HER2-overexpressing Metastatic Breast Cancer Research Articles

Central nervous system progression among patients with metastatic breast cancer responding to trastuzumab treatment

Central nervous system (CNS) metastases from breast cancer are common and can present as the first or solitary site of disease progression. The CNS has been reported to act as a sanctuary site that denies access to many chemotherapeutic agents. We present here, a series of 10 metastatic breast cancer patients who developed CNS metastases after an initial response to trastuzumab treatment. Forty one patients with metastatic HER2-overexpressing breast cancer, without evidence of CNS involvement prior to the initiation of trastuzumab treatment, were followed during trastuzumab treatment. A neurological evaluation was performed in those patients who developed neurological signs or symptoms during the course of treatment. The clinical course and pattern of CNS involvement in these patients are discussed. Thirty two patients (78%) showed an initial response to trastuzumab treatment. Ten (31%) of the responding patients developed either isolated CNS relapse or concurrent CNS and systemic progression at a median of 43 weeks after the initiation of trastuzumab treatment. Trastuzumab as a single agent was continued following control of brain symptoms in three patients, two showed signs of systemic disease progression at 11 and 15 weeks following the diagnosis of CNS metastases, respectively. In two other patients, trastuzumab in combination with weekly chemotherapy was continued for more than 20 weeks after CNS relapse without evidence of disease progression. The incidence of CNS involvement in our group of patients was higher than expected. With more successful and prolonged systemic anti-tumour effects achieved by novel drug combinations, the risk of developing CNS metastases might be even greater. Evaluation of prophylactic cranial irradiation strategies might be studied for high-risk patients.

Combination of trastuzumab and vinorelbine in metastatic breast cancer.

Since the clinical introduction of trastuzumab (Herceptin) for metastatic breast cancers that overexpress human epidermal growth factor receptor 2 (HER2), this anticancer agent has played an important role in breast cancer treatment. We examined the effects of trastuzumab and vinorelbine (Navelbine) as a second- or third-line therapy in 24 patients whose HER2-positive tumors did not respond to or relapsed after administration of trastuzumab alone or in combination with taxane. Trastuzumab was administered at 2 mg/kg (loading dose 4 mg/kg) once weekly and vinorelbine at 25 mg/m(2) once weekly. The median treatment duration was 118.5 days (range, 22-351 days). The response rate was 42% (95% confidence interval (CI): 22%-63%). The adverse events of NCI-CTC grade 3 or above consisted of neutropenia in three patients; other adverse events, including vasculitis, generalized fatigue, anemia and thrombocytopenia, were grade 1 or 2. All adverse events were reversible after treatment withdrawal and were easily manageable. A combination of trastuzumab and vinorelbine can be safely administered on an outpatient basis, and is useful in the treatment of patients with HER2-overexpressing metastatic breast cancer.

Ongoing adjuvant trials with trastuzumab in breast cancer

Trastuzumab has had a major impact in the treatment of HER2-positive metastatic breast cancer. In combination with chemotherapy, trastuzumab provides significant clinical benefit in terms of increased response rate and extended survival compared with chemotherapy alone in patients with HER2-positive advanced breast cancer. Trastuzumab also has therapeutic activity as monotherapy in the front-line management of HER2-overexpressed or HER2-amplified metastatic breast cancer. Given its proven efficacy in the metastatic setting, the combination and sequential use of trastuzumab with adjuvant and neoadjuvant chemotherapy are the focus of several ongoing clinical studies. In this review, the design of the four major phase III multicenter adjuvant trastuzumab trials will be described and their major differences highlighted. Because therapy with trastuzumab has been associated with cardiac toxicity, especially with prior or concurrent anthracyclines, the evaluation of cardiac dysfunction in the adjuvant trial setting is also a priority. For now, the use of trastuzumab as adjuvant therapy is still investigational, but its integration has tremendous potential to improve treatment outcomes in patients with primary breast cancer.

Absence of HER2 overexpression in metastatic malignant melanoma.

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. 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. 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. 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.

