Pharmacology and therapeutic use of trastuzumab in breast cancer.

The development, pharmacology, safety, efficacy, and dosage and administration of trastuzumab are reviewed. The discovery of HER2 gene amplification in up to 30% of women with breast cancer led to the development of trastuzumab, a humanized recombinant monoclonal antibody directed against the HER2-receptor protein on breast cancer cells. In large, multicenter trials of trastuzumab as a single agent or in combination with chemotherapy as first-line or second-line therapy for metastatic breast cancer (MBC), response rates have ranged from 12% to 23% for single-agent trastuzumab and from 25% to 62% for trastuzumab plus chemotherapy. Trastuzumab increased time to disease progression and survival time when administered in combination with chemotherapy. The National Comprehensive Cancer Network guidelines for the treatment of breast cancer now include trastuzumab and paclitaxel as an option for patients with MBC or recurrent breast cancer in which the HER2-receptor protein is overexpressed. Trastuzumab is administered weekly, with an initial i.v. dose of 4 mg/kg followed by weekly doses of 2 mg/kg. Most clinical trials continued treatment until disease progression occurred. Adverse effects include infusion-related reactions manifested by fever and chills, exacerbation of chemotherapy-induced gastrointestinal toxicity and myelosuppression, and cardiotoxicity. Trastuzumab, either as a single agent or in combination with chemotherapy, can be an effective therapeutic option for MBC patients who overexpress the HER2-receptor protein and has changed the standard of care.     

Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer

Trastuzumab (Herceptin) is a humanised monoclonal antibody used in the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), which is associated with clinically aggressive disease and a poor prognosis. The addition of intravenous trastuzumab to first-line chemotherapy improved the time to disease progression, objective response rate, duration of response, and overall survival in randomised, multicentre trials in women with HER2-positive metastatic breast cancer. As such, trastuzumab has become the standard of care in this setting, despite its high acquisition cost and potential for cardiac events, and is licensed for use in combination with paclitaxel (Europe and the US) or docetaxel (Europe). In addition, trastuzumab monotherapy is approved for use in patients with HER2-positive metastatic breast cancer who have previously received chemotherapy for their metastatic disease. Recent data from large phase III trials with trastuzumab in the adjuvant setting revealed significant improvements in disease-free and overall survival. Thus, trastuzumab is also rapidly becoming a standard component of adjuvant therapy for patients with HER2-positive early-stage breast cancer.     

Trastuzumab: new indication. Metastatic breast cancer, in combination with docetaxel: promising, but more evaluation is needed

(1) There is no consensus on the optimal chemotherapy for metastatic breast cancer. Patients who have never previously received chemotherapy are generally given an anthracycline-based combination of cytotoxic agents. Options for patients who have already received an anthracycline include a taxane such as paclitaxel or docetaxel. The median survival time with these treatments is only about 2 to 2.5 years. (2) Trastuzumab is a monoclonal antibody directed against HER-2, a protein overexpressed by certain tumours, including about 25% of breast tumours. In 2000, the approved indications included first-line treatment of metastatic breast cancer in combination with paclitaxel. One clinical trial had shown, albeit with a low level of evidence, a median increase in survival of about 4 to 5 months. Trastuzumab is now approved for first-line treatment of metastatic breast cancer, in combination with docetaxel. (3) Evaluation data include the results of an open-label trial comparing docetaxel + trastuzumab with docetaxel monotherapy in 186 patients. The median survival time was significantly longer with the combination (31.2 versus 22.7 months). There are no relevant comparisons with other widely used cytotoxic drugs. Indirect comparison suggests that survival is similar with docetaxel + trastuzumab and paclitaxel + trastuzumab. (4) Data on the trastuzumab-docetaxel combination confirm the known adverse effects of trastuzumab, which include heart failure and diarrhea. Trastuzumab increases the frequency of docetaxel-induced neutropenia, which carries a risk of infections. (5) In summary, the results of clinical trials show that median survival time is increased by a few months when trastuzumab is added to a cytotoxic drug. However, the best cytotoxic agent is not known, and adverse effects are poorly documented. (6) In practice, trastuzumab has only been shown to benefit a minority of women with breast cancer, namely those whose tumours overexpress HER-2. Trastuzumab therapy is an option for metastatic breast cancer treatment, provided patients are enrolled in studies designed to answer the many outstanding questions.     

