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PubMed1995

Bispecific HER2 x CD3 antibodies enhance T-cell cytotoxicity in vitro and localize to HER2-overexpressing xenografts in nude mice.

Recently, we reported the development of fully humanized bispecific F(ab')2 antibodies with dual binding specificities to human T-lymphocytes and to tumor cells overexpressing HER2. These antibodies were shown to effectively mediate targeted HER2-overexpressing tumor cell killing by freshly isolated human T-cells. In this report we extend our studies to describe the interaction of the bispecific antibody with activated T-lymphocytes (ATL) maintained in culture for an extended period of time. A microtiter plate radioreceptor assay was used to elucidate the affinity of bispecific antibody binding to ATL. The data show that ATL maintained in vitro for up to 5 weeks continued to express high-affinity CD3 surface markers that bound to bispecific antibody with a Kd of 2.49 nM and exerted cytolytic activities against targets overexpressing HER2. In addition, we demonstrated the specific localization of HER2 x CD3 bispecific antibody to HER2-overexpressing tumor xenografts in nude mice. Furthermore, HER2 x CD3 bispecific antibody has the ability to inhibit the proliferative activities of breast tumor (SKBR-3) cells in vitro. The clinical implications of these data are discussed.

Animals↗
PubMed2006

Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis.

Gastric cancer metastasised to the liver was found to overexpress HER2 at a significantly higher incidence than primary gastric cancers. The purpose of the present study was to investigate the possibility of molecular therapy targeting HER2 overexpression in gastric cancer liver metastasis. We developed three new HER2-overexpressing gastric cancer cell lines (GLM-1, GLM-2, GLM-4) without epidermal growth factor receptor (EGFR) mutations derived from such liver metastasis, two of which had HER2 gene amplifications. All these GLM series of cell lines were highly sensitive to gefitinib in vitro, a specific inhibitor of EGFR tyrosine kinase (Iressa) rather than anti-HER2 antibody trastuzumab (Herceptin), whereas most of the HER2 low-expressing counterparts were not. In these HER2-overexpressing GLM series, protein kinase B (Akt), but not extracellular signal-regulated kinase 1/2 (ERK1/2), was constitutively phosphorylated, and gefitinib efficiently inhibited this Akt phosphorylation, induced strong apoptosis in vitro and exhibited antitumour activity in tumour xenografts in nude mice. This gefitinib-mediated antitumour effect in xenograft was significantly potentiated by trastuzumab treatment. On the other hand, gefitinib-resistant cells (GLM-1R) exhibited increased EGFR expression, followed by constitutive activation of mitogen-activated protein kinase (MAPK) pathway. These results suggest that the antitumour effect of gefitinib is due to the effective inhibition of HER2-driven constitutive activation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway, and that the acquired resistance to gefitinib is due to the constitutive activation of Ras/MAPK pathway in compensation for PI3K/Akt pathway. Gastric cancer liver metastasis with HER2 overexpression would be a potential molecular target for gefitinib and trastuzumab.

Animals↗
PubMed2005

A hypoxia-independent hypoxia-inducible factor-1 activation pathway induced by phosphatidylinositol-3 kinase/Akt in HER2 overexpressing cells.

HER2 overexpression, a known prognostic factor in many human cancers, can activate phosphatidylinositol-3 kinase (PI-3K)/Akt pathways and plays an important role in mediating cell survival and tumor development. Hypoxia-inducible factors (HIFs) promote angiogenesis and energy metabolism and thereby enhance tumor growth and metastasis. HIFs, composed of alpha and beta subunits, are activated in most human cancers, including those that overexpress HER2. Previous reports have suggested that increased PI-3K/Akt or decreased PTEN activity may activate the HIF pathway in various tumors, but the detailed mechanism is still not completely understood. Here we reported an interaction between the HIF and PI-3K/Akt pathways in HER2-overexpressing cancer cells. Our results indicate that HER2 overexpression, which results in constitutively active Akt, turns on HIF-1alpha independently of hypoxia, and this activation is weaker than that under hypoxic condition. Further investigation showed that Akt is required for the hypoxia-independent HIF activity. The PI-3K/Akt pathway did not affect the HIF-1alpha binding with its E3 ligase von Hippel-Lindau but enhanced the binding affinity between the HIF-1 alpha and beta subunits. Furthermore, we found that Akt interacts with HIF-1beta and regulates HIF activity. Our results indicated that HER2 can induce HIF activation via the activation of Akt suggesting that activation of HER2/Akt pathway may promote angiogenesis independent of hypoxia, which may have important implications for the oncogenic activity of HER2 and Akt.

