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PubMed2026

Molecular and immune profiling of HER2-low, HER2 ultra-low, and HER2-null male breast cancer.

BACKGROUND: HER2 expression is described along a biological continuum from null to positive and serves as a critical biomarker for therapeutic guidance in breast cancer (BC). While HER2-low and ultra-low categories have emerged as actionable targets for antibody-drug conjugates (ADCs) in female BC, their molecular and immune characteristics remain largely unexplored in male breast cancer. METHODS: We profiled 214 male breast tumors using next-generation sequencing and whole-transcriptome sequencing to assess mutational, transcriptomic, and immune landscapes. Tumor mutational burden (TMB) was defined as high if > 10 mutations/Mb. Immune cell fractions were inferred using Quantiseq deconvolution. RESULTS: Among 214 samples, 66 (30.8%) were HER2-null, 53 (24.8%) HER2 ultra-low, 80 (37.4%) HER2-low, and 15 (7.0%) HER2-positive. HER2 ultra-low tumors exhibited a higher prevalence of PIK3CA mutations (39.2% vs 22.6%, p ≤ 0.05) compared to HER2-null. No significant differences were observed in TMB-high frequency or PD-L1 expression across subgroups. Immune composition differed primarily between HER2-null and HER2-expressing subgroups: HER2-ultra-low tumors showed higher B-cell infiltration, whereas HER2-null tumors were enriched in neutrophils. Transcriptomic analysis revealed upregulation of selected stemness-associated genes (NANOG, KLF4, POU5F1) and CEACAM1 in HER2-null tumors, while HER2-low and HER2-ultra-low tumors were largely similar across most molecular and immune readouts in this cohort. CONCLUSIONS: HER2-null male breast cancer appears to represent the most biologically divergent subgroup within the HER2-negative spectrum, whereas HER2-low and HER2-ultra-low tumors were largely similar in this cohort. These findings support further investigation of HER2-null disease as a distinct biological state and provide hypothesis-generating data for biomarker development in this rare population.

Male↗

PubMed2002

Antihuman epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab enhances cytolytic activity of class I-restricted HER2-specific T lymphocytes against HER2-overexpressing tumor cells.

The monoclonal antibody trastuzumab (Herceptin) directed against the human epidermal growth factor receptor 2 (HER2) results in tumor regressions when administered to patients with HER2-overexpressing breast cancer. One of the underlying mechanisms of this antibody-induced tumor regression is based on the internalization and degradation of HER2 by tumor cells on interaction with trastuzumab, subsequently inhibiting signal transduction pathways. As antibody-induced degradation of HER2 is likely to be accompanied with increased numbers of HER2 peptides presented with MHC, we asked whether trastuzumab-treated tumor cells were more susceptible to CTL-mediated lysis. Here we show that the cytolytic activity of human, HER2-specific CD8(+) CTLs is augmented by anti-HER2 antibody trastuzumab. HER2-reactive CTL clones lyse class I-matched, HER2-overexpressing tumor cells more efficiently after treatment with trastuzumab. The potentially synergistic activity of HER2-specific antibody and CTL encourages the development of an HER2-targeted immunotherapy using a combination of inhibitory antibodies and CTLs for patients with HER2-overexpressing tumors.

Antibodies, Monoclonal↗

PubMed2003

Quantitative analysis of HER2-mediated effects on HER2 and epidermal growth factor receptor endocytosis: distribution of homo- and heterodimers depends on relative HER2 levels.

Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR) family. Many cell types express multiple EGFR family members (including EGFR, HER2, HER3, and/or HER4) that interact to form an array of homo- and heterodimers. Differential trafficking of these receptors should strongly affect signaling through this system by changing substrate access and heterodimerization efficiency. Because of the complexity of these dynamic processes, we used a quantitative and computational model to understand their integrated operation. Parameters characterizing EGFR and HER2 interactions were determined using experimental data obtained from mammary epithelial cells constructed to express different levels of HER2, enabling us to estimate receptor-specific internalization rate constants and dimer uncoupling rate constants. Significant novel results obtained from this work are as follows: first, that EGFR homodimerization and EGFR/HER2 heterodimerization occur with comparable affinities; second, that EGFR/HER2 heterodimers traffic as single entities. Furthermore, model predictions of the relationship of HER2 expression levels to consequent distribution of EGFR homodimers and EGFR/HER2 heterodimers suggest that the levels of HER2 found on normal cells are barely at the threshold necessary to drive efficient heterodimerization. Thus, altering HER2 concentrations, either overall or local, could provide an effective mechanism for regulating EGFR/HER2 heterodimerization and may explain why HER2 overexpression found in some cancers has such a profound effect on cell physiology.

