治疗方案.
曲妥珠单抗虽已取得良好的Ⅱ、Ⅲ期临床疗效, 但仍有超过一半的HER2过表达患者未获得临床受益, 对于曲妥珠单抗耐药的患者, 帕妥珠单抗(Pertuzumab)作为互补药物进入公众的视线. 帕妥珠单抗作用机制有别于曲妥珠单抗, 通过结合HER2阻止其与其他HER家族受体形成异源二聚化的单克隆抗体. 在乳腺癌体外研究[35]中, 曲妥珠单抗联合帕妥珠单抗已被证实能减少HER2/EGFR和HER2/HER3异源二聚体形成, 体外诱导肿瘤细胞凋亡.
Yamashita-Kashima等[36]在HER2阳性患者NCI-N87胃癌细胞移植瘤小鼠模型中, 证实了帕妥珠单抗联合曲妥珠单抗可抑制肿瘤细胞的生长, 并增加抗血管生成活性作用, 从而给HER2阳性的胃癌患者带来临床受益.
帕妥珠单抗已取得体外实验的成功, Tabernero等[37]报道了一项随机、双盲、安慰剂对照的Ⅲ期临床试验, 旨在评价帕妥珠单抗+曲妥珠单抗+化疗治疗HER2阳性转移性胃癌或胃食管结合部癌的安全性及疗效, 研究结果值得期待.
拉帕替尼(Lapatinib)是口服小分子双重酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKI), 能够同时抑制HER2和EGFR相关的下游信号传导而发挥抗肿瘤作用[38]. 葛兰素史克公司对其进行了两项多中心随机对照试验(NCT00486954/TyTAN、NCT00680901/LOGiC), 然而两项研究均未达到主要研究终点.
2013年ASCO会议报道了一项多中心、随机、对照、双盲的Ⅲ期临床试验LOGIC研究[39], 用以评价拉帕替尼联合奥沙利铂、卡培他滨一线治疗晚期HER2阳性胃、食管或胃食管结合部腺癌患者的疗效, 与单纯化疗相比, 拉帕替尼与化疗联合并没有带来统计学意义的OS获益(P = 0.35), 但次要终点无进展生存期(progression free survival, PFS)和缓解持续时间则得到了改善; 亚组分析显示, 在年龄<60岁以及亚洲的患者中观察到OS显著获益. 对此, 需要进一步研究明确拉帕替尼可能带来生存获益的特殊人群.
另一项亚洲的TyTAN实验[40]研究HER2阳性晚期胃癌患者的二线治疗, 虽然总体结果OS仍为阴性(P = 0.2088), 但在亚组分析中, HER2强表达IHC+++组的OS分别是14 mo和7.6 mo(P = 0.0176).
EXPAND研究、REAL3研究和LOGIC研究均未能达到主要研究终点, 提示EGFR在晚期胃癌中并不是主要驱动基因. 因此, 相比单靶点抑制剂, 拉帕替尼的HER2、EGFR双靶点抑制作用并不会带来更多的优势, 其临床效果仍需更加有针对性临床病例观察.
T-DM1是一种HER2抗体-药物偶联物, 是将曲妥珠单抗与一种小分子抗微管抑制物DM1耦联的新型聚合抑制剂, 具有抗HER2活性和靶向胞内递送作用, 可特异性的将DM1释放到HER2过表达的肿瘤细胞内, 干扰有丝分裂和促进细胞凋亡.
Yamashita-Kashima等[41]通过培养NCI-N87细胞EGF发现, 相比单独的抑制剂, T-DM1和帕妥珠单抗联合应用能够显著抑制胱肽蛋白酶3/7增殖的活性. 通过联合抑制EGFR或HER3及其下游因子AKT磷酸化, 显著增强抗体依赖性细胞毒性(antibody-dependent cell-mediated cytotoxic, ADCC), 增加在HER2阳性胃癌AKT信号抑制和ADCC显著抗肿瘤活性.
T-DM1已在HER2阳性乳腺癌中取得良好的临床效果, 成为乳腺癌第4个批准上市的抗HER2药物[42]. 一项探索T-DM1与标准紫衫类化疗方案在HER2阳性胃癌二线治疗中的疗效及安全性的研究(NCT01641939)正在进行中[43], 相对于曲妥珠单抗的临床获益, T-DM1的临床效果目前仍在探索中, 结果值得期待.
