Human Epidermal Growth Factor Receptor-2 Levels Research Articles

Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers

Human epidermal growth factor receptor2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [177Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [177Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [177Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [177Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.

The Role of Serum CD26 in the Diagnosis of Gastric Cancer.

PurposeThe value of serum cluster of differentiation 26 (CD26) in gastric cancer remains unknown. We investigated serum CD26 as a non-invasive serological marker for the diagnosis of gastric cancer and its relationship with serum human epidermal growth factor receptor-2 (HER2) levels.Patients and MethodsWe enrolled 393 gastric cancer patients treated with endoscopic resection or surgery, and 90 healthy controls. HER2 positivity in tissue was evaluated by immunohistochemistry staining, and the serum CD26 and HER2 levels were measured using an enzyme-linked immunosorbent assay.ResultsSerum CD26 levels were significantly lower in gastric cancer patients than in healthy controls (582.2 ± 254.3 vs 862.7 ± 410.6 ng/mL, P<0.001). Serum CD26 levels were significantly lower in advanced gastric cancer compared to early gastric cancer (642.2 ± 333.9 vs 503.4 ± 332.7 ng/mL, P<0.001), and tended to decrease with gastric cancer progression. To diagnose gastric cancer, the optimal cut-off value of serum CD26 was 762.7 ng/mL with 75.6% sensitivity and 64.4% specificity. Serum CD26 levels were weakly correlated with serum HER2 levels (rs=0.363, P<0.001). However, no difference in serum CD26 levels was observed between tissue HER2-negative and HER2-positive gastric cancer groups (586.2 ± 362.1 vs 579.6 ± 264.8 ng/mL, P=0.898).ConclusionCD26 is a useful non-invasive serological marker for gastric cancer diagnosis; however, its levels do not correlate with HER2 status.

HER-2-Targeted Nanoparticles for Breast Cancer Diagnosis and Treatment.

Simple SummaryDespite tremendous efforts in finding new therapeutic strategies and promoting screening programs to increase early diagnosis, breast cancer is still a major cause of death in the female worldwide population. Preclinical and clinical evidence have shown that nanotechnologies can significantly contribute to improving both therapeutic and diagnostic aspects. This is particularly true for human epidermal growth factor receptor-2 (HER-2) overexpressing (HER-2+) breast cancer, where recurrence rates and drug resistance still make it one of the most aggressive breast cancer subtypes, despite the development of promising targeted therapies. The aim of this review is to provide an update on the most promising nanoparticle-based approaches developed in the last decade in the context of HER-2-positive breast cancer therapy and diagnosis.Human epidermal growth factor receptor-2 (HER-2) overexpressing breast cancer is a breast cancer subtype characterized by high aggressiveness, high frequency of brain metastases and poor prognosis. HER-2, a glycoprotein belonging to the ErbB receptor family, is overexpressed on the outer membrane of cancer cells and has been an important therapeutic target for the development of targeted drugs, such as the monoclonal antibodies trastuzumab and pertuzumab. These therapies have been available in clinics for more than twenty years. However, despite the initial enthusiasm, a major issue emerged limiting HER-2 targeted therapy efficacy, i.e., the evolution of drug resistance, which could be tackled by nanotechnology. The aim of this review is to provide a first critical update on the different types of HER-2-targeted nanoparticles that have been proposed in the literature in the last decade for therapeutic purposes. We focus on the different targeting strategies that have been explored, their relative outcomes and current limitations that still need to be improved. Then, we review the nanotools developed as diagnostic kits, focusing on the most recent techniques, which allow accurate quantification of HER-2 levels in tissues, with the aim of promoting more personalized medicinal approaches in patients.

