HER-2过表达与乳腺癌治疗的研究进展

人类表皮生长因子受体-2（HER-2）是一种与乳腺癌发生、发展密切相关的癌基因。HER-2过表达可能预测对内分泌治疗和细胞毒性化疗药物敏感性。Herceptin是针对HER-2的分子靶向药物，其肿瘤治疗作用受到广泛关注。HER-2过表达乳腺癌病人在肿瘤发展的各个病期中表现为预后差。全文是根据使用曲妥珠单抗来治疗转移性乳腺癌或作为术后辅助治疗情况下获得的数据来说明HER-2阳性表达在乳腺癌治疗中的作用．或者作为独立的预后因子，或作为预测抗癌治疗反应的一项标志物.     

曲妥珠单抗生物仿制药治疗HER-2阳性乳腺癌的临床研究进展

近年来,研究证明曲妥珠单抗可以显著改善人表皮生长因子受体-2（human epidermal growthfactor receptor 2,HER-2）阳性乳腺癌患者的生存预后,但由于其价格高昂,使患者选择受限。曲妥珠单抗生物仿制药的诞生有望节约成本、增加药物可及性,近年来已得到迅速发展。YL-1401O（Ogivri）、CT-P6（Herzuma）、SB3（Ontruzant）、PF-05280014（Trazimera）和ABP980（Kanjinti）,它们现已被美国食品药品监督管理局（Food and Drug Administration,FDA）批准用于HER-2阳性乳腺癌;我国HLX02已被欧洲药品管理局（The European Medicines Agency,EMA）和国家药品监督管理局（National Medical Products Administration,NMPA）批准上市。本文就近几年曲妥珠单抗生物仿制药在HER-2阳性乳腺癌中的研究进展进行综述,以期为HER-2阳性乳腺癌的靶向治疗提供参考。     

TCH与TAC新辅助化疗在HER-2过表达乳腺癌中的疗效观察

  目的  观察TCH与TAC新辅助化疗方案在HER-2过表达乳腺癌的临床疗效。  方法  收集深圳市第二人民医院甲乳外科自2008年5月至2012年9月收治的64例HER-2过表达的乳腺癌患者,随机分为两组:TCH组39例,采用曲妥珠单抗联合多西他赛及卡铂治疗方案;TAC组25例,采用多西他赛、表阿霉素及环磷酰胺治疗方案。新辅助化疗6个周期后进行疗效对比。  结果  TCH与TAC两组患者总有效率（OR）分别为94.9%（37/39）和72.0%（18/25）,差异有统计学意义（P < 0.05）;病理完全缓解率（pCR）分别为69.2%（27/39）和32.0%（8/25）,差异有统计学意义（P < 0.05）;两组患者在心功能障碍、骨髓抑制及肝功能损害等不良反应方面疗效均无显著性差异。  结论  在HER-2过表达乳腺癌的新辅助化疗中,多西他赛及卡铂联合曲妥珠单抗疗效良好,病理完全缓解率高。      

曲妥珠单抗对HER-2过表达乳腺癌细胞株mTOR信号通路影响的观察

目的:探讨曲妥珠单抗对HER-2过表达乳腺癌细胞株mTOR信号通路的影响。方法:在培养的乳腺癌细胞株MDA-MB-453中加入曲妥珠单抗,采用蛋白质印迹法检测细胞中mTOR、S6、4EBP1和Akt的蛋白磷酸化水平,同时检测该药对MDA-MB-453增殖及克隆形成的影响。结果:乳腺癌细胞株MDA-MB-453在加入曲妥珠单抗作用下,mTOR、S6、4EBP1和Akt磷酸化明显受抑制,并具有浓度依赖性;乳腺癌细胞株MDA-MB-453在加入曲妥珠单抗后,细胞相对增殖率随着药物浓度增大由(77±6.3)%降至(21±1.5)%,克隆形成率随着药物浓度增大由(55±4)%降至(4±1)%。结论:曲妥珠单抗可通过抑制mTORC1和mTORC2信号通路,从而抑制乳腺癌细胞株MDA-MB-453的生长与增殖。     

HER-2过表达与乳腺癌治疗的研究进展

人类表皮生长因子受体-2（HER-2）是一种与乳腺癌发生、发展密切相关的癌基因。HER-2过表达可能预测对内分泌治疗和细胞毒性化疗药物敏感性。Herceptin是针对HER-2的分子靶向药物，其肿瘤治疗作用受到广泛关注。HER-2过表达乳腺癌病人在肿瘤发展的各个病期中表现为预后差。全文是根据使用曲妥珠单抗来治疗转移性乳腺癌或作为术后辅助治疗情况下获得的数据来说明HER-2阳性表达在乳腺癌治疗中的作用．或者作为独立的预后因子，或作为预测抗癌治疗反应的一项标志物.     

