曲妥珠单抗耐药机制的最新研究进展

人类表皮生长因子受体2(human epidermal growth factor receptor 2,Her-2)在20%～25%的侵袭性乳腺癌中有过度表达,且其过度表达与乳腺癌的侵袭性和生存率相关.曲妥珠单抗(商品名:赫赛汀,herceptin)是一种己广泛应用于临床治疗的抗Her-2的单克隆抗体,其与化疗药物联用可以明显延长患者的无病生存期,但Her-2表达阳性的乳腺癌细胞易对曲妥珠单抗产生耐药性.本文系统总结了曲妥珠单抗的耐药机制及相关最新研究进展,包括PI3K/AKT信号通路过度激活、表皮生长因子受体家族(epidermal growth factor receptor family,EGFR family)及其配体的异常表达、Her-2或曲妥珠单抗封闭、胰岛素样生长因子1受体(insulin-like growth factor 1 receptor,IGF-IR)旁路活化P13K/AI(T通路、Darpp-32和t-Darpp过度表达、肿瘤细胞自体吞噬、热休克蛋白27(heat shock protein 27,HSP27)过度表达等.     

曲妥珠单抗在HER2阳性胃癌中耐药机制研究进展

曲妥珠单抗是晚期人表皮生长因子受体2（HER2）阳性胃癌患者治疗的一线用药,耐药问题是曲妥珠单抗治疗中面临 的主要挑战。曲妥珠单抗治疗的耐药机制除了与HER2自身状态有关外,也与PI3K/AKT、MEK/ERK等经典信号通路以及有丝 分裂相关的非经典信号通路的异常激活有关,胃癌肿瘤微环境中代谢及免疫调控的改变也会导致患者对曲妥珠单抗耐药,目前 抗体药物偶联物等新型治疗方案可以克服并改善曲妥珠单抗的耐药性。本文聚焦曲妥珠单抗在HER2阳性胃癌中的耐药机制及 其克服曲妥珠单抗耐药新型疗法的研究进展,为临床优化曲妥珠单抗治疗HER2阳性胃癌提供了新思路。     

曲妥珠单抗获得性耐药机制及应对策略

摘 要：曲妥珠单抗是靶向人表皮生长因子2(HER2)的单克隆抗体药物,对HER2表达阳性乳腺癌及胃癌治疗效果确切。然而多数患者在用药1年内出现了获得性耐药,导致其疗效降低甚至无效。研究表明,信号通路异常激活;表皮生长因子受体(EGFR)及其配体异常表达及肿瘤诱发上皮—间质转化(EMT)均可成为曲妥珠单抗耐药的重要机制,联合使用PI3K/AKT/mTOR通路抑制剂及其相关生存信号通路抑制剂可逆转曲妥珠单抗耐药。本文就曲妥珠单抗耐药机制及逆转耐药策略进行综述。     

含曲妥珠单抗二线治疗HER2阳性乳腺癌的临床价值及安全性分析

目的探讨含曲妥珠单抗二线治疗人表皮生长因子受体2(HER2)阳性乳腺癌的临床价值及安全性。方法选择采用二线方案治疗的78例HER2阳性乳腺癌患者为研究对象,根据患者治疗方式不同分为A组与B组。2组患者均接受吉西他滨联合卡培他滨二线治疗方案,B组患者同时接受曲妥珠单抗治疗。比较2组近期疗效、2年生存率及不良反应发生率。结果 A组与B组治疗有效率及临床获益率均无显著差异(P>0.05);B组2年生存率显著优于A组(P<0.05)。骨髓抑制及消化道不良反应是2组常见的化疗不良反应;曲妥珠单抗的主要不良反应为发热及疼痛,经对症治疗后均完成治疗。结论含曲妥珠单抗二线治疗方案治疗HER2阳性乳腺癌可延长患者生存期,安全性好。     

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.     

以曲妥珠单抗为基础的HER-2阳性乳腺癌双靶向治疗进展

HER-2阳性乳腺癌侵袭性强、复发率高,针对HER-2的单靶向治疗虽使患者生存期得以延长,但仍有患者发生复发转移。双靶向治疗因其作用机制不重叠,具有协同作用,使患者生存期得以进一步延长。本文以曲妥珠单抗靶向治疗为基础,对与联合抗HER-2的双靶向治疗的研究现状和进展进行综述。      

曲妥珠单抗耐药机制及HER2阳性乳腺癌耐药后的治疗策略

曲妥珠单抗治疗人表皮生长因子受体2(Human epidermal growth factor receptor 2,HER2)阳性乳腺癌的效果确切,但高耐药率限制了其临床应用。本文对HER2阳性乳腺癌曲妥珠单抗耐药机制进行回顾与总结,并分析耐药后HER2阳性乳腺癌的治疗策略,以期为进一步的研究及临床治疗方案制定提供参考。     