Cell Line↗

PubMed2004

A case of metastatic breast cancer with outgrowth of HER2-negative cells after eradication of HER2-positive cells by humanized anti-HER2 monoclonal antibody (trastuzumab) combined with docetaxel.

A 38-year-old woman with cancer of the left breast underwent a modified radical mastectomy with lymph node dissection. Twenty-one months later, massive liver metastases and pleural carcinomatosis occurred. The liver metastases responded completely to chemotherapy with trastuzumab combined with docetaxel, but the pleural carcinomatosis was refractory to the therapy. Fluorescence in situ hybridization showed that both the primary tumor and the metastatic tumors of the lymph nodes were composed of HER2 amplification-positive and HER2 amplification-negative cancer cells. This analysis also detected a single cell with HER2 amplification in the pleural effusion that was taken at the completion of the chemotherapy, but four follow-up tests showed no amplified cells. It is speculated that in the liver metastases, the trastuzumab was cytotoxic to both HER2-amplified and nonamplified cancer cells and may have acted through its antiangiogenic effect. However, in the pleural effusion, the effect of trastuzumab was more specific to HER2-amplified cells and caused outgrowth of cancer cells lacking expression of HER2 receptors.

Adult↗

PubMed2026

Clinical and Molecular Evaluation of HER2-Low and HER2-Ultralow Breast Cancer in the Penelope-B Clinical Trial Cohort.

The DestinyBreast (DB)04 and DB06 trials have shown clinical activity of trastuzumab-deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer. The identification of HER2-low and HER2-ultralow breast cancer is therefore essential for personalized therapy with T-DXd. We evaluated 723 residual tumors from the Penelope-B trial (NCT01864746) and correlated different levels of HER2 protein expression with prognosis and messenger RNA (mRNA) profiles, including HER2 transcripts. In Penelope-B, 57.68% (n = 417) of 723 residual tumors were HER2 low. The HER2-ultralow category was assigned to 109 (15.08%) tumors, and 197 (27.25%) tumors were completely HER2 negative (HER2 0). In Kaplan-Meier analysis, there were no survival differences among these 3 subgroups. There was no significant difference in HER2 mRNA expression between HER2-0 and HER2-ultralow tumors (P = .08). In contrast, there was a highly significant difference in HER2 mRNA expression between HER2-ultralow and HER2-low tumors (P < .0001) and between HER2-low and HER2-positive tumors (P < .0001). The extracellular protease cathepsin L, which has been suggested as a biomarker for extracellular cleavage of T-DXd, was detectable in all HER2-related subgroups and was a negative prognostic factor for invasive disease-free survival and overall survival (P = .0001) in preneoadjuvant core biopsies. In our study, we were able to characterize HER2 low as a clinically relevant and molecular defined tumor group with significantly increased HER2 expression. In contrast, for HER2 ultralow, we did not observe a defined molecular phenotype, despite the clinically relevant regulatory approval of T-DXd also in the ultralow subgroup. Additional investigations are needed to identify biomarkers beyond HER2 for T-DXd response as a basis for refined criteria for treatment eligibility.

Adult↗

PubMed2006

Predicting tissue HER2 status using serum HER2 levels in patients with metastatic breast cancer.

BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) are reliable ways to identify overexpression or amplification of the HER-2/neu (HER2, symbol ERBB2) gene, but each technique requires a high-quality tissue sample, which may not be available. We investigated whether serum concentrations of the HER2 extracellular domain (ECD) can be used as an alternative to tissue HER2 status in metastatic breast cancer, and we defined an optimal decision-level concentration of serum HER2 for prediction of tissue HER2 status. METHODS: In 195 patients with metastatic breast cancer, we determined HER2 expression by IHC and performed FISH analysis on tumors for which IHC staining was graded as 2+. We measured serum HER2 by immunoassay and used ROC curve analysis to determine optimal serum HER2 ECD concentrations for differentiation between positive and negative HER2 status. RESULTS: IHC results were 0/1+ for 30 (15%) of the patients, 2+ for 89 (46%), and 3+ for 76 (39%). FISH revealed HER2 amplification in 19 (21%) of the IHC 2+ tumors. Mean (SE) serum HER2 ECD was 22.2 (5.1) microg/L in the tissue HER2-negative group, significantly lower than the concentration of 363 (96) microg/L in the tissue HER2-positive group (P<0.0001). ROC curve analysis showed 95% specificity and 62% sensitivity for tissue HER2 positivity at 37 microg/L of serum HER2. CONCLUSION: To use serum HER2 concentration as an alternative to direct determination of tissue HER2 status, we suggest 37 microg/L as a cutoff for predicting positive tissue HER2 with 95% specificity. Sensitivity, however, is low.

Adult↗

PubMed2006

HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated fatty acid, alpha-linolenic acid (ALA; 18:3n-3), in breast cancer cells: the "fat features" of the "Mediterranean diet" as an "anti-HER2 cocktail".

BACKGROUND: Data derived from epidemiological and experimental studies suggest that alphalinolenic acid (ALA; 18:3n-3), the main omega-3 polyunsaturated fatty acid (PUFA) present in the Western diet, may have protective effects in breast cancer risk and metastatic progression. A recent pilot clinical trial assessing the effects of ALA-rich dietary flaxseed on tumor biological markers in postmenopausal patients with primary breast cancer demonstrated significant reductions in tumor growth and in HER2 (erbB-2) oncogene expression. HYPOTHESIS: The molecular mechanism by which ALA inhibits breast cancer cell growth and metastasis formation may involve a direct regulation of HER2, a well-characterized oncogene playing a key role in the etiology, progression and response to some chemo- and endocrine therapies in approximately 20% of breast carcinomas. METHODS: Using HER2-specific ELISA, flow cytometry, immunofluorescence microscopy, Western blotting, RT-PCR and HER2 promoter-reporter analyses, we characterized the effects of exogenous supplementation with ALA on the expression of HER2 oncogene, a master key player in the onset and metastasis formation of breast cancer disease. Metabolic status (MTT) assays were performed to evaluate the nature of the cytotoxic interaction between ALA and the humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin). To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the HER2 oncogene. RESULTS: ALA treatment dramatically suppressed the expression of HER2-coded p185Her-2/neu oncoprotein as determined by ELISA, flow cytometry, immunofluorescence microscopy and immunoblotting techniques. Interestingly, ALA-induced down-regulation of p185Her-2/neu correlated with a transcriptional response as no HER2 mRNA signal could be detected by RT-PCR upon treatment with optimal concentrations of ALA (up to 20 microM). Consistent with these findings, ALA exposure was found to dramatically repress the activity of a Luciferase reporter gene driven by the HER2 promoter. Moreover, the nature of the cytotoxic interaction between ALA and trastuzumab (Herceptin) revealed a significant synergism as assessed by MTT-based cell viability assays. CONCLUSIONS: i) These findings reveal that the omega-3 PUFA ALA suppresses overexpression of HER2 oncogene at the transcriptional level, which, in turn, interacts synergistically with anti-HER2 trastuzumab- based immunotherapy. ii) Our results molecularly support a recent randomized double-blind placebo-controlled clinical trial suggesting that ALA may be a potential dietary alternative or adjunct to currently used drugs in the management of HER2-positive breast carcinomas. iii) Considering our previous findings demonstrating the < > of the omega-6 PUFA linolenic acid (LA; 18:2n-6) and the < > of the omega-3 PUFA docosahexaenoic acid (DHA; 22:6n-3) and of the omega-9 monounsaturated fatty acid oleic acid (OA; 18:1n-9), it is reasonable to suggest that a low omega-6/omega-3 PUFA ratio and elevated MUFA levels, the two prominent < > of the < >, should be extremely efficient at blocking HER2 expression in breast cancer cells.

Antibodies, Monoclonal↗

PubMed2001

Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells.