Progress in systemic therapy for breast cancer: an overview and perspectives

This review will focus on progress for advanced and early breast cancer in systemic medical therapy, which consists of three main modalities: endocrine therapy (ET), chemotherapy (CT) and biological therapies (BTs). In advanced disease, we did witness two consecutive shifts in our classical sequence of ET: in the first one, the potent third-generation aromatase inhibitors took the second place after tamoxifen failure (a shift that is level 1 evidence based), making megestrol acetate a third option, while in the second, they are challenging tamoxifen as the ‘gold standard’ first line ET (a shift that is level 2 evidence based). As far as CT is concerned, most of the progress has been seen in anthracycline-resistant disease with the taxanes (docetaxel in particular) becoming the preferred treatment option on a level 1 evidence basis. In patients with no or limited anthracycline exposure, at least 10 randomised clinical trials involving the taxanes have been conducted, but in view of their conflicting results, no new standard of care has emerged. Third-line CT following anthracyclines and taxanes remains a wide-open research opportunity, with oral capecitabine being the only agent approved in this indication. Herceptin® (trastuzumab) is the first BTs available for the treatment of breast cancer. Its impressive clinical activity in metastatic breast cancer (MBC) prompted the registration of the drug for use as monotherapy in patients with HER-2 overexpressing MBC who have failed anthracyclines and taxanes, as well as for use upfront in combination with paclitaxel. There is substantial room for further progress with the use of Herceptin® in the management of breast cancer and much hope is placed in the combination of Herceptin® with other agents targeting important signaling pathways, such as the MAPKinase pathway or the PI 3 kinase cell survival pathway. Such strategies will be briefly discussed. In the area of early breast cancer management, BTs (namely Herceptin® and bisphosphonates) are being evaluated in randomised clinical trials, while ET has consolidated its prominent role for all women whose tumours express hormone receptors, as outlined in the 2000 NIH Consensus Conference and in the latest treatment guidelines proposed by the St-Gallen consensus panel in 2001. Substantial mutations in our standards of care are also expected in the field of adjuvant ET, with the early positive results of the large ATAC trial showing superior efficacy and tolerability of anastrozole over tamoxifen. The added benefits from adjuvant CT in patients receiving optimal ET remain difficult to ascertain and may be quite small in certain sub-groups. Only translational research efforts carry the hope for a much needed understanding of this complex interplay between ET and CT. With further improvement expected with new hormonal agents, it is possible that the role of CT will diminish in the future management of endocrine-responsive breast cancer, while the role of ET±BTs will grow.

Antibodies as molecular target-based therapy: trastuzumab.

The HER2 gene is overexpressed or amplified in approximately 30% of breast cancers. Breast cancer patients with HER2 overexpression or amplification have shortened disease-free and overall survivals. The HER2 protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER2 gene. The recombinant humanized anti-HER2 monoclonal antibody, trastuzumab (Herceptin) is now available for clinical use. In a large phase II trial, trastuzumab produced a favorable response rate as a single agent in patients with metastatic breast cancer who had received one or two prior chemotherapies. Furthermore, a large phase III trial showed that trastuzumab plus chemotherapy as a first-line treatment for metastatic breast cancer significantly improved response rate, time to disease progression, and overall survival compared with chemotherapy alone. As a single agent and in combination with chemotherapy, trastuzumab was generally well tolerated. Thus, trastuzumab plays an important role in the treatment strategy of metastatic breast cancer overexpressing HER2 protein. In this article, details of this novel biologic agent are reviewed, in conjunction with an overview of clinical studies performed in Japan.

Continuation of Trastuzumab Beyond Disease Progression Is Feasible and Safe in Patients with Metastatic Breast Cancer: A Retrospective Analysis of 80 Cases by the Hellenic Cooperative Oncology Group

Despite the widespread use of trastuzumab in the management of patients with HER2-overexpressing metastatic breast cancer, its optimal duration of administration is unknown. We retrospectively reviewed the medical records of 80 such patients who received trastuzumab monotherapy or combination chemotherapy beyond disease progression in order to register their clinical course. Median age of the patients was 54 years. Ninety-one percent had 3+ HER2 overexpression and 9% had 2+ HER2 overexpression. Fifty-six percent of patients had previously been treated with chemotherapy for advanced disease. The most commonly used combinations in first- and second-line treatments were trastuzumab with paclitaxel and trastuzumab with vinorelbine, respectively. In total, 32 responses were observed, most of them during the second or third line of treatment. Severe toxicities frequently seen (in ≥ 5% of patients) were neutropenia (25%), thrombocytopenia (11.5%), infection (10%), peripheral neuropathy (9%), nausea/vomiting (6%), stomatitis (6%), diarrhea (6%), constipation (6%), edema (6%), and myalgias/arthralgias (5%). Median survival from diagnosis of advanced disease was 43.4 months (range, 6.4–91.7+), whereas median survival from disease progression after trastuzumab administration was 22.2 months (range, 0.01-32.9+). In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic breast cancer is feasible and safe. Randomized studies are warranted.