Trastuzumab: in HER2-positive metastatic gastric cancer

Trastuzumab is a recombinant humanized IgG? monoclonal antibody directed against the extracellular domain of the human epidermal growth factor receptor type 2 (HER2) that inhibits HER2-dependent tumour cell proliferation and survival. Proliferation of gastric cancer cells overexpressing HER2 is inhibited by trastuzumab in vitro and in vivo. HER2-positive expression (defined as immunohistochemistry 3+ or fluorescence in situ hybridization-positive) was observed in 22.1% of almost 4000 metastatic gastric cancers in patients who were screened for randomization in the open-label, multicentre, phase III ToGA trial. In patients with HER2-positive metastatic gastric cancer (n?=?584), median overall survival (primary endpoint) was significantly longer for recipients of intravenous trastuzumab plus chemotherapy (comprising cisplatin and either fluorouracil or capecitabine) than in those receiving chemotherapy alone in the ToGA trial. Furthermore, the overall response rate was significantly higher and the median time to disease progression and median time of progression-free survival were also significantly longer with trastuzumab plus chemotherapy than with chemotherapy alone. In general, combination therapy with trastuzumab and chemotherapy was relatively well tolerated in patients with metastatic gastric cancer with no reports of new or unexpected adverse events.     

Trastuzumab,a humanized anti-HER2 monoclonal antibody,for the treatment of breast cancer

The HER2/neu gene encodes a 185 kDa transmembrane receptor (HER2) that belongs to the epidermal growth factor receptor family and has intrinsic tyrosine kinase activity. HER2 is overexpressed in 25-30% of breast cancers and is suggested to have a direct role in the pathogenesis and clinical aggressiveness of HER2 overexpressing tumors. A murine monoclonal antibody, 4D5, directed against the extracellular domain of HER2, is a potent inhibitor of growth of human breast cancer cells overexpressing HER2 in vitro and in xenograft models. To facilitate clinical investigation, 4D5 was humanized by inserting the complementary determining regions of 4D5 into the framework of a consensus human IgG1. The resulting recombinant humanized anti-HER2 MAb, trastuzumab, was found to inhibit the growth of human cancer cells and tumor xenografts overexpressing HER2. Data from phase II trials in women with breast cancer whose tumors overexpress HER2 have shown that trastuzumab has a favorable toxicity profile, is active as a single agent and induces long-lasting objective tumor responses. In combination studies, there was no evidence that trastuzumab enhanced the toxicity of cisplatin and the pharmacokinetic parameters of trastuzumab were unaltered by coadministration of cisplatin. Furthermore, clinical response rates were higher than those reported with either agent alone in a similar patient population. Results of a multicenter, phase III clinical trial of chemotherapy (doxorubicin- or paclitaxel-based) plus trastuzumab as compared to chemotherapy alone in patients with advanced breast cancers overexpressing HER2 showed a significant enhancement in the effects of chemotherapy on time to disease progression, response rates and survival with coadministration of trastuzumab, without increases in overall severe adverse events. Myocardial dysfunction syndrome, similar to that observed with anthracyclines, was reported more commonly with chemotherapy plus trastuzumab. Positive results from clinical studies led to the approval of trastuzumab in the U.S in October 1998 for the treatment of metastatic breast cancer in patients with tumors overexpressing HER2. Since then, the MAb has also been marketed in Switzerland and Canada.     

Role of trastuzumab in adjuvant therapy for locally invasive breast cancer.