HER2 is a ligand-less tyrosine kinase receptor of the ErbB family that is frequently overexpressed in breast cancer. It undergoes proteolytic cleavage that results in the release of the extracellular domain and the production of a truncated membrane-bound fragment, p95. We show that HER2 shedding is activated by 4-aminophenylmercuric acetate (APMA), a well-known matrix metalloprotease activator, in HER2-overexpressing breast cancer cells. The HER2 p95 fragment, which appears after APMA-induced cleavage, is phosphorylated. We analyzed 24 human breast cancer specimens, and a phosphorylated M(r) 95,000 HER2 band could be detected in some of them, which indicated that the truncated receptor is also present in vivo. The activation of HER2 shedding by APMA in cells was blocked with batimastat, a broad-spectrum metalloprotease inhibitor. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody directed at the HER2 ectodomain, which has been shown to be active in patients with HER2-overexpressing breast cancer, inhibited basal and induced HER2 cleavage and, as a consequence, the generation of phosphorylated p95. This inhibitory effect of trastuzumab was not shared by 2C4, an antibody against a different epitope of the HER2 ectodomain. The inhibition of basal and APMA-induced cleavage of HER2 by trastuzumab preceded antibody-induced receptor down-modulation, which indicated that the effect of trastuzumab on cleavage was not attributable to a decrease in cell-surface HER2 induced by trastuzumab. We propose that the inhibition of HER2 cleavage and prevention of the production of an active truncated HER2 fragment represent a novel mechanism of action of trastuzumab.

Adenocarcinoma↗

PubMed2003

Coregulation of epidermal growth factor receptor/human epidermal growth factor receptor 2 (HER2) levels and locations: quantitative analysis of HER2 overexpression effects.

Elevated expression of human epidermal growth factor receptor 2 (HER2) is known to alter cell signaling and behavioral responses implicated in tumor progression. However, multiple diverse mechanisms may be involved in these overall effects, including signaling by HER2 itself, modulation of signaling by epidermal growth factor receptor (EGFR), and modification of trafficking dynamics for both EGFR and HER2. Because these processes are so tightly interrelated, the net effect of HER2 overexpression is difficult to reliably attribute to any single particular mechanism. To take an important first step toward dissecting the effects of HER2 overexpression on cell responses in terms of the various specific underlying mechanisms, we have developed and validated a quantitative model of the relevant trafficking processes. We then use our model for successful prediction of EGFR and HER2 level and location changes attributable to HER2 overexpression in 184A1 human mammary epithelial cells expressing a series of HER2 levels by retroviral infection. Model predictions are based on our independent experimental measurement of key trafficking parameters for both EGFR and HER2. In terms of trafficking processes, HER2 overexpression reduces the EGFR internalization rate constant and increases the fraction of EGFR recycled. Consequently, our model successfully predicts that HER2 increases the overall level of activated EGFR by both enhancing its recycling and reducing its internalization, but it increases activated EGFR localization at the cell surface almost solely by its reduction of internalization. Furthermore, the model also successfully predicts the effects of monoclonal antibody 2C4, which interferes with HER2/EGFR heterodimerization, on EGFR and HER2 levels and compartmental locations. We anticipate that this model should ultimately be useful in parsing the relative contributions of direct effects of HER2 via signaling vis-a-vis indirect effects of HER2 via modification of EGFR signaling.

Breast↗

PubMed2026

Clinicopathological response and survival outcomes of HER2-low versus HER2-zero early breast Cancer: A systematic review and Meta-analysis.

BACKGROUND: Breast cancer is the most common malignant tumor in women. Human epidermal growth factor receptor 2 (HER2) is a key biomarker for classification and treatment. A subgroup with HER2-low expression has been identified, but existing evidence is heterogeneous. This systematic review and meta-analysis compared pathological response and survival outcomes between HER2-low and HER2-zero early-stage breast cancer to clarify prognostic features. METHODS: This study followed PRISMA guidelines and was registered in PROSPERO (CRD420251120506). PubMed, Embase, Web of Science, ClinicalTrials.gov, and major oncology conferences were searched through September 2025. Cohort studies of early-stage breast cancer comparing HER2-low (IHC 1+/2+ and ISH-negative) vs. HER2-zero with extractable pCR, DFS, or OS data were included. Studies involving HER2-positive patients or inconsistent definitions were excluded. Meta-analyses were performed using RevMan 5.3. RESULTS: Twenty-eight studies involving 115,182 patients were included. HER2-low patients showed significantly lower pCR rates (OR = 0.58, 95% CI: 0.52-0.65). DFS favored HER2-low (multivariate HR = 0.75, 95% CI: 0.69-0.83), especially in HR+ tumors, with a weaker effect in HR- cases. OS also favored HER2-low (HR = 0.80, 95% CI: 0.72-0.89), mainly driven by the HR- subgroup; no OS difference was seen in HR+ tumors. Sensitivity analyses and funnel plots indicated robust results with no apparent publication bias. Overall study quality was high (17 high-quality, 11 moderate-quality). CONCLUSION: HER2-low early breast cancer shows lower pCR after neoadjuvant therapy but better long-term survival. These findings support the clinical relevance of HER2-low as a biologically meaningful subgroup within HER2-negative disease, while its status as a stable and independent subtype still requires further validation through prospective studies, standardized testing, and multi-omics investigation.

Humans↗

PubMed2006

HER2-specific T-cell immune responses in patients vaccinated with truncated HER2 protein complexed with nanogels of cholesteryl pullulan.

PURPOSE: We developed a complex of tumor antigen protein with a novel nanoparticle antigen delivery system of cholesteryl pullulan (CHP). To target HER2 antigen, we prepared truncated HER2 protein 1-146 (146HER2) complexed with CHP, the CHP-HER2 vaccine. We designed a clinical study to assess the safety of the vaccine and HER2-specific T-cell immune responses measured by the newly developed enzyme-linked immunospot assay with mRNA-transduced phytohemagglutinin-stimulated CD4(+) T cells in HLA-A2402-positive patients with therapy-refractory HER2-expressing cancers. EXPERIMENTAL DESIGN: Nine patients with various types of solid tumors were enrolled. Each patient was s.c. vaccinated biweekly with 300 microg of CHP-HER2 vaccine for three times followed by booster doses. HER2-specific T-cell responses were evaluated by enzyme-linked immunospot assay by targeting autologous phytohemagglutinin-stimulated CD4(+) T cells transduced with 146HER2-encoding mRNA to cover both identified peptides and unknown epitopes for MHC class I and class II that might exist in the sequence of the vaccine protein. RESULTS: CHP-HER2 vaccine was well tolerated; the only adverse effect was grade 1 transient skin reaction at the sites of vaccination. HER2-specific CD8(+) and/or CD4(+) T-cell immune responses were detected in five patients who received four to eight vaccinations, among whom both T-cell responses were detected in these patients. In four patients with CD8(+) T-cell responses, two patients reacted to previously identified HER2(63-71) peptide and the other two reacted only to 146HER2 mRNA-transduced cells. CONCLUSIONS: CHP-HER2 vaccine was safe and induced HER2-specific CD8(+) and/or CD4(+) T-cell immune responses.

Adult↗

PubMed2005

Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase.

Immunologic targeting of the oncoprotein HER2/neu with monoclonal antibodies is an important component of current therapeutic strategies for patients with locally and systemically advanced breast cancer. Engineered antibodies targeting HER2 may have agonist or antagonist effects on HER2, but little is known about whether endogenous antibodies modulate HER2 activity. Vaccination of patients with HER2 peptides successfully induced antibodies in a minority of patients with HER2-expressing malignancy. A subset of antibodies specifically suppressed phosphorylation of HER2 on tyrosine Y1248, a residue critical for HER2 signaling through extracellular signal-regulated kinase. These antibodies also suppressed extracellular signal-regulated kinase phosphorylation and inhibited colony formation in soft agar. The majority of the antibodies that suppressed HER2 phosphorylation displayed specificity for amino acids 328 to 345 and 369 to 384. The isotype of anti-HER2 antibodies was predominantly IgG3 of low avidity, suggesting a Th1 response to peptide vaccine. Endogenous anti-HER2 antibodies can effectively suppress HER2 kinase activity and downstream signaling to inhibit the transformed phenotype of HER2-expressing tumor cells.

Antibodies, Neoplasm↗

PubMed2005

Co-expressed type of ER and HER2 protein as a predictive factor in determining resistance to antiestrogen therapy in patients with ER-positive and HER2-positive breast cancer.

