贝伐珠单抗联合紫杉类药物一线治疗局部复发或转移性乳腺癌患者的安全性及疗效

[目的]研究贝伐珠单抗联合紫杉类药物一线治疗Her-2阴性的局部复发或转移性乳腺癌患者的安全性和疗效。[方法]32例Her-2阴性的复发或转移性乳腺癌患者,一线接受贝伐珠单抗联合紫杉类方案的化疗,直至疾病进展或不良反应不能耐受或患者要求出组。研究者选择化疗方案：贝伐珠单抗15mg／kg静滴d1,多西他赛75mg／m^2,静滴d1,21d为一个周期;或贝伐珠单抗10mg／kg静滴d1,15紫杉醇80mg／m^2,静滴d1,8,15,为一个周期。每3个周期评价疗效。[结果]32例可评价疗效和副作用,PR16例,SD15例,PD1例,总有效率50％,中位TTP为7.25个月。3级以上不良反应为阴道出血、粒细胞下降以及腹泻。[结论]贝伐珠单抗联合紫杉类药物治疗晚期乳腺癌不良反应可以耐受,具有一定疗效。     

贝伐单抗联合多西他赛化疗方案对转移性乳腺癌患者的临床疗效

目的 探讨贝伐单抗联合多西他赛化疗方案对转移性乳腺癌患者的临床疗效.方法 入组87例患者依据随机数字表法随机分为观察组(45例)和对照组(42例).观察组采用贝伐单抗联合多西他赛化疗,对照组采用卡培他滨联合多西他赛化疗.2组均以21 d为1周期,共化疗3周期.对比分析2组总有效率、生活质量以及不良反应.结果 观察组有效率(64.45%)显著高于对照组(40.47%),差异有统计学意义(P<0.05);观察组生活质量改善率(68.89%)高于对照组(40.48%),差异有统计学意义(P<0.05);观察组胃肠道反应、骨髓抑制、手足综合征等不良反应发生率均低于对照组,差异有统计学意义(P均< 0.05);2组1 a生存率比较差异无统计学意义(P>0.05).结论 贝伐单抗联合多西他赛化疗方案对转移性乳腺癌患者临床疗效显著,可明显改善患者生活质量,降低不良反应发生率,值得进一步推广应用.     

贝伐珠单抗联合多西他赛治疗Her-2阴性复发转移性乳腺癌的疗效观察

背景与目的:贝伐珠单抗是首个抗血管生成的分子靶向药物,可以与多种化疗药物联合用于治疗复发转移性乳腺癌.本研究旨在观察贝伐珠单抗联合多西他赛治疗复发转移性乳腺癌的疗效和不良反应.方法:28例Her-2阴性的复发转移性乳腺癌患者均接受贝伐珠单抗联合多西他赛方案治疗,多西他赛75 mg/m2静滴,第1天:同时给予贝伐珠单抗15 mg/kg,第1天;21 d为1个周期.每个周期评价疗效同时记录不良反应.结果:27例患者可评价疗效和不良反应,其中CR 1例,PR 21例,有效率(CR+PR)为81.5%.粒细胞减少及白细胞减少是主要的不良反应,Ⅳ度粒细胞减少发生率为85.2%.研究中观察到高血压3例,静脉血栓1例,分级均为1级.蛋白尿12例,鼻衄15例,均为1～2级.结论:贝伐珠单抗联合多西他赛是治疗Her-2阴性的复发转移性乳腺癌患者的有效方案,其不良反应能够耐受.     

