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.

Researchers 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.

Researchers 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.

For more information
Balduzzi S., Mantarro S., Guarneri V., Tagliabue L., Pistotti V., Moja L., D'Amico R.- Trastuzumab containing regimens for metastatic breast cancer. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.:CD006242. DOI: 10.1002/14651858.CD006242.pub2.

MDN