ZD1839和曲妥珠单抗联合治疗对NSCLC细胞生长的协同抑制作用

近来抗癌治疗的重要进展是分子靶向药物的发展,如表皮生长因子受体(EGFR)-靶向药物ZD1839(Iressa)和H E R-2靶向抗H E R-2个单克隆抗体曲妥珠单抗(Herceptin)。ZD1839和曲妥珠单抗分别被报告可以改善非小细胞肺癌(NSCLC)和乳癌的治疗效果,单药单独应用的效果并不十分理想。NSCLC细胞时常表达EGFR和HER-2。因此我们试图研究ZD1839和曲妥珠单抗联合是否可以增强抗肿瘤效果。在培养物中,ZD1839抑制了四个表达不同水平的EGFR(HER-2,HER-3,和HER-4)的NSCLC细胞系(A549,NCI-H23,NCI-H727,和NCI-H661)的生长。在A549细…     

lapatinib可延长某些肾癌患者生存时间

一项大规模开放标签的Ⅲ期试验报告，EGFR（表皮生长因子受体）高水平表达的晚期肾细胞癌患者用lapatinib（I）作二线治疗获得有希望的结果。（I）是EGFR及HER-2（人表皮生长因子受体-2）的细胞内酪氨酸激酶域的双重抑制剂。     

029 新药研究与开发

葛兰素史克公司的双靶向药拉帕替尼Ⅱ期临床结果显效双靶向(EGFR/Her2)抗癌药，葛兰素史克公司的拉帕替尼(lapatinib)，在对转移乳腺癌用Her2靶向的曲妥珠单抗无效后改用该药的两次Ⅱ期临床试验中间结果显示有效。此结果在维也纳ESMO会议上提出，支持该药进行Ⅲ期临床试验。     

拉帕替尼联合卡培他滨治疗HER-2阳性晚期乳腺癌疗效观察

<正>拉帕替尼(lapatinib)是一种口服的表皮生长因子受体(EGFR)及抑制HER1、HER2双靶点的小分子酪氨酸激酶抑制剂。2007年被美国食品药品管理局(FDA)批准用于HER-2阳性既往接受过曲妥珠单抗治疗的晚期或转移性乳腺癌。本研究回顾性观察了2013年5月至2014年5月就诊于山西省肿瘤医院乳腺科的25例晚期患者,探讨拉帕替尼联合卡培他滨在晚期乳腺癌中的作用。现报告如下。     

新型抗肿瘤药二对甲苯磺酸拉帕替尼及其临床特点和市场潜力

二对甲苯磺酸拉帕替尼单水合物(lapatinib distosylate monohydrate/Tykerb,以下简称为拉帕替尼)是一能够同时靶向人表皮生长因子受体(EGFR)和人表皮生长因子受体-2(HER2)的小分子激酶抑制剂,它由GlaxoSmithKline公司开发并已于2007年3月获得美国FDA批准,用于合用Roche公司的卡培他滨(capecitabine/Xeloda)治疗已经接受过包括一种蒽环类药物、一种紫杉烷类药物和曲妥珠单抗(trastuzumab/Herceptin)在内在先疗法治疗且肿瘤过度表达有HER2的进行性或转移性乳腺癌.本文就此新型抗肿瘤药及其临床特点和市场潜力作一概要论述.     

乳腺癌晚期患者应用紫杉醇与铂类的临床治疗效果及对HER-2、EGFR的影响研究

目的分析紫杉醇与铂类应用于乳腺癌晚期疗患者的临床治疗效果及对HER-2、EGFR的影响研究。方法回顾性选取于2015年1月至2017年1月在医院诊治的乳腺癌患者80例,病理分级属于晚期,按照数字随机法分为两组,每组各40例患者,其中对照组采用表阿霉素+环磷酰胺治疗,研究组采用紫杉醇+顺铂治疗。3周为1个疗程,治疗3个疗程后,比较两组患者的临床有效率及HER-2、EGFR阳性表达情况。结果 (1)治疗后,研究组的临床治疗有效率为82.50%水平显著高于对照组的57.50%(P均<0.05);(2)研究组患者的HER-2表达及EGFR表达率监测结果优于对照组(P均<0.05)。结论紫杉醇联合铂类化合物对乳腺癌晚期患者,具有较显著的临床治疗效果,同时对HER-2、EGFR的异常高表达有积极的改善作用,可作为临床治疗的优选方案。     