曲妥珠单抗耐药的机制和对策研究进展

曲妥珠单抗是人表皮生长因子受体2(HER2)过表达乳腺癌患者的重要治疗手段之一.但即使是HER2高表达或是基因扩增的患者,曲妥珠单抗单药的有效率也仅为12%～34%,中位缓解期约9个月,许多患者在接受治疗的12个月内出现疾病进展.对曲妥珠单抗的耐药机制进行研究,有助于我们为曲妥珠单抗耐药的患者寻找新的治疗药物和方法.     

曲妥珠单抗在HER-2阳性乳腺癌患者新辅助治疗中的应用研究进展

曲妥珠单抗是人表皮生长因子受体-2（human epidermal growth factor receptor-2,HER-2）的特异性抑制剂,在HER-2阳性乳腺癌患者新辅助治疗中的应用日益广泛。大规模的随机、对照临床试验证实,新辅助化疗联合曲妥珠单抗与单纯化疗比较能显著提高病理完全缓解（pathologic complete response,pCR）率。在曲妥珠单抗联合化疗的基础上加用拉帕替尼较单用曲妥珠单抗可大大提高pCR率。蒽环与非蒽环类化疗药物均可作为曲妥珠单抗的联合用药,内分泌治疗也可作为雌激素受体阳性患者的联合用药。pCR是曲妥珠单抗新辅助治疗后生存获益的独立预后因素,HER-2转阴而未达到pCR的患者为不良预后因素。本文将对曲妥珠单抗在HER-2阳性乳腺癌患者新辅助治疗中的研究进展进行综述。      

Src,a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma

Background:

Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas.

Methods:

We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients'' outcome.

Results:

Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab.

Conclusions:

Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients.     

曲妥珠单抗耐药后HER 2阳性转移性乳腺癌靶向治疗策略

人表皮生长因子受体2（human epidermal growth factor receptor 2,HER 2）是一种跨膜酪氨酸激酶受体,可以激活下游一系列信号通路,导致肿瘤细胞增殖和存活。HER 2阳性乳腺癌是乳腺癌的特殊类型,恶性程度高,预后差。抗HER 2单克隆抗体曲妥珠单抗能够改善该类乳腺癌治疗效果,但最终仍难逃耐药的结局。近年来,针对曲妥珠单抗耐药机制的研究、新型靶向药物的研发以及治疗策略的探索,在克服曲妥珠单抗耐药性方面取得了重大进展,本文将对其耐药后治疗策略及临床试验数据进行综述。     

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer.     

Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study

BACKGROUND:

A series of retrospective studies have reported that patients with human epidermal growth factor receptor 2(HER2)‐positive breast cancer are at a greater risk of central nervous system (CNS) metastases. Trastuzumab, which does not cross the blood‐brain barrier, has been associated with this increased risk.

METHODS:

The authors evaluated incidence, survival, and risk factors for CNS metastases in the incident breast cancer population systematically collected by the Parma Province Cancer Registry over the 4‐year period between 2004 and 2007.

RESULTS:

A total of 1458 patients with a diagnosis of stage I to III invasive breast cancer were analyzed for study purposes. At a median follow‐up of 4.1 years, CNS events were observed in 1.3% and 5% of HER2‐negative patients and HER2‐positive patients, respectively (P < .0001). The administration of trastuzumab either as adjuvant therapy or for metastatic disease was associated with a significantly increased risk of CNS involvement at first disease recurrence and after first extracranial recurrence, respectively. According to multivariate analysis, HER2‐positive status and trastuzumab treatment, high Ki‐67 index, and hormone receptor negativity remained independent risk factors for the development of CNS metastasis.

CONCLUSIONS:

To the authors' knowledge, this is the first population‐based cancer registry study analyzing factors associated with CNS recurrence in a general population of newly diagnosed breast cancer patients with known HER2 status. The data from the current study provide evidence that patients with HER2‐positive breast cancer have a significantly higher incidence of CNS metastasis after treatment with trastuzumab. Improvements in systemic control and overall survival associated with trastuzumab‐based therapy may lead to an “unmasking” of CNS disease recurrence that would otherwise remain clinically silent before a patient's death. Cancer 2011. © 2010 American Cancer Society.     

Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

Background:

Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed.

Methods:

We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation.

Results:

We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P⩽0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P⩽0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P⩽0.019; Cox analysis).

Conclusion:

Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas.