Efficacy and safety of trastuzumab in metastatic breast cancer

Tumours characterised by the presence of the HER2 protein are found in about one in five women with metastatic breast cancer. These tend to be more aggressive and the prognosis and choice of treatment are affected. Trastuzumab (Herceptin®) is a targeted biological drug (a monoclonal antibody) that attaches to the HER2 protein, blocking the growth of malignant cells.

We included seven trials with 1497 women who had HER2-positive metastatic breast cancer in this review. They were assigned by chance to receive trastuzumab with or without chemotherapy (taxane, anthracycline or capecitabine in four studies), hormonal therapy (aromatase inhibitors including letrozole or anastrozole in two studies) or targeted therapy (lapatinib in one study). Women treated with trastuzumab were followed up until disease progression in five studies and beyond disease progression in two studies. The length of trastuzumab administration varied between 8.7 and 30 months, and follow-up averaged two years after starting trastuzumab.

All studies found that trastuzumab extends time to disease progression, with gains varying between two and 11 months, and in five studies it extended time to death by between five and eight months. However, some patients develop severe heart toxicity (congestive heart failure) during treatment. While trastuzumab reduces breast cancer mortality by one-fifth, the risk of heart toxicity is between three and four times more likely. If 1000 women were given standard therapy alone (with no trastuzumab) about 300 would survive and 10 would have heart toxicities. With the addition of trastuzumab to this treatment, an additional 73 would have their lives prolonged, and an additional 25 would have severe heart toxicity. Omitting the anthracycline-trastuzumab arms (which would not be regarded as standard of care) 21 patients would have severe heart toxicity (11 more than the chemotherapy alone group). These heart toxicities are often reversible if the treatment is stopped once heart disease is discovered. Women with advanced disease might choose to accept this risk. On balance, this review shows that with trastuzumab the time to disease progression and survival benefits outweigh the risk of heart harm.

Trastuzumab does not increase the risk of haematological toxicities, such as neutropenic fever and anaemia; however, it seems to raise the risk of neutropenia. There were insufficient data on the impact of trastuzumab on quality of life, treatment-related deaths and brain metastases to reach a conclusion for these outcomes.

We rated the overall quality of the evidence as moderate, with the main weaknesses being the fact that all studies included were open-label (not blinded), which may have affected the outcome assessments for time to disease progression and toxicities, and that two studies have not published their results for mortality. Furthermore, the recruitment in three out of seven studies was stopped early and in three trials more than 50% of patients in the control groups were permitted to switch to the trastuzumab arms at disease progression, making it more difficult to understand the real net benefit of trastuzumab on mortality. The evidence to support the use of trastuzumab beyond disease progression is limited.

It is important to highlight that, although trastuzumab is used for women with HER2-positive early breast cancer, the women enrolled in these metastatic trials were not previously treated with trastuzumab. The effectiveness of trastuzumab for women relapsing after adjuvant trastuzumab is still an open issue, although it is likely that it is offered to the majority of them.

Authors' conclusions: 

Trastuzumab improved overall survival and progression-free survival in HER2-positive women with metastatic breast cancer, but it also increased the risk of cardiac toxicities, such as congestive heart failure and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab as first-line treatment, or along with a taxane-based regimen, improved mortality outcomes. The evidence to support the use of trastuzumab beyond progression is limited. The recruitment in three out of seven studies was stopped early and in three trials more than 50% of patients in the control groups were permitted to switch to the trastuzumab arms at progression, making it more difficult to understand the real net benefit of trastuzumab.

Trastuzumab is generally used for women with HER2-positive early breast cancer in clinical practice, while women enrolled in most of the trials in the metastatic setting were naive to trastuzumab. The effectiveness of trastuzumab for women relapsing after adjuvant trastuzumab is therefore still an open issue, although it is likely that the majority are being offered it again.

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Background: 

Patients with breast cancer are classified as having cells that over-express the human epidermal growth factor receptor 2 (known as HER2-positive) or not (HER2-negative). Typically, patients with HER2-positive disease have a worse prognosis. Trastuzumab is a selective treatment that targets the HER2 pathway. The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system.

Objectives: 

To assess the evidence on the efficacy and safety of therapy with trastuzumab (overall) and in relation to the type of co-administered regimen and the line of treatment, i.e. first-line or beyond progression, in women with HER2-positive metastatic breast cancer.

Search strategy: 

We searched the Cochrane Breast Cancer Group's (CBCG) Specialised Register and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL (2013, Issue 1), MEDLINE, EMBASE, BIOSIS, the WHO International Clinical Trials Registry Platform (ICTRP) search portal and ClinicalTrials.gov (up to 17 January 2013).

Selection criteria: 

RCTs comparing the efficacy and safety of trastuzumab alone or in combination with chemotherapy, hormonal therapy or targeted agents in women with HER2-positive metastatic breast cancer.

Data collection and analysis: 

We collected data from published trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included type of regimen (taxane-containing, anthracycline-containing, aromatase inhibitor-containing or other) and treatment line (first-line, beyond progression).

Main results: 

The review found seven trials, involving 1497 patients, which met the criteria to be included. The trials were generally of moderate methodological quality; two studies have not published their results on overall survival so the presence of selective outcome reporting bias cannot be ruled out. None of the studies used blinding to treatment allocation, though this is unlikely to have biased the results for overall survival. Studies varied in terms of co-administered regimen and in terms of treatment line. In four studies, trastuzumab was administered with a chemotherapy, such as a taxane-containing, anthracycline-containing or capecitabine-containing regimen. Two studies considered postmenopausal women and administered trastuzumab with hormone-blocking medications, such as an aromatase inhibitor. One study administered trastuzumab in addition to lapatinib. Five studies out of seven included women treated with trastuzumab administered until progression as first-line treatment and two studies considered trastuzumab beyond progression. The combined HRs for overall survival and progression-free survival favoured the trastuzumab-containing regimens (HR 0.82, 95% confidence interval (CI) 0.71 to 0.94, P = 0.004; and HR 0.61, 95% CI 0.54 to 0.70, P < 0.00001, respectively; moderate-quality evidence). Trastuzumab increased the risk of congestive heart failure (RR 3.49, 90% CI 1.88 to 6.47, P = 0.0009; moderate-quality evidence) and left ventricular ejection fraction (LVEF) decline (RR 2.65, 90% CI 1.48 to 4.74, P = 0.006). For haematological toxicities, such as neutropenic fever and anaemia, there was no clear evidence that risks differed between groups, while trastuzumab seemed to raise the risk of neutropenia. The overall survival improvement was maintained when considering patients treated as first-line or patients receiving taxane-based regimens. The progression-free survival improvement was maintained when considering patients receiving taxane-based regimens, and patients treated as first-line or subsequent lines. Few data were collected on central nervous system progression. Similarly, few studies reported on quality of life and treatment-related deaths.

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