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.     

Neratinib: an oral,irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer

Background: The revolutionary success of imatinib, a specific inhibitor of the BCR-ABL tyrosine kinase (TK) in the treatment of chronic myelogenous leukemia ushered in the era of targeted therapies in cancer. The erythroblastic leukemia viral oncogene homolog family of receptor TKs, to which EGFR (HER1) and human epidermal growth factor receptor 2 (HER2)/neu TKs belong, has been implicated in a variety of cancers, and several agents that inhibit these TKs are in clinical use, with many more in various stages of development. Objectives: To summarize current knowledge about neratinib (HKI-272), an oral, irreversible dual inhibitor of EGFR and HER2 and to define its future clinical role, especially in the context of related agents that are either available or in the pipeline. Methods: A Medline search using Pubmed was conducted using the keywords neratinib, HKI-272, EGFR, HER2, lapatinib, trastuzumab, erlotinib, gefitinib, cetuximab and panitumumab. Relevant abstracts presented at the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings were also reviewed. Conclusions: Both preclinical and human studies have shown that neratinib has promising activity in both advanced breast cancer and NSCLC with an acceptable safety profile. The data support its continued clinical development.     

HER2、EGFR、ER、PR在乳腺癌中的表达及其临床意义

目的 探讨人表皮生长因子受体2(HER2)、表皮生长因子受体(EGFR)、雌激素受体(ER)、孕激素受体(PR)在乳腺癌中的表达及其临床意义.方法 用免疫组化方法检测182例乳腺浸润性导管癌和小叶癌患者HER2、EGFR、ER、PR的表达情况,并进行比较.结果 HER2、EGFR、ER、PR表达阳性率分别为36.8%、42.3%、53.8%、50.5%.HER2的表达与EGFR呈正相关性(P<0.05),与ER和PR呈负相关(P<0.05).HER2、EGFR、ER、PR表达与乳腺癌的组织学分级相关(P<0.05).HER2、EGFR、ER表达与淋巴结转移相关(P<0.05),HER2、EGFR、ER、PR与乳腺癌的病理学类型、患者年龄及肿瘤大小无关(P>0.05).结论 乳腺癌中HER2、EGFR表达提示患者预后不良,ER、PR表达提示患者预后良好,HER2、EGFR、ER、PR是判断乳腺癌预后的有效指标,并可作为临床选择内分泌治疗或基因靶向治疗的指南.     

ETS-1、p53、VEGF、EGFR、HER-2、COX-2在胰腺癌中的表达

目的 研究胰腺癌组织中E26转录因子1(ETS-1)、p53、血管内皮生长因子(VEGF)、表皮生长因子受体(EGFR)、人类表皮生长因子受体2(HER-2)和环氧化酶2(COX-2)的蛋白表达及其与胰腺癌临床病理学特征的相关性.方法 收集40例胰腺癌患者组织标本,免疫组化SP法检测肿瘤组织中各蛋白表达水平.分析ETS-1蛋白表达与患者临床病理学特征的相关性和ETS-1蛋白表达与p53、VEGF、EGFR、HER-2、COX-2蛋白表达之间的相关性.结果 ETS-1、p53、VEGF、EGFR、HER-2、COX-2蛋白在胰腺癌组织中阳性表达率分别为65.0％、60.0％、37.5％、62.5％、37.5％、55.0％.ETS-1蛋白表达水平越高,脉管内癌栓发生率越高,肿瘤分期越晚(P＜0.05).胰腺癌中ETS-1蛋白呈高表达时,p53、COX-2蛋白也呈高表达状态(P＜0.05).结论 胰腺癌组织中存在 ETS-1、p53、VEGF、EGFR、HER-2、COX-2蛋白表达.ETS-1 高表达的胰腺癌患者肿瘤分期晚,预后差.ETS-1蛋白高表达促胰腺癌发生发展机制可能与p53、COX-2蛋白高表达相关.     