GSK双重靶位的lapatinib有希望的Ⅱ期试验资料

GlaxoSmithKline公司的双重EGFR／Her2靶向抗癌药lapatinib(过去称GW572016)(Ⅰ)在两项用Roche的Her2靶向产品Herceptin(trastuzumab)(Ⅱ)治疗失败的转移性乳腺癌妇女参加的Ⅱ期试验中显示有希望的中期结果，这一结果支持正在进行的(Ⅰ)Ⅲ期试验。     

美国FDA批准葛兰素史克公司的抗肿瘤药物Tykerb用于治疗转移性乳腺癌

葛兰素史克(GSK)公司致力于推进抗肿瘤药物的研发,似乎终获回报,最近其抗肿瘤产品Tykerb(lapatinib)获美国FDA批准,与罗化公司开发的化疗药物卡培他滨(capecitabine,Xeloda)联用治疗那些使用罗氏/Genentech公司抗肿瘤产品Herceptin(trastuzumab)治疗无效的转移性人表皮生长因子受体2(HER2或ErbB2)阳性乳腺癌患者.     

人胃腺癌中c-MET、EGFR和HER-2的表达及其与临床病理特征的关系

目的检测人胃腺癌组织中c-MET、EGFR和HER-2表达状况,并分析其与胃腺癌组织病理间的关系。方法选取2017年8月-2018年8月于绵阳市中心医院行胃癌根治术患者200例,采用免疫组化染色法对c-MET、EGFR和HER-2染色和检测,同时与病理检测结果进行比较和分析。结果 200例胃腺癌组织中,c-MET表达率为44.00%(88/200),其中神经受累、肿瘤浸润深度深及弥漫型Lauren分型组织中c-MET表达阳性率更高(P<0.05)。EGFR表达率为11.00%(22/200),其中病理组织检测可见血管癌栓阳性率较无血管侵犯者高(P<0.05)。HER-2表达率为34.00%(68/200),其中病理组织检测提示远处转移和Lauren分型(肠型)、中高分化者阳性率更高(P<0.05)。相关性分析显示,人胃腺癌组织中c-MET、EGFR和HER-2高表达与肿瘤组织中Ki-67高增殖指数呈正相关性(P<0.05)。结论检测人胃腺癌组织中c-MET、EGFR和HER-2表达情况有助于判断患者病情状况,有利于指导临床治疗,更好地改善患者预后。     

卡培他滨联合替吉奥对结直肠癌患者血清EGFR及HER-2表达的影响

目的探究卡培他滨联合替吉奥对结肠癌患者血清表皮生长因子受体(EGFR)及人类表皮生长因子受体-2(HER-2)表达的影响。方法选取我院2017年7月至2018年12月收治的208例晚期结直肠癌患者,随机分为对照组和研究组,各104例,前者给予单纯卡培他滨口服治疗,后者进行卡培他滨联合替吉奥治疗,比较两组患者的临床疗效、不良反应发生情况及两组患者治疗前后血清EGFR及HER-2水平的变化情况。结果研究组患者有效率、CR构成比均显著高于对照组(79.81%vs. 50.96%,32.69%vs. 12.50%,P<0.01);研究组患者胃肠道反应(30.77%vs. 13.46%)和粒细胞降低(37.50%vs. 11.54%)的发生率显著高于对照组(P<0.01);治疗后,研究组患者血清EGFR[(4.27±1.34)mg/L vs.(6.49±1.62)mg/L]和HER-2[(4.93±1.68)mg/L vs.(8.40±1.94)mg/L]水平显著低于对照组,差异均有统计学意义(P<0.05)。结论卡培他滨联合替吉奥治疗晚期结直肠癌能够取得良好的短期疗效,有助于提高患者的生存率,联合用药耐受良好,同时能够降低患者血清EGFR和HER-2水平,改善预后。     

