曲妥珠单抗靶向治疗胃癌的进展

人表皮生长因子受体2（HER2）参与多种肿瘤的发生、发展。根据ToGA试验结果,欧盟和美国于2010年先后批准曲妥珠单抗用于HER2阳性的晚期胃腺癌和胃食管交界处癌患者的一线治疗。然而,目前胃癌中尚无统一的HER2检测评分系统,其耐药机制需进一步研究。本文就近年来曲妥珠单抗靶向治疗胃癌的进展作一综述。     

HER2基因扩增和蛋白表达与胃癌临床病理特征和预后的关系

背景：曲妥珠单抗在人表皮生长因子受体2（HER2）阳性胃癌分子靶向治疗中的作用已得到确认,研究HER2评分与患者临床结局的关系可确定哪些患者可能从曲妥珠单抗治疗中获益。目的：探讨HER2基因扩增和蛋白表达与胃癌临床病理特征和预后的关系。方法：应用美国食品药品管理局（FDA）认证的检测试剂盒和Hofmann等报道的共识小组推荐胃癌HER2评分系统．采用荧光原位杂交（FISH）和免疫组化方法（IHC）检测177例胃癌组织的IqER2基因扩增和蛋白表达。比较不同临床病理特征胃癌亚组间HER2阳性率的差异．以Kaplan—Meier生存曲线分析HER2与预后的关系。结果：177例胃癌组织中31例（17．5％）HER2阳性．肠型胃癌阳性率显著高于弥漫型,混合型胃癌（28．1％对12．5％,P=0．0109）．分化较好的胃癌阳性率显著高于分化较差的胃癌（37．0％对10．7％,P〈0．0001）。HER2与性别、年龄、肿瘤部位和TNM分期无关。HER2阳性与阴性者总体生存率无明显差异,但在分化较好的胃癌中,HER2阳性者预后差于HER2阴性者（P=0．0084）。结论：肠型胃癌和分化较好的胃癌是曲妥珠单抗治疗的主要候选人群。HER2尚不能作为独立指标判断胃癌预后。     

匹多莫德联合靶向治疗HER阳性晚期胃癌患者的疗效及对腹水IL-17、IL-37水平的影响

目的探讨匹多莫德联合曲妥珠单抗靶向治疗晚期HER阳性胃癌患者的疗效及对腹水IL-17、IL-37含量的影响。方法选取2011年10月至2015年2月确诊为HER阳性的胃癌患者116例作为研究对象,随机分为观察组(66例)和对照组(50例)。对照组患者给予曲妥珠单抗进行靶向治疗,观察组患者给予匹多莫德联合曲妥珠单抗治疗,治疗3周为1个周期,共治疗6个周期。比较两组患者的疗效、中位生存时间,检测比较两组患者治疗前后腹水IL-17、IL-37含量。结果观察组患者中位生存时间为166 d,对照组患者为44 d。观察组患者的治疗有效率为71.2%,对照组为42.0%,两组比较差异具有统计学意义(P0.05)。治疗后两组患者腹水IL-17、IL-37水平均显著降低(P0.05),观察组患者腹水IL-17、IL-37水平均显著低于对照组(P0.01)。结论与单用曲妥珠单抗进行靶向治疗比较,匹多莫德联合曲妥珠单抗治疗晚期胃癌患者,可显著提高患者的治疗有效率,延长患者中位生存时间;患者腹水IL-17、IL-37水平对评估治疗效果及判断预后具有一定的价值。     

HER2阳性非小细胞肺癌靶向治疗的研究进展

非小细胞肺癌（NSCLC）是肺癌最常见的组织学类型，占肺癌总数的80%～85%。人表皮生长因子受体2(HER2)是一种细胞来源的癌基因。HER2变异包括基因突变、扩增或蛋白过表达，是NSCLC的重要致癌变异。现阶段国内针对HER2阳性NSCLC的一线治疗，主要为以铂类为基础的化疗联合抗血管生成治疗，而被批准的靶向治疗药物有限。HER2靶向治疗药物包括小分子酪氨酸激酶抑制剂（TKIs）、抗HER2单克隆抗体以及抗体-药物偶联物（ADC）。其中，TKIs包括阿法替尼、达克替尼、奈拉替尼、波齐替尼、吡咯替尼、Tarloxotinib、莫博赛替尼等，抗HER2单克隆抗体主要为曲妥珠单抗、帕妥珠单抗，ADC主要为恩美曲妥珠单抗、德曲妥珠单抗。由于抗HER2单克隆抗体的疗效有限，TKIs和ADC有望成为HER2阳性NSCLC重要的治疗选择。但目前大多数评价HER2靶向治疗药物在HER2阳性NSCLC患者中疗效的研究规模较小，尚需进一步研究证实。     

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

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H E R2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.     