Mode of action of docetaxel – a basis for combination with novel anticancer agents

Different tumors have different aberrations in signaling and growth stimulation pathways that drive cancer growth. An understanding of these processes is key to the development of new anticancer agents and to identifying optimal treatment strategies and patient populations suitable for specific therapies. It is becoming clear that certain chemotherapeutic drugs such as docetaxel are not simply inhibitors of mitosis and may interact with these tumorigenic mechanisms at a number of levels. This review describes docetaxel’s mechanism of action, and provides a basis for understanding how its antitumor activity can integrate with that of different novel agents. Against this background, key docetaxel–novel agent combinations that are currently under clinical investigation are reviewed. How these strategies can be targeted towards specific patient populations ( e.g., HER-2 overexpressing metastatic breast cancer patients) to provide optimal therapy is highlighted.

Trastuzumab in Combination with Chemotherapy

Trastuzumab has been widely studied in combination with chemotherapy. Efficacy and safety data have been established for several combination regimens. Because trastuzumab in combination with chemotherapy has been shown to improve survival for women with HER2-overexpressing metastatic breast cancer when compared to treatment with chemotherapy alone, the use of combination therapy is the preferred initial treatment for such patients. Comparative studies of combination therapy versus single agent trastuzumab therapy have not been done. The optimal trastuzumab/chemotherapy combination is not known, nor is the optimal time of initiation of trastuzumab nor the optimal duration of therapy established.

The Addition of Carboplatin to Trastuzumab/Paclitaxel Improves Efficacy in HER2-Overexpressing Metastatic Breast Cancer

The Addition of Carboplatin to Trastuzumab/Paclitaxel Improves Efficacy in HER2-Overexpressing Metastatic Breast Cancer

Development of HER2-specific humanized antibody Herceptin (trastuzumab).

HER2 is a member of the human epidermal growth factor receptor family, possessing protein kinase activity in its cytoplasmic domain. There were evidences indicating that (1) amplification of HER2/neu gene and HER2 protein over-expression in tumor cells was observed in 25-30% of human breast cancer and (2) amplification of HER2/neu correlated with poor prognosis, including shorter disease-free and overall survival. These evidences suggested HER2 was a promising candidate for novel molecular targets of breast cancer therapy. Herceptin is a recombinant humanized monoclonal antibody generated by Genentech, Inc. for the treatment of HER2 over-expressed/HER2 gene amplified metastatic breast cancer (MBC). Preclinical studies demonstrated that the antibody had anti-tumor activity in vivo and in vitro, and additive or synergistic enhancement of anti-tumor activity of the antibody was observed in combination with various anti-tumor agents in mouse models. In clinical studies, apparent extension of overall survival was observed in HER2 overexpressing MBC patients. Herceptin is the first anticancer drug whose use as a treatment for MBC patients is decided based on the status of the HER2 gene amplification/HER2 protein over-expression. The development and standardization of HER2 test were a key strategy in clinical development of this drug, since appropriate selection of patients with HER2 over-expression was the essential point for success.

Is Fluorescence In Situ Hybridization Really Superior to HercepTest?

Is Fluorescence In Situ Hybridization Really Superior to HercepTest?

Trastuzumab/chemotherapy combinations in metastatic breast cancer.

The past decade has seen many advances in the treatment of advanced breast cancer, including the development of both new chemotherapy drugs and novel targeted agents. Trastuzumab, a humanized monoclonal antibody directed against the HER2/neu protein, has been shown to be an efficacious treatment for HER2-overexpressing metastatic breast cancer, both as a single agent and when used in combination with chemotherapy. The US Food and Drug Administration has approved the use of trastuzumab and paclitaxel as first-line treatment of HER2-overexpressing metastatic breast cancer, based on the results of a randomized phase III clinical trial showing that this combination produced higher response rates and longer survival duration than treatment with chemotherapy alone. Further trials are currently underway evaluating the use of trastuzumab in combination with other forms of chemotherapy, including vinorelbine, docetaxel, anthracyclines, and platinum agents. Hopefully, information from these trials will help resolve questions regarding the efficacy of various combinations and dosing schedules so that trastuzumab may be used most effectively in the treatment of HER2-overexpressing breast cancer in both the metastatic and the adjuvant settings.