The purpose of this study was to analyze whether inter-site variation types on estrogen receptor (ER) and HER2 expression may be a predictive factor for evaluating the effectiveness of endocrine therapy in patients with ER-positive and HER2-positive breast cancer. A total of 366 consecutive women with invasive breast cancer who had undergone curative surgical treatment between 1996 and 2001 were included in this study. ER status was evaluated using the Allred score and HER-2 status was evaluated according to the HercepTest. In ER-positive and HER2-positive tumors, the expression of ER and HER2 was described as the co-expressed type or the differently expressed type using double staining with ER and HER2. Of the 366 patients, 249 (68.1%) were positive for ER and 74 (20.2%) were positive for HER2. ER-positive and HER2-negative tumors were found in 221 patients (60.4%), ER-negative and HER2-negative in 71 (19.4%), ER-negative and HER-2-positive in 46 (12.6%), and ER-positive and HER2-positive in 28 (7.7%). HER2 status was inversely correlated (p<0.01) with ER status. In ER-positive tumors, an inverse correlation between ER and HER2 was also observed. The co-expressed type was found in 10 patients, and the differently expressed type was found in 18. There was no difference in tumor size and nodal involvement between the two types. There was no significant difference in disease-free survival between patients with the co-expressed type tumor and the differently expressed type tumor. In patients with the differently expressed type tumor, those who received antiestrogen therapy showed a significantly better disease-free survival rate than those who did not receive antiestrogen therapy. As for patients with the co-expressed type of tumor, no significant difference in disease-free survival was observed between patients with and without antiestrogen treatment. The present study suggests that the co-expressed type of tumour might be a resistant factor to antiestrogen therapy in ER-positive and HER2-positive breast cancer.

Adult↗

PubMed2004

Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease.

The purpose of this study was to evaluate the feasibility, efficacy, safety, and pharmacokinetics of trastuzumab plus cisplatin and gemcitabine in patients with Her2-overexpressing stages IIIB or IV non-small cell lung cancer (NSCLC) and to study the relationship between results from the two methods for determining levels of Her2 overexpression. Chemonaive patients were eligible if they had stages IIIB or IV NSCLC with either a Her2 score of at least 1+ by immunohistochemical (IHC) analysis or a serum Her2 shed antigen level of at least 15 ng/ml by enzyme-linked immunosorbent assay (ELISA). Treatment consisted of cisplatin 75 mg/m(2) day one plus gemcitabine 1250 mg/m(2) days one and eight plus trastuzumab 4 mg/kg day one and 2 mg/kg weekly thereafter on a 21-day cycle for six cycles followed by weekly maintenance trastuzumab therapy. Of the 21 patients enrolled, 8 (38%) patients had a partial response. The 1-year survival rate was 62% (13/21). Median time to progression was 36 weeks. Pharmacokinetic studies revealed no interaction between trastuzumab and gemcitabine plus cisplatin. In patients screened for this study, Her2 expression was zero in 283/360 (79%); 1+ in 32/360 (9%); 2+ in 27/360 (8%); and 3+ in 18/360 patients (5%). Serum Her2 shed antigen was >15 ng/ml in 27/ 288 (9%) patients. Of patients who had both Her2 assays, 24% (4/17) with ELISA scores >15 ng/ml had IHC scores of 3+, compared with only 2% (3/145) of the patients <15 ng/ml and 4% (7/162) of all patients. The addition of trastuzumab to cisplatin and gemcitabine was well tolerated, but further study will be required to determine whether this combination is superior to chemotherapy alone. This may be demonstrated if only those patients with Her2, having a score of IHC 3+ were eligible. Since IHC 3+ is rare in NSCLC, performing IHC in only those patients with serum Her2 shed antigen >15 ng/ml would greatly increase the efficiency of IHC screening though at the cost of excluding nearly half the patients with Her2 scores of 3+ on IHC analysis. Thus, if sequential screening consisting of serum ELISA followed by IHC analysis is implemented, it may make a trastuzumab trial feasible but should ultimately be supplanted by another screening system if trastuzumab is shown to be beneficial to some patients with IHC Her2 scores of 3+.

Aged↗

PubMed2006

Anti-HER2/neu IgG3-(IL-2) and anti-HER2/neu IgG3-(GM-CSF) promote HER2/neu processing and presentation by dendritic cells: implications in immunotherapy and vaccination strategies.