曲妥珠单抗治疗失败的HER-2阳性乳腺癌患者不同后续治疗方案的疗效及影响因素分析

目的:观察人表皮生长因子受体2（human epidermal growth factor receptor-2,HER-2）阳性乳腺癌患者曲妥珠单抗治疗失败后不同后续治疗方案的疗效,分析影响因素。方法:回顾性分析2014年1月至2016年12月在我院肿瘤科治疗的曲妥珠单抗治疗失败的94例HER-2阳性晚期乳腺癌患者,根据其后续治疗方案不同将其分为A组（接受单纯化疗）、B组（接受曲妥珠单抗+化疗）和C组（接受拉帕替尼+化疗）;比较三组患者治疗效果,并分析可能影响抗HER-2治疗效果的相关因素。结果:94例患者均完成随访,中位随访时间22.3个月。三组患者中位无进展生存期（median progression free survival,mPFS）分别为3个月、4.5个月及6个月,差异有统计学意义（P<0.000 1）;C组PFS较A组及B组均明显延长,B组PFS较A组明显延长。A、B、C三组客观有效率（objective response rate,ORR）分别为8.7%、29.7%、38.2%,三组的临床获益率（clinical benefit rate,CBR）分别为21.7%、54.1%、64.7%,以上差异均有统计学意义（P<0.05）。对可能影响PFS的单因素进行分析,拉帕替尼、一线疗程（曲妥珠单抗）获益时间≥6个月、无内脏转移是PFS的影响因素;而拉帕替尼、一线疗程（曲妥珠单抗）获益时间≥6个月是PFS的独立影响因素。结论:对于曲妥珠单抗治疗失败的HER-2阳性晚期乳腺癌患者,后续治疗方案中含抗HER-2靶向药物可改善患者预后。     

曲妥珠单抗联合新辅助化疗对HER-2阳性乳腺癌患者近远期疗效的影响

目的 探讨曲妥珠单抗联合新辅助化疗对表皮生长因子受体-2(HER-2)阳性乳腺癌患者的疗效.方法 选取HER-2阳性乳腺癌患者58例,随机分为观察组和对照组,各29例.对照组给予表柔比星联合多西他赛的方案进行新辅助化疗,观察组在对照组的基础上给予曲妥珠单抗治疗.比较两组患者的近期、远期疗效.结果 观察组有效率(RR)及病理完全缓解(pCR)率明显优于对照组,5年总生存率(OS)及5年无病生存率(DFS)明显高于对照组.结论 曲妥珠单抗联合新辅助化疗治疗HER-2阳性乳腺癌近期疗效显著,并可有效改善患者预后,值得临床推广应用.     

帕妥珠单抗在HER-2阳性乳腺癌治疗中的临床转化

帕妥珠单抗(pertuzumab)作为一种新的抗人表皮生长因子受体-2(human epidermal growth factor receptor,HER-2)治疗药物,其作用区域不同于曲妥珠单抗,两者联合可以发挥更全面的HER-2抑制作用,基础和临床转化研究均证实帕妥珠单抗和曲妥珠单抗有协同的抗肿瘤作用.Ⅱ期和Ⅲ期临床转化试验结果显示,抗HER-2两药治疗(帕妥珠单抗+曲妥珠单抗)联合化疗可使HER-2阳性晚期乳腺癌的中位无疾病进展时间(progression-free survival,PFS)延长到18个月以上,中位总生存时间(overall survival,OS)接近5年(56.5个月),显著改善了晚期HER-2阳性乳腺癌患者的预后.两项Ⅱ期新辅助治疗临床转化研究也确认帕妥珠单抗联合曲妥珠单抗的协同作用疗效同样突出,病理完全缓解(pathological complete response,pCR)率最高可达66.2％.安全性分析发现,即使是与蒽环类药物联用,加用帕妥珠单抗治疗也并未增加心脏毒性.本文对帕妥珠单抗在HER-2阳性乳腺癌治疗中的上述相关临床转化研究进行综述.     