Animals↗
PubMed2004

Enhancement of the p27Kip1-mediated antiproliferative effect of trastuzumab (Herceptin) on HER2-overexpressing tumor cells.

The oncogenic activity of the overexpressed HER2 tyrosine kinase receptor requires its localization in the plasma membrane. The antitumor effect of anti-HER2 antibodies (Abs) is mainly dependent on receptor downregulation and comprises p27Kip1-mediated G1 cell cycle arrest. However, one major limitation of anti-HER2 therapy is the reversibility of tumor growth inhibition after discontinuation of treatment caused by the mitogenic signaling associated with cell surface receptor re-expression. We found that the level of p27Kip1 upregulation, inhibition of Cdk2 activity and magnitude of G1 arrest induced by the humanized Ab trastuzumab (Herceptin, HCT) on BT474 and SKBr3 HER2-overexpressing breast cancer cells correlates with the level of cell surface receptor. Thus, continuous exposure of cells to HCT for 72 hr results in downregulation of the cell surface receptor and a concurrent increase in the level of p27Kip1 protein. Discontinuation of Ab exposure after the first 8 hr results in failure to upregulate p27Kip1 and arrest of cell cycle progression. We show that the lysosomotropic amine chloroquine (CQ) augments receptor internalization in HER2-overexpressing cells either pretreated or continuously treated with HCT and leads to an increased and sustained inhibitory effect. The enhanced CQ-dependent loss of functional HER2 from the cell surface resulted in sustained inactivation of the serine/threonine kinase Akt, upregulation of p27Kip1 protein and inhibition of cyclin E/Cdk2 activity. Potentiation of the inhibitory effect of HCT by CQ was directly related to loss of HER2 from the plasma membrane since prevention of Ab-mediated receptor endocytosis by engagement of the receptor with immobilized HCT abrogated the effect of CQ.

Antibodies, Monoclonal↗
PubMed2006

Selective proapoptotic activity of a secreted recombinant antibody/AIF fusion protein in carcinomas overexpressing HER2.

Apoptosis-inducing factor (AIF) represents a caspase-independent apoptotic pathway in the cell, and a mitochondrial localization sequence-truncated AIF (AIFDelta1-120) can be relocated from the cytoplasm to the nucleus and exhibit a constitutive proapoptotic activity. Here, we generated a chimeric immuno-AIF protein, which comprised an HER2 antibody, a Pseudomonas exotoxin translocation domain and AIFDelta1-120. Human Jurkat cells transfected with the immuno-AIF gene could express and secrete the chimeric protein, which selectively recognized HER2-overexpressing tumor cells and was endocytosed. Subsequent cleavage of truncated AIF from immuno-AIF and its release from the internalized vesicles resulted in apoptosis of tumor cells. Intramuscular injection of the immuno-AIF gene caused significant suppression of tumors and substantially prolonged mice survival in an HER2-overexpressing xenograft tumor model. Our study demonstrates the feasibility of the immuno-AIF gene as a novel approach to treating cancers that overexpress HER2.

ADP Ribose Transferases↗
PubMed2002

[Herceptin and its therapeutic strategy in patients with breast cancer overexpressing HER2].

