乳腺癌分子靶向治疗临床研究进展

乳腺癌是威胁妇女健康的主要恶性肿瘤，化疗和内分泌治疗是乳腺癌主要的全身治疗手段，在复发转移乳腺癌的解救治疗和早期乳腺癌的辅助治疗中取得明确疗效。分子肿瘤学研究成果，义使分子靶向药物在乳腺癌治疗中取得显著疗效。赫赛汀(Herceptin)是针对癌细胞Her-2基因靶点的第一个分子靶向药物，为乳腺癌临床治疗带来了新的突破。     

三阴乳腺癌研究进展

三阴乳腺癌是指雌激素受体(ER)、孕激素受体(PR)、人类表皮生长因子受体-2(Her-2)均不表达的乳腺癌,是乳腺癌的一种特殊亚型,有着特殊的生物学特性和临床病理特征,对内分泌治疗及针对Her-2的靶向药物赫赛汀无效,对化疗敏感,但是远期疗效不佳.三阴乳腺癌的特点,以及治疗方案的选择,是近年研究的热点.     

三阴性乳腺癌的靶向治疗研究进展

 三阴性乳腺癌（TNBC）是乳腺癌的一种特殊亚型,对内分泌治疗无效,针对Her-2靶点的靶向治疗如赫赛汀、拉帕替尼等也并不适用。目前,常规化疗是内科治疗TNBC的惟一途径。寻找TNBC的治疗靶点是目前乳腺癌的研究热点之一,正在研发的新靶向治疗药物包括PARP-1抑制剂、EGFR抑制剂、CXCR4抑制剂、抗血管生成、Src酪氨酸激酶抑制剂、mTOR抑制剂等。     

乳腺癌抗Her-2治疗进展

分子靶向药物与细胞毒药物相比具有选择性高、毒副反应低的优点,成为肿瘤治疗领域的研究热点。目前乳腺癌分子靶向治疗主要为抗Her-2和抗血管生成。赫赛汀、帕妥珠单抗、T-DM1等新的抗Her-2药物给患者带来了明显的生存获益和更多的选择。本文对乳腺癌抗Her-2治疗的研究进展进行综述。     

不同生物学标志物对乳腺癌新辅助化疗疗效的预测价值

背景与目的:寻找乳腺癌新辅助化疗疗效预测指标将有助于筛选对化疗敏感的患者,指导个体化治疗.因此,本研究旨在探讨不同生物学标志物对紫杉醇类药物联合蒽环类药物的新辅助化疗方案治疗乳腺癌的疗效预测价值.方法:对160例行4个周期紫杉醇类药物联合蒽环类药物的新辅助化疗方案治疗的乳腺癌患者资料进行回顾性分析.采用免疫组织化学法检测术前肿瘤穿刺标本中雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PgR)、人类表皮生长因子受体2(human epidermal growth factor receptor-2,Her-2)、Topo-Ⅱ和Ki-67蛋白的表达,分析其与临床疗效及病理改变的关系.结果:总临床有效率为85%,其中临床完全缓解为46例(28.8%),部分缓解率为90例(56.3%);病理完全缓解23例.单因素分析发现ER、PgR表达阴性及Her-2过表达均可预测临床完全缓解及病理完全缓解(P＜0.05).多因素分析发现Her-2过表达仍是预测临床完全缓解的独立变量(P=0.011),仅ER阴性为预测病理完全缓解的独立变量(P=0.001).结论:Her-2过表达、ER阴性的患者对紫杉醇类药物联合蒽环类药物的新辅助化疗方案更敏感,可作为该方案的疗效预测参考指标.     

