HER2阳性乳腺癌中CD44v6的表达与曲妥珠单抗耐药的关系

目的:探讨曲妥珠单抗在治疗HER2阳性的转移性乳腺癌时,产生耐药性与CD44v6表达的相关性。方法:共66例HER2阳性转移性乳腺癌患者入组。接受曲妥珠单抗治疗的患者37例,其中18例获得了治疗前和治疗后转移性癌组织。采用免疫组化S-P法对治疗前、治疗后的不同乳腺组织进行CD44v6表达的研究。结果:CD44v6在经曲妥珠单抗治疗产生耐药的活检组织中阳性表达程度明显高于治疗前。结论:CD44v6的表达与曲妥珠单抗耐药相关。     

曲妥珠单抗治疗HER2阳性乳腺癌的耐药机制及新疗法探索

研究表明大约有20％的乳腺癌患者存在HER2过表达现象。HER2的异常表达及异常信号通路与乳腺癌的侵袭转移、治疗抵抗及不良预后密切相关。在临床上,对于HER2阳性的初期乳腺癌患者常联合曲妥珠单抗及化学药物治疗,但部分患者对曲妥珠单抗产生耐药。因此,研究其耐药机制对于HER2阳性乳腺癌患者的治疗、预后及新疗法的探索具有重要的临床意义。目前引起曲妥珠单抗抵抗的主要机制有：p95-HER2累积、P13K／AKT／mTOR信号异常激活、HER家族受体和IGF-1R信号增加、非受体酪氨酸激酶c-SRC活性增加等。将对上述机制及治疗HER2阳性乳腺癌的新疗法进行综述。     

曲妥珠单抗辅助或新辅助治疗HER2 阳性转移性乳腺癌的临床结果

目的:比较人表皮生长因子受体2过表达(HER2+)的患者既往接受以曲妥珠单抗为基础辅助或新辅助治疗后再次接受针曲妥珠单抗治疗的临床结果。方法:共247例(I-III期170例,IV期77例)HER2+转移性乳腺癌患者,其中首次接受曲妥珠单抗治疗患者211例(I-III期134例,IV期77例),再次接受曲妥珠单抗治疗患者36例(I-III期)。使用Cox比例风险回归和logistic回归分析首次或提前接受曲妥珠单抗治疗的患者的预后的临床结果,生存评估使用Kaplan-Meier法。结果:I-III期HER2+转移性乳腺癌患者中,未预先接受曲妥珠单抗治疗组的中位总生存期为36个月和预先接受曲妥珠单抗治疗组为28个月(危害比[HR],1.45;95%CI,1.05-2.02[P=0.012]);I-IV期HER2+转移性乳腺癌患者中,未预先使用曲妥珠单抗组的中位总生存期为37个月,客观缓解率58%;临床获益率77%;预先使用曲妥珠单抗组为25个月,客观缓解率28%;临床获益率37%;调整后的比值比为客观缓解率0.37(9%CI,0.18-0.77;P=0.010)和临床获益率0.28(95%CI,0.14-0.59;P=0.014)。单因素分析没有提前接受曲妥珠单抗治疗组中位总生存率较长(P=0.012)。多因素分析发现总生存率没有显著差异(P=0.19)。结论:当曲妥珠单抗用于转移性疾病,没有提前接受曲妥珠单抗治疗的HER2+乳腺癌患者临床结果优于提前接受曲妥珠单抗治疗的患者。     

无岩藻糖修饰曲妥珠单抗的研究进展

乳腺癌是女性常见癌症中致死率最高的恶性肿瘤疾病之一,严重危害女性的生命健康。其中,以HER2阳性乳腺癌发病率和致死率最高。曲妥珠单抗在治疗HER2阳性乳腺癌上具有显著的临床疗效,然而由于患者耐药性的产生、HER2表达异常、用药成本高等原因,曲妥珠单抗在实际临床使用过程中存在极大的局限性。研究发现敲除抗体Fc段寡糖的核心岩藻糖可明显提高曲妥珠单抗的ADCC效应,改善其临床疗效。综述了如何敲除曲妥珠单抗的核心岩藻糖、无岩藻糖修饰曲妥珠单抗的临床优势以及提高其ADCC效应的其他Fc段改造方法。     

HER2 阳性乳腺癌转移患者最佳治疗方案的研究进展

针对人表皮生长因子受体HER2 的靶向制剂曲妥珠单抗,显著改善了HER2 阳性乳腺癌转移患者疾病的发展状况,提高了 患者的总体生存期（OS）,然而耐药现象时有发生。其它靶向制剂如帕妥珠单抗,酪氨酸激酶受体抑制剂拉帕替尼和ado-transtusumab emtansine等克服了其耐药性,为治疗提供了更多选择。这些HER2 靶向制剂单用或联用已显示出良好的临床功效,但最 佳治疗次序依然未知。随着新型靶向制剂的出现,最佳治疗方案的研究成为热点。本篇综述重点阐述了目前HER2 阳性乳腺癌转 移患者最佳治疗方案的研究进展,以及新型靶向制剂的现有状况。     

曲妥珠单抗在HER-2阳性乳腺癌治疗中的研究进展

乳腺癌是女性最常见的恶性肿瘤之一,中国女性乳腺癌发病率逐年上升。人表皮生长因子受体2(human epidermal growth factor receptor-2,HER-2)在近三分之一的乳腺癌患者中呈现基因扩增或受体蛋白高表达。HER-2阳性的乳腺癌患者预后差,术后复发风险高、生存期短。曲妥珠单抗是人表皮生长因子受体-2的特异性抑制剂[1],在HER-2阳性乳腺癌患者的治疗中得到了广泛的应用,并且曲妥珠单抗分子靶向治疗相比于传统的化疗,具有特异性较强,毒副反应相对较小等优点。它改变了HER-2阳性乳腺癌患者的自然疾病进程,延长了患者的生存时间。本文将从四个方面对曲妥珠单抗在HER-2阳性乳腺癌患者治疗中的研究、应用及进展进行综述。     

曲妥珠单抗联合多西紫杉醇在HER-2 阳性晚期乳腺癌中的应用

目的:探讨曲妥珠单抗联合多西紫杉醇在HER-2阳性晚期乳腺癌中的应用。方法:收取2010年2月至2016年1月我院收治的82例HER-2阳性晚期乳腺癌患者作为研究对象,根据不同治疗方案分为观察组及对照组。观察组43例患者给予曲妥珠单抗联合多西紫杉醇治疗,多西紫杉醇以3周为1个周期连续用药4个周期,曲妥珠单抗连续使用8周~52周。对照组39例患者只给予曲妥珠单抗单药治疗。对两组患者临床疗效、临床受益反应指数以及不良反应发生情况进行观察与比较。结果:51P1察组总有效率(60.47%)高于对照组(43.59%),但差异无统计学意义(P0.05)。观察组疾病控制率(90.70%)显著高于对照组(71.79%),差异有统计学意义(P0.05)。观察组临床受益反应有效率(76.74%)显著高于对照组(41.03%)差异有统计学意义(P0.05)。两组患者不良反应无显著差异(P0.05)。结论:曲妥珠单抗联合多西紫杉醇对于HER-2阳性晚期乳腺癌有较好的临床疗效及安全性,患者临床受益高。     

曲妥珠单抗联合NSC 74859 对曲妥珠耐药的乳腺癌细胞的抑制作用研究

目的:观察曲妥珠单抗(Trastuzumab)与转录信号转导子与激活子3蛋白(STAT3)抑制剂NSC 74859联用对曲妥珠耐药细胞株SK-BR-3R的生长抑制作用及机理研究。方法:采用四甲基偶氮唑蓝(MTT)法鉴定曲妥珠耐药的SK-BR-3R细胞株并检测曲妥珠单药处理、NSC 74859单药处理以及两药联用处理对SK-BR-3R细胞的生长抑制程度。建立SK-BR-3R的皮下肿瘤模型,观察两药联用对肿瘤生长的抑制效果;通过免疫印迹(Western Blot)实验检测SK-BR-3R细胞中磷酸化HER2(p-HER2),磷酸化STAT3(p-STAT3)及磷酸化AKT(p-AKT)的水平。结果:当曲妥珠浓度在50 nmol/L及NSC 74859的浓度在50μmol/L联用时,较之两药单用显示了显著的抑制效果,其差异具有统计学意义;进一步在建立的SK-BR-3R小鼠肿瘤模型中观察到了曲妥珠联合NSC74859治疗组显示了比曲妥珠或NSC 74859单独使用时更显著的抑瘤效果。最后,免疫印迹实验显示了曲妥珠和NSC74859联合处理显著降低了SK-BR-3R细胞的HER2,STAT3及AKT的磷酸化水平。结论:曲妥珠单抗联合NSC 74859使用可显著抑制曲妥珠耐药的乳腺癌细胞SK-BR-3R的生长,其机制可能是药物协同抑制了对肿瘤生长重要的PI3K/AKT信号通路。本研究可为临床上治疗曲妥珠耐药的乳腺癌提供参考。     