Effect of the ACY‑1 gene on HER2 and TRAIL expression in rectal carcinoma

The incidence of rectal carcinoma (RC) is increasing and the age at onset of the disease is reducing. Therefore, elucidating the pathogenesis of RC is beneficial for early diagnosis and improving the prognosis. Aminoacylase-1 (ACY-1) is abnormally expressed in various malignant tumor tissues. Furthermore, the human epidermal growth factor receptor-2 (HER2) gene is involved in tumor metastasis and invasion, while tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumor cell apoptosis. The aim of the present study was to investigate the effect of the ACY-1 gene on the expression of HER2 and TRAIL in RC. Cancerous and adjacent tissues from RC patients were collected. ACY-1 expression was analyzed by immunohistochemistry. The rectal cancer cell lines HT29 and SW620, and normal colorectal mucosal epithelial fetal human cells were cultured in vitro. ACY-1 gene and protein expression levels were tested by reverse transcription-quantitative PCR and western blotting. ACY-1 small interfering RNA (siRNA) was transfected into HT29 and SW620 cells. Cell proliferation was detected by thiazolyl blue MTT assay. Caspase-3 activity was assessed using a commercial kit. HER2 and TRAIL expression levels were determined by western blotting. ACY-1 expression was significantly increased in cancer tissue compared with adjacent tissue (P<0.05). ACY-1 expression was elevated in HT29 and SW620 cells compared with normal colorectal mucosal epithelial cells (P<0.05). ACY-1 siRNA transfected into HT29 cells downregulated its expression, inhibited cell proliferation, enhanced caspase-3 activity, reduced HER2 expression and upregulated TRAIL expression (P<0.05). ACY-1 expression was found to be increased in rectal cancer tissue. Therefore, targeting the ACY-1 gene may regulate HER2 and TRAIL expression levels, and may reduce the occurrence and inhibit the development of rectal cancer.

Analysis of plasma HER2 copy number in cell-free DNA of breast cancer patients: a comparison with HER2 extracellular domain protein level in serum

HER2 (human epidermal growth factor receptor 2) status has been evaluated in breast cancer (BC) tissues by immunohistochemistry or in situ hybridization. We evaluated HER2 copy number (CN) assay in plasma cell-free DNA (cfDNA) from blood samples and compared it with protein measurements of HER2 extracellular domain (ECD) in serum. Serum HER2-ECD levels were measured by chemi-luminescence immunoassay using anti-HER2 monoclonal antibodies. Analyses were performed on 120 cases of primary BC, 30 cases of metastatic BC and 34 cases treated by neoadjuvant chemotherapy (NAC). This study was approved by Medical Research Review Advancement No. 1857 for Kumamoto University. There was a positive correlation between HER2-CN ratios and HER2-ECD levels, in primary (n = 54) and metastatic (n = 30) HER2-positive BC (P = 0.003 and P < 0.001, respectively). HER2-ECD levels were significantly higher in patients with a larger number of metastatic sites (P = 0.02). The usefulness of HER2 levels in discriminating primary and metastatic HER2-positive BC evaluated by ROC curve analysis was better in the HER2-ECD assay than in the HER2-CN assay. In 34 patients who received NAC, there was a small decrease in HER2-CN ratios between before and after NAC (P = 0.10), while there was an obvious decrease in HER2-ECD levels between before and after NAC (P < 0.001). Compared to HER2-ECD levels, the clinical usefulness of HER2-CN ratio was somewhat inferior. Improved measurement methods and further examination of the association with long-term prognosis and the response to anti-HER2 treatment analyzed by HER2-CN and HER2-ECD assay are required.

PET imaging of a 68Ga labeled modified HER2 affibody in breast cancers: from xenografts to patients.

Overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancers provides promising opportunities for imaging and targeted therapy. Developing HER2 targeted positron emission tomography (PET) probes might be benefit for management of the disease. Small high-affinity scaffold proteins, affibodies, are ideal vectors for imaging HER2 overexpressed tumors. Despite of the initial success on development of 18F labeled ZHER2:342 affibody, the tedious synthesis producers, low yields and unfavorable pharmacokinetics may hinder the clinical use. 68Ga is an attractive positron emitter for PET imaging. A simple preparation of 68Ga labeled ZHER2:342 analog, 68Ga-NOTA-MAL-Cys-MZHER2:342, was reported in the study. The in vivo performances of the tracer for assessing HER2 status in breast cancers were also evaluated. NOTA-MAL conjugated Cys-MZHER2:342 was radiolabeled with 68Ga. The probe was evaluated by in vitro tests including stability and cell binding studies in breast cancer cells with different HER2 levels. In vivo evaluation was performed in mice bearing tumors using microPET imaging and biodistribution experiments. A PET/CT imaging study was initially performed in patients with breast cancers. The tracer was synthesized in a straightforward chelation method with satisfactory non-decay corrected yield (81±5%) and radiochemical purity (>95%). In vivo micro-PET imaging showed that HER2 high levels expressed BT474 xenografts were more clear visualized than HER2 low levels expressed MCF-7 tumors (16.12 ± 2.69 ID%/g vs 1.32 ± 0.19 ID%/g at 1 h post-injection). The outcome was consistent with the immunohistochemical analysis. No significant radioactivity was accumulated in healthy tissues (less than 2% ID/g) except kidneys. In a preliminary clinical study, 68Ga-NOTA-MAL-Cys-MZHER2:342 PET imaging allowed more high-contrast detection of HER2 positive primary tumors (maximum standardized uptake value = 2.16±0.27) than those in HER2 negative primary focus (maximum standardized uptake value = 0.32±0.05). No detectable side-effects were found. In summary, this study indicates the significant efficiency of the 68Ga labeled HER2 affibody. Preclinical and clinical studies support the possibility of monitoring HER2 levels in breast cancers using 68Ga-NOTA-MAL-Cys-MZHER2:342. The research investigated the feasibility of a 68Ga labeled HER2 affibody modified with a hydrophilic linker for breast cancer PET imaging. Favorable outcomes showed that the probe might be valuable for determining HER2 status of the disease.