联合应用表柔比星与多西他赛辅助化疗三阴乳腺癌的疗效分析

三阴乳腺癌是指雌激素受体、孕激素受体、人表皮生长因子受体2均为阴性的乳腺癌［1］。可分为Luminal型、Her-2＋型及 Basal-like 型。恶性程度高,病死率高,复发转移快,无法从内分泌治疗及抗Her-2靶向治疗中受益而使得治疗手段相对其他乳腺癌受到限制［2］。本研究对我院2009年8月-2013年10月收治的80例三阴乳腺癌患者给予表柔比星联合多西他赛（ET）方案辅助化疗治疗,取得良好效果,报道如下。     

赫赛汀联合长春瑞滨治疗晚期乳腺癌疗效观察

目的:评价赫赛汀和长春瑞滨联合化疗在治疗晚期乳腺癌中的疗效和不良反应。方法:将50例晚期乳腺癌患者分为两组。26例患者采用赫赛汀联合长春瑞滨方案治疗:赫赛汀静脉滴注,首次4mg/kg,其后每周1次,2mg/kg,连续使用;长春瑞滨25mg/m2静脉滴注,d1,8;每3周为1周期。24例患者采用长春瑞滨和顺铂方案(NP方案)治疗:长春瑞滨40mg/天,d1,8;顺铂25mg/m2,d1,3,每3周为1周期。结果:赫赛汀联合长春瑞滨方案有效率为65.4%,NP方案有效率为54.2%,(P<0.05)。结论:赫赛汀联合长春瑞滨治疗晚期乳腺癌是有效且安全的治疗方案,不良反应可耐受,可作为晚期乳腺癌一线方案应用。     

血清Her-2检测在乳腺癌诊治中的应用

原癌基因Her-2／neu(也称cerbB-2或erbB-2)扩增见于包括乳腺癌、卵巢癌、胃癌和肺癌等在内的多种恶性肿瘤，其在原发性乳腺癌中的发生率为20％-40％。Her-2是独立的预后指标。大量的研究表明，Her-2受体过表达的乳腺癌患者生存期短，复发快，对内分泌治疗和化疗相对耐药。虽然Her-2受体的组织学检测对于判断预后、指导用药价值     

赫赛汀联合长春瑞滨治疗晚期乳腺癌疗效观察

目的：评价赫赛汀和长春瑞滨联合化疗在治疗晚期乳腺癌中的疗效和不良反应。方法：将50例晚期乳腺癌患者分为两组。26例患者采用赫赛汀联合长春瑞滨方案治疗：赫赛汀静脉滴注,首次4mg／kg,其后每周1次,2mg／kg,连续使用;长春瑞滨25mg／m2静脉滴注,d1,8;每3周为1周期。24例患者采用长春瑞滨和顺铂方案（NP方案）治疗：长春瑞滨40mg／天,d1,8;顺铂25mg／m2,d1,3,每3周为1周期。结果：赫赛汀联合长春瑞滨方案有效率为65．4％,NP方案有效率为54．2％,（P〈0．05）。结论：赫赛汀联合长春瑞滨治疗晚期乳腺癌是有效且安全的治疗方案,不良反应可耐受,可作为晚期乳腺癌一线方案应用。     

乳腺癌化疗联合内分泌治疗的新进展

内分泌治疗和化疗是乳腺癌全身治疗的主要手段,在乳腺癌的治疗中具有极其重要的地位。当前的临床实践中,对于激素受体阳性的乳腺癌患者,早期辅助治疗、局部晚期新辅助治疗或晚期解救治疗,无论月经状态和使用何种药物,内分泌治疗与化疗都普遍采取序贯的方式。化疗与内分泌治疗联合是否会影响疗效及药物的安全性,目前仍存在一定争论。既往的研究表明将两者同时使用并没有产生预期的疗效叠加结果,反而影响化疗疗效。但近年来一系列研究进展显示出化疗与内分泌治疗联合具有一定的临床应用价值,本文就乳腺癌化疗联合内分泌治疗的最新研究进展作一综述。     

Current status of antibody therapy for breast cancer

Antibody therapy with trastuzumab has greatly impacted breast cancer treatment. Combination treatment with trastuzumab is regarded currently as a first-line therapy for metastatic breast cancers that overexpress Her-2. It has become routine practice to examine the status of Her-2 expression in primary tumors. The impact of this therapy might be as great as that of endocrine therapy from a historical point of view. A number of new approaches using trastuzumab for seeking individualized treatment are being tested in current clinical trials. We reviewed recent advances in trastuzumab treatment and discuss the future of antibody therapy for breast cancer.     

