Human Epidermal Growth Factor Receptor-2 Overexpression Research Articles

Immunohistochemical expression of HER2 in urothelial bladder carcinoma and its correlation with p53 and p63 expression

This study assessed the human epidermal growth factor receptor-2 (HER2) protein expression in urothelial bladder carcinoma and its relationship with p53 and p63 expression. In 151 patients, paraffin-embedded tissues of transurethral resection or cystectomy were evaluated by immunohistochemistry (IHC), using antibodies against HER2, p53 and p63. HER2 overexpression (score 3+), p53 overexpression and decreased expression of p63 were detected in 14 (9.3%), 48 (31.8%) and 58 (38.4%) tumors, respectively. HER2 overexpression, p53 overexpression and decreased expression of p63 were associated with high tumor grade (p=0.0002, p=0.0002 and p=0.046, respectively) and advanced TNM stage (p=0.017, p=0.012 and p=0.001, respectively) of urothelial bladder carcinoma. In univariate analysis HER2 overexpression was significantly associated with decreased expression of p63 (p=0.037). In multivariate analysis, only tumor grade was correlated with HER2 overexpression (p=0.006). In this study, HER2 is overexpressed in 9.3% of urothelial bladder carcinomas. HER2 overexpression was strongly correlated with tumor grade but not with TNM stage, p53 and p63. The development of target therapies using anti-HER2 and the identification of patients which who benefit from those therapies need further studies.

Cytoplasmic Overexpression of HER2: A Key Factor in Colorectal Cancer

Trastuzumab, a humanized mouse monoclonal antibody directed against HER2 (Human Epidermal Growth Factor Receptor 2), is currently a keystone in the treatment of breast cancer. Meanwhile, trastuzumab has been validated for use in other types of cancer too. But the data on HER2 expression in colorectal cancer are ambiguous, with reported overexpression of HER2 varying between zero and 84%. In this review these studies are evaluated and compared. It shows that many factors influence the determination of HER2-expression, especially of the intracellular fraction of HER2. It is concluded that although membranous overexpression of HER2 is low in colorectal cancer with only 5% of all patients being positive, a significant proportion of the patients (30%) shows cytoplasmic HER2 overexpression. The clinical impact of enhanced intracellular HER2 is not known, because the nature and origin have not completely been revealed yet. Enlightening this process could be a stepping stone towards targeting of intracellular HER2 as a treatment option.

PTU-174 Systematic review and meta-analysis of the influence of human epidermal growth factor receptor 2 (HER2) expression and amplification on survival in patients with oesophageal cancer

IntroductionSurvival and recurrence rates following oesophagectomy remain poor despite the use of neoadjuvant therapy. Human epidermal growth factor receptor-2 (HER2) overexpression is associated with poorer survival in patients with gastric...

The association of human epidermal growth factor receptor-2 (HER-2) expression with clinicopathologic findings in patients with colorectal cancer receiving adjuvant therapy.

e14089 Background: Colorectal cancers (CRC) are the third frequent cancer worldwide. Like in other cancers; factors which might be associated with prognosis and treatment of the disease are investigated in molecular basis. In this study, it was aimed to determine the levels of HER-2 expression and it’s association with clinicopathological findings in patients with CRC receiving adjuvant therapy. Methods: A total of 80 patients (48 female, 32 male) whom were diagnosed with CRC and received adjuvant FOLFOX-4 from March 2006 to September 2010 were included in the study. The parameters; age, gender, histopathological diagnosis, tumor localization, presence of obsruction-perforation-bleeding history, grades, presence of perineural-lymphovascular invasion, pathological TNM staging at time of diagnosis, findings of relapse-metastasis, history of surgery and radiotherapy, the chemotherapy regimens received in adjuvant and metastatic stages, follow up intervals and survival data were analyzed. HER-2 receptors were stained immunohistochemically. FISH was performed for samples which were stained (++) or (+++). Statistical analysis was performed for the data. Results: Median follow up was found 24 months (min-max: 1-67) and median age was 59 (min-max: 33-84). Thirteen patients (16%) died and 17 patients relapsed (21%) during follow-up. The median disease-free survival was found 55 months (95% CI: 42.84-55.95). Themedian overall survival was not reached yet.In immunohistochemical stainings; (+++) staining was found in 2 patients (2.5%) while (++) was in 13 (16%) patients. All of 15 patients were performed FISH for HER-2; samples which were (+++) showed positivity but the ones with (++) were negative for FISH. No significant correlation was found between HER-2 expression and clinicopathological findings (p>0.05). Also, no statistical significance was found between HER-2 expression and survival (p>0.05). Conclusions: To current data; prognostic and predictive value of HER-2 overexpression for CRC seems to be poor. Larger, prospective and long-lasting studies are required to clarify this controversial topic.