贝伐单抗联合化疗一线治疗转移性结直肠癌的Meta分析

目的 评价贝伐单抗（bevacizumab,BEV)联合化疗一线治疗转移性结直肠癌（metastaticcolorectal cancer, mCRC）的有效性和安全性。方法 通过The Cochrane Library、PubMed、EMBASE和中国生物医学文献数据库（CBM）、中国期刊全文数据库（CNKI）、维普数据库（VIP）、万方数据库等检索有关BEV联合化疗一线治疗mCRC的随机对照试验（randomized control trial, RCT）;主要研究指标是无进展生存时间（progression free survival, PFS）和总生存时间（overall survival,OS）,次要研究指标包括有效率（objective response rate, ORR）和不良反应;采用相对危险度（relative risk, RR）和风险比（hazard ratios, HR）为效应量,各效应量以95%置信区间（95%CI）表示,Stata 11.0统计软件进行Meta分析。结果 共纳入9项RCT,共3 930例mCRC患者,Meta分析结果显示,与单纯化疗相比,贝伐单抗(bevacizumb, BEV)联合化疗可以降低疾病进展风险（HR=0.62,P<0.0001, 95%CI: 0.64~0.74）和疾病死亡风险（HR=0.84, P<0.001,95%CI: 0.73~0.95）,提高mCRC的ORR（RR=0.80, P<0.001,95%CI: 0.60~0.93）。亚组分析显示BEV联合双药方案可降低疾病进展风险（HR=0.68, P<0.001, 95%CI: 0.46~0.89）,但并没有降低疾病死亡风险（HR=0.85, P=0.068,95%CI:0.68~1.03）;BEV联合氟尿嘧啶类单药降低疾病进展风险（HR=0.56,P<0.001, 95%CI: 0.47~0.64）和疾病死亡风险（HR=0.83,P<0.001,95%CI:0.68~0.97）。在不良反应方面,B E V 联合化疗没有增加治疗相关死亡率（RR=0.97, P=0.91,95%CI:0.62~1.54）;增加BEV相关不良反应发生率。结论 BEV联合化疗一线治疗能提高mCRC患者PFS、OS和RR。BEV联合不同化疗方案所带来生存获益大小不同。虽然BEV相关不良反应增加,但是可控的。     

贝伐株单抗联合化疗在HER2阴性进展期乳腺癌治疗中的疗效和安全性分析

目的：观察贝伐珠单抗（BV）联合化疗治疗HER2阴性进展期乳腺癌的疗效和安全性。方法回顾性分析接受贝伐株单抗治疗的15例进展期乳腺癌患者的临床资料,按照实体肿瘤疗效评价标准（RECIST 1.1）和美国国立癌症研究所不良反应事件通用术语标准评价疗效和不良反应,每2个月评估疗效,主要观察终点是无进展生存期（progression free survival,PFS）,每个周期评价不良反应。结果15例患者的中位PFS为4个月;治疗10个周期以上的患者为4例,6个周期以上者3例,其余8例均不足4个周期;15例患者均可评价疗效,5例（33.33%）PR中4例伴胸壁转移;5例SD（33.33%）,5例PD（33.33%）;主要不良反应为高血压4例、少量鼻出血3例、蛋白尿2例、贫血2例、血小板减少2例,经对症治疗后均好转,4例停药。结论贝伐珠单抗联合化疗作为二线及以上方案治疗进展期乳腺癌仍有一定疗效,对于伴胸壁转移的患者疗效尤其显著,不良反应可耐受。     

贝伐单抗治疗复发或晚期转移性乳腺癌的临床价值

分子靶向治疗是当前乳腺癌治疗领域研究的热点,贝伐单抗是第一个获得批准上市的抑制肿瘤血管生成的药,也是继抗Her-2靶向治疗领域之后另一全新领域。抗肿瘤血管靶向治疗领域;但目前关于贝伐单抗用于乳腺癌的有效性及安全性具有争议。本文汇总国内外关于贝伐单抗治疗乳腺癌的最新研究进展,并评价其临床使用价值。     

贝伐珠单抗联合化疗治疗转移性结直肠癌的研究进展

结直肠癌目前常规化疗方案为FOLFOX方案(氟尿嘧啶、亚叶酸钙、奥沙利铂),大量临床试验证明贝伐珠单抗联合FOLFOX方案治疗恶性肿瘤安全有效,但有高血压、神经毒性、胃肠道出血和穿孔等不良反应产生.对转移性结直肠癌患者应用此联合方案对整体生存时间、肿瘤应答率和生存质量进行的研究得出了不同的结论,其安全性和有效性仍需大样本随机对照试验或Meta分析来进一步研究证明.     

贝伐单抗治疗三阴性乳腺癌1例

患者，67岁，老年女性，于2004年1月8日行右乳腺癌根治术。术后病理示右乳腺乳晕区单纯癌，中间型，组织学Ⅲ级，乳头（＋），伴派杰病，皮肤（＋），中上、中下、中外、中内（-），淋巴结a／20，病理学分期：T4bNlbivM0，ⅢB期。免疫组化：ER（-），PR（-），Her2（-）。术后行CMF方案辅助化疗6周期，未行内分泌治疗及放疗。患者于2008年4月发现右胸壁手术瘢痕处出现质硬结节，     

贝伐单抗治疗转移性结直肠癌研究进展

贝伐单抗(bevacizumab)是一种重组人源化抗血管内皮生长因子的单克隆抗体,可与肿瘤细胞上的血管内皮生长因子(VEGF)特异性结合,通过抑制血管生成而抑制肿瘤生长.贝伐单抗已于2004年2月获FDA批准,与5-氟尿嘧啶为基础的化疗方案联合一线治疗转移性结直肠癌.推荐剂量为5 mg/kg,每14天给药1次,静脉滴注.贝伐单抗的耐受性良好,较常见的不良反应有高血压、出血和血栓形成.     

