HER-2阳性胃癌的研究进展
2019-03-09牛悦白建平卢建跃
牛悦 白建平 卢建跃
摘要:胃癌是我国最常见的消化道恶性肿瘤之一,随着我国社会经济的发展、人们食物谱的改变,我国的胃癌发病率呈显著上升趋势。人类表皮生长因子受体2(HER-2)是一种原癌基因,在部分胃癌患者中存在高表达,针对HER-2的靶向治疗,可使HER-2阳性的晚期胃癌患者获得显著的生存收益。ToGA研究是胃癌靶向治疗史上的一座里程碑,它首次在大规模样本中证实看联合应用化疗药及曲妥珠单抗可有效延长患者生存期。本文就HER-2阳性胃癌的研究进展作一综述。
关键词:人类表皮生长因子受体2;胃癌;靶向治疗
中图分类号:R735.2 文献标识码:A DOI:10.3969/j.issn.1006-1959.2019.01.015
文章編号:1006-1959(2019)01-0044-03
Progress in Research of HER-2 Positive Gastric Cancer
NIU Yue,BAI Jian-ping,LU Jian-yue
(General Surgery,the 254th Hospital of Chinese PLA,Tianjin 300143,China)
Abstract:Gastric cancer is one of the most common malignant tumors of the digestive tract in China. With the development of China's social economy and the changes in people's food spectrum, the incidence of gastric cancer in China has shown a significant upward trend. Human epidermal growth factor receptor 2 (HER-2) is a proto-oncogene that is highly expressed in some patients with gastric cancer. Targeted therapy against HER-2 can significantly improve HER-2 positive patients with advanced gastric cancer. Survival gains. The ToGA study is a milestone in the history of targeted therapy for gastric cancer. It was first demonstrated in large-scale samples that the combination of chemotherapeutic drugs and trastuzumab can effectively prolong patient survival. This article reviews the research progress of HER-2 positive gastric cancer.
Key words:Human epidermal growth factor receptor-2;Gastric cancer;Targeted therapy
人类表皮生长因子受体2(human epidermal growth factor receptor-2,HER-2)具有酪氨酸激酶活性,在肿瘤的发生发展中发挥着重要作用[1]。生理情况下,HER-2处于非激活状态,当受到某些不良因素刺激后可被异常激活,通过多个信号通路参与调控细胞增殖及凋亡、促肿瘤因子生成、新生血管形成、肿瘤浸润转移等[2,3]。在乳腺癌中,有近30%的患者存在HER-2过表达,且阳性表达的患者预后显著差于HER-2阴性患者[4]。在胃癌中,HER-2表达也被认为是影响患者预后的独立性危险因素。本文就HER-2阳性胃癌的研究进展作一综述。
1 HER-2的特性及在胃癌中表达
1.1 HER-2的特性 HER-2蛋白是表皮生长因子受体家族的成员之一,该家族还包括 HER-1、HER-2、HER-3及HER-4,都有相似的结构基团,包括胞外结构域、螺旋形跨膜单位及胞内酪氨酸激酶域[5,6]。当被受体与配体结合后,多条下游信号通路被激活,形成复杂的信号调控网络。HER-2定位于人染色体17q21,编码糖跨膜蛋白参与细胞信号转导,可通过高水平扩增使细胞获得致癌性[7]。
1.2 HER-2在胃癌中的表达 目前的研究表明,HER-2在膀胱癌、卵巢癌、结直肠癌、肺癌等多种恶性肿瘤的发生发展中发挥着重要作用[8]。例如,在侵袭性乳腺癌中,约15%~36%的患者存在HER-2异常高表达,这类患者患者的预后也显著更差[9]。在胃癌中,约11%~28%的患者存在HER-2过表达,但在不同地区、不同生活习性的人群中检出率差异较大。欧洲学者的报到率大多低于20%,且以肠型胃癌的检出率更高[10]。在北美地区,HER-2过表达的发生率约为12%,同样以肠型胃癌的检出率更高[11]。中国学者的报道率大多在14%~25%,王昆宇等[12]报道称,与低分化腺癌相比,高-中分化程度腺癌的HER-2阳性明显更高,肠型胃癌的检出率明显高于其他类型。但患者年龄、性别、TNM分期、肿瘤定位对HER-2的表达状态无明显影响。