Clinicopathologic Characteristics and Prognostic Factors in Patients with Operable HER-2 Overexpressing Breast Cancer

To study the relationship between clinical pathologic characteristics, treatment modalities and prognostic factors in HER-2 (Human Epidermal growth factor Receptor-2) overexpressed breast carcinoma. Major clinico-pathological factors including therapeutic modalities and survival status of 371 breast cancer patients with HER2 over-expression, teated at Yantai Yuhuangding Hospital from March of 2002 to December of 2010 were retrospectively studied, with special attention focused on survival-related factors. The median age of the total 371 patients in this study was 48 years at time of diagnosis, among which, the leading pathological type was infiltrating ductal carcinoma (92.5%); 62.8% presented with a primary tomor larger than 2 cm in diameter at diagnosis, 51.0% had axillary lymph node (ALN) metastases; ER (Estrogen receptor) /PR (Progesterone receptor) double negative occured in 52.8% of cases, and PCNA (proliferation cell nuclear antigen) (+ + +) was found in 55.1%. HER-2 overexpressed patients were usually in advanced stage when the diagnosis was made (72.8% at stages IIA~IIIC). The prognosis and survival were assessed in 259 patients with complete follow-up data. 5-year DFS (disease-free survival) and OS (overall survival) rate was 68.0% and 78.0% respectively. Univariate analysis revealed that age, tumor size, ALN metastases, LVSI (lymph-vascular space involvement), PCNA status, hormonal therapy, chemotherapy cycles, and HER-2 overexpression, correlated closely with the prognosis. ALN metastases, LVSI, PCNA status and chemotherapy cycles were independent predictors of survival. HER-2 overexpressed breast cancer has special clinical and pathological characteristics, with advanced clinical stages and high rate of ER/PR double negative. Lymph node metastases, LVSI, PCNA and chemotherapy cycles are independent predictors of prognosis.

Over-expression of HER-2 is associated with the stage in carcinomas of the urinary bladder

BackgroundThe frequency of over-expression of human epidermal growth factor receptor-2 (HER-2) in bladder cancer is one of the highest among all human malignancies. This over-expression is thought to play a role in aberrant proliferation of cancer cells. Studies on HER-2 expression in bladder carcinoma have shown heterogeneous results.PurposeThe aim of the study was to evaluate the status of HER-2 protein expression in patients with invasive carcinomas of the urinary bladder as related to tumor grade and stage.Materials and methodsArchival samples from 39 patients (6 women, 33 males) with urinary bladder cancer were analyzed for HER-2 over-expression, using immunohistochemistry with the HercepTest.ResultsHER-2 over-expression was observed in 23/39 tumors (59%) and was more frequent in high-grade than in low-grade carcinomas, but the difference was not statistically significant. A significant correlation was established between HER-2 over-expression and tumor stage (p=0.011). HER-2 expression was more frequent in transitional cell carcinomas (TCC) and adenocarcinomas (AC) as compared with squamous cell carcinoma (SCC). Patients’ age and sex were not related to HER-2 over-expression.ConclusionOver-expression of HER-2 was frequent in carcinomas of the urinary bladder. Knowing the HER-2 status would be helpful in formulating a rational treatment strategy for patients with urinary bladder cancer.

Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology

To assess human epidermal growth factor receptor-2 (HER2)-status in gastric cancer and matched lymph node metastases by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). 120 cases of primary gastric carcinomas and 45 matched lymph node metastases from patients with full clinicopathological features were mounted onto multiple-punch and single-punch tissue microarrays, respectively, and examined for HER2 overexpression and gene amplification by IHC and CISH. Twenty-four tumors (20%) expressed HER2 immunohistochemically. An IHC score of ≥ 2+ was observed in 20 tumors (16.6%). HER2 amplification was detected by CISH in 19 tumors (15.8%) and in their matched lymph node metastases. A high concordance rate was found between HER2 positivity (as detected by IHC) and HER2 gene amplification (as detected by CISH), since 19 of the 20 IHC positive cases were amplified (95%). All amplified cases had 2+ or 3+ IHC results. Amplification was associated with intestinal phenotype (P < 0.05). No association with grading, staging or survival was found. In gastric cancer, HER2 amplification is the main mechanism for HER2 protein overexpression and is preserved in lymph node metastases.