PURPOSE: The role of trastuzumab in adjuvant therapy for locally invasive breast cancer is discussed. SUMMARY: Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor-2 (HER2). Currently, trastuzumab is indicated for use in HER2-positive patients with metastatic breast cancer. Because trastuzumab specifically targets a receptor that is overexpressed in tumor cells, it is less likely to cause the cytotoxic adverse effects of traditional chemotherapy. Cardiotoxicity has been a major concern, however. Several trials were started to evaluate trastuzumab in the adjuvant setting in patients diagnosed with early-stage breast cancer. The interim results of these trials have shown a promising effect of adjuvant therapy with trastuzumab in improving overall survival, disease-free survival, relapse-free survival, and distant-disease-free survival. CONCLUSION: The use of trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer can lead to increased survival. The appropriateness of trastuzumab therapy should be considered based on HER2 status, cost, and risk of toxicity.     

What's so special about [symbol: see text] trastuzumab?

The growth and multiplication of cells are regulated, in part, by polypeptide growth factors that bind to high-affinity receptors typically found on the plasma membrane. One such receptor is human epidermal growth factor receptor 2 (HER2). In around a quarter of all primary breast cancers, cells possess abnormally high numbers of (overexpress) HER2. [symbol: see text] Trastuzumab (pronounced tra-stoo-zoo-mab; Herceptin-Roche), a recombinant humanised mouse monoclonal antibody directed against HER2, is available as a treatment for certain patients with metastatic breast cancer. It is licensed as a first-line treatment in combination with [symbol: see text] paclitaxel for those whose cancer cells overexpress HER2 and for whom an anthracycline is unsuitable, and as a third-line treatment used alone when treatment with (where appropriate) an anthracycline, a taxane and hormonal therapy has failed. The National Institute for Clinical Excellence (NICE) has recommended trastuzumab as a treatment option for metastatic breast cancer in accordance with the licensed indications. What does trastuzumab offer?     

Trastuzumab: a pharmacoeconomic review of its use in early breast cancer

Trastuzumab (Herceptin) is a monoclonal antibody approved for the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2). Well designed clinical trials in women with early breast cancer have demonstrated that 1 years' therapy with adjuvant intravenous trastuzumab (a loading dose followed by 6 mg/kg every 3 weeks or 2 mg/kg weekly) significantly improves disease-free survival and overall survival compared with observation (subsequent to chemotherapy) or chemotherapy alone in women with HER2-positive disease. In the HERA trial, disease-free survival was estimated to improve by 6.3% at 3 years in the trastuzumab group compared with the observation group. Trastuzumab is generally well tolerated. The most common adverse events are infusion-related symptoms, such as fever and chills, which usually occur with administration of the first dose. Cardiotoxicity occurs in a small proportion of patients receiving trastuzumab, particularly when coadministered with anthracyclines, and cardiac assessment is recommended for all patients at baseline and at 3-monthly intervals. In modelled cost-effectiveness analyses based on data from clinical trials in patients with HER2-positive early breast cancer, adjuvant trastuzumab was predicted to be cost effective from a healthcare payer or societal perspective in several countries. Incremental costs per QALY or life-year gained with trastuzumab administered subsequent to or concurrent with chemotherapy compared with chemotherapy alone were consistently within accepted local thresholds for cost effectiveness. Sensitivity analyses demonstrated that these results remained generally robust to plausible changes in key model assumptions. In conclusion, in patients with HER2-positive early breast cancer, the addition of adjuvant trastuzumab is clinically effective in improving disease-free survival. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of adjuvant trastuzumab for 1 year as a cost-effective treatment relative to chemotherapy alone in this patient population.     

Lapatinib ditosylate: expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer

Receptor tyrosine-protein kinase erbB-2 (HER2)-positive breast cancer is a specific entity with an aggressive behavior. Trastuzumab, a monoclonal antibody targeting erbB-2 (HER2) deeply transformed the outcome in patients. Nevertheless, resistance to trastuzumab is still a major concern. Lapatinib ditosylate is an orally available, small molecule targeting the tyrosine activity of the HER2 receptor. Lapatinib as a single agent and in combination therapy showed interesting activity in trastuzumab-resistant advanced tumors. In addition, lapatinib use seemed suitable in recurrent locally advanced inflammatory breast cancer and brain metastases. More recently, the Neo-ALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial showed that lapatinib in combination with trastuzumab and paclitaxel significantly improved the pathological complete response in a neoadjuvant setting. Several clinical trials are still ongoing and data that may change current clinical practice are awaited with much interest.     