索拉非尼对HER2阴性转移性乳腺癌治疗效果Meta分析

目的 索拉非尼是首个获准上市的多靶点酪氨酸激酶抑制剂.近年来探讨索拉非尼治疗HER2阴性转移性乳腺癌的临床试验不断开展,但试验结论并不一致.本研究通过Meta分析评价索拉非尼联合化疗治疗HER2阴性转移性乳腺癌的有效性和安全性.方法 通过检索Pubmed、Embase以及Central等数据库,截止时间为2016-10,筛选索拉非尼联合化疗治疗HER2阴性的转移性乳腺癌的随机对照试验.试验结果应用Review Manager 5.3进行分析.结果 纳入5个临床试验共计1 381例HER2阴性转移性乳腺癌患者,索拉非尼联合化疗与单纯化疗相比,使患者的疾病进展时间(time to progression,TTP)明显延长,2组之间差异有统计学意义,HR=0.77,95％CI为0.60～0.99,P=0.04;而无病生存期(progression-free survival,PFS;HR=0.83,95％CI为0.64～1.07,P=0.14)、总生存期(overall survival,OS;HR=1.06,95％CI为0.90～1.23,P=0.49)、客观反应率(objective response rate,ORR;RR=1.12,95％CI为0.97～1.30,P=0.14)2组之间差异无统计学意义.3～4度的手足综合征、乏力、皮疹、胃炎及贫血发生率明显增多,P＜0.05;而中性粒细胞减少、血小板减少、腹泻以及高血压的发生率并未明显增加,P＞0.05.结论 相比单纯化疗,HER2阴性转移性乳腺癌患者可以从索拉非尼联合化疗治疗中获益,但手足综合征、皮疹等不良事件发生率有所增加.     

HER-2阳性乳腺癌患者新辅助化疗联合曲妥珠单抗治疗的影响因素及预后分析

目的:探讨人类表皮生长因子受体（human epidermal growth factor receptor 2,HER-2）阳性乳腺癌患者应用新辅助化疗联合曲妥珠单抗的疗效及其预后的影响因素。方法:选取2014年01月01日至2018年12月31日郑州市第三人民医院乳腺甲状腺外科收治经穿刺病理证实为乳腺癌的患者151例,免疫组化结果均显示为HER-2阳性,并行新辅助化疗,根据患者经济条件及意愿选择是否接受曲妥珠单抗治疗,将其分为单纯新辅助化疗组（neoadjuvant chemotherapy,NAC）94例,新辅助化疗联合曲妥珠单抗组（NAC+H）57例,对比两组患者无病生存期（disease-free survival,DFS）和总生存期（overall survival,OS）情况,并分析影响预后的相关因素。结果: 151例HER-2阳性乳腺癌患者中,NAC+H组患者DFS（P=0.046）和OS（P=0.026）均明显优于NAC组,两组比较差异具有统计学意义。术前淋巴结状态、术后淋巴结状态、肿瘤大小、MP分级是影响患者DFS和OS的主要影响因素（P值分别为0.032、0.018、0.038、0.010）。结论:接受新辅助化疗联合曲妥珠单抗的HER-2阳性乳腺癌患者预后较好,两组在新辅助治疗后肿瘤大小、淋巴结状态及MP分级结果存在明显差异,该结果对选择合理的治疗方案、判断预后有重要作用。     

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.     

曲妥珠单抗联合TC化疗对HER-2阳性晚期乳腺癌外周血及预后影响

目的:探究曲妥珠单抗联合TC（环磷酰胺＋多西他赛）化疗对人类表皮生长因子受体-2（HER-2）阳性晚期乳腺癌患者外周血T淋巴细胞亚群、组织多肽特异性抗原（TPS）水平及预后的影响。方法:选取2015年1月-2017年3月我院72例HER-2阳性晚期乳腺癌作为研究对象,依据随机数字表法分组,各36例。对照组于乳腺癌改良根治术前予以TC化疗,观察组于对照组基础上予以曲妥珠单抗治疗。统计两组客观缓解率、无进展生存期及治疗前后血清T淋巴亚群、糖链抗原125（CA125）、TPS水平及生存质量（KPS）评分。采用方差、卡方进行统计学分析。结果:观察组客观缓解率44.44%较对照组22.22%高,差异有统计学意义（P=0.046）;观察组治疗后血清CD3+、CD4+、CD8+、CD4+/CD8+与对照组相比,差异无统计学意义（P>0.05）;观察组治疗后血清CA125水平［（32.10±3.46）IU/ml］、TPS水平［（263.41±53.84）IU/ml］低于对照组［（38.59±2.39）IU/ml,（355.26±47.84）IU/ml］,差异具有统计学意义（P均＜0.001）;观察组治疗后KPS评分［（91.06±3.85）分］高于对照组［（85.49±5.32）分］,差异具有统计学意义(P＜0.001）;观察组无进展生存期为（19.22±1.37）个月较对照组（15.43±1.35）个月长,差异有统计学意义（P=0.000）。结论:对HER-2阳性晚期乳腺癌患者予以TC化疗同时,加用曲妥珠单抗,可明显提高化疗效果,有效降低患者血清CA125、TPS水平,延长无进展生存期,提高生存质量,且未增加免疫功能损伤,值得临床推广与应用。     