Role of HER2 status in the treatment of brain metastases arising from breast cancer by stereotactic radiosurgery.

117 Background: Overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to be an independent risk factor of development of brain metastases (BM). However, the role of HER2 on the radiosensitivity of BM remains controversial. We investigated the efficacy of single fraction stereotactic radiosurgery (SRS) in the treatment of limited BM from breast cancer, based on the HER2 status. Methods: From 2004 to 2010, 57 patients with limited BM were treated with SRS using Leksell Gamma-Knife to a median dose of 20 Gy (range 12-20 Gy) prescribed to the 50% isodose line. The median number of lesions treated were 2 (range 1-7) and the median tumor volume was 92.8 mm3 (range 3.4 -793.7 mm3). There were 27 HER2 positive patients, with 32 ER positive and 22 PR positive patients. Six patients were triple negative. ER/PR information was not available for 4 patients. Overexpression of HER2 was defined as HER2 +++ by immunohistochemistry using the DAKO HercepTest or fluorescent in situ hybridization (FISH) analysis. Time to local recurrence, time to development of new brain metastases, progression-free survival (PFS), and overall survival (OS) were assessed from the date of SRS. Results: With a median follow-up of 11 months (range 1-66 months), 12 patients developed recurrence at the previously treated site (9 HER2 positive patients) and 30 developed new brain metastases (16 HER2 positive patients) The median PFS and OS for all patients were 8 and 16 months respectively. The median PFS for HER2 positive patients compared to HER2 negative patients were 7 and 11 months, respectively (p=0.352). HER2 positive patients had a median OS of 20 months, compared to 14 months in HER2 negative patients (p=0.086). Five patients went on to develop leptomeningeal disease, all of whom were HER2 positive. Conclusions: HER2 overexpression does not increase the risk of recurrence at the site of treatment or appearance of new BM. It does not affect PFS or OS following SRS. However, it remains a risk factor for the development of leptomeningeal disease.

Combination Treatment with HER-2 and VEGF Peptide Mimics Induces Potent Anti-tumor and Anti-angiogenic Responses in Vitro and in Vivo

HER-2 is a member of the EGF receptor family and is overexpressed in 20-30% of breast cancers. HER-2 overexpression causes increased expression of VEGF at both the RNA and protein levels. HER-2 and VEGF are therefore considered good targets for cancer treatment, which has led to the development of two humanized monoclonal antibodies (mAb) pertuzumab and bevacizumab. Although passive immunotherapy with these Abs are approved for treatment of advanced breast cancer, a number of concerns exist. Treatment is expensive, has a limited duration of action, and is usually accompanied by serious side effects. We hypothesized that therapy with conformational peptide mimics aimed at blocking receptor-ligand interaction is potentially safer with little toxicity, cheaper with a longer half-life, and has greater penetrating abilities than mAbs. We designed and synthesized peptides based on the binding of HER-2 with pertuzumab and VEGF with VEGFR2. We show that treatment with the peptide mimics induces potent anti-tumor responses in vitro as determined by cell viability, proliferation, and HER2 phosphorylation assays. We also demonstrate in a transplantable BALB/c mouse tumor model that treatment with the peptide mimics resulted in a greater delay in tumor growth and development. Similarly, treatment with the peptide mimics inhibited angiogenesis in vivo as assessed by a Matrigel plug assay. To address the problem of degradability of L-amino acid peptides in vivo, we synthesized the retro-inverso D-peptide mimics that resulted in higher efficacy in treatment. Our study shows that combination treatment with HER-2 and VEGF peptide mimics provides greater efficacy than individual treatments.

