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Abstract

Breast cancer is a heterogenous disease with several clinical and biologic subtypes. Human epidermal growth factor receptor 2 (HER 2) is overexpressed in approximately 20% of breast cancers. This overexpression is usually due to HER 2 gene amplification, and results in a more aggressive tumor with a worse prognosis. Trastuzumab (Herceptin®) is the first humanized monoclonal antibody to be commercially available for the treatment of breast cancer and it is directed against HER 2. Trials have demonstrated trastuzumab's activity in metastatic breast cancer both as a single agent and in combination with a number of chemotherapy agents. Recently, benefits for trastuzumab have also been shown in the neoadjuvant and adjuvant setting.

Keywords

breast cancer human epidermal growth factor receptor 2 monoclonal antibody trastuzumab

Breast cancer is the most common malignancy among women in the USA and Europe. Despite advances in the diagnosis and treatment of this disease, breast cancer remains incurable once metastatic spread has occurred. Human epidermal growth factor receptor 2 (HER 2, c-erbB-2) is a member of the transmembrane erbB epidermal growth factor receptor tyrosine kinase family. It is overexpressed in approximately 20–30% of breast cancers [1,2]. A number of studies have shown that overexpression of HER 2 in breast cancer is associated with an adverse prognosis including higher relapse and mortality rates [3 –5]. Trastuzumab (Herceptin®) is a humanized monoclonal antibody targeted to the extracellular domain of HER 2. In vitro studies have demonstrated growth inhibition of human tumor cells with trastuzumab and subsequent in vivo data confirmed its efficacy in animal xenografts overexpressing HER 2 [6 –9]. This has led to its clinical development in Phase I, II and III trials, which are reviewed below.

Pharmacodynamics

Trastuzumab has been shown to inhibit HER 2-overexpressing breast tumor cells both in vivo and in vitro, but the exact mechanism of its action has yet to be fully elucidated. Acceleration of degradation of the HER 2 receptor, induction of antibody-dependent cellular cytotoxicity, inhibition of HER 2 cleavage mediated by metalloproteases and interaction with other signaling pathways have all been suggested as possible mechanisms for its anticancer effects in vivo and in vitro [6 –8,10]. However, human pharmacodynamic end points are currently under evaluation, particularly in neoadjuvant and adjuvant studies.

Pharmacokinetics

Trastuzumab is not orally bioavailable. It follows a dose-dependent nonlinear pharmacokinetic profile [Roche, data on file]. The metabolism of trastuzumab is not fully understood but it is thought that elimination of the drug may involve clearance of immunogloulin (Ig) G through the reticuloendothelial system. There are no active or inactive metabolites. Its half-life increases and clearance decreases with increasing dose. The half-life of trastuzumab was initially reported as 5–7 days based on sparse Phase I data and a one-compartment pharmacokinetic model. From this, the current registered schedule of 4 mg/kg loading dose intravenously and then 2 mg/kg intravenously weekly thereafter was instigated [11,12]. However, analysis of further pharmacokinetic data for weekly trastuzumab indicated that its half-life was 28.5 ± 5.0 days, which supported less frequent dosing [13]. Indeed, 3-weekly trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) has been administered successfully as a monotherapy and in combination with paclitaxel in patients with HER 2-positive metastatic breast cancer with favorable response rates and no new or unexpected toxicity [14].

Techniques for HER 2 testing

HER 2 testing of breast cancer has implications not only for its prognostic value, but also with regard to the clinical benefit achieved with trastuzumab. HER 2 status needs to be determined by an accurate and validated assay. The most widely used and established methods for HER 2 testing are immunohistochemistry (IHC), which demonstrates overexpression of cell surface protein, and fluorescence in situ hybridization (FISH) [15]. IHC is relatively inexpensive, widely available and highly sensitive and specific. It involves staining paraffin-embedded tumor tissue with an antibody specific for HER 2, with staining graded on a semi-quantitative scale from 0 (no expression) to 3+ (high-level overexpression). This technique lacks full objectivity in view of its semiquantitative and subjective score interpretation. FISH analysis detects the amount of HER 2 gene amplification and, while it is costly, has been shown to be more sensitive and specific than IHC [16]. HER 2-positive tumors likely to respond to trastuzumab are those that are IHC 3+ and/or FISH positive. There have been reports of poor concordance between HER 2 findings of local and central laboratories, suggesting that HER 2 testing should only be performed by experienced laboratories, thereby yielding more consistent results.