From HER2 to herceptin

HER2 overexpression occurs in 25% of breast cancers and seems to correlate with poor prognosis. HER2 overexpression may predict tamoxifen failure and different response rates to chemotherapeutic agents such as the taxanes and anthracyclines. The detection of HER2 and its overexpression is performed using fluorescent in situ hybridisation (FISH) and/or immunohistochemistry (IHC). Trastuzumab [Herceptin (H)] is a humanised IgG monoclonal antibody specific for the growth factor receptor HER2. Pre-clinical trials using monoclonal antibodies have shown inhibition of breast tumour growth in athymic nude mice. Phase II and III clinical trials have evaluated the efficacy and safety of Herceptin in women with metastatic breast cancer in combination with other agents and as a single agent. Currently, Trastuzumab and paclitaxel is the only combination indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2. It is also indicated as a single agent in women with HER2-overexpressing metastatic breast cancer that has progressed after previous chemotherapy. Herceptin is a well-tolerated drug and the side-effects that are commonly seen with chemotherapy, such as neutropenia, alopecia and mucositis, are rarely observed. The main risk factors for cardiotoxicity are concurrent or previous anthracycline exposure. The potential role of Herceptin in the adjuvant setting is currently being evaluated.     

Efficacy and safety of trastuzumab

The human epidermal growth factor receptor (HER) 2 is overexpressed in ～ 20 – 25% of human breast cancers and is an independent adverse prognostic factor. Targeted therapy directed against this receptor has been developed in the form of a humanised monoclonal antibody, trastuzumab. This antibody has shown activity as a single agent in metastatic breast cancer both prior to chemotherapy and in heavily pretreated patients. A pivotal Phase III trial has demonstrated that its use in combination with an anthracycline or paclitaxel results in a significant improvement in survival, time to progression, and response. This has recently been reinforced by another trial with docetaxel. The HER2 status of a tumour is a critical determinant of response to trastuzumab-based treatment. Those that express HER2 at the highest level on immunohistochemistry (IHC), 3+, derive more benefit from treatment with trastuzumab than those with overexpression at the 2+ level. Benefit correlates best with tumours that are positive on fluorescence in situ hybridisation for HER2, regardless of IHC status. Treatment with trastuzumab is generally well tolerated with a low incidence of adverse events. Some patients may experience fever, chills, dyspnoea and pain, particularly with the first administration. Unexpectedly, cardiac toxicity has developed in some patients treated with trastuzumab, and this has a higher incidence in those treated in combination with an anthracycline. ‘Cross-talk’ between the oestrogen receptor and HER2 pathway has stimulated interest in using trastuzumab in combination with endocrine therapy. Current clinical trials are investigating the role of this agent in the adjuvant setting.     

Efficacy and safety of trastuzumab

The human epidermal growth factor receptor (HER) 2 is overexpressed in approximately 20-25% of human breast cancers and is an independent adverse prognostic factor. Targeted therapy directed against this receptor has been developed in the form of a humanised monoclonal antibody, trastuzumab. This antibody has shown activity as a single agent in metastatic breast cancer both prior to chemotherapy and in heavily pretreated patients. A pivotal Phase III trial has demonstrated that its use in combination with an anthracycline or paclitaxel results in a significant improvement in survival, time to progression, and response. This has recently been reinforced by another trial with docetaxel. The HER2 status of a tumour is a critical determinant of response to trastuzumab-based treatment. Those that express HER2 at the highest level on immunohistochemistry (IHC), 3+, derive more benefit from treatment with trastuzumab than those with overexpression at the 2+ level. Benefit correlates best with tumours that are positive on fluorescence in situ hybridisation for HER2, regardless of IHC status. Treatment with trastuzumab is generally well tolerated with a low incidence of adverse events. Some patients may experience fever, chills, dyspnoea and pain, particularly with the first administration. Unexpectedly, cardiac toxicity has developed in some patients treated with trastuzumab, and this has a higher incidence in those treated in combination with an anthracycline. 'Cross-talk' between the oestrogen receptor and HER2 pathway has stimulated interest in using trastuzumab in combination with endocrine therapy. Current clinical trials are investigating the role of this agent in the adjuvant setting.     