Suppression of Heregulin‐β1/HER2‐Modulated Invasive and Aggressive Phenotype of Breast Carcinoma by Pterostilbene via Inhibition of Matrix Metalloproteinase‐9, p38 Kinase Cascade and Akt Activation

Invasive breast cancer is the major cause of death among females and its incidence is closely linked to HER2 (human epidermal growth factor receptor 2) overexpression. Pterostilbene, a natural analog of resveratrol, exerts its cancer chemopreventive activity similar to resveratrol by inhibiting cancer cell proliferation and inducing apoptosis. However, the anti-invasive effect of pterostilbene on HER2-bearing breast cancer has not been evaluated. Here, we used heregulin-β1 (HRG-β1), a ligand for HER3, to transactivate HER2 signaling. We found that pterostilbene was able to suppress HRG-β1-mediated cell invasion, motility and cell transformation of MCF-7 human breast carcinoma through down-regulation of matrix metalloproteinase-9 (MMP-9) activity and growth inhibition. In parallel, pterostilbene also inhibited protein and mRNA expression of MMP-9 driven by HRG-β1, suggesting that pterostilbene decreased HRG-β1-mediated MMP-9 induction via transcriptional regulation. Examining the signaling pathways responsible for HRG-β1-associated MMP-9 induction and growth inhibition, we observed that pterostilbene, as well as SB203580 (p38 kinase inhibitor), can abolish the phosphorylation of p38 mitogen-activated protein kinase (p38 kinase), a downstream HRG-β1-responsive kinase responsible for MMP-9 induction. In addition, HRG-β1-driven Akt phosphorylation required for cell proliferation was also suppressed by pterostilbene. Taken together, our present results suggest that pterostilbene may serve as a chemopreventive agent to inhibit HRG-β1/HER2-mediated aggressive and invasive phenotype of breast carcinoma through down-regulation of MMP-9, p38 kinase and Akt activation.

Trastuzumab in gastric cancer

Trastuzumab is a fully humanised monoclonal antibody directed at the human epidermal growth factor receptor-2 (HER-2) which has been a component of standard therapy for advanced and resected HER-2-positive breast cancers for almost a decade. HER-2 over-expression, defined as HER-2 protein over-expression using immunohistochemistry scored as 3+ and/or erbB-2 amplification detected by fluorescent in situ hybridisation, was detected in 22.1% of 3807 patients with advanced gastric and oesophagogastric junction (OGJ) adenocarcinoma screened for eligibility for the phase III ToGA study. The validated scoring system for HER-2 positivity in gastric cancers differs from that recommended for breast cancer due to an increased frequency of incomplete membranous immunoreactivity and heterogeneity of HER-2 expression in gastric cancers. The highest rates of HER-2 over-expression are observed in patients with OGJ rather than gastric tumours and intestinal-type rather than diffuse or mixed histology. The international multicentre randomised phase III ToGA study assessed the addition of trastuzumab to a cisplatin plus fluoropyrimidine (FP) chemotherapy doublet for patients with HER-2-positive advanced gastric or OGJ adenocarcinoma. The investigators reported a clinically and statistically significant benefit in terms of response rate (47.3% versus 34.5%, p = 0.0017), median progression-free survival (6.7 versus 5.5 months, p = 0.0002) and median overall survival (13.8 versus 11.1 months, p = 0.0046). Trastuzumab plus FP chemotherapy is now the standard of care for patients with advanced gastric and OGJ cancers which over-express HER-2. Further research to evaluate trastuzumab delivered beyond progression, in combination with alternative first-line chemotherapy regimens, and in the perioperative and adjuvant setting is urgently needed. Additionally, research into mechanisms of resistance and strategies to overcome primary or acquired resistance to trastuzumab must now be expedited, using lessons learnt over the past decade in HER-2-positive breast cancer to maximise the benefit from this agent.

Trastuzumab induced in vivo tissue remodelling associated in vitro with inhibition of the active forms of AKT and PTEN and RhoB induction in an ovarian carcinoma model