榄香烯注射液联合曲妥珠单抗及化疗治疗HER2阳性进展期胃癌的疗效观察

[目的]观察榄香烯注射液联合曲妥珠单抗及卡培他滨(XELOX)方案治疗抗人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)阳性进展期胃癌患者的疗效及对血清标志物、免疫功能的影响。[方法]选取2015年1月～2018年10月在我院住院治疗的HER2阳性进展期胃癌患者60例为研究对象,按随机数字表法分为观察组及对照组,各30例。对照组予以曲妥珠单抗治疗及XELOX方案化疗,在此基础上,观察组加用榄香烯注射液治疗。比较2组治疗后的近期临床疗效、血清标志物水平及免疫功能。[结果]治疗后,观察组ORR及DCR高于对照组(P0.05);观察组VEGF、COX-2及MMP-2水平低于对照组(P0.05);观察组CD4~+细胞比例和CD4~+/CD8~+高于治疗前(P0.05),观察组CD4~+细胞比例和CD4~+/CD8~+高于对照组(P0.05)。[结论]榄香烯注射液联合曲妥珠单抗及XELOX方案治疗HER2阳性进展期胃癌能降低患者血清VEGF、COX-2及MMP-2水平,改善免疫功能,提高临床疗效。     

乳腺癌抗HER2单克隆抗体研究进展

［摘要］　在过去几十年,人们对人表皮生长因子受体2（HER2）致癌机制认识的提高促进了HER2靶向疗法的开发,例如抗HER2单克隆抗体、酪氨酸激酶抑制剂、双特异性抗体以及抗体偶联药物,这些药物目前通常用于HER2阳性乳腺癌。单克隆抗体曲妥珠单抗是目前HER2靶向治疗的基石,其作用机制是通过抗体的抗原结合片段识别肿瘤细胞表面的HER2位点,然后通过可结晶段（Fc）与免疫细胞表面的Fc受体(FcR)结合,介导抗体依赖性的细胞毒作用（ADCC）和抗体依赖的细胞吞噬作用（ADCP）,其中Fcγ受体（FcγR）是主要发挥作用的FcR家族成员。但人体内FcγR存在基因的多态性,不同基因表型的个体与曲妥珠单抗之间有不同的亲和力,亲和力低的患者使用曲妥珠单抗抗肿瘤效果差,所以基于曲妥珠单抗的结构,通过对其Fc段进行改造,如糖基化修饰和氨基酸变异,可增强Fc与FcR之间的亲和力和结合密度,进而增强ADCC和ADCP作用,其中Fc段氨基酸变异的抗HER2单抗马吉妥昔单抗已应用于临床。同时单克隆抗体的抗原结合片段也可通过进一步改造识别不同的HER2表位或者同时识别非HER2表位,增加了免疫细胞表面FcγR结合位点的密度并促进ADCC,此类药物包括帕妥珠单抗、双特异性抗体等。该文对乳腺癌抗HER2单克隆抗体研究进展作一综述。     

胃癌靶向治疗及其耐药机制的研究进展

胃癌是一种高度异质性疾病,其发生、发展是遗传因素、环境因素、宿主因素等综合作用的结果。近年来,随着对胃癌发病分子机制研究的不断深入,靶向药物成为晚期胃癌治疗的新选择。目前,针对晚期胃癌仅有人表皮生长因子受体2(HER2)、血管内皮生长因子（VEGF）两个分子靶点,其中针对HER2的靶向药物主要有曲妥珠单抗、帕妥珠单抗,针对VEGF的靶向药物主要有贝伐珠单抗、雷莫芦单抗,这些靶向药物能够使晚期胃癌患者获益明显。但随着这些靶向药物的临床应用,许多患者表现出了耐药性。这些靶向药物的耐药机制涉及药物外排率增加、药物代谢改变、药物靶点突变、凋亡信号通路失活、DNA损伤修复能力增强以及上皮间质转化和局部肿瘤微环境改变等。深入了解胃癌靶向治疗现状及其耐药机制,将使更多的晚期胃癌患者从这些靶向治疗中获益。     