Evaluation of Human Epidermal Growth Factor Receptor-2 in Iraqi Women with Breast Cancer

Background:Breast cancer (BC) is the most common malignancy in Iraqi women in the recent years. There are many indicated marker for detection BC and determination the development of the tumor stage, one of the most important marker is human epidermal growth factor receptor-2 (HER2). Objective:To evaluation of serum and tissue HER2 levels among BC women and non BC women. Patients and Methods: Preoperative blood samples were collected from breast cancer women. Patients were newly diagnosing and did not receive neither radiotherapy nor chemotherapy treatment preoperatively.For the control, blood sample was collected from non-breast cancer women. All blood samples subjected to determine the serum HER-2 level. Results: A total of 52 patients with breast cancer and 30 of control were included in this study. The result showed increasing significant in serum concentration of HER-2 among BC patient compared to control and tissue her-2 positive BC patient have significantly higher serum concentration of HER-2 compared to BC patients who were tissue her-2 negative (16.23±10.37 ng/ml, 10.33±5.73 ng/ml) respectively. Conclusion: Serum HER-2 level was positively associated with tissue HER-2 level, for that is an important marker for diagnosis and monitoring BC progression.

Investigating the Levels of Shed Extracellular Domain of HER2 Protein in the Sera of Bladder Cancer Patients

Background: Receptor tyrosine-protein kinase ERBB2, also known as human epidermal growth factor receptor-2 (HER2), is heterogeneously expressed in a variety of human cancers, including bladder cancer. Based on previous studies that show its association with bladder cancer progression, HER2 has been included in novel multiplatform biomarkers for prediction of bladder cancer prognosis. However, the clinical significance of HER2 status remains underinvestigated and poorly linked to the patients’ clinicopathological features. Here, we aim to scrutinize the levels of the extracellular domain of HER2 in the sera of bladder cancer patients and correlate these levels with clinicopathological features of the tumor.Methods: In the present analytical cross-sectional study, we enrolled 60 pathologically confirmed bladder cancer patients along with 20 age-sex matched healthy controls, and compared their serum HER2 levels as measured by enzyme-linked immunosorbent assay.Results:We observed no statistically significant difference when comparing the levels of HER2 in the sera of cases and controls (P>0.05). Interestingly, serum HER2 levels of controls were higher than bladder cancer patients who had lymph node metastasis (P=0.036). Serum levels of HER2 were also higher in controls than bladder cancer patients with perineural invasion (P=0.028). We observed significantly higher HER2 serum levels in transitional cell carcinoma patients in comparison to non-transitional cell carcinoma patients (P=0.016).Conclusion: Our observations are suggestive of the absence of any association between bladder cancer prognostic factors and serum HER2 levels. To draw any definitive conclusion, further studies with larger sample sizes that examine the presence of neutralizing auto-antibodies against serum HER2, immunohistochemistry examination of HER2 in bladder tumor and lymph node samples, and urinary HER2 levels, along with measurement of its serum levels would be helpful.