Clinical efficacy

Trastuzumab in the metastatic setting

Single-agent trastuzumab

The first Phase II monotherapy study of trastuzumab in metastatic breast cancer explored its efficacy and safety in 222 women with HER 2-positive metastatic breast cancer (IHC 2+ or 3+) whose cancer had progressed after one or two chemotherapy regimens [11]. Trastuzumab was given at a loading dose of 4 mg/kg then at 2 mg/kg at weekly intervals. The primary end point was objective tumor response. In the intention-to-treat population there were eight (4%) complete responders and 26 (11%) partial responders, resulting in an objective response rate of 15%. The median duration of response was 9.1 months (range: 1.6–26 months). Adverse events were uncommon, usually occurring during the first infusion of trastuzumab and included fever, chills and dyspnea. Unexpectedly, the clinically most significant adverse effect was cardiac dysfunction in ten (4.7%) patients. A total of nine of these patients had received prior anthracycline treatment. This very important early trial demonstrated proof of principle that single-agent trastuzumab was clinically active against HER 2 metastatic breast cancer and had a good toxicity profile. A subsequent study explored the use of first-line single-agent weekly trastuzumab in 114 women with HER 2 (IHC 2+ and 3+) metastatic breast cancer, before chemotherapy [43]. Two dose levels of trastuzumab were compared. In the intent-to-treat population the objective response rate was 26% with seven (6%) complete responders and 23 (20%) partial responders. In addition, 13 women had a minor response or stable disease for more than 6 months, giving a clinical benefit rate of 38%. Again, treatment-related adverse effects were uncommon and similar to the previous Phase II study described. A retrospective review indicated that nearly all the responses were seen in HER 2 IHC 3+ tumors. A more recent Phase II study by Baselga and colleagues assessed the efficacy and safety of single-agent trastuzumab once every 3 weeks in 105 women with previously untreated HER 2-positive metastatic breast cancer (IHC 3+ or FISH positive). The objective response rate in the intention-to-treat group was 19% (Table 1) [17].

Table 1.

Single-agent trastuzumab.

Phase	Number of patients	Overall response rate (%)	Clinical response (%)	Partial response (%)	TTP (months)	Ref.
II	222	15	4	11	3.1	[11]
II	114	26	6	20	3.5 (4 mg/kg) 3.8 (2 mg/kg)	[12]
II	105	19	2	17	3.4	[15]

TTP: Time to tumor progresson.

Trastuzumab in combination with chemotherapy

Preclinical in vitro data suggested additive and synergistic effects between trastuzumab and certain chemotherapy agents (including vinorelbine, docetaxel, paclitaxel, carboplatin, doxorubicin and epirubicin) in HER 2-overexpressing breast cancer cell lines [19]. The safety and efficacy of trastuzumab combined with chemotherapy were therefore evaluated in a pivotal Phase III randomized, controlled trial [12]. A total of 469 patients with HER 2-positive metastatic breast cancer who had not received chemotherapy for metastatic disease were assigned to receive either doxorubicin (AC), epirubicin and cyclophosphamide (EC) or paclitaxel (if they had already received adjuvant anthracyclines), with or without trastuzumab. Primary end points were time to disease progression and the incidence of adverse effects. Secondary end points were duration and rate of responses, time to treatment failure and overall survival. The addition of trastuzumab to chemotherapy was associated with a longer time to progression (7.4 vs 4.6 months; p < 0.001) and a significantly improved survival (25.1 vs 20.3 months; p = 0.046). The size of survival benefit is unusual in therapeutic metastatic breast cancer trials and occurred despite the fact that around 70% of women treated with chemotherapy alone went on to be treated with open-label trastuzumab when their disease progressed. Approximately 25% of patients had mild-to-moderate infusion-related reactions, usually with the first course only. The incidence of sepsis was low with no significant difference between the subgroups. Unexpectedly, 18 patients (8%) developed clinical signs of cardiac dysfunction and 15 of these were in the anthracycline-based combination. This prompted a retrospective analysis of all cases of cardiac dysfunction by an independent Cardiac Review and Evaluation Committee (CREC).