HER2-positive breast cancer: current and future treatment strategies

In the year 2006, breast cancer was estimated to affect >200,000 American women and cause nearly 56,000 deaths. Furthermore, breast cancer is the most common cancer diagnosed and second most common cause of cancer-related deaths in women. The current treatment armamentarium for breast cancer includes chemotherapy, endocrine therapy and biological therapy. Treatment has become more individualised based on characteristics of the tumour including overexpression of the human epidermal growth factor receptor (HER)-2. Between 20 and 30% of all breast cancers overexpress HER2, which means 40,000 - 60,000 patients will have this type of cancer.Previously, overexpression of HER2 was a negative prognostic and predictive risk factor for survival; however, with the advent of trastuzumab, patients' prognosis is improving in all treatment settings. Much controversy exists in the use of trastuzumab, including (i) the sequence of adjuvant trastuzumab (concurrent with chemotherapy or sequential); (ii) the treatment duration (<1 year, 1 year or 2 years); and (iii) the treatment choice upon disease progression (whether to continue or not with trastuzumab and add another cytotoxic agent). Current trials are ongoing to help answer these questions.Furthermore, there has been interest in predicting which HER2-positive patients would require anthracycline therapy, and which could avoid anthracycline therapy and its toxicities. Novel therapeutics, such as lapatinib, an oral tyrosine kinase inhibitor, which blocks both the epidermal growth factor receptor and HER2 receptor has recently been approved by the US FDA. Whereas pertuzumab, a humanised monoclonal antibody, directed against heterodimerisation of HER2 and HER3 has entered phase II and III clinical trials.     

Glycosylation pathways as drug targets for cancer: glycosidase inhibitors

The combined and ordered sequential action of glycosidases and glycosyltransferases in mammalian cell compartments leads to the addition of defined glycans to proteins and lipids. Altered glycosylation patterns, neoexpression, underexpression or overexpression of glycans are a hallmark of cancer. These changes are either found in the core or the terminal structures of the carbohydrates of glycoproteins. Affected proteins can be either cellular, cell-surface or secreted proteins, and glycosylation modifications frequently result in a modified expression, metabolism, functions, properties, stability and/or cellular localization of glycoproteins in cancer cells, resulting in part in their uncontrolled growth and aggressive behavior. Therefore glycosylation pathways, and the glycosidases and glycosyltransferases of these pathways, represent potential innovative modalities for drug development in cancer therapies which are just beginning to be explored. This review proposes to summarize the published information for glycosidases and their inhibitors in cancer.     

乳腺癌术后纤维粘连蛋白、S-CD105、HER2及VEGF的检测意义研究

目的探讨乳腺癌术后纤维粘连蛋白、S-CD105、HER2及VEGF的检测意义。方法选取2005年1月至2011年2月的乳腺癌术后无复发转移的42例患者为对照组,同时选取同期的42例发生复发转移的患者为观察组,后将两组患者的血清纤维粘连蛋白、S-CD105、HER2及VEGF水平进行检测及比较。结果观察组的血清纤维粘连蛋白、S-CD105、HER2及VEGF水平均高于对照组,且转移患者明显高于无转移的患者,（P〈0.05或P〈0.01）。结论乳腺癌术后纤维粘连蛋白、S-CD105、HER2及VEGF水平的检测对于判断有无复发转移有着积极的作用。     

Food increased the bioavailability of BMS-690514, an orally active EGFR/HER2/VEGF receptor kinase inhibitor, in healthy subjects

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS-690514. Two open-label, randomized, single-dose, 2-treatment, 2-period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a high-fat meal, and in study 2 (N = 17), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T)), area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) of BMS-690514 increased by 55%, 33%, and 34%, respectively, following a high-fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS-690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS-690514 was increased when given along with a meal, probably through inhibition of intestinal first-pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS-690514 in the absence and presence of food.     

Overcoming treatment resistance in HER2-positive breast cancer: potential strategies

Human epidermal growth factor receptor (HER)-2 overexpression or amplification occurs in about 20% of all breast cancers and results in a worse prognosis. Nevertheless, anti-HER2 treatments have recently been developed, resulting in dramatic improvements in the clinical outcome of patients with HER2-positive breast cancer. Trastuzumab has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease. Other anti-HER2 agents are being investigated. Mechanisms of resistance to trastuzumab treatment include crosstalk with heterologous receptors and amplification of HER2 signalling; amplification of the phosphoinositide 3-kinase (PI3K)/AKT pathway; alteration in binding of trastuzumab to HER2; and loss of HER2 expression. Proposed mechanisms of resistance to lapatinib involve derepression and/or activation of compensatory survival pathways through increased PI3K/AKT or estrogen receptor (ER) signalling. Several strategies to overcome resistance to anti-HER2 treatment are in different phases of development and include treatment with pertuzumab, T-DM1 and mammalian target of rapamycin (mTOR) inhibitors.     