曲妥珠单抗治疗乳腺癌致精神症状1例报告

曲妥珠单抗是一种重组DNA人源化单克隆抗体,可选择性的与人表皮生长因子受体-2（HER2）基因调控的细胞表面p185糖蛋白结合,从而阻止胞内酪氨酸激酶的激活,抑制HER2依赖性肿瘤细胞的增殖与存活。其常见不良反应有过敏反应、心脏毒性、皮疹、腹泻等。我们在临床工作中遇到1例曲妥珠单抗治疗乳腺癌导致严重精神症状的患者。现报告如下。     

紫杉醇联合曲妥珠单抗治疗HER-2阳性转移性乳腺癌效果观察

目的 探讨紫杉醇联合曲妥珠单抗治疗表皮生长因子受体-2（HER-2）阳性转移性乳腺癌（MBC）的疗效和安全性。方法 对12例HER2阳性MBC患者予紫杉醇联合曲妥珠单抗治疗。每8周复查1次,参照2000年实体瘤疗效评价标准进行疗效判定,按照美国国立癌症研究所通用毒性标准（NCI-CTC3．0版）评价毒副反应。结果完全缓解2例、部分缓解5例、稳定3例、疾病进展2例,客观有效率为58．33％,中位肿瘤进展时间为18个月,中位总生存时间为23个月;毒副反应主要表现为I-Ⅱ度骨髓抑制和消化道反应。结论紫杉醇联合曲妥珠单抗治疗HER-2阳性MBC近期疗效好、安全,其远期疗效有待于扩大样本量进一步研究。     

Advanced HER2-positive gastric cancer: Current and future targeted therapies

The prognostic value of human epidermal growth factor receptor 2 (HER2) in gastric cancer is controversial. Consensus guidelines have standardized the testing of HER2 status in gastric cancer. Overexpression of this receptor occurs in approximately 20% of gastric and gastro-esophageal junction adenocarcinomas, predominantly those of the intestinal type. Recently, trastuzumab has emerged as the first targeted drug to improve overall survival when combined with chemotherapy in advanced HER2-positive gastric cancer. Primary and secondary resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed. A high percentage of advanced HER2-positive gastric cancer patients who progress on trastuzumab therapy are candidates for second-line therapy. New families of targeted drugs, including tyrosine kinase inhibitors (TKIs) such as lapatinib and PF-00299804, mammalian target of rapamycin (mTOR) pathway inhibitors such as everolimus, heat-shock protein 90 (HSP90) inhibitors such as AUY922, HER dimerization inhibitors such as pertuzumab, and antibody-chemotherapy conjugates such as trastuzumab-emtansine (T-DM1), could offer alternative second-line treatments when trastuzumab-based first-line therapy fails.     

Advances in the Management of HER2-positive Advanced Gastric and Gastroesophageal Junction Cancer

In the past, patients with advanced or metastatic gastric or gastroesophageal junction cancer have had few treatment options and generally poor survival rates. The human epidermal growth factor receptor 2 (HER2) has been identified as a potential therapeutic target because of its overexpression or gene amplification in 6% to 35% of gastric or gastroesophageal junction cancers, although the methods of assessment and prognostic value of HER2 have been subject to debate. The phase III Trastuzumab for Gastric Cancer (ToGA) trial showed that adding the HER2-targeted humanized monoclonal antibody trastuzumab to chemotherapy significantly improves survival without negatively impacting quality of life in patients with advanced gastric or gastroesophageal junction cancer. As a result, trastuzumab is now the sole HER2-targeted therapy approved in several countries for this indication. The ToGA trial also demonstrated that patients who expressed higher levels of HER2 (determined by immunohistochemical screening) received the greatest benefit from trastuzumab therapy. This finding underlines the importance of accurate HER2 testing. Because of the unique characteristics of gastric cancer, a new gastric cancer-specific scoring system for HER2 expression was proposed during the ToGA trial. The aim of this review is to inform the gastroenterologist of the potential role of HER2-targeted therapy, to discuss the importance of accurate and reliable HER2 testing, and to discuss ongoing studies with HER2-targeted therapies that may have an impact on the future treatment of HER2-positive gastric cancer.     

