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1.
Oncogene ; 32(19): 2463-74, 2013 May 09.
Article in English | MEDLINE | ID: mdl-22751112

ABSTRACT

Truncated-ERBB2 isoforms (t-ERBB2s), resulting from receptor proteolysis or alternative translation of the ERBB2 mRNA, exist in a subset of human breast tumors. t-ERBB2s lack the receptor extracellular domain targeted by therapeutic anti-ERBB2 antibodies and antibody-drug conjugates, including trastuzumab, trastuzumab-DM1 and pertuzumab. In clinical studies, expression of t-ERBB2 in breast tumors correlates with metastasis as well as trastuzumab resistance. By using a novel immuno-microarray method, we detect a significant t-ERBB2 fraction in 18 of 31 (58%) of immunohistochemistry (IHC)3+ ERBB2+ human tumor specimens, and further show that t-ERBB2 isoforms are phosphorylated in a subset of IHC3+ samples (10 of 31, 32%). We investigated t-ERBB2 biological activity via engineered expression of full-length and truncated ERBB2 isoforms in human mammary epithelial cells (HMECs), including HMEC and MCF10A cells. Expression of p110 t-ERBB2, but not p95m (m=membrane, also 648CTF) or intracellular ERBB2s, significantly enhanced cell migration and invasion in multiple cell types. In addition, only expression of the p110 isoform led to human breast epithelial cell (HMLE) xenograft formation in vivo. Expression of t-ERBB2s did not result in hyperactivation of the phosphoinositide kinase-3/AKT or mitogen-activated protein kinase signaling pathways in these cells; rather, phosphoproteomic array profiling revealed attenuation of phosphorylated signal transducer and activator of transcription 5 (STAT5) in p110-t-ERBB2-expressing cells compared to controls. Short hairpin-mediated silencing of STAT5 phenocopied p110-t-ERBB2-driven cell migration and invasion, while expression of constitutively active STAT5 reversed these effects. Thus, we provide novel evidence that (1) expression of p110 t-ERBB2 is sufficient for full transformation of HMEC, yielding in vivo xenograft formation, and (2) truncated p110 t-ERBB2 expression is associated with decreased phosphorylation of STAT5.


Subject(s)
Breast Neoplasms/pathology , Cell Movement/physiology , Receptor, ErbB-2/metabolism , STAT5 Transcription Factor/metabolism , Animals , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Female , Humans , Immunohistochemistry , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Invasiveness , Peptide Fragments/metabolism , Phosphorylation , STAT5 Transcription Factor/genetics , Signal Transduction , Transplantation, Heterologous
2.
Breast Cancer Res Treat ; 132(1): 215-23, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22138748

ABSTRACT

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Receptor, ErbB-2/metabolism , Adolescent , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Cisplatin/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Docetaxel , Doxorubicin/administration & dosage , Drug Combinations , Female , Glutathione Disulfide/administration & dosage , Humans , Immunity, Cellular/drug effects , Kaplan-Meier Estimate , Mastectomy , Middle Aged , Neoadjuvant Therapy , Neoplasm Invasiveness , Neoplasm Staging , Taxoids/administration & dosage , Treatment Outcome , Young Adult
3.
Ann Oncol ; 20(6): 1026-31, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19179558

ABSTRACT

BACKGROUND: This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy. PATIENTS AND METHODS: Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500 mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH. RESULTS: Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for >or=24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%). CONCLUSIONS: Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.


Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Quinazolines/therapeutic use , Adult , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Breast Neoplasms/pathology , Breast Neoplasms/secondary , Disease Progression , Female , Humans , Lapatinib , Middle Aged , Receptor, ErbB-2/biosynthesis , Trastuzumab , Treatment Failure , Treatment Outcome
4.
Ann Oncol ; 17(4): 597-604, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16403812