曲妥珠单抗联合榄香烯注射液治疗乳腺癌的疗效及对血清BNP、cTnⅠ表达的影响

摘要 目的：探究曲妥珠单抗联合榄香烯注射液治疗乳腺癌的疗效及对血清BNP、cTnⅠ表达的影响。方法：2018年2月至2021年6月于我院接受治疗的78例乳腺癌患者,将其按照治疗药物的不同分为观察组（39例）与对照组（39例）,观察组给予曲妥珠单抗联合榄香烯注射液治疗,对照组仅给予曲妥珠单抗注射液治疗,对比两组患者治疗效果、术前术后T淋巴细胞亚群水平、生活质量、毒性反应、血清脑利钠肽（BNP）和高敏心肌肌钙蛋白（cTnⅠ）水平情况。结果：（1）观察组治疗总有效率较对照组高（P<0.05）;（2）观察组毒性反应总发生率为15.38 %显著低于对照组的35.90 %（P<0.05）;（3）治疗后观察组的CD3⁺、CD4⁺水平均较对照组高,CD8⁺水平较对照组低（P<0.05）;（4）治疗后血清cTnⅠ、BNP水平逐渐升高,且每一周期对照组血清cTnⅠ水平高于观察组（P<0.05）。（5）治疗后观察组躯体功能、认知功能、总体健康状况评分显著高于对照组（P<0.05）。结论：曲妥珠单抗联合榄香烯注射液治疗乳腺癌的可行性较好,能显著提高治疗有效率,改善患者的生活质量和免疫功能,同时还能降低血清BNP和cTnⅠ水平,值得临床推广应用。     

CISH技术在乳腺癌Her-2基因检测中的应用

原癌基因Her-2是人类表皮生长因子受体家族的第二个成员,该家族中的受体均位于细胞膜上,在许多组织中都能发现。乳腺癌居女性癌症发病率之首,研究显示Her-2在20％-30％的乳腺癌中过度表达,与乳腺癌的侵袭转移及预后密切相关。目前随着靶向药物曲妥珠单抗（赫赛汀）的发展,乳腺癌复发率及死亡率大大降低,曲妥珠单抗（赫赛汀）靶向治疗的关键是Her-2基因是否扩增,常用的Her-2基因检测方法是免疫组化（IHC）法和荧光原位杂交（FISH）法,但其结果之间一致性较差。     

miR‐200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer

Resistance to trastuzumab remains a major obstacle in HER2‐overexpressing breast cancer treatment. miR‐200c is important for many functions in cancer stem cells (CSCs), including tumour recurrence, metastasis and resistance. We hypothesized that miR‐200c contributes to trastuzumab resistance and stemness maintenance in HER2‐overexpressing breast cancer. In this study, we used HER2‐positive SKBR3, HER2‐negative MCF‐7, and their CD44⁺CD24^? phenotype mammospheres SKBR3‐S and MCF‐7‐S to verify. Our results demonstrated that miR‐200c was weakly expressed in breast cancer cell lines and cell line stem cells. Overexpression of miR‐200c resulted in a significant reduction in the number of tumour spheres formed and the population of CD44⁺CD24^? phenotype mammospheres in SKBR3‐S. Combining miR‐200c with trastuzumab can significantly reduce proliferation and increase apoptosis of SKBR3 and SKBR3‐S. Overexpression of miR‐200c also eliminated its downstream target genes. These genes were highly expressed and positively related in breast cancer patients. Overexpression of miR‐200c also improved the malignant progression of SKBR3‐S and SKBR3 in vivo. miR‐200c plays an important role in the maintenance of the CSC‐like phenotype and increases drug sensitivity to trastuzumab in HER2+ cells and stem cells.     