2胃癌组织中的HER-2检测
准确有效的HER-2检测对制定进一步治疗方案、判断预后有重要作用。免疫组化法及原位杂交法是目前最主流的检测方法[13]。胃癌细胞具有特殊的结构,其肿瘤异质性明显,基底染色模式不完整,若采用与乳腺癌、肺癌相似的评判标准判读染色结果,会使HER-2阳性率偏低,假阳性率显著上升,导致后续治疗保守,难以奏效[14]。因此,目前国际上普遍采用HOFMAN等[15]的建议方法,以组织标本10%为临界值,此法也被ToGA试验采纳,结果显示3803例标本中,HER-2阳性率约为为16.6%。2011年中华医学会发布权威指南指出[16],免疫组化法是检测胃癌HER-2表达的首选方法,根据染色程度的不同,分为IHC3+、IHC2+、IHC1+及0四个等级,其中,0与IHC1+级判读为阴性,IHC3+为阳性,IHC2+需进一步加作原位杂交检测。2016年胃癌HER-2检测指南进行了更新[17],在实际操作中,有时需对活检标本进行检测,但目前关于活检标本的HER-2检测未被廣泛应用,而原位杂交法的检测效率不高,导致部分IHC2+的患者不能明确诊断HER-2表达状态,这在文献中反映为部分研究者的报道率差异较大。这也是在实际临床中需要进一步解决完善的问题。
3 HER-2阳性胃癌中的治疗
3.1一线治疗 目前的研究已证实[1],曲妥珠单抗联合联合化疗药,如5-氟尿嘧啶、顺铂等对HER-2阳性的晚期患者有显著疗效。HerMES试验[18]对383例HER-2阳性晚期胃癌患者进行随访后发现,仅有28.7%的患者完整接受了曲妥珠单抗+5-Fu/卡培他滨+顺铂的治疗方案,半数以上的患者接受了如化疗联合亚叶酸钙、多西他赛或曲妥珠单抗单药等方案,全组患者的中位无病生存期为7.73个月,与ToGA试验的6.7个月相近。在亚洲国家,S-1+顺铂仍然是治疗局部进展期胃癌的标注方案之一,在HERBIS-1研究中[19],全组患者的中位生存期为16个月,无进展生存期为7.8个月,疾病进展时间分别为5.7个月,这表明,对HER-2阳性的转移性胃癌患者而言,曲妥珠单抗联合SP方案也有较好的应用前景。
3.2二线治疗 曲妥珠单抗在HER-2阳性胃癌的一线治疗中显示出了独特优势,基于这些成果,研究者们开始更加关注其对二线治疗患者的效能[20]。紫杉类化疗药物是5-氟尿嘧啶治疗失败后,晚期胃癌患者的备选二线方案之一,在许多研究中,均被选为联合化疗药。在一项回顾性研究中,Dai GH等[21]选取了既往行曲妥珠单抗+5-Fu治疗失败的患者为研究对象,在二线治疗中应用曲妥珠单抗+紫杉类方案,结果发现,无病生存期与总体生存期达到了可喜的6.8个月与16个月,这一结果在Ⅱ期临床试验JFMC45-1102中也得到验证[22]。目前,曲妥珠单抗+紫杉醇的联合方案是既往未接受曲妥珠及5-FU失败后的HER-2(+)患者的最佳备选方案。
3.3转化及新辅助治疗 已有许多研究者报道称,曲妥珠单抗联合化疗是十分有效的新辅助化疗方案。HER-FLOT研究是一项旨在明确曲妥珠单抗联合FLOT化疗方案对HER-2阳性的进展胃食管腺癌疗效的Ⅱ期临床试验,其随访发现,4个周期的新辅助化疗后,患者完全缓解率为23%[23]。2015年美国肿瘤临床学会发布了多中心Ⅱ期临床NEOHX试验的结果[22],确认了曲妥珠单抗+卡培他滨/奥沙利铂对HER-2阳性可切除胃食管腺癌的疗效,约71%的患者生存超过18个月。这些大规模的临床试验都证实了曲妥珠单抗在HER-2阳性胃-食管腺癌或胃腺癌新辅助化疗中的价值。
4 HER-2与胃癌预后的关系
目前,关于HER-2表达对患者预后影响的研究结论尚未达成一致。ToGA试验将HER-2(+)患者随机分为单纯化疗组与化疗+曲妥珠单抗组,结果显示,两组患者的中位总体生存期分别为11.1个月与13.8个月,表明联合治疗比单纯化疗更能使患者获益,HER-2高表达对规律治疗的患者而言意味着更好的预后,但试验研究者同时也指出,HER-2高表达与患者预后的关系仍需要更多的循证医学证据证明。Bang YJ等[24]研究则指出,HER-2高表达与胃癌高侵袭性、高转移率密切相关,是预后不良的信号。在一项Meta分析中[25],研究者发现HER-2高表达是胃癌患者预后不良的强烈信号,且HER-2表达状态及程度与肿瘤分化程度、Bormann分型、劳伦斯分型密切相关。在中国学者的诸多研究中也有相似结论。
但也有研究者提出了不同结论,Grabsch H等[26]对924例进展期手术胃癌患者进行随访研究后发现,HER-2高表达虽然会使患者预后产生一定的消极影响,但并不是影响预后的独立性危险因素。Kang YK等[27]对169例原发性胃腺癌及食管-胃结合处腺癌患者随访后发现,HER-2表达对患者预后无任何预测意义。Satoh T等[28]实施了一项包含726例胃癌患者的大规模研究,结果也认为HER-2高表达不能作为判断预后的独立性指标。
5总结
在世界范围内,胃癌是恶性肿瘤相关的第三大病因,HER-2是目前胃癌基因分子分型研究中的重要组成。曲妥珠单抗在胃癌的一线、二线以及新辅助化疗中均显示出了独特疗效,在目前关于晚期胃癌转化治疗、局部进展期胃癌的治疗也有望发挥更大作用。但目前包括HER-2状态与胃癌预后关系等许多问题仍充满争议,还需要进一步的循证医学证据,才能对HER-2阳性胃癌患者实施更科学、更有效的治疗管理。
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