ABSTRACT

BACKGROUND: Survivin, a novel inhibitor of apoptosis, is one of the most cancer-specific proteins identified to date. In this study we (a) evaluated the association between survivin and HER2, vascular endothelial growth factor (VEGF) and uPA/PAI-1 expression and (b) defined its effect on clinical outcome in a large breast cancer patient cohort. PATIENTS AND METHODS: Survivin expression was measured by ELISA in primary breast cancer tissue extracts from 420 patients with long-term clinical follow-up. RESULTS: Survivin was detected in 378 (90%) of the 420 primary breast cancer cases. Increased survivin levels were significantly associated with high nuclear grade (P < 0.0001), negative hormone receptor status (P = 0.0028), HER2 overexpression (P = 0.0094), VEGF expression (P < 0.0001), high uPA (P = 0.0002) and PAI-1 levels (P = 0.0002). Using the 25th percentile (1.4 ng/mg) as a cut-off point, patients expressing elevated survivin had a significantly worse disease-free survival (DFS: P = 0.0007, RR 1.97) and overall survival (OS: P = 0.0009, RR 2.11) compared with patients expressing lower levels of survivin. In multivariate analysis, this prognostic value of survivin was independent of both traditional and novel clinicopathologic factors for both DFS (P = 0.0076, RR 1.72) and OS (P = 0.0155, RR 1.76). CONCLUSIONS: The independent prognostic relevance of survivin, when combined with previous data from model systems implicating survivin in the inhibition of apoptosis, suggests that survivin may be a suitable target for future therapeutic strategies.


Subject(s)
Breast Neoplasms/metabolism , Microtubule-Associated Proteins/metabolism , Neoplasm Proteins/metabolism , Plasminogen Activator Inhibitor 1/metabolism , Receptor, ErbB-2/metabolism , Treatment Outcome , Urokinase-Type Plasminogen Activator/metabolism , Vascular Endothelial Growth Factor A/metabolism , Cohort Studies , Female , Humans , Inhibitor of Apoptosis Proteins , Survivin
5.
Oncologist ; 6 Suppl 3: 22-5, 2001.
Article in English | MEDLINE | ID: mdl-11346681

ABSTRACT

Randomized controlled studies have demonstrated that both docetaxel and Herceptin are capable of increasing survival in patients with metastatic breast cancer. The two agents show synergy in vitro, and their use in combination is not likely to be associated with the problem of enhanced cardiotoxicity. In two trials of Herceptin plus docetaxel in patients with advanced breast cancer, preliminary data are available for 35 patients. These early results show that the combination is well-tolerated. No symptomatic cardiotoxicity has occurred. The preliminary response rates (RR) in these first- and second-line patients are 44% in one study and 63% in the other. In the subgroups of patients who were HER-2 3+ overexpressers, the RRs are currently 55% and 73%. In an attempt to maximize the efficacy of Herceptin, its use has also been studied in combination with docetaxel and a platinum salt, producing a preliminary RR of 78% in patients positive for HER-2 on the fluorescence in situ hybridization assay. These data are sufficiently promising to justify a study of the role of Herceptin in combination with adjuvant chemotherapy regimens containing docetaxel or docetaxel plus a platinum. The combination of Herceptin with adjuvant therapy containing docetaxel and a platinum may provide a helpful alternative to the potentially cardiotoxic Herceptin/anthracycline-containing regimens currently under investigation.


Subject(s)
Antineoplastic Agents/pharmacology , Paclitaxel/analogs & derivatives , Taxoids , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Docetaxel , Drug Therapy, Combination , Forecasting , Humans , Paclitaxel/administration & dosage , Trastuzumab
6.
Clin Breast Cancer ; 2 Suppl 1: S15-9, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11970740

ABSTRACT

Overexpression of the p185/HER2 protein is seen in 20%-25% of primary breast cancers and is associated with poor prognosis. Recent phase II and III clinical trials demonstrate that trastuzumab is active against breast tumors, both as a single agent and in combination with chemotherapy. In patients with HER2-overexpressing metastatic breast cancer, use of trastuzumab in combination with chemotherapy is associated with a 20% reduction in relative risk of death and an increase in median survival from 20.3 to 25.1 months compared to chemotherapy alone. Side effects include fever and chills and an unexpected increase in doxorubicin/trastuzumab-associated cardiomyopathy. Clinical development is now focused on trastuzumab in combination with chemotherapy regimens that do not contain an anthracycline. Trastuzumab in combination with docetaxel is synergistic in vitro. Data from ongoing clinical trials are consistent with this finding. Preliminary data from 3 phase II studies suggest a 44%-63% response rate when the combination is used first or second line in HER2-overexpressing metastatic breast cancer. The combination of docetaxel with trastuzumab is well tolerated and has not been associated with significant cardiotoxicity. Given in vitro evidence that platinum salts act synergistically with trastuzumab and docetaxel, and phase II data suggesting clinical efficacy and good tolerability, the combination of platinum salt plus trastuzumab and docetaxel is now being assessed in adjuvant trials