Single-agent trastuzumab versus trastuzumab plus cytotoxic chemotherapy in metastatic breast cancer: a single-institution experience

Trastuzumab has shown significant single-agent activity in patients with Her-2/neu overexpressing metastatic breast cancer, and increased response rates, progression-free and overall survival when added to standard chemotherapy. Despite higher response rates, the combination with chemotherapy has higher toxicity and it remains unknown whether single-agent trastuzumab is equally effective as the combined treatment in terms of progression-free and overall survival. We therefore carried out a retrospective multivariate analysis of 117 patients with Her-2/neu overexpressing metastatic breast cancer who were treated with trastuzumab with or without chemotherapy at a single institution between November 1999 and December 2003. Response rates tended to be higher in patients receiving trastuzumab in combination with chemotherapy (34 versus 8%, p=0.060). However, this did not translate into a benefit in progression-free survival: median (95% confidence interval) progression-free survival was 6.2 (4.45-7.95) months in patients receiving trastuzumab plus chemotherapy versus 4.2 (1.77-6.63) months in those receiving single-agent trastuzumab (p=0.560). Likewise, no significant difference in overall survival was observed: 27.0 (19.9-34.0) versus 23.1 (16.2-30.0) months (p=0.809). We conclude that in the absence of extensive visceral involvement necessitating a higher response rate, single-agent trastuzumab may be a safe and less-toxic alternative to its combined use with other chemotherapy agents. This needs to be confirmed in prospective randomized trials.     

Bevacizumab: a review of its use in combination with paclitaxel or capecitabine as first-line therapy for HER2-negative metastatic breast cancer

Bevacizumab (Avastin?) is a humanized monoclonal antibody directed against vascular endothelial growth factor. In patients with human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer, bevacizumab is indicated as first-line therapy in combination with paclitaxel, or in combination with capecitabine when treatment with other chemotherapy options, including taxanes or anthracyclines, is not considered appropriate. This article reviews the efficacy and tolerability of these combination therapies in the first-line treatment of patients with metastatic breast cancer, and summarizes the pharmacological properties of bevacizumab. In randomized, controlled, phase III trials in patients with predominantly HER2-negative metastatic or locally recurrent breast cancer, the addition of bevacizumab to paclitaxel or capecitabine significantly prolonged progression-free survival (PFS; investigator assessment) by a median of 5.9 and 2.9 months, respectively, relative to paclitaxel or capecitabine alone. It also significantly increased the objective response rate, but not overall survival. Independent reviews of data supported the results of the primary analyses of investigator-assessed PFS. However, as the efficacy of bevacizumab in combination with capecitabine appears to be less than that of other available options, it should be used only if treatment with other chemotherapy options are not considered appropriate. The addition of bevacizumab to paclitaxel had no significant adverse effects on health-related quality of life. Efficacy data from two routine clinical practice studies were generally consistent with those from the phase III trials. Bevacizumab had generally acceptable tolerability when administered in combination with paclitaxel or capecitabine as first-line therapy in these studies, and adverse events were consistent with the known tolerability profiles of the individual agents. The most common adverse events associated with bevacizumab combination therapy in phase III trials were sensory neuropathy and grade ≥3 hypertension, occurring more frequently with combination therapy than with chemotherapy alone. Potentially life-threatening events, such as venous thromboembolism, gastrointestinal perforation, arterial thromboembolism, haemorrhage and left ventricular dysfunction, occurred in ≤5% of patients receiving combination therapy in these trials. In conclusion, bevacizumab administered in combination with paclitaxel, or in combination with capecitabine if other chemotherapy regimens are not appropriate, may be considered as an option for the first-line treatment of patients with HER2-negative metastatic breast cancer.     