Background:The incidence of ovarian cancer has been increasing worldwide and it is currently the leading cause of death from gynaecological malignancy. Unlike breast cancer, the prognostic role of the human epidermal growth factor receptor-2 (HER-2) in ovarian carcinoma remains controversial.Methods:The aim of this preclinical study was to further characterise the biological, molecular and cellular effects of trastuzumab (Herceptin) using NIH-OVCAR-3 and derived cell lines both in vitro and in vivo.Results:In vitro assessments have shown that trastuzumab treatment inhibited total and phosphorylated HER-2. This was associated with inhibition of the phosphorylated form of phosphatase and tensin homologue (PTEN), mitogen-activated protein kinase and AKT, and the total level of p27kip. Inhibition of PTEN is associated with phosphorylated MEK1/2 upregulation, suggesting a specific inhibition of the protein phosphatase function of PTEN. Moreover, trastuzumab induced the upregulation of RhoB. These molecular modifications promote inhibition of cell migration and potentially restoration of tumour cell contact inhibition. RhoB induction in NIH-OVCAR-3 control cell lines mimics the molecular and cellular trastuzumab long-time exposition effects. RhoB inhibition in NIH-OVCAR-3 long-time exposed to trastuzumab cell line reverses the cellular and molecular effects observed in this model. In vivo examinations have shown that these changes are also associated with the restoration of structural, morphological and normal functions of the peritoneum of an ovarian carcinoma mouse model.Conclusion:These results provide an indication of the mechanisms underlying the anti-tumour activity of trastuzumab that strongly implicate RhoB in an ovarian carcinoma model that does not show HER-2 amplification or overexpression. These findings highlight that trastuzumab effects involve a possible cross-talk between RhoB and PTEN in the early stages of tumour re-growth in a model of micrometastatic ovarian cancer.

Method of detection of DCIS to predict HER2 overexpression.

1557 Background: Overdiagnosis of DCIS has become a major concern. Overexpression of the human epidermal growth factor receptor-2 (HER2) has been introduced as a prognostic marker that correlates with a higher biologic aggressiveness of breast cancer. We investigated the rate of HER2 overexpression of DCIS diagnosed by breast MRI compared to the DCIS diagnosed by mammography. Aim was to find out whether the additional DCIS diagnosed by MRI represents prognostically relevant disease or whether it will lead to additional overdiagnosis. Methods: During a 5-year period 7,319 women underwent breast MRI in addition to mammography for screening or for diagnostic assessment. A total of 167 women received the final surgical pathology diagnosis of pure DCIS. HER2 receptor status was established by standardized methods and dichotomized as positive (DAKO score 3+ or c-erbB2-amplifikation at FISH) or negative (DAKO score < 3+ or FISH negative). It was available in 127/137 women. We investigated the detection rate of breast MRI and of mammography for DCIS. We compared the HER2 receptor status of all MRI-detected versus all mammography-detected DCIS. Furthermore we compared the HER2 receptor status off only mammography-detected versus only MRI-detected DCIS. Results: Of the 127 DCIS, 95 (75%) were categorized as HER2 negative, and 32 (25%) as HER2 positive. Of the 32 HER2 positive DCIS, 13 (41%) were diagnosed through mammography, and 31 (97%) through MRI. Of the 10 DCIS which were only mammography-detected, one (10%) was HER2 positive. Of the 52 DCIS which were only MRI detected, 21 (40%) were HER2 positive. In the entire cohort, two-thirds of HER2-positive DCIS (66%, 21/32) were only detected by MRI (p < 0.005). Conclusions: DCIS not visible at MRI is virtually always HER2 negative. Two-thirds of HER2 positive DCIS are not visible on mammography, but only diagnosed by MRI. The method of detection of a DCIS correlates with its biologic aggressiveness: Detectability by mammography is correlated with a lower aggressiveness compared with detectability by MRI. MRI-detected additional DCIS are associated with a higher biologic aggressiveness. We conclude that MRI-detected DCIS do not add to mammography-induced overdiagnosis, but represent prognostically relevant disease. No significant financial relationships to disclose.

Abstract 4154: Intratumoral heterogeneity of HER2/neu expression in diffuse-gastric carcinoma of European patients and its relevance for patients’ management