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Taxoids/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Clinical Trials as Topic , Docetaxel , Female , Humans , In Situ Hybridization, Fluorescence , Receptor, ErbB-2/biosynthesis , Survival Analysis , Taxoids/administration & dosage , Taxoids/adverse effects , Trastuzumab
8.
Semin Oncol ; 27(6 Suppl 11): 21-5; discussion 92-100, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11236023

ABSTRACT

Previous studies have shown a synergistic interaction between trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) and the cytotoxic drug cisplatin in human breast cancer cells. To define the nature of the interaction between trastuzumab and other classes of cytotoxic drugs, we applied multiple drug effect/combination index isobologram analysis to a variety of chemotherapeutic drug/trastuzumab combinations in vitro. Synergistic interactions at clinically relevant drug concentrations were observed for trastuzumab in combination with cisplatin, docetaxel, thiotepa, 4-OH cyclophosphamide, vinorelbine, and etoposide. Additive cytotoxic effects were observed with trastuzumab plus doxorubicin, paclitaxel, methotrexate, and vinblastine. One drug, 5-fluorouracil was found to be antagonistic with trastuzumab in vitro. In vivo drug/trastuzumab studies were conducted with HER-2/neu-transfected MCF7 human breast cancer xenografts in athymic mice. Combinations of trastuzumab plus cisplatin, docetaxel, cyclophosphamide, doxorubicin, paclitaxel, methotrexate, etoposide, and vinblastine in vivo resulted in a significant reduction in xenograft volume compared to chemotherapy-alone controls (P < .05). The synergistic interaction of trastuzumab with specific chemotherapeutic agents suggests rational combinations for testing in human clinical trials.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/therapeutic use , Breast Neoplasms/genetics , Drug Interactions , Drug Screening Assays, Antitumor , Drug Synergism , Genes, erbB-2 , Humans , Trastuzumab , Tumor Cells, Cultured
9.
Oncogene ; 18(44): 6050-62, 1999 Oct 28.
Article in English | MEDLINE | ID: mdl-10557094

ABSTRACT

The heregulins are a family of ligands with ability to induce phosphorylation of the p185HER-2/neu receptor. Various investigators have reported a variety of responses of mouse and human breast and ovarian cells to this family of ligands including growth stimulation, growth inhibition, apoptosis and induction of differentiation in cells expressing the HER-2/neu receptor. Some of the disparity in the literature has been attributed to variations in the cell lines studied, ligand dose applied, methodologies utilized or model system evaluated (i.e. in vitro or in vivo). To evaluate the effects of heregulin on normal and malignant human breast and ovarian epithelial cells expressing known levels of the HER-2/neu receptor, this report presents the use of several different assays, performed both in vitro and in vivo, in vitro proliferation assays, direct cell counts, clonogenicity under anchorage-dependent and anchorage-independent conditions, as well as the in vivo effects of heregulin on human cells growing in nude mice to address heregulin activity. Using a total of five different biologic assays in nine different cell lines, across two different epithelia and over a one log heregulin dose range, we obtained results that clearly indicate a growth-stimulatory role for this ligand in human breast and ovarian epithelial cells. We find no evidence that heregulin has any growth-inhibitory effects in human epithelial cells. We also quantitated the amount of each member of the type I receptor tyrosine kinase family (RTK I, i.e. HER-1, HER-2, HER-3 and HER-4) in the cell lines employed and correlated this to their respective heregulin responses. These data demonstrate that HER-2/neu overexpression itself affects the expression of other RTK I members and that cells expressing the highest levels of HER-2/neu have the greatest response to HRG.