Assessment of the clinical utility of chip-based digital PCR for HER2 assessment in formalin fixed paraffin-embedded breast carcinoma tissue.

e23120 Background: 15%-25% of breast cancer neoplasms exhibit Human epidermal growth factor receptor-2(HER2) amplification, as the driver mutation.Techniques to identify HER2 amplification include Immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH). Digital PCR (dPCR) has been increasingly explored in determining HER2 status in cases of indeterminate results on IHC, mainly in archived samples. In this study, we aim to demonstrate the clinical utility of the Quantstudio 3D Digital PCR system to evaluate HER2 levels from Formalin Fixed Paraffin Embedded (FFPE) tissue with RNaseP as a control target. Methods: 61 tissue samples were analyzed by IHC and dPCR in parallel in a double blinded manner. IHC equivocal samples were reflexed to FISH and compared to the results obtained from dPCR. Samples suboptimal for IHC or FISH were satisfactorily processed by dPCR. dPCR results were analyzed on the Thermofisher Cloud platform. The general turnaround time(TAT) was about 2 and 3 days for IHC and FISH respectively with that of dPCR being 24 hours. Results: All 9 IHC positive and 35 negative samples had similar results on dPCR using an amplification ratio threshold for a positive result of 1.8. Of 17 IHC-equivocal samples, 5 resulted as positive, 10 negative and 2 as equivocal by dPCR. There was 100% concordance between the dPCR and FISH results. Two IHC equivocal samples that were unanalyzable by FISH were negative on dPCR Conclusions: Our results demonstrate that the chip based dPCR was non-inferior for HER2 detection in FFPE samples in a clinical setting. Superior TAT's and objective results were obtained compared to more subjective techniques like FISH and IHC even with low sample input. dPCR requires controls but no standards for calibration as it gives absolute copy numbers. Further study is needed to understand dPCR interpretation in cases of chromosomal aneuploidy. [Table: see text]

High HER2 protein levels correlate with increased survival in breast cancer patients treated with anti-HER2 therapy

IntroductionCurrent methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments. MethodsUsing selected reaction monitoring mass spectrometry (SRM-MS), we quantified HER2 protein levels in formalin-fixed, paraffin-embedded (FFPE) tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by immunohistochemistry (IHC). Receiver operator curve (ROC) analysis was conducted to obtain optimal HER2 protein expression thresholds predictive of HER2 status (by standard IHC or in situ hybridization [ISH]) and of survival benefit after anti-HER2 therapy. ResultsAbsolute HER2 amol/μg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p < 0.0001). A HER2 threshold of 740 amol/μg showed an agreement rate of 94% with IHC and ISH standard HER2 testing (p < 0.0001). Discordant cases (SRM-MS-negative/ISH-positive) showed a characteristic amplification pattern known as double minutes. HER2 levels >2200 amol/μg were significantly associated with longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and with longer OS in a metastatic setting. ConclusionQuantitative HER2 measurement by SRM-MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy.

HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer

Overexpression of the human epidermal growth factor receptor-2 (HER2) in breast cancer strongly correlates with aggressive tumors and poor prognosis. Recently, a positive correlation between HER2 and MIF (macrophage migration inhibitory factor, a tumor-promoting protein and heat-shock protein 90 (HSP90) client) protein levels was shown in cancer cells. However, the underlying mechanistic link remained unknown. Here we show that overexpressed HER2 constitutively activates heat-shock factor 1 (HSF1), the master transcriptional regulator of the inducible proteotoxic stress response of heat-shock chaperones, including HSP90, and a crucial factor in initiation and maintenance of the malignant state. Inhibiting HER2 pharmacologically by Lapatinib (a dual HER2/epidermal growth factor receptor inhibitor) or CP724.714 (a specific HER2 inhibitor), or by knockdown via siRNA leads to inhibition of phosphoactivated Ser326 HSF1, and subsequently blocks the activity of the HSP90 chaperone machinery in HER2-overexpressing breast cancer lines. Consequently, HSP90 clients, including MIF, AKT, mutant p53 and HSF1 itself, become destabilized, which in turn inhibits tumor proliferation. Mechanistically, HER2 signals via the phosphoinositide-3-kinase (PI3K)–AKT– mammalian target of rapamycin (mTOR) axis to induce activated pSer326 HSF1. Heat-shock stress experiments confirm this functional link between HER2 and HSF1, as HER2 (and PI3K) inhibition attenuate the HSF1-mediated heat-shock response. Importantly, we confirmed this axis in vivo. In the mouse model of HER2-driven breast cancer, ErbB2 inhibition by Lapatinib strongly suppresses tumor progression, and this is associated with inactivation of the HSF1 pathway. Moreover, ErbB2-overexpressing cancer cells derived from a primary mouse ErbB2 tumor also show HSF1 inactivation and HSP90 client destabilization in response to ErbB2 inhibition. Furthermore, in HER2-positive human breast cancers HER2 levels strongly correlate with pSer326 HSF1 activity. Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer.

