Elsevier

The Lancet Oncology

Volume 3, Issue 3, March 2002, Pages 137-144
The Lancet Oncology

Review
Trastuzumab: hopes and realities

https://doi.org/10.1016/S1470-2045(02)00676-9Get rights and content

Summary

Despite improvements in care of patients with breast cancer, up to half develop refractory or resistant disease. There is therefore a need for new, modified anticancer therapies with greater effectiveness, tolerability to patients, and tumour specificity. Trastuzumab (Herceptin) is the first clinically available oncogene-targeted therapeutic agent for treatment of solid tumours. Clinical trials in patients positive for HER2 (human epidermal-growth-factor receptor 2) show that trastuzumab is effective and well tolerated; as a single-agent second-line or third-line treatment, the drug produced durable tumour responses. First-line trastuzumab in combination with chemotherapy, particularly paclitaxel, significantly improved time to disease progression, duration of response, and time to treatment failure. Combination therapy resulted in a 25% improvement in overall survival compared with chemotherapy alone. Patients with HER2 gene amplification, high overexpression of HER2 (3+ on immunohisto-chemistry), or both features, obtained the greatest clinical benefit. Trastuzumab is the first monoclonal antibody with efficacy in breast cancer and the first gene-product-targeted therapy to produce a significant survival advantage in this disease. Trastuzumab is likely to find its ultimate role in the adjuvant setting. Its development provides a model for the integration of other gene-targeted therapies into breast-cancer management to improve survival and quality of life. Lancet Oncol 2002; 3: 137–44

Section snippets

HER2: a cornerstone of hope

In the assessment of patients with breast cancer, tumour size, hormone-receptor status, and axillary-node status are well-established prognostic factors.9 However, molecular abnormalities specific to cancer cells may be able to provide prognostic or predictive information, as well as being critically important to the development of effective anticancer treatments. Identification of such markers allows the rational design and development of compounds that interact with precise cellular targets.

Rational development of a monoclonal antibody to HER2

The high frequency of HER2 overexpression on the surface of breast-cancer cells (a location that makes the molecule accessible to antibodies), together with the recognised prognostic and potentially predictive value of HER2, provided sufficient rationale for the development of a biological therapy to target HER2 specifically. Murine monoclonal antibodies that specifically bind to the HER2 extracellular domain were developed as the first approach to anti-HER2 therapy.25, 26 Many of these

Clinical trials of trastuzumab

The therapeutic efficacy and tolerability of trastuzumab have been investigated in various studies, including large pivotal phase II and III clinical trials. Trastuzumab was administered as a single agent and as second-line or third-line therapy, or as first-line therapy in combination with paclitaxel or anthracycline and cyclophosphamide to women with HER2-positive metastatic breast cancer. For both trials, HER2-positive patients were identified by use of the clinical trials assay, an

Who benefits most from trastuzumab?

Analysis of data from both pivotal trials and the first-line monotherapy trial indicates that patients with metastatic breast cancer in which HER2 is highly overexpressed or amplified derive the greatest clinical benefit from trastuzumab therapy. Subgroup analyses of data from the phase II monotherapy trial showed that patients with high HER2 overexpression (immunohistochemistry 3+) had a better response rate than those with immunohistochemistry 2+ tumours (18% vs 6%).38

These findings mirror

Clinical safety

A major motive in the development of antibodies for cancer therapy has been the potential to exploit the specificity of the immune system to achieve selective therapeutic effects without the toxicity of chemotherapy. Overall, safety data from pivotal trials confirm this principle and indicate that trastuzumab therapy is generally very well tolerated and does not cause typical chemotherapy side-effects. The commonest side-effects seen in trials were mild to moderate chills and fever, associated

Management and monitoring of patients

With regard to infusion-related reactions, monitoring for symptoms during and after the first infusion is recommended. Risk/benefit assessment has been suggested before trastuzumab therapy is started for patients who have severe dyspnoea at rest due to the complications of cancer or who require supplementary oxygen therapy. Severe reactions should be treated appropriately, with therapy such as oxygen, beta-antagonists, and corticosteroids, followed by either continuation or withdrawal of

Future hopes for trastuzumab

The optimum use of trastuzumab remains to be established. Different combinations and schedules have the potential to provide greater clinical benefits. Our current understanding of the mechanism of action is not definitive, but the drug appears to antagonise the growth-stimulating properties of the HER2 system, to trigger intrinsic immune mechanisms to eliminate cancer cells, and to augment the cytotoxicity of chemotherapy (Figure 1).48 Further understanding of these mechanisms will contribute

Trastuzumab in the adjuvant setting: rationale and promises

Many women with primary breast cancer will have undergone surgery and will be symptom-free, so therapies with few side-effects are an attractive option. Furthermore, since HER2 overexpression or amplification is an early event in the development of breast cancer,21 a logical approach would be to target this abnormality early in the disease process. The possible role of trastuzumab in the adjuvant setting is therefore under investigation. Two large US cooperative group trials have recently

Conclusions

Trastuzumab is the first oncogene-targeted therapeutic agent for solid tumours to be clinically available. Its development shows a clear shift in the development of anticancer therapies. Through identification of HER2 as a precise cellular target with prognostic value and predictive potential in breast cancer and the development of specific monoclonal antibodies targeted to this antigen, trastuzumab has emerged as an effective and well-tolerated therapy. This rational design process is certain

Search strategy and selection criteria

Articles for this review were identified by searches of MEDLINE using the terms ‘Herceptin’, ‘trastuzumab’ and ‘rhuMAb-HER2’. Only articles published in English up to 2001 were used. In addition, relevant abstracts from the following meetings were also included: 1997–2001, annual meetings of the American Society of Clinical Oncology; 1999, European Congress of Clinical Oncology; 2000, meeting of the European Society of Medical Oncology; and 1999–2000, San Antonio Breast Cancer Symposia.

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