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。     

Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites.

BACKGROUND: The humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) is a new treatment modality for metastatic breast cancer, the efficacy of which is directly correlated with the HER-2 status of the tumour, evaluated either by immunohistochemistry (IHC) and/or by fluorescence in situ hybridisation (FISH). This analysis is generally performed on the primary tumour. There are few data regarding the HER-2 status in the corresponding distant metastases. METHODS: HER-2 status in 107 patients with a primary breast tumour and at least one distant metastatic lesion was analysed by IHC and FISH. RESULTS: We found similar levels of amplification (25% and 24%) and overexpression (13% and 19%) of HER-2 in primary and metastatic samples, respectively. Among paired primary/metastatic tumours, six (6%) showed discordance by HercepTest(TM) (n = 100): all six cases showed greater Her-2 overexpression in the metastatic tissue. By FISH (n = 68), five (7%) cases were discordant: two cases were amplified in the primary tumour but not in the metastasis, and three samples showed amplification in the metastasis but not in the primary. Finally, we analysed HER-2 status in different metastatic lesions from 17 patients that had at least two distant metastatic sites. Discordance between different sites from the same patient was 18% by IHC and 19% by FISH. CONCLUSIONS: Between the paired primary tumour and distant metastatic lesions, 94% and 93% of samples had concordant HER-2 status when analysed by IHC or FISH, respectively. These results do not support routine determination of HER-2 on metastatic sites, particularly when FISH results from the primary tumour are available.     

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.     

曲妥珠单抗联合微波热疗治疗HER-2阳性晚期乳腺癌的临床疗效分析

目的:探讨曲妥珠单抗联合微波热疗治疗HER-2阳性晚期乳腺癌患者的临床疗效。方法:选取我院2018年1月至2018年12月收治的HER-2阳性晚期乳腺癌患者54例,按随机表法分为治疗组与对照组,每组27例。两组均采用曲妥珠单抗治疗,治疗组同时给予微波热疗。比较两组患者免疫功能、循环肿瘤细胞（CTCs）、生存质量、近期疗效、总生存期及不良反应情况。结果:治疗组免疫功能和生存质量提高（P<0.05）,CTCs数量下降（P<0.05）;治疗组近期疗效及总生存期优于对照组（P<0.05）;两组不良反应发生率比较差异无统计学意义（P>0.05）。结论:曲妥珠单抗联合微波热疗治疗HER-2阳性晚期乳腺癌患者具有良好的临床疗效且安全性较高。     

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阴性乳腺癌中VEGF、COX-2的表达及相关性研究

目的:研究血管内皮生长因子（VEGF）、环氧化酶-2（COX-2）在91例HER-2阴性乳腺癌组织中的表达及相互关系,分析其与临床病理特征及预后的关系。方法:采用免疫组化SABC法,检测91例HER-2阴性乳腺癌组织中VEGF、COX-2蛋白的表达,并与临床病理特征进行相关性分析。结果:HER-2阴性乳腺癌组织中VEGF阳性表达率为94.5%,其中47.2%为高表达（+++）,VEGF的表达与肿瘤大小、淋巴结转移相关（P<0.05）。HER-2阴性乳腺癌组织中COX-2阳性表达率为86.8%,其中34.0%为高表达（+++）,COX-2的表达与患者年龄、组织学分级、肿瘤大小、淋巴结转移及TNM分期无关（P>0.05）。VEGF与COX-2的表达呈正相关（r=0.1798,P=0.018）,VEGF/COX-2均高表达的患者淋巴结转移率高。结论:VEGF、COX-2在HER-2阴性乳腺癌组织中均高表达且两者呈正相关,联合检测VEGF、COX-2的表达对HER-2阴性乳腺癌预后判断可能具有重要价值。