A similarly designed randomized Phase II international trial compared docetaxel alone or in combination with trastuzumab in 188 patients with previously untreated metastatic HER 2-positive breast cancer [18]. The objective response rate was 61% in the combination arm compared with 34% in the group treated with docetaxel alone (p = 0.0002). Median time to progression was 11.7 months in the combination arm and 6.1 months in the doctaxel arm (p = 0.0001). Overall survival was again significantly better in the combination arm than in the doctaxel group (31.2 vs 22.7 months; p = 0.0325).

Further to preclinical studies [8], a number of other chemotherapy agents have been combined with trastuzumab in smaller studies to establish efficacy in the metastatic breast cancer setting (Table 2) [19]. These include vinorelbine [19 –22], gemcitabine [23,24], capecitabine [25] and liposomal doxorubicin [26]. Certainly, a number of these Phase II studies suggest positive efficacy and safety results, which may well provide further treatment options for women with metastatic HER 2-positive breast cancer. Trastuzumab has also been investigated as part of triple combinations with chemotherapy, including in particular docetaxel and carboplatin or cisplatin, a combination that is now being investigated as an adjuvant therapy [27].

Table 2.

Trastuzumab in combination with chemotherapy.

Chemotherapy used	Number of patients	ORR (%) (ITT)	Ref.
Vinorelbine	40	75	[20]
Vinorelbine	54	68	[21]
Vinorelbine	40	78	[22]
Gemcitabine	61	38	[23]
Gemcitabine	28	36	[24]
Capecitabine	16	50	[25]
Liposomal doxorubicin	34	59	[26]

ITT: Interntion-to-treat; ORR: Objective response rate.

Trastuzumab in the neoadjuvant setting

Preoperative/neoadjuvant systemic therapy is an established therapeutic strategy in women with both large operable and locally advanced breast cancer. It provides an in vivo assessment of tumor response to the particular drug regimen [28] and also increases the rate of breast conserving surgery by downstaging the primary tumor [29]. Primary systemic therapy is as effective as adjuvant chemotherapy in terms of both disease-free survival and overall survival, so no risk is posed by ‘postponing’ surgery [29,30]. Randomized studies with a number of different chemotherapy agents have consistently demonstrated high rates of clinical response with complete pathologic response rates varying between 10 and 33% [29]. Complete pathologic response (pCR) independently predicts for survival outcomes and translates into long-term clinical benefit. Women with objective tumor response to primary chemotherapy have better long-term outcomes compared with nonresponders [29,31,32].

Trastuzumab before surgery, including singleagent use, has been investigated in a number of Phase II trials. Burstein and colleagues investigated the use of neoadjuvant trastuzumab (4 mg/kg once, then 2 mg/kg weekly for 11 weeks) and paclitaxel (175 mg every 3 weeks in four cycles), followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in 40 women with HER 2-positive Stage II and III breast cancer [33]. Clinical response (CR) was achieved in 30 (75%) patients. A pCR was observed in seven (18%) patients. The clinical response rate in women with HER 2 IHC 2+ tumors was lower than in those with an overexpression at the IHC 3+ level (CR of 38 and 84%, respectively; p = 0.01). The median follow-up was 25 months with seven patients developing distant metastases. There were no recurrences in those with complete pathologic response. Of the ten patients without clinical response to neoadjuvant therapy, four developed recurrent disease. A further three responding patients also developed a recurrence. Toxicities reflected the known side effects of the respective treatments. Reversible asymptomatic decrease in left ventricular ejection fraction was noted in four patients.

