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Management of women at high breast cancer risk by carriage of a high-risk breast cancer predisposition gene mutation



Herceptin is a new form of drug therapy that utilises monoclonal antibody technology. The proper name of this drug is trastuzumab and Herceptin is the trade name. It works at the level of a growth factor receptor called HER-2. HER-2 stands for the Human Epidermal Growth Factor Receptor and is the second member of a family of four receptor types. Only about 20% of breast cancers carry this receptor. Expression of the HER-2 is associated with a more aggressive breast cancer type that carries a worse prognosis. Breast cancers that express HER-2 carry too many copies of a gene called HER-2 neu. This controls how cells grow, divide and repair themselves.

Herceptin is a drug that illustrates the concept of magic bullet technology. It is a chemical that binds directly to the HER-2 receptor and thereby inhibits breast cancer growth and proliferation.

Established clinical applications of Herceptin in advanced breast cancer

Herceptin has been used in patients with locally advanced or metastatic breast cancer whose tumours express the HER-2 receptor. In advanced breast cancer, Herceptin is usually used in combination with chemotherapy. The role of Herceptin in treating advanced and metastatic breast cancer is established. An important multicentre randomized trial reported a comparison of patients receiving six cycles of docetaxel with or without Herceptin. The women receiving Herceptin compared to those who did not had a superior median overall response rate (61% vs 34%), overall survival (31.2 vs 22.7 months) and time to treatment failure (9.8 vs 5.3 months).1

Clinical application of Herceptin in early breast cancer

An important challenge in the treatment of women with early breast cancer is whether Herceptin can improve overall survival and disease free survival. Two major clinical trials reported a positive benefit of Herceptin in treating women with early breast cancer that express HER-2.

In the first international clinical trial of Herceptin involving more than 5000 women with HER-2 positive breast cancer used in addition to standard adjuvant treatment, patients were assigned to one of three groups. In combination with chemotherapy, patients were given Herceptin for either one year (n=1694), two years (n=1694) or no Herceptin treatment (n=1693). Patients who received Herceptin received this drug intravenously every 3 weeks. The results of women who require two years of Herceptin are not yet available but the preliminary results of women treated for one year with Herceptin showed that the drug reduced the relapse risk of cancer recurrence by approximately 50% (hazard ratio 0.54, 95% confidence interval 0.43-0.67). In this study, 220 women in the control group developed a breast cancer event or died compared to 127 women who took Herceptin for one year.2

Herceptin in the neo-adjuvant setting

Another important application of Herceptin is whether it has a role to be used as part of primary therapy in addition to chemotherapy in patients with early breast cancer but with the intent of making the tumour smaller to facilitate less surgery. This may enable, for example, facilitating wide local excision of the tumour rather than a mastectomy. The use of medical therapy in this way before surgery for early breast cancer is termed neoadjuvant therapy. A trial has been published that evaluated 42 women with HER-2 positive operable breast cancer and compared Herceptin plus four cycles of Paclitaxel followed by four cycles of anthracycline based chemotherapy versus chemotherapy alone without Herceptin.3 The pathology complete response rate was 66.8% in the Herceptin and chemotherapy versus25% in the chemotherapy alone group. As a result of these very encouraging results, the trial was abrogated early at 34 patients because of the benefit observed. The role of Herceptin in the neoadjuvant setting requires to be investigated further in clinical trials.

Probable adverse effects

Herceptin appears to be well tolerated. There have been concerns regarding a cardiotoxic effect of Herceptin that may be aggravated by concomitant anthracycline chemotherapy use but the risks appear to be low. Bone marrow suppression and neutropaenic related infections are also higher in women receiving simultaneous chemotherapy.

The future

There is strong evidence that Herceptin improves treatment outcome in early breast cancer and the response rate in advanced breast cancer. In the UK, the license for Herceptin currently only covers metastatic breast cancer. A decision is soon to be made from recommendations to be issued by the National Institute of Clinical Excellence on the use of Herceptin as adjuvant treatment in early breast cancer. We await developments on the neoadjuvant use of Herceptin with interest.


Marty M, Cognetti F, Maraninchi D, et al. Randomised phase II trial of the efficacy and safety of trastuzumab combined with Docetaxel in patients with human epidermal growth factor receptor 2-postiive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005; 23: 4265-74

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2 positive breast cancer. New Engl J Med 2005; 353:1659-72.

Buzdar AU. Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rates after neoadjuvant therapy with trastuzumab, paclitaxel and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005; 23; 3676-85

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