Trastuzumab : in HER2 and hormone receptor co-positive metastatic breast cancer

Trastuzumab is a humanised IgG1 monoclonal antibody, which selectively binds to the human epidermal growth factor receptor 2 (HER2), inhibiting cell proliferation and survival in HER2-dependent tumours. In a randomised phase III trial in postmenopausal women with HER2 and hormone receptor (HR) co-positive metastatic breast cancer, median progression-free survival (primary endpoint) was significantly longer in patients receiving intravenous trastuzumab plus oral anastrozole than in those receiving anastrozole alone. Overall response rate and clinical benefit rate were also significantly higher, and median time to disease progression was significantly longer with trastuzumab plus anastrozole versus anastrozole alone. There were no reports of new or unexpected adverse events with trastuzumab plus anastrozole combination therapy in the randomised phase III trial. In a noncomparative phase II study of trastuzumab plus letrozole in postmenopausal women with HER2 and HR co-positive metastatic breast cancer, the majority of adverse events were mild or moderate in severity.     

表没食子儿茶素没食子酸酯联合曲妥珠单抗对HER2过表达乳腺癌细胞增殖的影响及其机制

目的 研究表没食子儿茶素没食子酸酯（EGCG）联合曲妥珠单抗对人表皮生长因子受体2(HER2)过表达乳腺癌细胞增殖的影响及其作用机制。方法 表达纯化曲妥珠单抗;用CCK-8细胞增殖检测试剂盒（CCK8）检测不同浓度EGCG、曲妥珠单抗及两药联用对HER2过表达乳腺癌细胞BT474、SK-BR-3的增殖抑制作用;用Western blot法检测EGCG、曲妥珠单抗及两药联用对BT474乳腺癌细胞中HER2,表皮生长因子受体（EGFR）,丝裂原激活的蛋白激酶（MAPK）和蛋白激酶B(Akt)及它们的磷酸化蛋白的表达水平的影响。结果 细胞增殖试验结果显示,EGCG、曲妥珠单抗以及二者联用均能有效抑制BT474和SK-BR-3细胞的增殖,且在一定浓度范围内,EGCG与曲妥珠单抗联用显示出协同增殖抑制作用。Western blot结果显示EGCG、曲妥珠单抗以及二者联合均能抑制BT474细胞中Akt,MAPK,EGFR,HER2的磷酸化蛋白表达,与单药相比,二者联合抑制作用显著增强,其差异具有统计学意义(P<0.05)。结论 EGCG联合曲妥珠单抗能协同抑制HER2过表达乳腺癌细胞的增殖,...     

Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer

Human epidermal growth factor receptor-2 (HER2/erbB-2) is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival and differentiation via multiple signal transduction pathways. Amplification of the HER2 gene occurs in 20–25% of human breast cancers. This amplification event is an independent adverse prognostic factor as well as a predictive factor for increased response to doxorubicin-based combination chemotherapy, response to trastuzumab and decreased response to hormonal therapy. Methods for detecting protein overexpression or gene amplification in clinical tumor specimens include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques, with the latter considered by some to be more accurate. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody which targets an epitope in the extracellular domain of the HER2 protein. Preclinical models demonstrated that this antibody has significant anti-tumor activity as a single agent and has synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancer that overexpress HER2 have shown that trastuzumab has clinical activity when used as first-, second- or third-line monotherapy, and improves survival when used as first-line therapy in combination with chemotherapy. Newer combinations with numerous chemotherapeutic drugs have also shown significant clinical activity in phase II studies. In all of these trials, trastuzumab was generally well-tolerated, but cardiac toxicity (particularly when the antibody was combined with anthracyclines) was an unexpected adverse effect. Although trastuzumab is currently usually administered on a weekly intravenous schedule, evidence suggests that a triple dose of the drug given once every three weeks has a pharmacokinetic profile expected to be equally efficacious. Neither the optimal schedule nor the optimal duration of trastuzumab therapy has yet been clearly defined in controlled clinical trials. Current clinical investigations of trastuzumab include its use in both the adjuvant and neoadjuvant settings as well as in combination with other chemotherapy drugs or new biologic targeted agents.     