Her-2/neu and EGFR tyrosine kinase activation predict the efficacy of trastuzumab-based therapy in patients with metastatic breast cancer

Her-2/neu overexpression in human breast cancer leads to an aggressive biological behavior and poor prognosis. Although the anti-Her-2/neu antibody trastuzumab (Herceptin(R)) has become a valuable therapeutic option for patients with Her-2/neu-overexpressing breast cancer, many patients do not benefit from this therapy. To evaluate the effect of receptor activation on tumor response, we have investigated the phosphorylation status of Her-2/neu and EGFR in 46 Her-2/neu-overexpressing tumor samples from trastuzumab-treated metastatic breast cancer patients by immunohistochemistry. Activated (p)tyr-1248 Her-2/neu was detected in 9 of 46 breast cancers (20%), and activated (p)tyr-845 and (p)tyr-1173 EGFR were both present in 6 tumors (13%) while EGFR was present in 16 cases (35%). ptyr-1248 Her-2/neu showed a trend to correlate with increased response to trastuzumab (p = 0.063), while ptyr-845, ptyr-1173 EGFR and EGFR did not. The presence of ptyr-1248 Her-2/neu and ptyr-845 or ptyr-1173 EGFR, however, was a strong predictor of both response to trastuzumab-based treatment (OR = 8.0, p = 0.021 and OR = 8.0, p = 0.021) and clinical benefit (OR = 5.47, p = 0.041 and OR = 6.22, p = 0.028 multivariate logistic regression analysis). Furthermore, ptyr-845 EGFR and ptyr-1248 Her-2/neu were both independent predictors of progression-free survival (RR = 0.21, p = 0.01 and RR = 0.45, p = 0.026, multivariate analysis). Patients with ptyr-845 EGFR positive tumors also tended toward increased overall survival (RR = 0.17, p = 0.082). Taken together, we have demonstrated that the determination of activated EGFR improves the utility of ptyr-1248 Her-2/neu staining in predicting the clinical outcome of patients undergoing trastuzumab treatment. We hypothesize that the activation state of both Her-2/neu and EGFR are key determinants for trastuzumab efficacy.     

Her-2阳性转移性乳腺癌的生物靶向治疗

目的:回顾性分析本院2010年至2012年Her-2阳性转移性乳腺癌患者的治疗经验,评价在曲妥珠单抗联合紫杉醇治疗的基础上联合与不联合帕妥珠单抗的疗效。方法:设定一定的入选及排除标准,筛选出符合要求的病例进行分析。采用曲妥珠单抗+帕妥珠单抗联合紫杉醇治疗的患者为观察组（54例）,曲妥珠单抗+紫杉醇治疗的患者为对照组（71例）,比较2种治疗方法的疗效。结果:相比于曲妥珠单抗+紫杉醇,曲妥珠单抗+帕妥珠单抗联合紫杉醇治疗在肿瘤缓解率及肿瘤无进展生存期方面具有明显优势,差异有统计学意义（P＜0.05）。结论:曲妥珠单抗+帕妥珠单抗联合紫杉醇治疗Her-2阳性转移性乳腺癌疗效更好,值得临床推广。     

曲妥珠单抗联合多西紫杉醇治疗Her-2/neu高表达转移性乳腺癌的疗效和不良反应

背景与目的:大约有20%～30%的乳腺癌患者Her-2/neu高表达,Her-2/neu高表达与患者的不良预后密切相关.化疗药物联合曲妥珠单抗可以显著提高Her-2/neu高表达乳腺癌患者的化疗有效率和生存率,多西紫杉醇是近年来治疗乳腺癌有效的化疗药物之一.本研究旨在观察曲妥珠单抗联合多西紫杉醇治疗Her-2/neu高表达转移性乳腺癌的疗效与不良反应.方法:22例Her-2/neu高表达转移性乳腺癌患者接受曲妥珠单抗联合多西紫杉醇方案治疗,曲妥珠单抗的首次剂量为8 mg/kg,以后的剂量为6 mg/kg.多西紫杉醇75mg/m2,每21 d重复一次.按WHO疗效评价标准评价疗效,按WHO化疗药物急性和亚急性不良反应评价标准评价不良反应.结果:全组22例患者共完成96个周期化疗(中位数3周期,范围2～6周期),所有患者均可评价疗效.22例患者中完全缓解2例,部分缓解12例,病情稳定4例,病情进展4例,客观有效率(CR PR)63.64%,中位疾病进展时间5.4个月,1年生存率59%.全组患者均可评价不良反应,主要不良反应为骨髓抑制,其中Ⅲ～Ⅳ度白细胞减少发生率为54.5%,部分患者有发热(第一次输注曲妥珠单抗时出现)和轻度的心肌劳损.结论:曲妥珠单抗联合多西紫杉醇方案治疗Her-2/neu高表达转移性乳腺癌近期疗效较高,不良反应轻,患者可以耐受.     

Her-2/<Emphasis Type="Italic">neu</Emphasis> as Predictive Marker for Endocrine Therapy and Chemotherapy in Patients with Metastatic Breast Cancer

While expression of estrogen receptor (ER) and/or progesterone receptor (PgR) predict for the efficacy of endocrine therapy and Her-2/neu overexpression/amplification predict (imperfectly) for the efficacy of treatment with trastuzumab, neither of these markers has proved effective at predicting antitumor response to other therapies. Overexpression/amplification of Her-2/neu has been one of the most extensively studied predictive parameters, but results have been controversial. In the present article we attempt to review articles published in peer-reviewed medical journals to summarize the evidence concerning Her-2/neu as a predictive factor for the efficacy of endocrine and chemotherapy, respectively. In addition, general limitations of published studies, encouraged and discouraged practices resulting from the available data and future directions which will clarify the role of Her-2/neu as a predictive parameter will be discussed.     

Her-2 targeted therapy: Beyond breast cancer and trastuzumab

Her-2 is a validated therapeutic target in breast cancer. The two critical questions that remain regarding Her-2 targeting concern 1) the relevance of Her-2 inhibition in other malignancies and 2) the ability of novel agents to achieve greater Her-2 inhibition than trastuzumab. The contribution of cell signaling effects and immunologic mechanisms to the effect of trastuzumab in vivo remains poorly understood. Thus, the preclinical data that support the greater efficacy of novel Her-2 antibodies or small molecule tyrosine kinase inhibitors remain to be validated in clinical trials. In this review, we discuss the evidence from recent trastuzumab clinical trials as a point of departure for consideration of novel Her-2 targeted therapies. Preliminary results from early clinical trials suggest that Her-2 tyrosine kinase inhibitors may extend the population for which this strategy offers therapeutic effect.     

EGFR activity in HER-2 over-expressing metastatic breast cancer: evidence for simultaneous phosphorylation of Her-2/neu and EGFR

Her-2/neu overexpression is an important prognostic parameter in breast cancer patients and has become a response predictor for trastuzumab treatment. Nevertheless, while trastuzumab is highly effective in many Her-2/neu overexpressing tumors, some do not respond. The reason for the differential effect is unknown, but it has been hypothesized that the complex interactions between Her-2/neu and other members of the EGFR family are involved in trastuzumab resistance. We have analyzed the protein expression of Her-2/neu, EGFR, and their activated forms, ptyr-1248 Her-2/neu, ptyr-845 EGFR and ptyr-1173 EGFR, in 57 Her-2/neu overexpressing breast tumors and investigated potential correlations between the receptors. By performing immunohistochemistry on paraffin-embedded tissue sections, we found that ptyr-845 EGFR was significantly co-expressed with Her-2/neu and ptyr-1248 Her-2/neu (p=0.043 and p=0.040, respectively), while ptyr-1173 EGFR was only correlated to Her-2/neu expression (p=0.042). Interestingly, EGFR and its activated forms were all significantly inversely correlated with PgR expression (p=0.011, p=0.033 and p=0.032, respectively), and ptyr-845 EGFR was also inversely correlated with ER expression (p=0.008). While we have previously shown that serum levels of the extracellular component of Her-2/neu are associated with tumoral ptyr-1248 Her-2/neu expression, we did not find a similar relationship between serum EGFR and intratumoral total/activated EGFR. We did, however, observe significantly higher levels of serum EGFR in women with 3+ overexpression of HER-2/neu (p=0.047). Taken together, we have demonstrated the activation pattern of EGFR and Her-2/neu in Her-2/neu overexpressing breast cancer. We suggest that EGFR inhibition might enhance the efficacy of trastuzumab by preventing cross-phosphorylation.     