Coudert and colleagues investigated the use of neoadjuvant trastuzumab (4 mg/kg once, then 2 mg/kg weekly) with docetaxel (100 mg/m² every 3 weeks in six cycles) in 33 patients with HER 2-positive locally advanced breast cancer [34]. A total of 30 were assessable for response. Complete clinical response (cCR) was observed in 73% of patients. A total of 47% (12 out of 30 assessable patients) had a pCR. Side effects were principally those known side effects of docetaxel treatment. A number of Phase II studies have evaluated trastuzumab in the neoadjuvant setting with non-anthracycline containing therapies (in particular vinorelbine), with pCR rates of 19–26% [35 –38].

More recently, researchers at the MD Anderson Cancer Center, USA, have published a prospective randomized Phase III study. Budzar and colleagues investigated whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase the pCR rate in patients with HER 2-positive Stage II or III disease [39]. A total of 42 patients were assigned to receive either four cycles of paclitaxel (225 mg/m² every 3 weeks) followed by four cycles of FEC (500 mg/m² fluorouracil i.v. on days 1 and 4, 500 mg/m² cyclophosphamide i.v. on day 1, epirubicin 75 mg/m² on day 1), or to receive the same chemotherapy with concurrent trastuzumab (4 mg/kg on day 1, then 2 mg/kg weekly) for 24 weeks. The planned sample size was 164 patients with a primary objective to demonstrate a 20% improvement in pCR with the addition of trastuzumab to chemotherapy. All tumors were HER 2-positive by FISH or HER 2 3+ by IHC. Adding trastuzumab to chemotherapy demonstrated a higher than anticipated pCR rate; of 42 randomized patients, a pCR was achieved in 26% of patients treated with chemotherapy, compared with 65% of patients treated with trastuzumab and chemotherapy (p = 0.016). The Data Monitoring Committee therefore suggested that the trial should be closed. Patient accrual into the experimental arm continues in order to obtain additional efficacy and safety data in larger numbers of patients. Treatment in both arms was generally well tolerated. However, 21 patients in the trastuzumab plus chemotherapy arm experienced grade 4 neutropenia compared with 11 patients in the chemotherapy arm. No clinical congestive cardiac failure was observed in this study. A small number of patients did show a transient drop in ejection fraction (five patients in the chemotherapy-alone arm, seven patients in the trastuzumab and chemotherapy arm). Left ventricular ejection fractions returned to baseline values on follow-up evaluation. Limitations of this study include its small size and the lack of long-term data on safety. It also does not address whether long-term disease end points are improved by the addition of trastuzumab.

The results of these Phase II and III studies suggest improved clinical efficacy and add to the growing literature demonstrating that HER 2-positive tumors benefit significantly from trastuzumab-based therapy. A number of Phase III trials are currently underway around the world, and will further define the role of trastuzumab in the pre-operative treatment of early breast cancer.

Trastuzumab in the adjuvant setting

Very recently, data were presented at the 2005 American Society of Clinical Oncology (ASCO) meeting showing a dramatic benefit for adjuvant trastuzumab.

Pooled results from two American trials, National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 and North Central Cancer Treatment Group (NCCTG) 9831, involving 3351 patients with HER2-overexpressing early breast cancer and nearly all with node-positive disease, showed that weekly trastuzumab, started with paclitaxel 3 weekly for four courses (B31) or weekly for 12 weeks (NCCTG 9831), after four courses of 3 weekly adriamycin and cyclophosphamide (AC) in standard dosage and continued for 1 year, greatly improved disease-free survival compared with the same chemotherapy alone [40]. The hazard ratio in favor of trastuzumab was 0.48 with the predicted 4-year disease-free survival 85 and 67%, respectively (2p = 3×10⁻¹²). The gain was independent of age and hormone receptor status. Despite the relatively short follow-up, a significant overall survival difference was also found with a hazard ratio of 0.67 and predicted 4-year overall survival difference of 91 versus 87% (2p = 0.015). The 3-year cumulative incidence of cardiac events was, however, higher with trastuzumab (4%) than in the control group (0.6%), although there were no cardiac deaths in the trastuzumab arm.