Subject(s)
Breast Neoplasms/metabolism , Neuregulin-1/metabolism , Neuregulin-1/pharmacology , Ovarian Neoplasms/metabolism , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Carcinogenicity Tests , Cell Division/genetics , Epithelial Cells/drug effects , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Nude , Neuregulin-1/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Receptor, ErbB-4 , Tumor Cells, Cultured
10.
Proc Natl Acad Sci U S A ; 96(23): 13023-8, 1999 Nov 09.
Article in English | MEDLINE | ID: mdl-10557266

ABSTRACT

We present an approach for evaluating the efficacy of combination antitumor agent schedules that accounts for order and timing of drug administration. Our model-based approach compares in vivo tumor volume data over a time course and offers a quantitative definition for additivity of drug effects, relative to which synergism and antagonism are interpreted. We begin by fitting data from individual mice receiving at most one drug to a differential equation tumor growth/drug effect model and combine individual parameter estimates to obtain population statistics. Using two null hypotheses: (i) combination therapy is consistent with additivity or (ii) combination therapy is equivalent to treating with the more effective single agent alone, we compute predicted tumor growth trajectories and their distribution for combination treated animals. We illustrate this approach by comparing entire observed and expected tumor volume trajectories for a data set in which HER-2/neu-overexpressing MCF-7 human breast cancer xenografts are treated with a humanized, anti-HER-2 monoclonal antibody (rhuMAb HER-2), doxorubicin, or one of five proposed combination therapy schedules.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Models, Biological , Animals , Drug Therapy, Combination , Female , Humans , Mice , Mice, Nude , Neoplasm Transplantation , Tumor Cells, Cultured
11.
Semin Oncol ; 26(4 Suppl 12): 89-95, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10482199

ABSTRACT

The anti-HER-2/neu antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) interferes with DNA repair induced by cisplatin and, as a result, promotes cytotoxicity in HER-2/neu-overexpressing tumor target cells in a synergistic fashion. This effect of trastuzumab, termed receptor-enhanced chemosensitivity, is specific for HER-2/neu-overexpressing cells, having no effect on cells without overexpression. Based on these findings, we conducted phase I and II clinical trials of trastuzumab plus cisplatin to determine the toxicity, pharmacokinetics, response rate, and response duration of this combination in patients with HER-2/neu-overexpressing metastatic breast cancer who had demonstrated disease progression (chemoresistance) while on active chemotherapy just prior to study entry. In phase I, four of 15 patients had objective clinical responses, including one complete response of several years' duration. Of 37 assessable patients enrolled in phase II, nine (24.3%) had objective clinical responses and an additional nine had minor responses or stable disease. The median time to progression among the responders was 8.4 months. The toxicity profile reflected that expected from cisplatin alone, with no apparent increase in toxicity caused by the addition of trastuzumab. Moreover, the pharmacokinetics of trastuzumab were unaltered by coadministration of cisplatin. We conclude that the combination of trastuzumab and cisplatin results in response rates higher than that reported for either single agent alone. Such receptor-enhanced chemosensitivity offers a new approach to target overexpressed growth factor receptors in a variety of cancers, which will lead to new, biologically based therapeutic strategies for clinical intervention.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Receptor, ErbB-2/immunology , Antibodies, Monoclonal, Humanized , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cisplatin/administration & dosage , Female , Humans , Neoplasm Metastasis , Trastuzumab
12.
Oncogene ; 17(17): 2235-49, 1998 Oct 29.
Article in English | MEDLINE | ID: mdl-9811454