Abstract Background: This study assessed the human epidermal growth factor receptor-2 (HER2) protein expression, its relationship with gene amplification and its intra-tumoral heterogeneity in diffuse-gastric carcinoma, a subset of gastric carcinoma that might benefit from Trastuzumab in case of HER2 amplification according to recently reported ToGA trial (J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4509) Patients and methods: The study included 51 European consecutive patients who underwent surgical resection in our institution between January 1991 and December 2007 for diffuse gastric carcinoma. A tissue-microarray was constructed using paraffin-embedded tissues of gastrectomy and matched lymph nodes. HER2 were evaluated by immunohistochemistry (IHC), using the same criteria than for breast cancer. All samples with a 2+ or 3+ HER2 overexpression were evaluated by FISH. Results: HER2 overexpression was observed in 2 (4%) tumors and there was intratumoral heterogeneity. The first tumour shows 2+/3+ immunostaining in lymph nodes with negative immunostaining in the primary tumor. The second tumor shows a focal 3+ HER2 immunostaining in the primary tumor without evidence of positive immunostaining in lymph nodes and peritoneal metastasis. Using FISH, HER2 3+ tumour areas had a gene amplification, whereas no amplification was found in 2+ tumor. The 2 HER2 positive tumors showed the same heterogeneous pattern, with adjacent 3+ positive and negative areas by both IHC and FISH. There was a 100% concordance between TMA and the tissue-sections. Despite complete resection, the 2 patients with HER2 expression died within 15 months. Conclusions: This study showed that 4% of resected diffuse gastric carcinoma had a heterogeneous distribution of HER2 gene amplification. These findings raise the question whether HER2 testing should be realized systematically in these patients and whether Trastuzumab may benefit in tumours with heterogeneous HER2 expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4154.

Assessing HER2 gene amplification as a potential target for therapy in invasive urothelial bladder cancer with a standardized methodology: results in 1005 patients

BackgroundThis study assessed the human epidermal growth factor receptor-2 (HER2) protein expression and its relationship with gene amplification in invasive bladder carcinoma, using the same criteria than for breast cancer. Patients and methodsIn 1005 patients, paraffin-embedded tissues of transurethral resection or cystectomy were evaluated by immunohistochemistry (IHC), using antibodies against HER2. All samples with a 2+ or 3+ HER2 overexpression were evaluated by FISH. ResultsHER2 overexpression was observed in 93 (9.2%) tumors (2+: 42 tumors and 3+: 51 tumors). Using FISH, all HER2 3+ tumors had a gene amplification, whereas no amplification was found in 2+ tumors. Intratumoral heterogeneity was observed in 35% of cases. These tumors showed the same heterogeneous pattern, with adjacent 3+ positive and negative areas by both IHC and FISH. ConclusionsThis study showed that 5.1% of invasive bladder carcinomas had a HER2 gene amplification. These findings may have clinical implications for the management of patients with HER2-positive locally advanced or metastatic bladder cancer, as they could be potential candidates for targeted therapy.

NF-κB-MediatedHER2Overexpression inRadiation-Adaptive Resistance

The molecular mechanisms governing acquired tumor resistance during radiotherapy remain to be elucidated. In breast cancer patients, overexpression of HER2 (human epidermal growth factor receptor 2) is correlated with aggressive tumor growth and increased recurrence. In the present study, we demonstrate that HER2 expression can be induced by radiation in breast cancer cells with a low basal level of HER2. Furthermore, HER2-postive tumors occur at a much higher frequency in recurrent invasive breast cancer (59%) compared to the primary tumors (41%). Interestingly, NF-kappaB is required for radiation-induced HER2 transactivation. HER2 was found to be co-activated with basal and radiation-induced NF-kappaB activity in radioresistant but not radiosensitive breast cancer cell lines after long-term radiation exposure, indicating that NF-kappaB-mediated HER2 overexpression is involved in radiation-induced repopulation in heterogeneous tumors. Finally, we found that inhibition of HER2 resensitizes the resistant cell lines to radiation. Since HER2 is shown to activate NF-kappaB, our data suggest a loop-like HER2-NF-kappaB-HER2 pathway in radiation-induced adaptive resistance in breast cancer cells.

Randomized Phase III Trial of Weekly Compared With Every-3-Weeks Paclitaxel for Metastatic Breast Cancer, With Trastuzumab for all HER-2 Overexpressors and Random Assignment to Trastuzumab or Not in HER-2 Nonoverexpressors: Final Results of Cancer and Leukemia Group B Protocol 9840