曲妥珠单抗联合拉帕替尼及多西紫杉醇一线治疗HER-2阳性晚期乳腺癌的安全性和有效性

目的:观察曲妥珠单抗联合拉帕替尼及多西紫杉醇一线治疗HER-2阳性晚期乳腺癌的安全性和有效性。方法:这是一项前瞻、单臂、开放标签的单中心Ⅱ期临床研究(ChiCTR1800015814)。HER-2阳性晚期乳腺癌一线治疗给予曲妥珠单抗(6 mg/kg,首剂8 mg/kg)联合拉帕替尼(1 000 mg/d)及多西紫杉醇(75 mg/m2),每3周重复。对非进展的患者继续用药直至疾病进展或毒性不可耐受,但最长用药时间不超过2年。主要研究终点是有效率,次要终点是PFS和OS。结果:自2016年9月至2019年5月共入组65例患者。本方案的剂量限制性毒性为腹泻,Ⅲ-Ⅳ度腹泻发生率为24.6%。总体有效率为69.2%(CR 3.1%,PR 66.1%),激素受体阴性患者有效率明显优于激素受体阳性患者(76.7% vs 57.1%,P＜0.01)。中位随访31个月,PFS为16.4个月(95%CI:13.4~19.6个月)。尚未达到中位OS时间。Log-rank检验显示是否内脏转移、是否多器官转移对PFS的影响具有统计学意义(P＜0.01和P=0.022)。结论:曲妥珠单抗联合拉帕替尼及多西紫杉醇毒性可耐受,疗效较好,作为HER-2阳性晚期乳腺癌一线治疗新的治疗策略,值得进一步研究。     

HER-2 overexpression/amplification and its interaction with taxane-based therapy in breast cancer.

Breast cancer (BC) is the most common cancer in women and it is incurable when metastases are diagnosed. Taxanes, namely docetaxel and paclitaxel, are effective chemotherapeutic agents in the metastatic, neoadjuvant and adjuvant settings. HER-2 overexpression/amplification is detected in 25-30% of BCs and confers aggressive tumor behavior as well as resistance to some systemic treatments; nevertheless, its association with response to taxane-based chemotherapy is still unclear, with conflicting results in both in vitro and in vivo preclinical studies. This review will address the impact of HER-2 overexpression/amplification in BC patients treated with taxanes. Prospective, randomized trials incorporating important biological hypotheses are either ongoing or just closed, and their results will hopefully help to shed more light on this issue.     

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

Background  Recently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab. Methods  We retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months. Results  Among the patients who received a trastuzumabcontaining regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2–14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0–45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (≤50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases. Conclusion  Patients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (≤50 years) who had recurrent breast cancer with liver metastases.     

HER-2阳性乳腺癌的新辅助治疗现状及展望

人表皮生长因子受体（HER-2）高表达被视为乳腺癌预后不良的重要预测因素,但随着抗HER 2治疗药物研发的进步、新辅助治疗理念的建立及临床经验的积累,其预后已得到改善。新辅助治疗是局部晚期乳腺癌的标准治疗,并被广泛用于可手术的早期患者,以提高保乳率。新辅助治疗与术后辅助治疗同样可以改善患者的无病生存期（DFS）和总生存期（OS）。近年来曲妥珠单抗等抗HER 2靶向药物及治疗方法发展迅速,新辅助治疗为药物的研究和开发提供很好的研究平台,HER-2阳性乳腺癌新辅助治疗相关问题已成为肿瘤学关注的热点问题,本文将对此作一简要综述。     

Central nervous system metastases in women with HER-2 positive metastatic breast cancer after treatment with trastuzumab

Background: Historically, central nervous system (CNS) metastases have been reported to occur in 10–16% of women with metastatic breast cancer (MBC) with a median survival of less than 1 year after diagnosis of CNS disease. A higher rate of CNS metastases has been described in women with metastatic breast cancer (MBC) over‐expressing HER‐2 who receive trastuzumab therapy. Aims: The aim of this study was to examine the frequency of and potential risk factors for CNS metastases in these women. Our a priori hypotheses were that in MBC patients treated with trastuzumab, CNS metastases occurred (i) more frequently than historical controls, and (ii) in women with controlled systemic disease. Methods: A retrospective cohort study of 28 consecutive patients with MBC over‐expressing HER‐2 and treated with trastuzumab and chemotherapy was performed. Results: A total of 22/25 (88%) patients who initially responded to trastuzumab had progressed within a median of 11.2 months after starting trastuzumab therapy. Central nervous system metastases occurred in 11/28 (39%) patients and the remaining 11 patients had progressed elsewhere. At diagnosis of CNS metastases, 9/11 (82%) had controlled systemic disease (CR = 2, PR = 6, SD = 1). There were trends for patients with CNS metastases to have greater than one site of metastatic disease at the commencement of trastuzumab therapy (P = 0.06), and to be hormone receptor negative at initial diagnosis (P = 0.14). The median time to diagnosis of CNS metastases after the commencement of trastuzumab therapy was 12 months (range 6–19 months). The median survival after diagnosis of CNS metastases was 12 months (range 2–22 months). Conclusions: This study demonstrates a high rate of CNS metastases (39%) in HER‐2 positive MBC patients treated with trastuzumab. At CNS metastases most patients had controlled systemic disease and the median survival after CNS relapse was 1 year. We suggest aggressive management of CNS disease in this population. Additional strategies to decrease the incidence of CNS metastases in these patients may include prophylactic whole brain irradiation and the development of novel pharmacological agents with successful CNS penetration.     