ABSTRACT

HER-2 oncogene encodes a transmembrane growth factor receptor that is overexpressed in 25-30% of patients with primary breast and ovarian cancer. A murine monoclonal antibody, 4D5, to the extracellular domain of HER-2 receptor elicits cytostatic growth inhibition of tumor cells overexpressing HER-2 protein, but clinical use of this antibody is limited by genesis of human anti-mouse antibodies. To avoid this problem, a recombinant humanized 4D5 monoclonal antibody (rhuMAb HER-2) was developed and tested using a human tumor xenograft model. Human breast and ovarian cancer cells which overexpress HER-2 were inhibited in vivo by the rhuMAb HER-2 antibody. Tumor growth relative to control was reduced at all doses of antibody tested, and the magnitude of growth inhibition was directly related to dose of rhuMAb HER-2. Tumor growth resumed on termination of antibody therapy, indicating a cytostatic effect. To elicit a cytotoxic response, human breast tumor xenografts were treated with a combination of antibody and antitumor drugs, cisplatin or doxorubicin. The combination of antibody with either cisplatin or doxorubicin resulted in significantly greater growth inhibition, with the cisplatin combination demonstrating a greater response. In addition, therapy with cisplatin and antireceptor antibody elicited complete tumor remissions after 2-3 cycles of therapy. The schedule of administration of anti-receptor antibody and cisplatin was critical for occurrence of antibody-induced potentiation in cisplatin cytotoxicity. Enhanced killing of tumor cells was found only if antibody and drug were given in close temporal proximity. Since interference with DNA repair pathways may contribute to this receptor-enhanced chemosensitivity, repair of cisplatin-damaged reporter DNA (pCMV-beta) was determined in human breast cells. As in studies of antibody-enhanced cisplatin cytotoxicity in vivo, treatment with rhuMAb HER-2 blocked the repair of cisplatin-damaged DNA only if the antibody was administered in close temporal proximity to transfection of the drug-exposed reporter DNA. An alternative measure of DNA repair, unscheduled DNA synthesis, was also assessed. Treatment with either cisplatin or doxorubicin led to an increase in unscheduled DNA synthesis that was reduced by combined therapy with antireceptor antibody specific to HER-2-overexpressing breast cancer cells. Using a direct measure of DNA repair, therapy of HER-2-overexpressing cells with rhuMAb HER-2 also blocked the removal of cisplatin-induced DNA adducts. Expression of p21/WAF1, an important mediator of DNA repair, was disrupted in breast cancer cells with HER-2 overexpression, but not in control cells, after treatment with HER-2 antibody, thus suggesting cross-communication between the HER-2 signaling and DNA repair pathways. These data demonstrate an in vivo antiproliferative effect of rhuMAb HER-2 on tumors that overexpress HER-2 receptor and a therapeutic advantage in the administration of the antireceptor antibody in combination with chemotherapeutic agents.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/therapy , Cisplatin/therapeutic use , Neoplasm Proteins/immunology , Ovarian Neoplasms/therapy , Receptor, ErbB-2/immunology , Animals , Breast Neoplasms/metabolism , Cisplatin/metabolism , Combined Modality Therapy , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , DNA Adducts/metabolism , DNA Repair , DNA, Neoplasm/biosynthesis , Doxorubicin/therapeutic use , Female , Genetic Vectors , Humans , Mice , Mice, Nude , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Ovarian Neoplasms/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Transfection , Transplantation, Heterologous , Tumor Cells, Cultured
13.
J Clin Oncol ; 16(8): 2659-71, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9704716

ABSTRACT

PURPOSE: To determine the toxicity, pharmacokinetics, response rate, and response duration of intravenous (i.v.) administration of recombinant, humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) plus cisplatin (CDDP) in a phase II, open-label, multicenter clinical trial for patients with HER2/neu-overexpressing metastatic breast cancer. PATIENTS AND METHODS: The study population consisted of extensively pretreated advanced breast cancer patients with HER2/neu overexpression and disease progression during standard chemotherapy. Patients received a loading dose of rhuMAb HER2 (250 mg i.v.) on day 0, followed by weekly doses of 100 mg i.v. for 9 weeks. Patients received CDDP (75 mg/m2) on days 1, 29, and 57. RESULTS: Of 37 patients assessable for response, nine (24.3%) achieved a PR, nine (24.3%) had a minor response or stable disease, and disease progression occurred in 19 (51.3%). The median response duration was 5.3 months (range, 1.6-18). Grade III or IV toxicity was observed in 22 of 39 patients (56%). The toxicity profile reflected that expected from CDDP alone with the most common toxicities being cytopenias (n = 10), nausea/vomiting (n = 9), and asthenia (n = 5). Mean pharmacokinetic parameters of rhuMAb HER2 were unaltered by coadministration of CDDP. CONCLUSION: The use of rhuMAb HER2 in combination with CDDP in patients with HER2/neu-overexpressing metastatic breast cancer results in objective clinical response rates higher than those reported previously for CDDP alone, or rhuMAb HER2 alone. In addition, the combination results in no apparent increase in toxicity. Finally, the pharmacology of rhuMAb HER2 was unaffected by coadministration with CDDP.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Cisplatin/administration & dosage , Genes, erbB-2 , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Disease Progression , Drug Resistance, Neoplasm , Female , Humans , Middle Aged , Trastuzumab
14.
Breast Cancer Res Treat ; 52(1-3): 65-77, 1998.
Article in English | MEDLINE | ID: mdl-10066073