Herceptin (trastuzumab) is a recombinant humanized murine monoclonal antibody that recognizes HER2/neu cell-surface receptors and has been shown to be active both in combination with adriamycin (epirubicin)/cyclophosphamide or taxanes and as a single agent, either in the 1st or 2nd/3rd line treatment of women with metastatic breast cancer with HER2 overexpression by IHC or gene amplification by FISH. Preliminary results of Herceptin with other agents such as vinorelbine, cisplatin and various hormonal agents are also promising, and these combinations warrant further clinical exploration. Large-scale multicenter trials including a European and an international study in adjuvant setting have started for high-risk women with HER2 overexpressing breast cancer, with total planned recruitment of nearly 10,000 women.

Antibodies, Monoclonal↗
PubMed2002

Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2.

Ansamycin antibiotics, such as 17-allylaminogeldanamycin (17-AAG), bind to Hsp90 and regulate its function, resulting in the proteasomal degradation of a subset of signaling proteins that require Hsp90 for conformational maturation. HER2 is a very sensitive target of these drugs. Ansamycins cause RB-dependent G1 arrest that is associated with loss of D-cyclins via a PI3 kinase, Akt dependent pathway. Downregulation of D-cyclin was due, in part, to loss of Akt expression in response to drug. Moreover, in HER2 overexpressing breast cancer cells, 17-AAG caused rapid inhibition of Akt activity prior to any change in Akt protein. Ansamycins caused rapid degradation of HER2 and a concomitant loss in HER3 associated PI3 kinase activity. This led to a loss of Akt activity, dephosphorylation of Akt substrates, and loss of D-cyclin expression. Introduction into cells of a constitutively membrane bound form of PI3 kinase prevented the effects of the drug on Akt activity and D-cyclins. Thus, in breast cancer cells with high HER2, Akt activation by HER2/HER3 heterodimers is required for D-cyclin expression. In murine xenograft models, non-toxic doses of 17-AAG markedly reduced the expression of HER2 and phosphorylation of Akt and inhibited tumor growth. Thus, pharmacological inhibition of Akt activation is achievable with ansamycins and may be useful for the treatment of HER2 driven tumors.

Animals↗
PubMed2005

Suppression of tumor growth in human gastric cancer with HER2 overexpression by an anti-HER2 antibody in a murine model.

New modalities are necessary for the treatment of patients with unresectable gastric cancer. The aim of this study was to investigate whether or not anti-HER2 antibody could suppress the growth of human gastric cancer cells with HER2 overexpression in vitro and in vivo. Four human gastric cancer cell lines, NCI-N87, MKN-45P, Kato-III, and MKN-1, were used in this study. The suppression of cell proliferation in vitro and of subcutaneous tumor growth in a nude mouse model after treatment with trastuzumab was examined. The expression of HER2 protein was investigated by Western blot analysis. The effect of trastuzumab on the survival rate of nude mice with peritoneal dissemination was examined. Trastuzumab significantly reduced proliferative activity in NCI-N87, a HER2-overexpressing human gastric cancer cell line, in vitro. In the nude mouse model with transplanted subcutaneous tumor, trastuzumab significantly suppressed the tumor growth of NCI-N87 cells, and then HER2 expression was reduced. Trastuzumab improved the survival rate of mice with peritoneal dissemination of MKN-45P cells. Trastuzumab therapy is a potential candidate for a novel treatment of HER2-overexpressing gastric cancer.

Animals↗
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

Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells.