Clinical pharmacology of trastuzumab

Trastuzumab is a monoclonal antibody that targets the extracellular domain of HER2, a member of the epidermal growth factor receptor (EGFR) family. Trastuzumab is currently approved for the treatment of breast cancer overexpressing HER2, given alone or in combination with paclitaxel or docetaxel. Trastuzumab pharmacokinetics are characterized by a low systemic clearance, a low volume of distribution (4l) and a very long half-life (28 days) comparable to that of endogenous immunoglobulins G. The elimination pathways are not yet defined and the clinical relevance of trastuzumab kinetic variability is unknown. Whether exposure might correlate with toxic effects or inadequate response has not been explored. No drug-drug interactions have been reported. This is not surprising because based on the current knowledge, no monoclonal antibody (including trastuzumab) has been found to interact with major molecular pharmacokinetic determinants such enzymes, drug transporters or orphan nuclear receptors. Dosage regimens of trastuzumab are similar either it is used in the adjuvant setting (postoperative) or in metastatic disease. According to the official labelling, trastuzumab is given by intravenous perfusion at a dose based on body weight, weekly (metastatic, adjuvant) or 3-weekly (adjuvant). The schedule also includes a loading dose at the initiation of the treatment. The recommended duration of treatment is currently one year (adjuvant) or until the progression of the disease (metastatic). Regarding the adjuvant setting, different dosage regimens have been tested (from 9 weeks to 2 years) but the optimal duration of treatment is unknown. The short course of trastuzumab (9 weeks) appears promising in terms of activity, tolerance and cost but should be compared to 1 or 2-years treatments. In addition, dosing regimens might be optimized by integrating pharmacokinetic elements. In the adjuvant setting, given the more favorable kinetic situation (absence of tumor penetration), a less intense dosage regimen might be appropriate when compared with that used in metastatic disease. Further body weight is weakly related to trastuzumab exposure and it is not proven that it significantly affects clinical activity. These pharmacokinetic considerations may support the use of fixed doses given monthly, on short periods, for the treatment of early breast cancer.     

Cardiac dysfunction associated with trastuzumab

The HER2/neu gene is amplified in approximately 25% of breast cancers, leading to HER2 protein overexpression and shortened overall survival and time to relapse. Trastuzumab is a humanised, monoclonal antibody against HER2, which improves survival for women with metastatic HER2-overexpressing breast cancer and reduces the risk of recurrence in women with early stage HER2-overexpressing breast cancer. Cardiac toxicity was an unexpected finding in the pivotal Phase III trial leading to the approval of trastuzumab, and prospective cardiac monitoring has, therefore, been incorporated into more recent clinical trials of trastuzumab. This article reviews the cardiac toxicity findings in key trastuzumab clinical trials and clinical characteristics of trastuzumab-associated cardiac toxicity.     

Cardiac dysfunction associated with trastuzumab

The HER2/neu gene is amplified in ～ 25% of breast cancers, leading to HER2 protein overexpression and shortened overall survival and time to relapse. Trastuzumab is a humanised, monoclonal antibody against HER2, which improves survival for women with metastatic HER2-overexpressing breast cancer and reduces the risk of recurrence in women with early stage HER2-overexpressing breast cancer. Cardiac toxicity was an unexpected finding in the pivotal Phase III trial leading to the approval of trastuzumab, and prospective cardiac monitoring has, therefore, been incorporated into more recent clinical trials of trastuzumab. This article reviews the cardiac toxicity findings in key trastuzumab clinical trials and clinical characteristics of trastuzumab-associated cardiac toxicity.