ABSTRACT

Amplification of the HER-2/neu (c-erbB-2) gene resulting in overexpression of the p185HER-2 growth factor receptor occurs in approximately 25% of early stage breast cancers. HER-2/neu has been established as an important independent prognostic factor in early stage breast cancer in large cohorts of patients and in cohorts with very long (30 year) follow-up duration. New data are emerging to suggest that HER-2/neu may be useful not only as a prognostic factor but also as a predictive marker for projecting response to chemotherapeutics, antiestrogens, and therapeutic anti-HER-2/neu monoclonal antibodies. In this review we highlight recent data on HER-2/neu as a predictive marker of response to breast cancer therapy and discuss the clinical implications of this information. The difficulty in comparing results from different data sets due to the wide variety of reagents and technologies used to detect HER-2/neu amplification/overexpression in clinical specimens is also discussed. Finally, we report results from experimental models of HER-2/neu overexpression which have been used in an effort to understand the relationship between HER-2/neu and response to chemotherapeutics and antiestrogens in breast cancer.


Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/drug therapy , Receptor, ErbB-2/analysis , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Breast Neoplasms/chemistry , Drug Resistance, Neoplasm , Female , Humans , Tamoxifen/therapeutic use , Trastuzumab
15.
Oncogene ; 15(5): 537-47, 1997 Jul 31.
Article in English | MEDLINE | ID: mdl-9247307

ABSTRACT

Recent studies indicate that oncogenes may be involved in determining the sensitivity of human cancers to chemotherapeutic agents. To define the effect of HER-2/neu oncogene overexpression on sensitivity to chemotherapeutic drugs, a full-length, human HER-2/neu cDNA was introduced into human breast and ovarian cancer cells. In vitro dose-response curves following exposure to 7 different classes of chemotherapeutic agents were compared for HER-2- and control-transfected cells. Chemosensitivity was also tested in vivo for HER-2- and control-transfected human breast and ovarian cancer xenografts in athymic mice. These studies indicate that HER-2/neu overexpression was not sufficient to induce intrinsic, pleomorphic drug resistance. Furthermore, changes in chemosensitivity profiles resulting from HER-2/neu transfection observed in vitro were cell line specific. In vivo, HER-2/neu-overexpressing breast and ovarian cancer xenografts were responsive to different classes of chemotherapeutic drugs compared to control-treated xenografts with no statistically significant differences between HER-2/neu-overexpressing and nonoverexpressing xenografts. We found no instance in which HER-2/neu-overexpressing xenografts were rendered more sensitive to chemotherapeutic drugs in vivo. HER-2/neu-overexpressing xenografts consistently exhibited more rapid regrowth than control xenografts following initial response to chemotherapy suggesting that a high rate of tumor cell proliferation rather than intrinsic drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in human cancers.


Subject(s)
Breast Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Ovarian Neoplasms/genetics , Receptor, ErbB-2/genetics , Animals , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Transplantation , Dose-Response Relationship, Drug , Female , Gene Expression Regulation, Neoplastic , Genetic Vectors , Humans , Mice , Mice, Nude , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/genetics , Ovarian Neoplasms/drug therapy , Receptor, ErbB-2/metabolism , Recombinant Proteins/drug effects , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Retroviridae/genetics , Transfection , Transplantation, Heterologous , Tumor Cells, Cultured
16.
Oncogene ; 10(12): 2435-46, 1995 Jun 15.
Article in English | MEDLINE | ID: mdl-7784095

ABSTRACT

Growth of human breast cells is closely regulated by steroid hormone as well as peptide hormone receptors. Members of both receptor classes are important prognostic factors in human breast cancer. Clinical data indicate that overexpression of the HER-2 gene is associated with an estrogen receptor-negative phenotype. In this study, we demonstrate that introduction of a HER-2 cDNA, converting non-overexpressing breast cancer cells to those which overexpress this receptor, results in development of estrogen-independent growth which is insensitive to both estrogen and the antiestrogen, tamoxifen. Moreover, activation of the HER-2 receptor in breast cancer cells by the peptide growth factor, heregulin, leads to direct and rapid phosphorylation of ER on tyrosine residues. This is followed by interaction between ER and the estrogen-response elements in the nucleus and production of an estrogen-induced protein, progesterone receptor. In addition, overexpression of HER-2 receptor in estrogen-dependent tumor cells promotes ligand-independent down-regulation of ER and a delayed autoregulatory suppression of ER transcripts. These data demonstrate a direct link between these two receptor pathways and suggest one mechanism for development of endocrine resistance in human breast cancers.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carrier Proteins/pharmacology , ErbB Receptors/metabolism , Estrogens/pharmacology , Glycoproteins/pharmacology , Neoplasms, Hormone-Dependent/metabolism , Neoplasms, Hormone-Dependent/pathology , Neuregulin-1 , Receptors, Estrogen/metabolism , Animals , Cell Division/drug effects , Cell Nucleus/metabolism , Down-Regulation , Drug Resistance , Estradiol/pharmacology , Humans , Mice , Phosphorylation , Receptors, Progesterone/metabolism , Tamoxifen/pharmacology , Tumor Cells, Cultured
17.
Oncogene ; 9(7): 1829-38, 1994 Jul.
Article in English | MEDLINE | ID: mdl-7911565