HER2 overexpression is one of the most recognizable molecular alterations in breast tumors known to be associated with a poor prognosis. In the study described here, we explored the effect of HER2 overexpression on the sensitivity of breast cancer cells to the growth-inhibitory effects of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a synthetic triterpenoid, both in vitro and in vivo in a xenograft model of breast cancer. Both cell growth and colony formation in the soft agar assay, a hallmark of the transformation phenotype, were preferentially suppressed in HER2-overexpressing cell lines at low concentrations of CDDO, whereas growth-inhibitory effects at high concentrations did not correlate with the expression level of HER2. CDDO dose-dependently inhibited phosphorylation of HER2 in HER2-overexpressing cells and diminished HER2 kinase activity in vitro. CDDO induced the transactivation of the nuclear receptor peroxisome proliferator-activated receptor-gamma in both vector control and HER2-transfected MCF7 cells. Dose-response studies showed that the growth inhibition seen at lower concentrations of CDDO correlated with induction of the tumor suppressor gene caveolin-1, which is known to inhibit breast cancer cell growth. CDDO also reduced cyclin D1 mRNA and protein expression. In vivo studies with liposomally encapsulated CDDO showed complete abrogation of the growth of the highly tumorigenic MCF7/HER2 cells in a xenograft model of breast cancer. These findings provide the first in vitro and in vivo evidence that CDDO effectively inhibits HER2 tyrosine kinase activity and potently suppresses the growth of HER2-overexpressing breast cancer cells and suggest that CDDO has a therapeutic potential in advanced breast cancer.

Animals↗
PubMed1997

HER2 overexpression and paclitaxel sensitivity in breast cancer: therapeutic implications.

Overexpression by the HER2 gene plays a significant role in breast cancer pathogenesis, and the phenomenon is commonly regarded as a predictor of a poor prognosis. HER2 overexpression has been linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoruracil) and anthracyclines. Studies of patients with advanced disease demonstrate that, despite the association of HER2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to taxanes were greater than three times those of HER2-negative patients. Further studies in preclinical models used combination therapy for breast cancer cells that overexpress HER2, and the use of agents that interfere with HER2 function plus paclitaxel (Taxol) resulted in significant antitumor effects.

Antibodies, Monoclonal↗
PubMed1999

Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Adult↗
PubMed2001

The role of overexpressed HER2 in transformation.

The HER family of receptors has an important role in the network of cell signals controlling cell growth and differentiation. Although the activity of the HER receptor is strictly controlled in normal cells, HER2 receptor overexpression plays a pivotal role in transformation and tumorigenesis. HER2 gene amplification and/or overexpression of the receptor has been detected in subsets of a wide range of human cancers including breast cancer, and is an indicator of poor prognosis. It is proposed that overexpressed HER2 in combination with HER3 causes high activity of cell-signaling networks, thereby resulting in tumor cell proliferation. Thus, the HER2 receptor is an attractive target for new anti-cancer treatments. Monoclonal antibodies directed against the receptor are the most promising of these, and the humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) has shown significant clinical efficacy in clinical trials. The anti-tumor mechanisms of anti-HER2 monoclonal antibodies are not completely understood. However, some tumor types are not sensitive to trastuzumab, suggesting that the response of a tumor to trastuzumab may not only be dependent on overexpressed HER2, but may also be influenced by other members of the HER receptor family expressed in the tumor cell.

Antibodies, Monoclonal↗
PubMed2001

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

BACKGROUND: The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. METHODS: We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). RESULTS: The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. CONCLUSIONS: Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.

Adult↗
PubMed2006

MNK1 and MNK2 regulation in HER2-overexpressing breast cancer lines.

MAPK-interacting protein kinases 1 and 2 (MNK1 and MNK2) function downstream of p38 and ERK MAPK, but there are large gaps in our knowledge of how MNKs are regulated and function. As proteins activated in the HER2/Ras/Raf/ERK pathway, the MNKs are of potential interest in HER2-overexpressing cancers. We utilized a panel of breast cell lines (HCC1419, AU565, SKBR3, MCF7, and MCF10A), three of which overexpress HER2, to characterize the amounts and activation status of MNKs and other pathway enzymes (ERKs and RSKs) in these cells. We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation. Increased phosphorylation and activity of the MNKs correlate with HER2 overexpression, and inhibition of the MNKs reduces colony formation in soft agar. Our work identifies the MNKs as potential therapeutic targets for breast cancer treatments.