Pancreaticoduodenectomy after neoadjuvant chemotherapy for gastric cancer invading the pancreatic head: A case report

BACKGROUND Pancreaticoduodenectomy(PD)for advanced gastric cancer is rarely performed because of the high morbidity and mortality rates and low survival rate.However,neoadjuvant chemotherapy for advanced gastric cancer has improved,and chemotherapy combined with trastuzumab may have a preoperative tumorreducing effect,especially for human epidermal growth factor receptor 2(HER2)-positive cases.CASE SUMMARY We report a case of successful radical resection with PD after neoadjuvant S-1 plus oxaliplatin(SOX)and trastuzumab in a patient(66-year-old male)with advanced gastric cancer invading the pancreatic head.Initial esophagogastroduodenoscopy detected a type 3 advanced lesion located on the lower part of the stomach obstructing the pyloric ring.Computed tomography detected lymph node metastasis and tumor invasion to the pancreatic head without distant metastasis.Pathological findings revealed adenocarcinoma and HER2 positivity(immunohistochemical score of 3+).We performed staging laparoscopy and confirmed no liver metastasis,no dissemination,negative lavage cytological findings,and immobility of the distal side of the stomach due to invasion to the pancreas.Laparoscopic gastrojejunostomy was performed at that time.One course of SOX and three courses of SOX plus trastuzumab were administered.Preoperative computed tomography showed partial response;therefore,PD was performed after neoadjuvant chemotherapy,and pathological radical resection was achieved.CONCLUSION We suggest that radical resection with PD after neoadjuvant chemotherapy plus trastuzumab is an option for locally advanced HER2-positive gastric cancer invading the pancreatic head in the absence of non-curative factors.     

Role of human epidermal growth factor receptor 2 in gastric cancer:Biological and pharmacological aspects

Amplification of the human epidermal growth factor receptor 2(HER2)gene and overexpression of the HER2protein is found in 15%-20%of patients with gastric and gastroesophageal junction cancer.The degree of HER2 overexpression and amplification varies with the location of the carcinoma,with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach.Further,HER2 overexpression and amplification also seems to be related to the Lauren histological classification,with higher levels found in the intestinal phenotype compared to the diffuse and mixed types.The prognostic properties of HER2 overexpression and amplification are still under debate,but a large number of studies seem to indicate that HER2 is a negative prognostic factor.The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial,where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive5-FU/capecitabine and cisplatin,either alone or in combination with trastuzumab.A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy.Patients with a strong overexpression of the HER2 protein(IHC3+)specifically benefited from the treatment,with a median overall survival of 17.9 mo.As a consequence of the positive results of the ToGA trial,patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2.The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab,ado-trastuzumab emtansine,lapatinib,afatinib,and dacomitinib,which are currently undergoing phaseⅡandⅢclinical testing.Overall,this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy.     

Surgical resection of advanced gastric cancer following trastuzumab/oxaliplatin/capecitabine combination therapy

Late-stage gastric adenocarcinoma patients have a poor prognosis because of high recurrence rates. To improve long-term outcomes, perioperative chemotherapies are combined with surgery. Human epidermal growth factor receptor 2 (HER2) overexpression had been noted in gastric cancer; therefore, trastuzumab has been used occasionally in this setting. A 63-year-old male Chinese patient, who was diagnosed with adenocarcinoma in the gastric antrum, as well as lymph node metastases along the left gastric and hepatic artery, and left adrenal area, was admitted to our hospital. HER2 expression was positive, and cluster amplification was detected in a fluorescence in situ hybridization assay. The patient received three cycles of a neoadjuvant trastuzumab/oxaliplatin /capecitabine regimen. He subsequently underwent distal gastrectomy, D2+ lymphadenectomy, left adrenalectomy, cholecystectomy and Billroth II anastomosis. Treatment was continued with another five postoperative cycles of the same medication and trastuzumab application for 1 year. No recurrence has been observed 18 mo after the operation. Trastuzumab as perioperative and adjuvant medication, in combination with oxaliplatin and capecitabine for a HER2-overexpressing advanced gastric adenocarcinoma, led to recurrence-free survival of at least 18 mo after surgery.     