HER2和HER3在胃癌中表达的临床意义

目的 探讨人表皮生长因子受体(HER)家族中的HER2、HER3的表达对胃癌患者预后的影响.方法 采用免疫组化对67例经手术切除的胃癌组织进行检测,将检测结果 与患者的临床特征进行相关性分析.结果 21例(31.3%)患者HER2高表达,38例(56.7%)患者HER3高表达,18例(26.9%)患者有HER2、HER3双重高表达.HER2高表达与患者的临床特征无相关性,HER3高表达仅与肿瘤位于近段有相关性(P<0.05),HER2表达与HER3表达有相关性(P<0.05).HER2和HER3高表达与患者的生存无相关性.结论 HER2和HER3高表达在胃癌中发生率较高,但它们的表达与患者的预后无相关性.     

Efficacy and safety of a combination of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer: a network meta-analysis

Background: Using network meta-analysis, we assessed the efficacy and safety of a combination regimen of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer.

Methods: We searched the Medline, Embase, and Cochrane Library electronic databases (through December 2016) for phase II/III randomized controlled trials that compared regimens of one or two HER2-targeted agents combined with trastuzumab or chemotherapy. A network meta-analysis including direct and indirect analyses was conducted in WinBUGS using fixed and random effects. Study quality was assessed following the Grading of Recommendations, Assessment, Development and Evaluations method. The primary outcome was overall survival.

Results: The network meta-analysis incorporated nine HER2-targeted regimens with 9 direct comparisons and 28 indirect comparisons for the main outcomes (8 studies; n = 3976). Combining direct and indirect effects showed significant increased efficacy of trastuzumab and docetaxel plus pertuzumab (TDP) over other regimens as first-line treatment. With indirect comparison of overall safety, TDP, TDM-1, and TDM-1 plus pertuzumab demonstrated a lower risk of grade 3–4 adverse events compared to other regimens.

Conclusions: TDPs are a preferred first-line treatment for HER2-positive metastatic breast cancer compared with other target agent regimens.     

Label-free LC-MS analysis of HER2+ breast cancer cell line response to HER2 inhibitor treatment

Background

Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome.

Methods

In order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib).

Results

Following 12 hours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 μM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons.

Conclusion

This proteomic study highlights several proteins that are closely associated with early HER2-inhibitor response and will provide a valuable resource for further investigation of ways to improve efficacy of breast-cancer treatment.     

胃腺癌组织中P21、HER2、EGFR表达临床病理关系探讨

目的 探讨P21、HER2、EGFR蛋白在胃腺癌组织中的表达特点及其临床病理关系.方法 应用免疫组织化学技术对65例胃腺癌病理切片进行P21、HER2和EGFR的联合检测,并结合检测结果进行统计学分析.结果 65例胃腺癌组织中P21、HER2、EGFR阳性表达率分别为56.9％（37/65）、43.1％（28/65）、30.8％（20/65）.经统计学分析,P21、HER2、EGFR蛋白的表达与胃腺癌组织的分化程度、浸润深度、是否有癌栓、淋巴结转移、远处转移和TNM分期密切相关（P＜0.05,P＜0.01）.与性别、年龄、肿瘤直径、肿瘤部位和组织学类型均无统计意义（P＞0.05）.P21表达与HER2、EGFR阳性表达,及HER2表达与EGFR阳性表达均有统计意义（P＜0.05）.结论 P21、HER2、EGFR的表达结果表明胃腺癌存在着多基因表达,这些基因可能共同参与了胃腺癌的发生和发展.三者的联合检测有助于判断胃腺癌的生物学行为和预后,也可为临床选择分子靶向药物治疗提供依据.     

Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer

The humanized monoclonal antibody pertuzumab is the first in a new class of drugs, the human epidermal growth factor receptor (HER) dimerization inhibitors. Given that pertuzumab binds to a different epitope of the HER2 extracellular domain than trastuzumab, combination therapy with pertuzumab plus trastuzumab may result in more comprehensive blockade of HER2 signalling than can be achieved with trastuzumab alone. The efficacy of adding pertuzumab to trastuzumab plus docetaxel for the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, multinational, phase III CLEOPATRA trial. Both independently assessed progression-free survival (primary endpoint) and investigator-assessed progression-free survival were significantly improved in patients receiving pertuzumab plus trastuzumab and docetaxel compared with those receiving placebo plus trastuzumab and docetaxel. The prespecified interim analysis of survival revealed a strong trend towards a survival benefit associated with pertuzumab, although this was not considered statistically significant. The objective response rate was higher with pertuzumab than with placebo. Intravenous pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the CLEOPATRA trial.