In a second worldwide trial, the HERception Adjuvant trial (HERA), which excluded the USA, 5090 patients with centrally confirmed HER 2 overexpression, more than 30% of whom had node-negative disease, were randomized to trastuzumab three-times weekly for 1 year or for 2 years versus no treatment, after at least four courses of standard adjuvant chemotherapy [41]. In the first analysis, comparing only 1 year with no further treatment, and with a median follow-up of only 12 months, trastuzumab again showed a very large disease-free survival benefit over control, with a hazard ratio of 0.54 and a predicted 2-year disease-free survival of 86 and 77%, respectively (p < 0.00001). The benefit was independent of age, nodal and hormone receptor status and type of chemotherapy used (only a minority of patients did not receive an anthracycline). A significant, but asymptomatic, decrease in left ventricular ejection fraction was seen in patients on trastuzumab compared with control (7.1 vs 2.2%). The clinical significance of these findings is unclear. Symptomatic cardiac failure (0.5 vs 0.06%) was slightly increased with trastuzumab, but there were no cardiac deaths in the treatment arm. It is important to remember that these data are only for the 1-year arm. The cardiac effects of the additional year of trastuzumab are currently awaited.

Results from a fourth trial run by the Breast Cancer International Research Group (BCIRG) are likely to be available around December 2005. This trial has a novel feature in that one arm involves the use of trastuzumab up front in combination with docetaxel and carboplatin, excluding anthracycline completely, and is based on in vitro synergy data. Data has already been presented at ASCO in May 2005, suggesting that an increase in cardiotoxicity is not observed in this arm of the study.

The results of these trials represent probably one of the biggest gains ever seen in breast cancer trials and strongly support the use of adjuvant trastuzumab in patients with HER 2-positive breast cancer. Important issues remain, however, including optimal duration, concurrent or sequential use with chemotherapy and optimal chemotherapy schedule to maximize gain and minimize the risk of cardiotoxicity. The long-term cardiac effects are not known, although the data from the joint US study do not suggest that the cardiac event rate continues at the same rate once a patient has been off trastuzumab therapy for a few months.

Postmarketing surveillance of trastuzumab

Infusion reactions

Severe hypersensitivity reactions have been reported, usually with the initial infusion; however, the onset and clinical course can be variable. These are rare, however, in contrast to moderate short-term reactions that are often seen with the first course of treatment. The reported incidence of infusion-related events overall was 0.3% (74 out of 25,000 patients) in one postmarketing surveillance study.

Exacerbation of chemotherapy-induced neutropenia

In randomized, controlled clinical trials there was an increased incidence of anemia, leucopenia and febrile neutropenia in patients receiving the combination of chemotherapy and trastuzumab compared with chemotherapy alone [12,18]. Deaths due to neutropenic sepsis have been reported in patients receiving trastuzumab and systemic chemotherapy. However, in controlled trials, the incidence of deaths due to neutropenic sepsis did not show a significant increase. Ongoing randomized, controlled trials will further clarify this issue.

Pulmonary events

Severe pulmonary toxicity has been reported that may or may not be associated with infusion reactions. Patients with extensive pulmonary metastatic involvement or symptomatic co-existing lung disease are at greater risk.