Phase II trials suggested that weekly paclitaxel might be more effective and less toxic than every-3-weeks administration for metastatic breast cancer (MBC). Cancer and Leukemia Group B (CALGB) protocol 9840 was initiated to address this question. Subsequently trastuzumab was demonstrated to improve outcomes of paclitaxel therapy for human epidermal growth factor receptor-2 (HER-2)-positive patients, and was therefore incorporated. Because inhibition of HER-family signaling had potential efficacy even without HER-2 overexpression, we randomly assigned for trastuzumab in this population. Patients were randomly assigned to paclitaxel 175 mg/m(2) every 3 weeks or 80 mg/m(2) weekly. After the first 171 patients, all HER-2-positive patients received trastuzumab; HER-2 nonoverexpressors were randomly assigned for trastuzumab, in addition to paclitaxel schedule. A total of 577 patients were treated on 9840. An additional 158 patients were included in analyses, for combined sample of 735. The primary end point was response rate (RR); secondary end points were time to progression (TTP), overall survival, and toxicity. Primary comparisons were between weekly versus every-3-weeks paclitaxel, and trastuzumab versus no trastuzumab in HER-2 nonoverexpressors. In the combined sample, weekly paclitaxel was superior to every-3-weeks administration: RR (42% v 29%, unadjusted odds ratio [OR] = 1.75; P = .0004), TTP (median, 9 v 5 months; adjusted HR = 1.43; P < .0001), and survival (median, 24 v 12 months; adjusted HR = 1.28; P = .0092). For HER-2 nonoverexpressors, trastuzumab did not improve efficacy. Grade 3 neuropathy was more common with weekly dosing (24% v 12%; P = .0003). Weekly paclitaxel is more effective than every-3-weeks administration for MBC. Trastuzumab did not improve efficacy for HER-2 nonoverexpressors. Neurotoxicity is a treatment-limiting toxicity for weekly paclitaxel.

A Trigger Squeezed

Qiu et al. (2008) add new weight to the very highly detailed understanding of how extracellular ligand binding-induced dimerization of a receptor tyrosine kinase is first manifested inside the cell.

Pathologic Complete Response to Trastuzumab-Based Neoadjuvant Therapy Is Related to the Level of HER-2 Amplification

Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are used to determine human epidermal growth factor receptor-2 (HER-2) status and patient eligibility for trastuzumab therapy. Using FISH and IHC, we analyzed the relationship between pathologic complete response to trastuzumab-based neoadjuvant therapy and level of HER-2 amplification in locally advanced breast cancer. Breast biopsies from 93 HER-2-positive patients treated with trastuzumab-based neoadjuvant therapy were centrally collected and analyzed retrospectively for HER-2 amplification using FISH and HER-2 overexpression using IHC. Tumors were classified by FISH as no, low, or high amplification. Biopsies were reassessed centrally by IHC and graded 0, 1+, 2+, or 3+. HER-2 status of tumor samples as assessed by FISH and IHC correlated: 16 no amplification (11 IHC 1+ and 5 IHC 2+), 27 low amplification (26 IHC 3+ and 1 IHC 2+), and 50 high amplification (all IHC 3+). Trastuzumab-based neoadjuvant therapy achieved pathologic complete response in 35 of 93 (37.6%) tumors. Pathologic complete response rate in low- and high-amplification tumors was significantly higher than in no-amplification tumors (44% versus 6%; P < 0.004). Pathologic complete response rate in high-amplification tumors was significantly higher compared with low-amplification tumors (56% versus 22%; P < 0.005). In the subgroup of low- plus high-amplification tumors, no correlation was found between pathologic complete response rate and IHC score, treatment regimen, T or N stage, tumor grade, or hormonal receptors. This is the first study to show positive correlation between level of HER-2 amplification assessed by FISH and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment.

Prognostic Implications of HER-2 Status in Steroid Receptor–Positive, Lymph Node–Negative Breast Carcinoma

Patients with lymph node-negative breast carcinoma (LNNBC) and positive hormone receptor (HR) status during estrogen-based endocrine therapy have different prognoses. The contribution of HER-2 (human epidermal growth factor receptor-2) has not been extensively evaluated. We stained 230 LNNBCs for estrogen and progesterone receptors (ER and PR) and HER-2. HER-2 gene status was studied in 150 randomly selected tumors by chromogenic in situ hybridization and cases with discordant or nondefinitive results by fluorescence in situ hybridization. Patients with ER+ and/or PR+ tumors were treated with tamoxifen. We found positive expression of ER, PR, and HER-2 in 73.7%, 67%, and 27.8%, respectively, and HER-2 amplification in 18.0%. Poorer outcome was seen for patients with ER+ and/or PR+/HER-2 overexpressing tumors and as a trend for patients with HER-2 amplification. ER/PR and HER-2 expression showed an independent prognostic value. In LNNBCs with positive HR status, HER-2 overexpression and/or amplification confer an aggressive tumor phenotype, and this might be related to tamoxifen unresponsiveness.