Background

Patients with metastatic breast cancer have a poor prognosis, with a median survival of 0.5-2.5 years.3 At this stage, drugs are the mainstay of treatment, while radiotherapy and surgery may be useful for palliation when the metastases are symptomatic and localised. Patients whose tumours express receptors for oestrogen and/or progesterone are usually offered an anti-oestrogen (e.g. tamoxifen) or, if the patient is premenopausal, a gonadorelin analogue (e.g. goserelin) or oophorectomy. Patients with metastatic tumours that are not hormone-responsive, nor in bone, usually receive cytotoxic chemotherapy. Treatment usually includes an anthracycline (e.g. doxorubicin) but the optimal chemotherapy regimen is not known. Factors that influence the choice of cytotoxic drug(s) include previous chemotherapy for primary and/or metastatic disease, the rate of disease progression, any co-existing medical conditions and unwanted effects of the drugs.

HER2 and trastuzumab

The level of expression of HER2 in breast cancer cells can be determined using immunohistochemical analysis of tumour sections (a score of 2+ or 3+ indicates overexpression) or fluorescent in-situ hybridisation (FISH). Cancers that overexpress HER2 are particularly aggressive, and affected patients have a shorter disease-free, and overall, survival than those with other breast cancers.1 In vitro and in vivo, trastuzumab inhibits proliferation of breast cancer cells that overexpress HER2.4

Trastuzumab is licensed only for use in patients with metastatic breast cancer with high HER2 overexpression (3+, as measured by immunohistochemistry). It is given as a 4mg/kg body weight loading dose followed after 1 week by 2mg/kg weekly until disease progression.

Clinical studies

Combination therapy

In an unblinded randomised controlled trial, 469 women with metastatic breast cancer (with 2+ or 3+ HER2 overexpression) who had not previously received chemotherapy for metastatic disease, received standard chemotherapy (6 courses at 3-weekly intervals), either alone or with trastuzumab (median of 36 doses).5 Patients who had not previously received an anthracycline (as an adjuvant to surgery for early disease) were treated with doxorubicin (or epirubicin) plus cyclophosphamide, either alone (138 women) or with trastuzumab (143 women). Patients who had previously received an anthracycline were treated with paclitaxel, either alone (96 women) or with trastuzumab (92 women).

Compared to patients who received standard chemotherapy alone, patients who received trastuzumab in addition had a longer median time to disease progression (the primary endpoint: 7.4 months vs. 4.6 months; p<.001), whatever chemotherapy they received (i.e. with an anthracycline + cyclophosphamide: 7.8 months vs. 6.1 months; with paclitaxel 6.9 vs. 3 months). They also had a higher objective response rate (50% vs. 32% with chemotherapy alone; p<.001), and a longer median survival (25.1 months vs. 20.3 months; p=0.046). However, there was no significant prolongation of median survival by the addition of trastuzumab in the two chemotherapy subgroups. Two-thirds of the patients who showed disease progression during the trial took up the option of receiving non-randomised, unblinded trastuzumab with or without other systemic therapy. Since their results were still included in the overall efficacy analysis, this reduced the chances of detecting any difference in overall survival between the two groups. The report concludes that the patients with 3+ HER2 overexpression benefited more from trastuzumab than did the patients with 2+ overexpression, but does not provide any supporting data. Among 400 of the women who completed at least one follow-up assessment, those who had received trastuzumab reported less fatigue compared with baseline after completing chemotherapy (at 32 weeks).6 Also, more of those who received trastuzumab reported improvement in health-related quality of life (i.e. at least a 10-point change in score on the EORTC QLQ-C30 questionnaire* at any time compared with baseline) (51% vs. 36% on chemotherapy alone).

* The 30-item European Organization for Research Treatment of Cancer Core Quality of Life Questionnaire.

Monotherapy

In one trial, 114 women with previously untreated HER2-overexpressing metastatic breast cancer (2+ or 3+) were randomised either to trastuzumab 4mg/kg as a loading dose followed by 2mg/kg weekly, or to an 8mg/kg loading dose followed by 4mg/kg weekly (i.e. trastuzumab monotherapy was used as first-line treatment).7 Response (shrinking or disappearance of the tumour - the primary endpoint) was assessed radiographically or visually by unblinded investigators. Overall, 26% of patients responded (95% CI 18.2%-34.4%) and median survival (a secondary outcome measure) was around 23-26 months, with no significant difference between the two regimens. In a retrospective analysis involving 111 assessable patients, the objective response rate in those with 3+ HER2 overexpression was 35%, but there was no objective response in those with 2+ overexpression.