TOGA研究中应用曲妥珠单抗近半数患者无效, 拉帕替尼的两项Ⅲ期临床研究的失败, 都提示着胃癌HER2抑制剂可能存在耐药, 对耐药机制的探索也在逐步深入. 目前研究较多的耐药机制包括PI3K/AKT/mTOR途径中磷酸酶和张力蛋白同系物(gene of phosphate and tension homology deleted on chromsome ten, PTEN)基因缺失、HER2受体截短形式(p95HER2)的缺乏、活化其他酪氨酸激酶受体, 包括胰岛素样生长因子1受体(insulinlike growth factor type 1 receptor, IGF-1R)的表达等[44,45].
多项研究证实HER3/PI3K/AKT信号传导途径不仅参与了肿瘤的发生、进展与转移等过程, 而且在多种肿瘤靶向治疗耐药过程中起着重要作用[46]. 避开PI3K/AKT/mTOR途径的组成性活化药物已被证实能逆转PTEN丢失引起的曲妥珠单抗的耐药性[47,48], HER2过表达肿瘤靶向治疗中HER3水平的升高将增加靶向治疗耐药性[49].
Zhang等[50]分析应用HER2抑制剂的48例患者基因与预后的关系, 发现其中47.9%患者出现编码磷酸酶和张力蛋白同系物PTEN基因缺失, 缺失者PFS显著缩短(4.9 mo vs 7.3 mo, P = 0.047). Zaitsu等[51]研究也证实HER2阳性的胃癌患者出现PTEN缺失者预后较差(P = 0.0050). 由此, PTEN缺失可能是胃癌患者抗HER2治疗耐药的预测因素, 及早检测PTEN基因从而筛查出抗HER2靶向治疗的适宜人群, 为个体化治疗打下基础.
有研究[52]表明肿瘤细胞对曲妥珠单抗的耐药由于p95HER2片段的存在, p95HER2较一般HER2具有更大的激酶活性, 截短型HER2阳性患者的预后较差, 曲妥珠单抗无法结合并抑制截短型HER2, 而拉帕替尼可抑制其磷酸化, 成为替代治疗的选择.
抑制IGF-1R表达可以阻止/抑制酪氨酸激酶活动, IGF-1R抑制剂NVP-AEW541可显著增加肿瘤细胞对曲妥珠单抗的敏感性[53]. Zhang等[54]研究发现MET、HER3、IGF-1R和胰岛素样生长因子受体信号通路的激活是HER2阳性胃癌对拉帕替尼耐药的潜在机制, 在治疗HER2阳性的胃癌患者中推荐联合使用这些途径的活化. Lee等[55]通过集成磷酸化蛋白质组学数据, 蛋白质网络和信号通路调制对细胞增殖的影响, 发现MET依赖PI3K/AKT和MAPK/ERK信号通路的活化.
目前抗HER2治疗的研究尚不透彻, 对其耐药机制的研究仅局限在旁路受体活化, 如HER3和MET; 下游信号通路失控, 如PTEN缺失; 通路的再活化, PI3K通路活化等. 刺激HER2下游途径的异常活化是恢复信号传导的基本机制[56].
曲妥珠单抗除可通过抗增殖效应抑制肿瘤生长外, 还可以通过调节细胞周期、降低DNA修复活性及HER2介导的抗血管作用发挥抗肿瘤效应. 一项Meta分析[57]显示: 一线接受含曲妥珠单抗治疗后发生疾病进展的HER2阳性转移性乳腺癌, 与停用曲妥珠单抗相比, 继续使用曲妥珠单抗能显著提高客观缓解率OR = 1.62(P = 0.02). 虽然肿瘤细胞对曲妥珠单抗产生一定的耐受, 但保留了其化疗敏化机制, 对其治疗耐药的患者继续应用该药仍然可能有效. 由此在使用曲妥珠单抗后未取得明显临床获益者, 可依据体力状况选用氟尿嘧啶类联合铂类、紫杉醇类、伊立替康等化疗药物.
对于EGFR、IGF1R等信号传导通路激活的胃癌患者, 应用EGFR、HER2双靶点酪氨酸激酶抑制剂(TKI)-拉帕替尼可以通过抑制EGFR通路逆转耐药, 从而继续发挥抗肿瘤效应[38].