Allellic HER-2 codon 655 polymorphism and the influence of plasma HER-2 levels in breast cancer Egyptian female patients

Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. Alterations of human epidermal growth factor receptor-2 (HER-2) proto-oncogene have been associated with carcinogenesis and poor prognosis of breast cancers. HER-2 DNA amplification is suggested to be the principal mechanism of HER-2 protein activation. The aim of the study was to clarify the possible association between HER-2 gene polymorphism at codon 655, free plasma HER-2 level, and breast cancer risk. Eighty Egyptian female patients (40 with early breast cancer and 40 with locally advanced breast cancer) were tested for HER-2 genetic polymorphism at codon 655 by restriction fragment length polymorphism–polymerase chain reaction assay. Also, the plasma level of HER-2 was measured using enzyme-linked immunosorbent assay. There was significant increase in mutant G allele frequency among locally advanced group compared to the control group and this conferred 12-fold increased disease risk among the studied group. No significant association could be detected between early breast cancer and HER-2 gene polymorphism. There is a statistically significant increase in the mean plasma HER-2 level among locally advanced breast cancer patients in comparison to the control group suggesting that plasma HER-2 contributes to the development, the higher stage, and dissemination of breast cancer.

Insulin‐like growth factor‐1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus

Insulin-like growth factor-1 receptor (IGF-1R) and human epidermal growth factor receptor-2 (HER2) receptor expression has been found to be a key regulator of tumorigenesis. The purpose of our study was to establish the prognostic significance of IGF-1R in esophageal cancer and to determine the effect of IGF-1R and HER2 targeting with alpha-IR3 and Herceptin antibodies on the proliferation of esophageal cancer cells in vitro. IGF-1R expression and clinicopathological correlations were analyzed with a tissue microarray containing 234 esophageal cancer specimens (133 adenocarcinomas and 101 squamous cell carcinomas). Proliferation changes associated with Herceptin and alpha-IR3 blockage were evaluated with the unique human esophageal cancer cell lines Pt1590 and LN1590. IGF-1R and HER2 expression levels, activation and phosphorylation status of downstream signaling proteins involved in the activation pathways were analyzed by Western blotting. IGF-1R overexpression was detected in 121 (52%) of the 234 esophageal tumors examined. In the subgroup of 87 HER2-positive tumors, 93.1% showed concordant overexpression for IGF-1R. IGF-1R was identified as a variable associated with reduced overall survival for adenocarcinoma (p = 0.05), but not for squamous cell carcinoma. The combination of Herceptin and alpha-IR3 was more effective in inhibiting in vitro proliferation than treatment with either agent alone (p < 0.01). This was associated with a decrease in HER2 and IGF-1R protein levels and suppression of Akt- and MAP kinase phosphorylation. IGF-1R expression can be used as a novel prognostic marker for adenocarcinomas of the esophagus. Cotreatment with IGF-1R and HER2 antibodies might become a valuable and effective treatment option in esophageal adenocarcinoma.

Serum HER-2 concentrations for monitoring women with breast cancer in a routine oncology setting

The purpose of this study was to determine the positive predictive value (PPV) of positive serum human epidermal growth factor receptor-2 (HER-2) for monitoring women with breast cancer following diagnosis and treatment in a routine clinical setting. Serum HER-2 was measured in 1348 patients with breast cancer: 837 during routine oncology clinic visits and 511 following new diagnosis. All patients with positive serum HER-2, 1/5 of negative patients from the oncology clinic, and all the newly diagnosed were followed; a total of 862 patients. Serum HER-2 was measured using the Bayer ADVIA Centaur assay. Tissue HER-2 was determined using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC +3 or IHC +2 and FISH>2.0 were positive. Patients were considered to have positive serum HER-2 when at least two values were >15 ng/mL. Recurrence, progression and regression were diagnosed according to usual clinical practice. Serum HER-2 concentrations did not contribute to diagnostic decision-making or selection of treatment. From January 2004 to January 2009, 149 patients were found to have positive serum HER-2. Of these, 35 were tissue HER-2 positive at surgery, 69 tissue-negative and 45 were not determined. Fifty-five of 149 that were serum HER-2 positive (37%, 95% CI: 29-45) had metastases. Among the 35 tissue-positive patients, 25 had recurrence in the form of metastases and there was good correlation between recurrence/progression and increase in serum HER-2 (p<0.0003). There was also a high correlation between effect of treatment and decline in serum HER-2 (p<0.0003). Of the 69 tissue-negative patients, 29 had recurrence in the form of metastases, and there was good correlation with serum HER-2 levels (p<0.000004). In this routine application of serum HER-2, the PPV for metastases recurrence detection in both tissue-positive and tissue-negative was 54 of 104 (52%, 95% CI: 42%-62%), in tissue-positive 25 of 35 (71%, 95% CI: 54%-85%), in tissue-negative 29 of 69 (42%, 95% CI: 30%-54%). The lead time of increases in serum HER-2 before recurrence could be determined in ten tissue-positive patients was 3-24 months (mean 11.3 months), when compared to standard clinical imaging methods. Serum HER-2 is a useful marker for the detection of recurrence of breast cancer and for monitoring the effect of treatment, especially in tissue HER-2 positive patients.