HER2 overexpressing metastatic breast cancer.

More than 40,000 women in the United States die each year from metastatic breast cancer. Elucidation of HER2 and its role in malignant transformation has helped define a subset of aggressive breast cancer that may be relatively resistant to non-anthracycline-based therapies and hormonal agents, but responds to targeted molecular therapy. Trastuzumab, an antibody against HER2, has proven effective as single agent therapy in women with HER2 overexpressed metastatic breast cancer. Moreover, in combination with chemotherapy, trastuzumab has been shown to delay disease progression and improve overall survival for women with HER2-positive advanced breast cancer. The combination of chemotherapy and trastuzumab is emerging as a standard of care in women with HER2 overexpressed metastatic breast cancer. Several combination regimens using trastuzumab with taxanes, vinca alkaloids, or platinum compounds have demonstrated efficacy in first- and second-line treatment settings. However, the development of anthracycline-based combinations has been limited by concerns of related cardiotoxicity. Newer multi-agent regimens are in development. The optimal combination, duration, and sequence of trastuzumab therapy remain unknown in patients with HER2-positive metastatic disease. The role of continuing treatment after disease progression is also unclear. Evidence from some retrospective analyses suggest HER2-positive tumors are relatively resistant to tamoxifen and perhaps more responsive to aromatase inhibitors, although such data are inconclusive. HER2 status should not be used routinely for clinical decision making regarding hormonal therapy options. Several ongoing trials are attempting to address these and other issues related to HER2 testing to select the most appropriate candidates for these emerging therapies. While many questions remain, the treatment of HER2 overexpressing metastatic breast cancer is rapidly evolving, and represents a new approach to treatment in oncology.

Non-small cell lung cancer clinical trials with trastuzumab: their foundation and preliminary results

The overexpression of HER2, a transmembrane glycoprotein tyrosine kinase, has been implicated in mitogenesis, cell survival, invasion and angiogenesis. Preclinical evidence suggests that HER2 overexpression contributes to tumor progression in non-small cell lung cancer (NSCLC) and retrospective clinical correlative studies show that it is probably associated with poor clinical outcome. Trastuzumab (Herceptin®, Genentech Inc., South San Francisco, CA) is a recombinant humanized monoclonal antibody that targets HER2 and is currently approved for use in the treatment of patients with HER2-overexpressing metastatic breast cancer. Two primary mechanisms proposed for the activity of trastuzumab are downregulation of HER2 and induction of antibody-dependent cell-mediated cytotoxicity. Evidence from preclinical studies of trastuzumab in NSCLC and other cell lines, the presence of HER2 overexpression in NSCLC clinical specimens and the clinical benefit derived from trastuzumab in phase II and III metastatic breast cancer trials have led to the development of clinical trials of trastuzumab in NSCLC. Phase II studies of trastuzumab in patients with stage IIIB or IV NSCLC are being conducted to test the efficacy of trastuzumab as a single agent or in combination with chemotherapy. Preliminary results show combinations of chemotherapy plus trastuzumab are well tolerated, with encouraging response rates of 21–40%. A randomized phase II trial of chemotherapy with or without trastuzumab showed promise in a small subgroup of patients with 3+ HER2 overexpression by immunohistochemistry or HER2 DNA amplification by fluorescence in situ hybridization. Taken together, these data indicate that trastuzumab warrants further investigation in a clinical study in selected patients with NSCLC.

Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer

PURPOSE: To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. RESULTS: The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. CONCLUSION: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2.