Breast Neoplasms↗
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↗
PubMed2003

Absence of HER2 overexpression in metastatic malignant melanoma.

BACKGROUND AND OBJECTIVES: Currently available systemic therapies for malignant melanoma produce low response rates in patients, and more effective treatment modalities are clearly needed. Trastuzumab (Herceptin), the antibody to the HER2 oncoprotein, has had a significant impact on therapy for patients with HER2-overexpressing metastatic breast cancer. This study examined the incidences of HER2 protein overexpression and HER2 gene amplification in metastatic malignant melanoma, which remain unclear in the literature. METHODS: The study evaluated patients with stage III and stage IV malignant melanoma who were treated between 1983 and 1999. Tissue blocks were retrieved and reviewed to confirm the diagnosis. From the 101 cases identified, 49 (31 stage III and 18 stage IV) had sufficient residual tumor sample to enable an assay to be performed. The blocks were tested for HER2 overexpression using the DAKO HercepTest immunohistochemical (IHC) assay. Any sample that tested 1+ or greater for HER2 expression on IHC and a randomly selected subset of HER2-negative samples were tested for the presence of HER2 gene amplification using the Vysis PathVysion fluorescence in situ hybridization (FISH) assay. RESULTS: The median age of the 49 selected patients was 52.2 years, and the male-to-female ratio was 1.23:1 (27 men to 22 women). All of the 49 cases of malignant melanoma were negative for HER2 overexpression by IHC. However, two samples (3%) were found to have a weak level of HER2 expression (1+ level of staining). Subsequent FISH results on the samples that were 1+ on IHC were negative for HER2 gene amplification. FISH results on 21 other randomly selected IHC-negative samples were also negative for HER2 amplification. Flow cytometry failed to show HER2 overexpression in two melanoma cell lines, and treatment of these cells with trastuzumab did not affect their proliferation rate. CONCLUSIONS: We found a low incidence of HER2 expression and no evidence of HER2 protein overexpression or HER2 gene amplification in metastatic malignant melanoma tissues. Therefore, routine testing for HER2 overexpression or HER2 amplification would not be of benefit in this patient population. These results also imply that anti-HER2 therapy with trastuzumab is highly unlikely to provide benefit for patients with metastatic melanoma.

Breast Neoplasms↗
PubMed2005

HER2 overexpression as a predictive marker in a randomized trial comparing adjuvant cyclophosphamide/methotrexate/5-fluorouracil with epirubicin in patients with stage I/II breast cancer: long-term results.

BACKGROUND: HER2 overexpression/amplification has been reported to be a predictor of prognosis in breast cancer and a potential marker for selecting the optimal adjuvant chemotherapy. PATIENTS AND METHODS: HER2 expression and its interaction with treatment were retrospectively evaluated in 266 of 348 patients in a trial comparing adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) with weekly epirubicin in stage I/II breast cancer. HER2 expression was determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Initially, any cell showing definite membrane staining was counted, and HER2 overexpression was analyzed as a continuous variable and as a dichotomous variable, with a cutoff of > 50% of positively stained cells. Subsequently, the same slides were reanalyzed with the HercepTest. RESULTS: Of the 266 tumors immunostained for HER2, 34% exhibited nearly homogeneous staining with > 50% positive cells. When the HercepTest was applied, 8% of tumors were IHC 3+ and 8% were IHC 2+. At 8 years, no statistically significant difference in relapse-free survival (RFS) and overall survival (OS) was observed between the treatment arms in patients with low versus high HER2 overexpression, although the number of events is low. The OS was statistically shorter in patients with high HER2 overexpression in the CMF arm, whereas no difference was observed in the epirubicin arm, suggesting that patients whose cancer overexpresses HER2 could benefit more from anthracycline-based therapy. CONCLUSION: HER2 overexpression was associated with a poorer OS but not a poorer RFS. However, a Cox regression model did not confirm the prognostic role of HER2 for OS.

Adult↗