ABSTRACT

Approximately 30% of human breast and ovarian cancers have amplification and/or overexpression of HER-2/neu gene which encodes a cell surface growth-factor receptor. Overexpression of this receptor, p185HER-2/neu, is associated with poor outcome and may predict clinical response to chemotherapy. Antibodies to HER-2/neu receptor have a cytostatic effect in suppressing growth of cells with overexpression of p185HER-2/neu. To elicit a cytocidal effect, therapy with antireceptor antibody was used in combination with the DNA-damaging drug, cisplatin, and this combined treatment produced a synergistic decrease in cell growth. In addition, antibody mediated an increased sensitivity to cisplatin in drug-resistant ovarian carcinoma cells containing multiple copies of HER-2/neu gene. To evaluate the mechanism for this synergy, unscheduled DNA synthesis was measured in cancer cells using incorporation of [3H]thymidine and autoradiography, and formation and repair of cisplatin-induced DNA adducts was also measured. Treatment with cisplatin led to a marked, dose-dependent increase in unscheduled DNA synthesis which was significantly reduced by combined treatment with antireceptor antibody in HER-2/neu-overexpressing cells. Therapy with antibody to HER-2/neu receptor also led to a 35-40% reduction in repair of cisplatin-DNA adducts after cisplatin exposure and, as a result, promoted drug-induced killing in target cells. This phenomenon which we term receptor-enhanced chemosensitivity may provide a rationale for more selective targeting and exploitation of overexpressed growth factor receptors in cancer cells, thus leading to new strategies for clinical intervention.


Subject(s)
Antibodies, Neoplasm/immunology , Breast Neoplasms/pathology , Cisplatin/pharmacology , DNA Adducts , DNA Repair , ErbB Receptors/immunology , Ovarian Neoplasms/pathology , Proto-Oncogene Proteins/immunology , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Breast Neoplasms/genetics , Breast Neoplasms/immunology , DNA , DNA Repair/drug effects , DNA, Neoplasm/biosynthesis , DNA, Neoplasm/drug effects , Drug Resistance , ErbB Receptors/genetics , Female , Gene Expression , Humans , Mice , Mice, Nude , Ovarian Neoplasms/genetics , Ovarian Neoplasms/immunology , Proto-Oncogene Proteins/genetics , Receptor, ErbB-2 , Tumor Cells, Cultured
18.
Am J Clin Pathol ; 88(2): 177-81, 1987 Aug.
Article in English | MEDLINE | ID: mdl-3618549

ABSTRACT

The utility of neutrophil parameters provided by two flow cytometric hematologic analyzers (the H-1 and H6000, Technicon Instruments Corporation, Tarrytown, NY) was investigated for the diagnosis of infective and/or inflammatory disorders. The test population of 156 hospital patients was selected on the basis of a blood culture request. Positivity or negativity for infective and/or inflammatory disease was inferred from chart review. The parameters evaluated included the absolute neutrophil count, the lobularity index, and the left shift flag from the H-1, the percentage of high peroxidase cells from the H6000, the routine laboratory band count, and a reference band count. Significant intercorrelations were observed between these parameters. The diagnostic performance of the routine laboratory band count was significantly inferior to that of all other parameters. At equivalent points on their receiver operating characteristic curves, the diagnostic efficiencies of the remaining tests ranged from 61.5% for the lobularity index to 67% for the left shift flag and the percentage of high peroxidase cells. These differences were not significant statistically.


Subject(s)
Flow Cytometry , Infections/diagnosis , Inflammation/diagnosis , Neutrophils/pathology , Humans , Leukocyte Count
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