Trastuzumab is a humanised monoclonal antibody developed to target the HER2 receptor which is overexpressed by some cancer cells, including 25 to 30% of breast cancers. Binding with high affinity to the extracellular domain of HER2, trastuzumab inhibits the proliferation of tumour cells that overexpress HER2. A large well designed multicentre study found that the addition of trastuzumab to either an anthracycline plus cyclophosphamide or to paclitaxel, as first-line therapy for metastatic breast cancer overexpressing the HER2 receptor, significantly increased time to disease progression, rate of objective response, duration of response and survival compared with chemotherapy alone. Single-agent trastuzumab was associated with an objective response in 15% of extensively pretreated patients with metastatic breast cancer overexpressing HER2, and 26% of previously untreated patients. Patients with a HER2 overexpression level of 3+ using immunohistochemical (IHC) assay or a positive HER2 result using fluorescence in situ hybridisation (FISH), benefit more from trastuzumab therapy than those with tumours overexpressing at a level of 2+. Trastuzumab has demonstrated synergistic action with several chemotherapy agents preclinically but the optimal combination clinically is yet to be determined. Trastuzumab is generally well tolerated by most patients; the most significant adverse effects being acute fever and/or chills and the potential to cause cardiac dysfunction. Serious adverse events, including anaphylaxis and death, have occurred in 0.25% of patients. Symptomatic or asymptomatic cardiac dysfunction occurred in 27% of patients receiving an anthracycline and cyclophosphamide combined with trastuzumab. Thus, combination therapy with anthracyclines is not recommended. Symptomatic or asymptomatic cardiac dysfunction occurred in 13% of patients receiving trastuzumab plus paclitaxel and in 4.7% of patients receiving trastuzumab alone. Intravenous trastuzumab is effective as a single-agent, and in combination with chemotherapy it significantly improves the median time to disease progression and survival time in patients with metastatic breast cancer overexpressing the HER2 receptor compared with chemotherapy alone. Cardiotoxicity is the main concern with therapy; particularly in patients with pre-existing cardiac dysfunction, the elderly and in combination with, or following, anthracyclines. Trastuzumab is indicated for use with paclitaxel as first-line therapy or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2. Investigation is ongoing to ascertain the optimal combination regimen containing trastuzumab and antineoplastic agents. In addition, current research is focusing on the optimal timing, sequencing and duration of therapy as well as administration in the neoadjuvant and adjuvant setting.

Trastuzumab/chemotherapy combinations in metastatic breast cancer

The past decade has seen many advances in the treatment of advanced breast cancer, including the development of both new chemotherapy drugs and novel targeted agents. Trastuzumab, a humanized monoclonal antibody directed against the HER2/ neu protein, has been shown to be an efficacious treatment for HER2-overexpressing metastatic breast cancer, both as a single agent and when used in combination with chemotherapy. The US Food and Drug Administration has approved the use of trastuzumab and paclitaxel as first-line treatment of HER2-overexpressing metastatic breast cancer, based on the results of a randomized phase III clinical trial showing that this combination produced higher response rates and longer survival duration than treatment with chemotherapy alone. Further trials are currently underway evaluating the use of trastuzumab in combination with other forms of chemotherapy, including vinorelbine, docetaxel, anthracyclines, and platinum agents. Hopefully, information from these trials will help resolve questions regarding the efficacy of various combinations and dosing schedules so that trastuzumab may be used most effectively in the treatment of HER2-overexpressing breast cancer in both the metastatic and the adjuvant settings. Semin Oncol 29 (suppl 11):38-43. Copyright 2002, Elsevier Science (USA). All rights reserved.

An overview of HER2

HER2 is a transmembrane growth factor receptor found in normal and malignant breast epithelial cells. Phosphorylation of the intracellular tyrosine kinase results in intracellular signaling and activation of genes involved in cell growth. Overexpression of HER2 has independent prognostic significance in early breast cancer and may also predict response to hormonal and cytotoxic therapies, although this latter role is less well studied. Prospective stratification of HER2 status in current clinical trials may more accurately delineate these roles. Anti-HER2 therapy, using a humanized monoclonal antibody, has enhanced survival when given with chemotherapy compared with chemotherapy alone in patients with metastatic HER2-overexpressing breast cancer. A potential limitation to its use in the adjuvant setting is the increased incidence of cardiotoxicity in patients treated either concurrently or previously with anthracyclines; carefully designed prospective adjuvant trials are currently being launched. HER2 is a relatively new prognostic marker and holds promise for predicting response to various therapies and for target-specific therapy.

Combining the Anti-HER2 Antibody Trastuzumab with Taxanes in Breast Cancer: Results and Trial Considerations

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.