Safety & tolerability of trastuzumab

Preclinical toxicology studies of trastuzumab assessed single and multiple dosing schedules of up to 6 months duration using weekly intravenous administration in animals [Roche, data on file]. No significant toxicities, including cardiac dysfunction, were detected at this stage. In Phase II/III studies, weekly intravenous trastuzumab was also well tolerated, but cardiac dysfunction was an unexpected adverse effect [42]. Of the women treated with trastuzumab monotherapy, 3–7% developed cardiac dysfunction [11,43]. In the pivotal Phase III trial combining trastuzumab with chemotherapy, the incidence of any cardiac dysfunction was 27% in the patients given trastuzumab, anthracycline and cyclophosphamide; 8% for those given anthracycline and cyclophosphamide alone; 13% for patients given trastuzumab and paclitaxel (most of whom had received previous anthracyclines) and 1% for those given paclitaxel alone [12]. As a result of these unexpected findings, an analysis of the trials was performed by CREC [44]. Of 1219 patients reviewed, 76% of those with cardiac dysfunction were symptomatic. A total of 79% of these patients improved with standard medical therapy for heart failure.

The mechanism of trastuzumab-induced cardiotoxicity is poorly understood but it is strongly associated with concurrent or prior anthracycline treatment. Results from ongoing randomized studies evaluating the use of trastuzumab in the adjuvant setting will help to clarify the underlying mechanisms and risk factors involved in the development of cardiotoxicity. The issue of continuing treatment with trastuzumab in patients who develop cardiotoxicity, when their disease is responding to therapy, will clearly require careful discussion and clinical judgement. Other common side effects encountered are mild-to-moderate infusion-related reactions in approximately 25% of patients, which tend to occur with the first infusion of trastuzumab and are easily manageable [12]. The large clinical trials of trastuzumab have shown it to be generally well tolerated.

Regulatory issues

Trastuzumab is licensed for the treatment of metastatic HER 2-positive breast cancer in the UK in the following settings:

In combination with docetaxel for the first-line treatment of patients who have not received chemotherapy for their metastatic disease

As a first-line treatment in combination with paclitaxel in patients who have received prior anthracyclines or for whom an anthracycline is not suitable^*

As a monotherapy in patients who have received prior treatment for their metastatic disease. Prior treatment must have included at least an anthracycline and a taxane, unless the patient is unsuitable for these treatments^*

^*The National Institute for Clinical Excellence recommendations for trastuzumab in advanced breast cancer. These guidelines are to be reviewed in April 2005.

Conclusion

Trastuzumab is a targeted biologic therapy, which has been extensively investigated and proven to be beneficial in the treatment of HER 2-positive metastatic breast cancer. In combination with chemotherapy it has been shown to prolong survival compared with chemotherapy alone [12]. The optimum combination has not yet been defined, but from a response and survival perspective the data are most compelling for combination with docetaxel. It is also active when used as a single agent, either first line or after progression through other treatments in the metastatic setting [11,43].

The optimal duration of trastuzumab in the treatment of metastatic breast cancer has not yet been established, but there are some anecdotal reports of patients with life-threatening disease, including liver metastases, who remain in remission after several years of trastuzumab treatment.

Importantly, trastuzumab is generally well tolerated with none of the typical adverse effects associated with standard cytotoxic agents. Cardiotoxicity emerged unexpectedly as an adverse effect in pivotal Phase II/III studies, with a higher incidence when trastuzumab was in combination with anthracycline therapy. The incidence of cardiac dysfunction has been much lower in further studies combining trastuzumab with other cytotoxic agents [18,20,22,27]. Ongoing trials will further evaluate this safety concern. At present many oncologists avoid concurrent use of trastuzumab and an anthracycline. Indeed, it is not licensed for use in this combination and cannot be recommended outside of a clinical trial. Baseline assessment of cardiac function should be documented prior to commencing trastuzumab therapy, and patients with pre-existing cardiac dysfunction should be monitored carefully if embarking on treatment with trastuzumab. In the adjuvant setting, early results show that trastuzumab will soon be incorporated into standard chemotherapy protocols, but the exact combination, sequence and potential for cardiac toxicity requires further investigation through ongoing randomized, controlled studies. It is quite possible that the optimum adjuvant trastuzumab therapy will be a combination of trastuzumab, carboplatin and docetaxel, based on the BCIRG trial and to minimize the risk of cardiotoxicity. Recent Phase II trials of trastuzumab in the neoadjuvant setting are yielding promising data, which will be further enhanced by results from randomized Phase III studies currently accruing around the world. Preclinical and clinical work indicates that tumors with HER 2 overexpression may be relatively resistant to endocrine treatment, particularly tamoxifen [45,46]. However, there is some evidence that HER 2-positive tumors may respond better to aromatase inhibitors than to tamoxifen [47].