HER-2, TOP2A and chromosome 17 alterations in breast cancer

HER-2 amplification is a biomarker for identifying patients who respond to trastuzumab and has been evaluated as a factor predicting the response to anthracyclines. The relationship between HER-2 and response to anthracycline therapy may also be the result of the close localization of TOP2A on 17q. It has been a matter of debate whether these two genes, HER-2 and TOP2A, behave separately on different amplicons or act together thus making it possible to predict the TOP2A status from the HER-2 status. In this study TOP2A, HER-2 and chromosome 17 aneusomy were investigated by fluorescent in situ hybridization (FISH) in 50 consecutive breast cancer patients. HER-2 amplification was detected in 11 patients (22%) and TOP2A changes were seen in 6 patients (12%); two amplifications and two deletions were observed in HER-2-amplified cases and two deletions in HER-2-nonamplified cases. Three of the TOP2A-deleted cases had polysomy 17. HER-2 copy number was higher than the TOP2A copy number in one patient with co-amplification. Polysomy was observed in 9 cases (18%) and monosomy in 6 cases (12%). Aneusomy was the sole anomaly in 11 patients (22%). We conclude that the TOP2A status cannot be predicted from the HER-2 status and evaluation of the TOP2A status only in patients with HER-2 overexpression may lead to missing cases with TOP2A deletion with possible resistance to therapy. Other factors modulating topo IIα activity may also affect the response to therapy. Studies evaluating different parameters that can modulate topo IIα activity and the response to the drugs targeting the enzyme are necessary.     

A monoclonal antibody against HER-2 (trastuzumab) for metastatic breast cancer: a model-based cost-effectiveness analysis.

BACKGROUND: The aim of this study was to evaluate the cost-effectiveness of trastuzumab in patients with metastatic breast cancer (MBC) in a model-based cost-effectiveness analysis (CEA). Trastuzumab has shown considerable activity in patients with MBC that overexpress HER2. However, significant resources have been allocated to finance this new therapy. Due to ever increasing pressures on health care budgets, economic evaluations are requested in order to compare health effects with costs. METHODS: All available data on trastuzumab in MBC presented at the San Antonio breast cancer conference in late 2003 and all data on Medline in December 2003 were analysed for life years (LY) gained and quality of life (QoL) with regard to the use of this new monoclonal antibody. Randomised studies comparing standard chemotherapy, with or without trastuzumab, were focused. The costs were calculated according to Norwegian prices as of January 2003. RESULTS: The LY gained ranged between 0.3 and 0.7 years. The median cost per patient treated was 44 196 yielding costs per life year saved in the range 63 137-162 417 depending on survival gain and discount rate employed. A sensitivity analysis documented the price of trastuzumab and the survival benefit the two major factors influencing the cost-effectiveness ratio. CONCLUSION: The economic evaluation indicates that trastuzumab is not cost effective in metastatic breast cancer. Reduced drug costs and/or improved survival may alter the conclusion.     

HER-2/neu肿瘤疫苗的研究进展

摘 要　原癌基因HER-2/neu在多种恶性肿瘤中有扩增及过表达,近30%的原发性乳腺癌患者有HER-2/neu过表达。针对HER-2靶点的特异性人源化抗体曲妥株单抗（trastuzumab;又名赫赛汀,Herceptin）在上世纪90年代已用于临床治疗。目前针对HER-2的肽疫苗、蛋白疫苗、细胞疫苗、DC相关疫苗、以及DNA疫苗等的研究,均已取得一定进展,如小肽E75（p369-399）与GM-CSF联合应用,在HLA-A2(+)/A3(+)乳腺癌患者的Ⅱ期临床试验中显示出一定疗效;针对编码HER-2的DNA疫苗已经进入临床试验阶段,这些疫苗均有可能成为乳腺癌治疗的又一个重要手段。但这些疫苗距临床实际使用尚有一定的距离,有许多问题有待解决和需要进一步的临床验证。