Is there a qualitative interaction between adjuvant trastuzumab and size of the primary tumor in breast cancer?

Benefit of adjuvant trastuzumab in breast cancer has been reported in four randomized trials of phase III, and these results are consistent in showing improvement in disease-free survival (DFS). Current evidence for homogeneity of this DFS benefit in subgroups of patients with the different size of the primary HER2-positive tumor treated according to the HERA trial is reviewed. It is evident that current published evidence is insufficient to rule out that there is a cohort of patients with HER2-positive disease who do not achieve a reduction in the risk of recurrence by adjuvant treatment with trastuzumab after completion of previous adjuvant chemo- and radiotherapy. An alternative interpretation of results of the HERA trial currently available in two primary reports (1-year, and 2-year median follow- up, respectively) is discussed. The risk factors of central nervous system (CNS) metastases in breast cancer and problem of CNS metastases in HER2-positive tumors are briefly reviewed. A hypothesis on the relations between brain metastases, their risk factors, the size of the primary tumor, and their impact on the DFS in patients with HER2-positive tumors treated with adjuvant trastuzumab is proposed based on the results of the HERA trial. Altogether, some direct evidence is presented here based on the published results of the HERA trial, and still more indirect evidence based on the information on related topics in literature, to show that current clinical practice of adjuvant trastuzumab in mono-therapy, which is based on assumption that there is a homogeneous benefit as for disease-free survival for all sizes of primary HER2-positive tumors above 1 cm, may not be based on such firm evidence as is commonly presented. Key words: breast cancer; trastuzumab; adjuvant; brain metastases.     

A narrative review of advances in treatment and survival prognosis of HER2-positive malignant lung cancers

Human epidermal growth factor receptor 2 (HER2), as a receptor tyrosine kinase of EGF receptor family, whose mutation is often associated with even if less frequency but poor prognosis and shorter survival in pulmonary malignant tumor. HER2 status include mutation, overexpression, amplification and also some rare genotypes, detected by next generation sequencing (NGS), immunohistochemistry (IHC), and also fluorescence in situ hybridization (FISH). Different genotypes represent different therapeutic targets and indicate different clinical prognosis concluded by previous studies. Unfortunately, no standard guidelines for first-line treatment are widely recognized, and current therapeutic schedules include chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Especially for patients with advanced metastasis, chemotherapy is based as a systemic therapy using studies of breast cancer or EGFR-positive lung adenocarcinoma as a template. Studies already explored treatment including EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and afatinib, and also trastuzumab and its conjugation like HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) and conjugate trastuzumab deruxtecan (T-DXd). Also, he researches explored combination therapy with chemotherapy and TKIs or monoclonal antibodies. This review describes commonly used therapies for HER2-positive/HER2-overexpression patients and general relationship between genotypes of HER2, drug selection and final prognosis in order to provide suggestions for future diagnosis and treatment.     

ErbB2: Zielstruktur für die Therapie beim Magenkarzinom

Most patients with gastric cancer present at an inoperable advanced stage. Although there is a proven benefit for chemotherapy in advanced gastric cancer, mortality remains high and new forms of treatment with acceptable toxicity are needed. Trastuzumab, a monoclonal antibody against HER2, monotherapy and in combination with chemotherapy showed antitumor activity in human gastric cancer models in vitro and in vivo. In clinical phase II trials the combination of trastuzumab and cisplatin showed a reponse with good tolerance. The phase III ToGA trial compared randomized combination chemotherapy protocols with fluorouracil or capecitabine and cisplatin plus or minus trastuzumab in patients with an adenocarcinoma of the gastric or gastro-oesophageal junction expressing HER2. The trial showed a benefit in overall survival in selected patients for the addition of trastuzumab to chemotherapy. The trial led to the approval of trastuzumab by the European Medicines Agency (EMA). Trastuzumab is the first approved biological agent targeting HER2 in gastric cancer.