HER2/neu, a transmembrane glycoprotein overexpressed in several types of human cancers, is a potential target for active immunotherapy. However, this protein and especially its extracellular domain (ECD(HER2)), is weakly immunogenic and is poorly processed by dendritic cells (DCs). Previously, we showed that anti-HER2/neu IgG3-(IL-2) and anti-HER2/neu IgG3-(GM-CSF) fusion proteins can enhance the immunogenicity of ECD(HER2) in mice, and that the non-covalent physical association between each antibody fusion proteins and ECD(HER2) was critical to elicit optimal protective immunity against HER2/neu expressing tumors. We now use the professional antigen-presenting DCs to investigate the effect of the antibody fusion protein binding to ECD(HER2) on its trafficking and presentation. We found that when the extracellular domain of HER2/neu fused to ovalbumin (OVA-ECD(HER2)) is bound by HER2/neu-specific antibody-(IL-2) or antibody-(GM-CSF) fusion proteins, the bound antigen is more efficiently processed by murine bone-marrow-derived dendritic cells (BMDCs) and presented to OVA-specific T-cells than the unbound OVA-ECD(HER2). We also found that ECD(HER2) bound by anti-HER2/neu IgG3-(IL-2) is very efficiently internalized and that the internalized ECD(HER2) is not retained in the early endosomal compartments but traffics to the antigen-processing compartments. These results are consistent with our earlier in vivo studies and suggest that both antibody-(IL-2) and antibody-(GM-CSF) fusion proteins can be used to enhance the immune response to poorly immunogenic antigens including tumor-associated antigens (TAAs).

Animals↗

PubMed2005

Serum HER2 extracellular domain in metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel: association with HER2 status by immunohistochemistry and fluorescence in situ hybridization and with response rate.

PURPOSE: We explored the relationship between circulating HER2 extracellular domain (ECD) and tissue HER2 status as determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). We also examined its predictive value in a cohort of metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel. METHODS: Eligible patients had pre- and post-treatment stored serum specimens and were treated on a previously reported phase II trial. Retrospective analysis evaluated: the association between pretreatment serum HER2 ECD and tissue HER2 status by IHC and FISH; and the association between change in serum HER2 ECD after 12 weeks of therapy and response proportion. RESULTS: Stored serum samples were available for 55/95 (58%) patients. Statistically significant associations were found between HER2 status as assessed by IHC and FISH, and baseline serum HER2 ECD level. Patients whose ECD normalized after 12 weeks of therapy had a higher response proportion compared with patients with persistently high ECD levels (68% versus 15%, P=0.005). A relative decline of over 55% from baseline HER2 ECD predicted response to therapy. CONCLUSION: A statistically significant association was observed between pretreatment serum HER2 ECD and tissue HER2 status as assessed by IHC and FISH. A decrease in serum HER2 ECD level was a significant predictor of response to trastuzumab-based therapy.

Adult↗

PubMed2006

Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells.

Overexpression and activating mutations of ErbB family members have been implicated in the development and progression of a variety of tumor types. Cleavage of the HER2 receptor by an as yet unidentified ectodomain sheddase has been shown to liberate the HER2 extracellular domain (ECD) leaving a fragment with constitutive kinase activity that can provide ligand-independent growth and survival signals to the cell. This process is clinically relevant since HER2 ECD serum levels in metastatic breast cancer patients are associated with a poorer prognosis. Thus, inhibition of the HER2 sheddase may provide a novel therapeutic approach for breast cancer. We describe the use of transcriptional profiling, pharmacological and in vitro approaches to identify the major source of HER2 sheddase activity. Real-time PCR was used to identify those ADAM family members which were expressed in HER2 shedding cell lines. siRNAs that selectively inhibited ADAM10 expression reduced HER2 shedding. In addition, we profiled over 1000 small molecules for in vitro inhibition of a panel of ADAM and MMP proteins; a positive correlation was observed only between ADAM10 inhibition and reduction of HER2 ECD shedding in a cell based assay. Finally, in vitro studies demonstrate that in combination with low doses of Herceptin, selective ADAM10 inhibitors decrease proliferation in HER2 overexpressing cell lines while inhibitors, that do not inhibit ADAM10, have no impact. These results are consistent with ADAM10 being a major determinant of HER2 shedding, the inhibition of which, may provide a novel therapeutic approach for treating a variety of cancers with active HER2 signaling.

ADAM Proteins↗

PubMed2006

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy.

We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro- and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

Animals↗