Future perspective

The emergence of trastuzumab has been an important milestone in the treatment of breast cancer. It has demonstrated proof of principle for so-called targeted therapy with the development of a monoclonal antibody against the HER 2 growth factor receptor, the overexpression of which is known to be associated with a more aggressive form of breast cancer growth and progression.

Its role is already firmly established in metastatic disease, and early results indicate that it will also very soon have an established role in adjuvant therapy for early breast cancer. Within the next year or two, formal HER 2 testing will become a mandatory part of breast cancer staging, and all women with HER 2 overexpressing metastatic breast cancer should be considered for treatment with trastuzumab at some time in their metastatic journey.

Unanswered questions in the adjuvant setting remain to be solved, including optimal duration of trastuzumab therapy, optimal choice of chemotherapy to maximize benefit and minimize the risk of cardiotoxicty, and sequencing in relation to chemotherapy. It also remains to be seen whether older women who would otherwise simply be treated with adjuvant endocrine therapy would also benefit from the addition of trastuzumab.

Finally, the proof of principle established with trastuzumab is already leading to the investigation of other novel therapies targeted against the HER family of receptors, tyrosine kinases and other downstream modulators of signal transduction pathways. It is likely that trastuzumab will be the first of a new generation of similar targeted agents.

Executive summary

Mechanisms of action

Trastuzumab is a humanized monoclonal antibody targeted to the extracellular domain of the transmembrane growth factor receptor HER 2. HER 2 is overexpressed in approximately 20–30% of breast cancers resulting in a more aggressive form of the disease.

In vitro studies have demonstrated growth inhibition of human tumor cells and subsequent in vivo data have confirmed the efficacy of trastuzumab in animal xenograft models overexpressing HER 2.

The exact mechanism of action of trastuzumab remains under investigation.

Pharmacokinetics

Trastuzumab is given intravenously.

Its half-life is 28 ± 5 days and the current registered dosing schedule is 4 mg/kg loading dose then 2 mg/kg weekly thereafter. However, recent studies and the long half-life support three-times weekly dosing.

Clinical efficacy

Single agent trastuzumab has been shown to be clinically active against HER 2 metastatic breast cancer, both as a first-line and subsequent treatment.

In combination with chemotherapy it has been shown to improve response rate and prolong survival in metastatic disease, compared with chemotherapy alone.

Trastuzumab improves the efficacy of chemotherapy in neoadjuvant therapy before surgery.

Very recently, trials have shown a dramatic improvement in disease-free survival with tratuzumab as adjuvant therapy for early breast cancer when given concurrently with, or sequentially after, chemotherapy.

Safety & tolerability

Trastuzumab is a generally well-tolerated drug with minimal side effects in most patients.

Infusion-related reactions, including fever and chills, occur in a minority of patients, but usually only with the first dose. If severe, these can be managed with standard medical intervention.

Concurrent use of anthracyclines and trastuzumab unexpectedly showed a significant incidence of clinical and subclinical cardiotoxicity (up to 27% in a pivotal Phase III trial) and subsequent data have confirmed an increased incidence with or after anthracyclines.

Clinical benefit far outweighs the risk of cardiotoxicity, but the use of trastuzumab concurrently with an anthracycline should be avoided. Baseline assessment of cardiac function should be documented prior to commencing trastuzumab therapy and patients with pre-existing cardiac dysfunction should be monitored carefully.

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