帕妥珠单抗可妨碍HER2与其他HER家族(HER1、HER3、HER4)的二聚体化, 从而阻断信号传导, 对于曲妥珠单抗耐药的患者可运用抑制异源二聚体形成的帕妥珠单抗, 以获得更好的抗肿瘤作用[35]. T-DM1已在HER2阳性乳腺癌中取得良好的临床效果, 在晚期胃癌患者的联合治疗中尚缺乏大样本临床研究.
在TOGA研究明确了曲妥珠单抗在胃癌患者靶向治疗中的地位之后, 靶向药物的联合应用应运而生, 旨在多靶点抑制肿瘤的复发转移. Wainberg等[58]对在HER2阳性细胞中联合使用曲妥单抗和拉帕替尼的效果进行了评价, 结果二者联合在抑制细胞生长上具有高度协同作用, 该组合也诱导AKT和ERK的激活, 明显降低G0-G1细胞周期的阻滞, 并增加了细胞凋亡率. 体内研究表明, 拉帕替尼和曲妥单抗联合使用具有比单药更强的疗效.
帕妥珠单抗联合曲妥珠单抗在Her-2阳性患者NCI-N87胃癌细胞移植瘤小鼠模型中, 已被证实可抑制肿瘤细胞的生长[39]. Kang等[59]对进展期胃癌进行了一项帕妥珠单抗联合曲妥珠单抗和化疗的Ⅱa期研究, 以第43天帕妥珠单抗血清浓度峰值作为安全性指标, 以检验其药代动力学和安全性. 结果显示帕妥珠单抗(850 mg, q3w)联合曲妥珠单抗和化疗耐受良好, 43 d检测血清浓度62.7 µg/L, 客观缓解率达86%.
随着靶向研究的深入, 势必有更多抗HER2靶向药物的诞生, 多靶点联合药物的研发, 靶向药物的联合应用, 都可能带来更加可观的临床受益.
随着临床实践及靶向研究的深入, 多种分子靶向药物的出现为胃癌患者的治疗效果带来了新的希望, 然而, 到目前为止, 曲妥珠单抗是第一, 也是惟一被胃癌靶向治疗Ⅲ期临床试验证实具有确切疗效的HER2靶向药物. 由于HER2检测率较低, 胃癌细胞的异质性, 不同细胞基因家族的差异性表达, 且目前研究只是片面的分析某种信号转导通路, 而忽视了其相互间的作用, 导致靶向药物个体化治疗的局限性. 探索其中机制并寻找克服耐药的方法, 筛选出靶向治疗真正敏感的患者, 才能实现胃癌的规范化、个体化靶向治疗.
TOGA试验中有超过一半的人类表皮生长因子受体2(human epidermal growth factor receptor-2, HER2)过表达患者未获得临床受益, 目前临床上尚无明确的个体化治疗策略, 研究其中的耐药机制, 寻找克服耐药增加疗效的方案将给患者带来生存的希望. 希望更多的目光投入其中以拓展靶向治疗的新领域.
徐建明, 主任医师, 军事医学科学院附属医院(解放军307医院); 张钰, 副研究员, 中国医学科学院肿瘤医院(肿瘤研究所)分子肿瘤学国家重点实验室
胃癌患者靶向治疗获益明显, 部分患者因耐药效果不尽如人意, 如何筛选适宜的抗HER2药物迫在眉睫.
尽管目前不同靶点靶向药物的联合在基础研究中已得到广泛运用, 实验室水平获益的报道也层出不穷, 但需严格控制各种靶向药物的禁忌证, 防止临床应用中治疗过度及治疗不及等情况的出现, 所以NCCN指南, ASCO会议等以及各大临床研究每年都会有所更新.
详细介绍了HER2在胃癌检测中的常见问题, 强调了抗HER2耐药的机制及现有临床对策, 并对近年来的新进展做了全面的阐释.
本文对于研究HER2靶向治疗有详尽以及最新的总结, 对于今后的研究有一定的指导意义. 对于临床医生来说, 确诊的胃癌患者应积极进行HER2检测, 以指导选择最佳的治疗方案.
本文从HER2基因的作用机制和检测方法, HER2的表达与胃癌预后的关系, HER2靶向药物的临床应用, 抗HER2治疗的耐药机制和抗HER2耐药的个体化对策等5个方面介绍HER2个体化靶向治疗的研究进展, 对临床及相关的基础研究有一定的指导意义.
编辑: 郭鹏 电编: 都珍珍
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