Preoperative Plasma HER2 and Epidermal Growth Factor Receptor for Staging and Prognostication in Patients with Clinically Localized Prostate Cancer

Human epidermal growth factor receptor-2 (HER2) and epidermal growth factor receptor (EGFR) expression have been associated with disease progression in patients with prostate cancer. We tested the hypothesis that plasma levels of HER2 and/or EGFR are associated with prostate cancer stage and prognosis in patients with clinically localized disease. We measured preoperative plasma HER2 and EGFR levels using commercially available ELISAs on banked plasma from 227 patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate adenocarcinoma. Median preoperative plasma EGFR and HER2 levels were 31.4 ng/mL (interquartile range, 19.2 ng/mL) and 10.0 ng/mL (interquartile range, 2.7 ng/mL), respectively. HER2 was elevated in patients with seminal vesicle invasion (P = 0.033). In separate multivariate analyses that adjusted for the effects of standard preoperative predictors, lower EGFR, higher HER2, and higher HER2/EGFR ratio were associated with prostate-specific antigen (PSA) progression (P = 0.003, P < 0.001, and P < 0.001, respectively). In separate multivariate analyses that adjusted for the effects of standard postoperative predictors, lower EGFR and higher HER2/EGFR ratio were associated with PSA progression (P = 0.027 and P < 0.001, respectively). Among the patients who experienced PSA progression, HER2 was significantly higher (P = 0.023) and EGFR was lower (P = 0.04) in those with features of aggressive disease (i.e., development of metastasis, PSA doubling time <10 months, and/or failure to respond to local salvage radiation therapy). Preoperative plasma HER2 and EGFR were associated with prostate cancer progression after radical prostatectomy. Plasma HER2 and EGFR may provide a tool for predicting long-term recurrence-free survival and early metastasis.

Inhibition of HER-2 by three independent targeting strategies increases paclitaxel resistance of SKOV-3 ovarian carcinoma cells

Current treatment options for ovarian cancer, which is one of the most widespread gynecological malignancies, are limited, mainly because patients with advanced-stage disease often develop resistance to chemotherapeutics. In breast cancer cells, several studies suggest that overexpression of the human epidermal growth factor receptor-2 (HER-2) leads to increased resistance against certain, but not all cytotoxic drugs. In ovarian carcinoma, conflicting data on the correlation of HER-2 expression and tumor cell sensitivity exist. In this paper, we explore the role of HER-2 expression and signaling levels pertaining to paclitaxel (Taxol) chemoresistance by applying three different and independent strategies in SKOV-3 ovarian carcinoma cells. Firstly, we show that treatment with the HER-2 inhibitory antibody trastuzumab (Herceptin), which is well established in tumor therapy, results in markedly increased, rather than decreased, cellular paclitaxel resistance. Next, we present two newly developed low molecular weight inhibitors of HER-2 tyrosine kinase activity, D-69491 and D-70166. With both drugs, the decrease in cellular paclitaxel sensitivity upon HER-2 inhibition is confirmed. Finally, for more detailed analysis we stably downregulate HER-2 expression by ribozyme-targeting. Using clonal ribozyme-transfected SKOV-3 cells with different residual HER-2 levels, we establish a 'HER-2 gene dose effect' of paclitaxel cytotoxicity. We show that this effect is due to differential induction of apoptosis and differential cell cycle inhibition by paclitaxel. Finally, paclitaxel- or HER-2-mediated alterations in the phosphorylation of MAP kinases p42/44, Stress-activated protein kinase/Jun-terminal kinase (SAPK/JNK), and p38, and effects on the activation of caspase-3, caspase-7, and bcl-2 are discussed. We conclude that paclitaxel cytotoxicity in SKOV-3 cells is 'HER-2 dose-dependent' and identify cell proliferation as one underlying cellular event of this effect.