Serum EGFR levels and efficacy of trastuzumab-based therapy in patients with metastatic breast cancer

The antibody trastuzumab inhibits signal transduction in Her-2/neu overexpressing human breast cancer. However, the activation of co-expressed EGFR has also been show to additionally modulate the anti-tumoural effects of this drug. Similar to Her-2/neu, the extra cellular binding region of EGFR is believed to be proteolytically released from the cell surface upon receptor activation and can be detected in patients' serum (sEGFR). Considering the biological significance of an interaction between EGFR and Her-2/neu signalling in other human malignancies, we have investigated if trastuzumab treatment would affect sEGFR in 33 patients with Her-2/neu overexpressing metastatic breast cancer. We detected EGFR expression in 33% of Her-2/neu overexpressing breast tumours. In contrast to serum Her-2/neu (ECD) levels, which were correlated with the degree of Her-2/neu expression (P=0.048, Mann-Whitney test), we did not detect significant differences between sEGFR serum levels in EGFR expressing or non-expressing tumours. Furthermore, sEGFR serum levels were not correlated with clinical parameters such as response or clinical benefit rates, and no association was found between increased sEGFR levels and progression-free survival or overall survival. While we have previously observed a selective and significant decrease of ECD levels in patients who derived a clinical benefit from trastuzumab treatment during the first weeks of treatment, we were unable to find similar alterations in sEGFR concentrations. We therefore conclude that the measurement of systemic sEGFR levels in addition to ECD serum concentrations do not allow the prediction of clinical course of trastuzumab-treated patients more accurately.     

Her-2阳性乳腺癌靶向治疗药物的研究进展

Her-2阳性乳腺癌患者预后较差。近年来化疗序贯曲妥珠单抗1年的辅助治疗已成为早期Her-2阳性乳腺癌患者的标准治疗方案,曲妥珠单抗的应用使乳腺癌患者的复发风险降低了40%,然而长期随访数据表明,15%~24%患者仍面临复发风险。后续抗Her-2药物的研制主要集中在预防和克服耐药性方面,帕妥珠单抗、拉帕替尼、T-DM1、来那替尼和吡咯替尼等药物研发改善了Her-2阳性乳腺癌患者的辅助治疗空间。     

曲妥珠单抗联合多西紫杉醇新辅助化疗Her-2/neu高表达局部晚期乳腺癌的疗效观察

目的观察曲妥珠单抗联合多西紫杉醇对Her-2/neu高表达的局部晚期乳腺癌新辅助化疗的疗效。方法 16例Her-2/neu高表达的局部晚期乳腺癌患者接受曲妥珠单抗联合多西紫杉醇的方案治疗。曲妥珠单抗的首次剂量为4mg/kg,以后剂量为2mg/kg,每7d一次。多西紫杉醇75mg/m2,每21d重复一次。按WHO疗效评价标准评价疗效,按WHO化疗药物急性和亚急性不良反应评价标准评价不良反应。结果全组16例患者术前共完成68次新辅助化疗（范围4～6次）,所有患者均可评价疗效。16例患者中完全缓解4例,部分缓解10例,病情稳定2例,客观有效率（CR＋PR）87.5%。全组均可评价不良反应,主要不良反应为骨髓抑制,其中Ⅲ～Ⅳ度白细胞减少发生率为62.5%,部分患者有轻度的心肌劳损。结论曲妥珠单抗联合多西紫杉醇对Her-2/neu高表达的局部晚期乳腺癌新辅助化疗的疗效较高,不良反应轻,患者可以耐受。