‘Simply stunning’ – trastuzumab in HER2-positive breast cancer

Human epidermal growth factor receptor-2 (HER-2)-positive metastatic breast cancer is a more aggressive disease than HER-2-negative metastatic breast cancer. The initial Phase III trial with the HER-2 antibody, trastuzumab, in this cancer suggested that, although trastuzumab was beneficial, cardiac adverse events would prevent it from being widely used. Recently trials suggest that, with close monitoring of left ventricular ejection fraction, trastuzumab can be used concurrently or sequentially with the standard adjuvant treatment of HER-2-positive metastatic breast cancer with good benefit. Therefore, with appropriate regimens, trastuzumab will be able to be used routinely in the treatment of HER-2-positive metastatic breast cancer.     

Opinion on the use of the antitumor drug trastuzumab (Herceptin) in patients with metastatic breast cancer in the county Mecklenburg-Vorpommern.

The recombinant humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) is directed against the human epidermal growth factor receptor on the surface of breast cancer cells. Herceptin was approved in Germany in September 2000 after evaluation in clinical trials involving women with metastatic breast cancer who had tumors overexpressing HER-2/neu. A prerequisite for its use is the diagnosis of the HER-2/neu receptor status in individual patients because trastuzumab is only effective in patients with a high (score +3) overexpression of the HER-2/neu receptor. The only approved diagnostic method is the immunohistochemical DAKO-Hercep test. Clinical experience with this novel biological agent has been obtained in 2 Phase III trials involving 469 and 222 patients, where trastuzumab was used as first- or second-line therapy. The addition of trastuzumab to chemotherapy regimens was associated with longer time to progression, a higher rate and duration of response and longer survival. When used as a single agent in metastatic breast cancer that had progressed after chemotherapy, there was an overall response rate of 15%. The median duration of response was 9.1 months and median survival was 13 months. Unwanted effects included potentially severe cardiotoxicity and in 40% of patients infusion-associated fever and/or shivering that usually occurred only during the first infusion. In patients with moderate HER-2/neu expression, unwanted drug effects outweigh a relatively weak therapeutic effect. In cases of high overexpression, the cancer may go into regression and survival may be prolonged with a relatively small impairment in the life quality. The costs of trastuzumab-therapy are high amounting to an additional 48,000 DM per patient per year. Recommendations for diagnosis and therapy in Mecklenburg-Vorpommern have been formulated in discussions between oncologists, practitioners, scientists and regulatory authorities.     

Simultaneous amplification of HER-2 (ERBB2) and topoisomerase IIalpha (TOP2A) genes--molecular basis for combination chemotherapy in cancer

The HER-2 (also known as ERBB2/ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also amplified in other forms of cancer. Beside its important role in tumor induction, growth and progression, HER-2 is also a target for new therapeutic approaches such as Herceptin (trastuzumab), a recombinant antibody designed to block signaling through the HER-2 receptor. In addition to Herceptin, which is in a wide clinical use for HER-2 amplified breast cancer, a number of various HER-2 directed immunological and genetic strategies, either targeting the HER-2 receptor, its signaling pathways or both HER-2 and epidermal growth factor receptor (EGFR) simultaneously, have demonstrated promising pre-clinical activity in HER-2 amplified carcinomas. Moreover, the HER-2 amplicon is known to contain more than 30 genes with altered copy numbers that could be therapeutic targets for chemotherapy. The topoisomerase IIalpha gene, TOP2A, is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted (with equal frequency) in a great majority of HER-2 amplified primary breast tumors and also in tumors without HER-2 amplification. Recent experimental as well as numerous, large, multi-center trials suggest that amplification (and/or deletion) of TOP2A may account for both sensitivity or resistance to commonly used cytotoxic drugs, i.e. topoII-inhibitors (anthracyclines etc.), depending on the specific genetic defect at the TOP2A locus. The understanding of HER-2 amplification and its role in the pathogenesis of cancer is expanding, and a number of therapeutic strategies targeting either the HER-2 or its signaling pathways in cancer therapy are being investigated. Combining HER-2 targeting therapies with conventional forms of cytotoxic chemotherapy, where additional diagnostic tests such as those ascertaining TOP2A status, may be helpful for the ideal selection of patients for the combination therapy of an HER-2 targeting drug together with a cytotoxic drug such as topoII-inhibitor especially in the case of TOP2A amplification.     

Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer

Lapatinib is an oral dual tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), both frequently overexpressed in human cancer. Preclinical data have shown that lapatinib is a potent and selective inhibitor of the tyrosine kinase domain of EGFR and HER2, and tumor cells that overexpress these receptors are growth inhibited by lapatinib both in vitro and in vivo. Phase I clinical trials have shown that lapatinib is well tolerated, with mild diarrhea and rash the most frequent toxicities, and early evidence of clinical efficacy has been reported especially in HER2-positive breast cancer. Phase II studies have shown activity for lapatinib in trastuzumab-refractory breast cancer either alone or in combination with trastuzumab. When used as first-line monotherapy for advanced breast cancer, objective tumor responses have been seen in 28% of patients with untreated HER2-positive advanced breast cancer. An extensive phase III program in advanced breast cancer is now in progress both for refractory disease and as first-line therapy in combination with chemotherapy with and without trastuzumab, and with endocrine therapy. Phase II studies have also been conducted in a variety of other tumors, including renal cell cancer. Parallel biomarker studies are starting to elucidate predictive molecular phenotypes that may indicate likelihood of response to lapatinib, and these may direct future trials with this oral tyrosine kinase inhibitor.     

Targeted therapy of breast cancer

Breast cancer is the most frequent tumor of women. The development of effective adjuvant therapy based on postoperative administration of short-term chemotherapy (4-6 months) or long-term hormone therapy (5 years) or both, significantly improved survival of patients. However, therapy of adjuvant/metastatic disease is still palliative with a very low probability to induce complete remission and definitive cure of disease. The relevant efforts of basic research to identify the key and selective molecular alterations, which sustain breast cancer growth and progression allowed the possibility to develop specific molecular target treatments. Trastuzumab, a humanized monoclonal antibody to HER-2, is the first molecular targeting agent approved for therapy of metastatic breast cancer, capable to significantly improve clinical outcome in combination with cytotoxic therapy. Recent preliminary data from randomized, prospective, clinical trials suggest that trastuzumab decreases the risk of early recurrence by 50% in patients with HER-2-positive disease. Other novel targeted treatments are in clinical evaluation, including antiangiogenic compounds (Bevacizumab, sunitinib, vatalanib, and others) and bi-functional drugs such as lapatinib (anti Her-2 and EGFR agent) showing promising activity. This review provides an updated overview of the status of development of targeted therapy in breast cancer, as well as the challenges related to the rational use of molecular targeting agents.     

Triple negative breast cancer: a brief review of its characteristics and treatment options

Triple negative breast cancer (TNBC), an aggressive variant of breast cancer, is characterized by lack of expression of the estrogen (ER) and progesterone receptors (PRs) and the human epidermal growth factor receptor (HER-2) that are commonly observed in other breast cancer subtypes. The TNBC subtype primarily occurs in younger women of African American or Hispanic descent and tumors tend to be high grade and initially responsive to chemotherapy. However, TNBC is characteristically aggressive with high recurrence, metastatic, and mortality rates. Treatment options are limited since the hormonal receptor and HER-2 antagonists typically used for other breast cancers are ineffective. As such, the mainstay of treatment of TNBC is traditional systemic cytotoxic chemotherapy. Potential future therapies for TNBC include targeted molecular strategies including poly (adenosine diphosphate ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents. Further research aimed at identifying unique genetic characteristics of TNBC may allow development of other targeted molecular chemotherapy treatment options.     

Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells

Overexpression of HER-2 in breast cancer is frequently associated with expression of EGFR, and EGFR expression influences response to HER-2 inhibition. The aim of this study was to examine the effects of combining dual inhibition of EGFR and HER-2, using trastuzumab, gefitinib and lapatinib, in HER-2 overexpressing breast cancer cells. Combination proliferation assays were performed in two HER-2 positive breast cancer cell lines, SKBR-3 and BT-474. Trastuzumab combined with lapatinib was also tested in BT-474 xenografts. In proliferation assays, dual targeting with trastuzumab and gefitinib or lapatinib showed synergy or additivity in both SKBR-3 and BT-474 cells. Trastuzumab (10 nM) or gefitinib (5 μM) alone did not induce significant apoptosis, whereas lapatinib (0.75 μM) induced significant apoptosis in SKBR-3 cells. Trastuzumab combined with lapatinib further enhanced apoptosis induction. Trastuzumab (10 nM) and gefitinib (5 μM) induced apoptosis comparable to lapatinib alone (0.75 μM), suggesting that inhibition of both EGFR and HER-2 may be required to induce apoptosis in these cells. Pre-treatment with trastuzumab and gefitinib or lapatinib enhanced response to chemotherapy in vitro. The combination of trastuzumab and lapatinib also effectively blocked tumour growth in vivo. Dual targeting of EGFR and HER-2, by combining trastuzumab with EGFR/HER-2 tyrosine kinase inhibitors, may improve response in HER-2 overexpressing breast cancer cells that also express EGFR.     

HER dimerization inhibitors: developing pertuzumab as an anticancer agent in women's oncology

Background: Pertuzumab is a novel monoclonal antibody that blocks the dimerization domain of the human epidermal growth factor receptor (HER)-2/neu receptor, disabling its ability to form heterodimers with the other members of its family. Objective: We review the background and scientific rationale, but more specifically cover current clinical trial outcomes of pertuzumab in solid tumors, with an emphasis on the work completed in women's cancers. Methods: Clinical trial results published or presented at national meetings are included in this review. Results: Pertuzumab shows promising activity with trastuzumab in the treatment of metastatic breast cancer. The results in ovarian cancer have been limited thus far but a post hoc analysis of the results of a completed randomized Phase II trial of gemcitabine with or without pertuzumab suggests that low HER3 levels may mark a group of women who may benefit from the addition of pertuzumab to chemotherapy. Conclusions: The efficacy of pertuzumab independent of HER-2/neu overexpression remains under investigation. Still, the benefits seen in HER-2/neu positive breast cancer is encouraging. Work in ovarian cancer remains preliminary but the possibility of using pertuzumab in a targeted population with low HER3 levels warrants further evaluation.     

Docetaxel/trastuzumab combination therapy for the treatment of breast cancer

Trastuzumab is a humanised monoclonal antibody that targets the extra cellular domain of human epidermal growth factor receptor-2 (HER-2), which is overexpressed in approximately 20% of human breast cancers. Clinical benefit has been shown in breast cancer patients with HER-2 amplification or overexpression when trastuzumab is used alone or in combination with chemotherapy. Docetaxel is one of the most potent chemotherapy agents in the treatment of patients with metastatic and early-stage breast cancer. The rationale for combining these two drugs is based not only on preclinical synergic data, but also on expanding clinical results. This article reviews the results of trials investigating this two-drug combination, as well as the triple combinations including docetaxel and trastuzumab with platinum salts. These combinations appear to be amongst the most active therapies for the treatment of patients with HER-2-positive breast cancer in metastatic and potentially adjuvant settings.