Targeting of preexisting and induced breast cancer stem cells with trastuzumab and trastuzumab emtansine (T-DM1)

The antibody trastuzumab (Herceptin) has substantially improved overall survival for patients with aggressive HER2-positive breast cancer. However, about 70% of all treated patients will experience relapse or disease progression. This may be related to an insufficient targeting of the CD44^highCD24^low breast cancer stem cell subset, which is not only highly resistant to chemotherapy and radiotherapy but also a poor target for trastuzumab due to low HER2 surface expression. Hence, we explored whether the new antibody-drug conjugate T-DM1, which consists of the potent chemotherapeutic DM1 coupled to trastuzumab, could improve the targeting of these tumor-initiating or metastasis-initiating cells. To this aim, primary HER2-overexpressing tumor cells as well as HER2-positive and HER2-negative breast cancer cell lines were treated with T-DM1, and effects on survival, colony formation, gene and protein expression as well as antibody internalization were assessed. This revealed that CD44^highCD24^lowHER2^low stem cell-like breast cancer cells show high endocytic activity and are thus particularly sensitive towards the antibody-drug conjugate T-DM1. Consequently, preexisting CD44^highCD24^low cancer stem cells were depleted by concentrations of T-DM1 that did not affect the bulk of the tumor cells. Likewise, colony formation was efficiently suppressed. Moreover, when tumor cells were cocultured with natural killer cells, antibody-dependent cell-mediated cytotoxicity was enhanced, and EMT-mediated induction of stem cell-like properties was prevented in differentiated tumor cells. Thus our study reveals an unanticipated targeting of stem cell-like breast cancer cells by T-DM1 that may contribute to the clinical efficacy of this recently approved antibody-drug conjugate.     

MicroRNA-21 as a predictor and prognostic factor for trastuzumab therapy in human epidermal growth factor receptor 2-positive metastatic breast cancer

Breast cancer is the second most common cancer diagnosed worldwide. Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents about 20% to 30% of all breast cancers. Trastuzumab is used in the treatment of HER2-positive breast cancer. MicroRNA-21 (miR-21) is an oncomiR that acts by inhibiting many tumor-suppressor genes. We analyzed the relative expression levels of serum miR-21 in 20 HER2-positive metastatic breast cancer patients before and after 3 months of treatment with trastuzumab. miR-21 levels decreased with a high significant difference after trastuzumab therapy (P = 0.001). Although miR-21 expression levels were lower in responders than in nonresponders, the difference was not statistically significant ( P = 0.6). Our results demonstrated a significant negative correlation between its basal expression, expression levels after treatment, and time to progression ( P = 0.03 and 0.01, respectively). These results make miR-21 a potential prognostic factor for HER2-positive metastatic breast cancer patients. Additionally, it can be an interesting potential target in therapy using antisense oligonucleotides for miR-21.     

Expression of HER2 in breast cancer

In breast cancer the membrane expression of HER2 receptor protein encoded by the HER2 proto-oncogene seems to have an ever growing clinical significance. In tissue cultures and animal experiments it was shown that the HER2 gene amplification induces malignant transformation and intensifies the aggressiveness of the tumour cells. Correlating with the so called pheno-and genotypic prognostic markers, the overexpression of HER2 in breast cancer predicts also poor prognosis and indicates enhanced potential for metastatisation. In some of the so called precancerous proliferations and "in situ" carcinomas we demonstrated the enhanced membrane staining of the HER2 receptor protein. In these cases we frequently observed DNA aneuploidy,the presence of p53 mutational protein and CD44v6 glycoprotein. The immunohistochemical studies of HER2 protein in invasive carcinomas have revealed, an interrelationship between the grade of differentiation, histological type, aggressiveness and biological behaviour of the "in situ" and invasive carcinomas. In clinical studies trastuzumab, a humanized monoclonal antibody recognizing extracellular domain of HER2 receptor protein, has proved to be effective in HER2 overexpressing metastatic breast cancer either as monotherapy or in combination with chemotherapeutical agents. The DAKO "HercepTest" is a semiquantitative, standardised method for the determination of HER2 overexpression.     

大肠癌组织及癌旁组织中c—myc，COX-2和CD44v6基因表达量差异的检测

目的：通过检测大肠癌组织和癌旁组织中c-myc,COX-2以及CD44v6的表达水平,探讨这三种基因在大肠癌发生和发展中的意义。方法：应用实时荧光定量PCR技术检测了10例大肠癌组织和相应癌旁组织中c-myc,COX-2以及CD44v6基因表达水平的差异,并探讨了各基因在癌纽织中的表达水平与大肠癌临床病理指标之间的关系。结果：c-myc,COX-2以及CD44v6在大肠癌组织和癌旁组织中的表达均有非常显著性差异（P〈0．01）;癌组织中COX-2和CD44v6的表达与淋巴结转移、分化程度及Dukes分期有关（P〈0．05）。结论：c—myc,COX-2和CD44v6的异常表达均与大肠癌密切相关,三者从不同方面对大肠癌的发生和发展起到了重要作用,可作为早期诊断和预后的参考指标。