In an uncontrolled trial, 222 women with HER2-overexpressing metastatic breast cancer (mostly 3+) that had progressed despite one or two chemotherapy regimens were treated with trastuzumab (i.e. as second- or third-line treatment).8 The objective response rate was 15%, median time to disease progression 3.1 months and median survival 13 months.

Unwanted effects

General

Around 25-40% of patients develop infusion-related symptoms such as fever and chills during and shortly after the first infusion of trastuzumab.5^,8 These symptoms are usually mild or moderate, and they are unlikely to occur with subsequent trastuzumab treatment. Severe, potentially fatal infusion reactions (including hypotension, dyspnoea, wheezing, bronchospasm and angioedema) can occur during, or up to several hours after, trastuzumab administration. About a quarter of patients develop diarrhoea.9 At least 10% of patients experience effects including abdominal pain, weakness, chest pain, headache, nausea, vomiting, arthralgia, myalgia and rash.9 The summary of product characteristics (SPC) states that human anti-trastuzumab antibodies have been detected in 1 patient out of 304 treated with trastuzumab either as monotherapy or in combination with paclitaxel, and that the patient had no allergic manifestations.

Cardiac

Cardiac toxicity can occur with trastuzumab and is thought to result from a direct effect of the drug on cardiac HER2 receptors.10 Reduced left ventricular ejection fraction and symptomatic, potentially fatal, congestive heart failure have been reported in patients treated with trastuzumab, particularly in patients who received anthracycline-based chemotherapy concomitantly with, or prior to, trastuzumab therapy (even if there had been a long interval between the two treatments). In clinical trials, cardiac toxicity occurred in 27% of patients concomitantly receiving trastuzumab, an anthracycline and cyclophosphamide (compared with 8% with an anthracycline alone).11 The SPC advises against using trastuzumab in combination with an anthracycline outside "a well-controlled clinical trial setting with cardiac monitoring". In patients given trastuzumab alone or in combination with paclitaxel, the incidence of symptomatic heart failure has been estimated at around 8-9%, compared with about 4% for paclitaxel alone (in clinical trials, many patients receiving paclitaxel had previously received anthracycline therapy).9 Of patients developing cardiac dysfunction in trials, 75% were symptomatic and 79% improved with standard treatment for congestive heart failure.

Contraindications and precautions

Trastuzumab is contraindicated in patients with severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy. Such patients may be at an increased risk of a fatal infusion reaction. The drug is also contraindicated in patients with known hypersensitivity to mouse proteins. The SPC warns that women should not breast-feed during, and for 6 months after, the last dose of trastuzumab therapy.

The SPC recommends that, before starting trastuzumab, all patients should undergo baseline cardiac assessment (including an ECG and measurement of left ventricular function by echocardiogram or multigated blood pool imaging of the heart [MUGA scan]) and that a careful benefit-harm assessment be made before deciding to use trastuzumab. Cardiac function should be monitored every 3 months during treatment, or every 6-8 weeks if asymptomatic reduction in left ventricular function is detected. The SPC advises that a patient developing symptomatic heart failure should receive standard therapy for this, and that the physician should consider stopping trastuzumab if the harm outweighs the benefit.

Cost

For a patient weighing 75kg, the approximate drug cost for the licensed regimen of trastuzumab is £815 for the loading dose plus £407 per week (e.g. the total drug cost to the NHS for 36 weeks' treatment with trastuzumab would be around £15,000).

Conclusion

▼Trastuzumab is a monoclonal antibody available for the treatment of patients with metastatic breast cancer that greatly overexpresses human epidermal growth factor receptor 2 (HER2). We recommend it be used in combination with ▼paclitaxel as first-line treatment of such patients. Used in this way, trastuzumab delays the further progression of the disease by around an additional 3-4 months and improves health-related quality of life compared with paclitaxel alone. Whether it prolongs overall survival is not clear. The drug causes heart failure in around 10% of patients receiving the combined treatment.

The place of trastuzumab alone as third-line therapy for patients who have received at least two chemotherapy regimens is unclear. There is only one published, uncontrolled, trial of trastuzumab monotherapy in the treatment of patients with HER2-overexpressing advanced breast cancer that is resistant or refractory to chemotherapy regimens. On the basis of this evidence, NICE has recommended the use of trastuzumab monotherapy as an option. Before we can recommend this, we would wish to see evidence of the advantages from randomised controlled trials.