Department of Gynaecology and Obstetrics
University of Schleswig-Holstein
To our current knowledge, metastatic breast cancer is incurable. The median time of survival after generalisation of the disease is two years. The time period varies and depends on many factors, such as the pattern and the extent of the affected organs and the disease-free interval. Therapy of metastatic breast cancer is palliative and should be individualised according to the patient’s expectations, wishes, symptoms, age, general condition, aggressiveness of the disease, localisation of metastases, previously received adjuvant and palliative treatment, expression of hormone receptors, expression of HER2-neu receptors and menopausal status. Therefore, scoring systems are not suitable for therapy decisions. Predictive factors for the use of palliative therapy are expression of hormone receptors for endocrine therapy, expression of HER2-neu oncogene for treatment with trastuzumab, bone metastases for use of bisphosphonates, and previous response on chemoendocrine therapy for further systemic and local therapy. Treatment will give relief from symptoms, maintain physical fitness, improve quality of life and prolong survival. Treatment should not harm the patient more than the disease. The aim is to achieve as much time as possible without symptoms and toxicity (TWIST: time without symptoms and toxicity).
In general, endocrine therapy should be administered before chemotherapy in hormone receptor-positive tumours, as it is less toxic than chemotherapy. The principle of sequential therapy should be used. As far as the choice of substances is concerned, there has been a change in paradigm in recent years. The first choice in first-line therapy is third-generation aromatase inhibitors (eg, letrozole, anastrozole or exemestane). Their effectiveness has been proven to be superior to megestrol acetate and also to tamoxifen in direct comparisons.(1–4) They are used in patients developing metastases after or during adjuvant therapy with tamoxifen, as well as in patients who have not yet been treated with endocrine substances. On the other hand, tamoxifen can be given in case of failure of aromatase inhibitors if the patient has not yet been treated with tamoxifen. However, before administering tamoxifen, a change of aromatase inhibitors, from a steroidal (eg, exemestane) to a nonsteroidal aromatase inhibitor (such as anastrozole or letrozole), or vice versa, should be tried, depending on the substance that has been used first. In premenopausal patients, suppression of ovarian function (luteinising hormone-releasing hormone [LHRH]-analogues, ovarectomy or radiation of ovaries) combined with tamoxifen is the therapy of choice. If this is not successful, tamoxifen should be replaced by aromatase inhibitors. After failure of aromatase inhibitors and tamoxifen, the pure anti-oestrogen fulvestrant is the next option. The last option in the endocrine cascade is high-dose gestagens. Only in cases of nonresponse to endocrine forms of therapy should chemotherapy be induced. Endocrine therapy is not indicated in hormone receptor-negative patients, in cerebral metastases or if rapid remission is necessary to avoid serious symptoms of the affected organ.
There are multiple indications for chemotherapy. In cases of negative hormone receptor status, extended visceral manifestation of the disease, rapid progression and strong symptoms, primary use of chemotherapy is inevitable. Polychemotherapy can be more effective than monochemotherapy, but it is also more likely to have higher rates of toxicity. Therefore, preference should be given to monotherapies, especially if the patient is in poor general condition, if symptoms are mild and if the disease shows slow progression. Anthracyclines, including liposomal and pegylated-liposomal forms, taxanes, gemcitabine, mitoxantrone, capecitabine and vinorelbine are generally used. The most effective monosubstances in the treatment of breast cancer are paclitaxel, docetaxel, epirubicin and doxorubicin. However, docetaxel was the only new substance that proved to be superior to the standard cytostatic therapy doxorubicin. In case of rapid progression and severe symptoms, polychemotherapy should be applied as far as the patient’s general condition allows it. Typical regimens are CMF (cyclophosphamide–methotrexate–5- fluorouracil), EC (epirubicin–cyclophosphamide), FEC (5-fluorouracil–epirubicin–cyclophosphamide) and MMM (mitomycin–methotrexate– mitoxantrone). New combinations include epirubicin–paclitaxel, vinorelbine– mitomycin C, vinorelbine–mitoxantrone, vinorelbine– doxorubicin and doxorubicin–docetaxel. High rates of remission have been reported for combinations of taxanes and anthracyclines. Therefore, these combinations qualify for use in high-risk patients. After failure of anthracycline therapy, the strongest activity is achieved with paclitaxel and docetaxel, which are the first-choice substances in this situation. Dose-intense or high-dose therapies have not shown an improvement of survival yet and, therefore, should be used in clinical trials only.
A new therapy option for patients with positive HER2-neu receptor expression is the use of the humanised antibody trastuzumab (Herceptin). Overexpression of HER2-neu is proved either by immunohistochemistry or by fluorescence in-situ hybridisation (FISH) in primary tumours or metastases. However, not all institutions are able to perform these analyses. Immunohistochemical examination reveals a score from 0 to 3+. In cases of a score of 0 or 1+, tumours are defined as HER2-neu-negative, and patients cannot benefit from trastuzumab therapy. If the score is 3+, trastuzumab can be used without further diagnostics. If the score is 2+, the amplification of the HER2-neu gene has to be proven by FISH analysis. If this test shows more than four gene copies per cell, the patient can be treated with trastuzumab. Trastuzumab can be used either as monotherapy or in combination with paclitaxel. Due to cardiac side-effects, trastuzumab cannot be combined with anthracyclines or other cardiotoxic drugs. Before and during therapy with trastuzumab, monitoring of cardiac function is inevitable. The mechanisms of cardiotoxicity associated with trastuzumab are not fully understood and are currently being examined in large research projects. As the substance shows good effectiveness in metastatic breast cancer, the use in adjuvant setting is presently being tested in a large trial, the HERA (HERceptin Adjuvant) trial.
Radiotherapy is the local therapy of choice in symptomatic bone metastases or when there is a risk of fracture. Indications for radiation are local pain, risk of loss of stability (eventually combined with operative therapy), reduction of mobility and function (especially neurological symptoms) and pathological fractures. Surgical therapy of bone metastases is used in pathological fractures, nonstable pathological fractures of vertebral bodies and progressive spinal or radicular compression.
In all patients with bone metastases, the use of bisphosphonates is indicated. First results have proven the positive influence not only on progression and symptoms of bone metastases, but also on the course of the disease itself.
Isolated metastases in brain, lungs or liver may sometimes be removed by surgery. However, this approach is possible only in individual patients.
- Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000;18:3758-67.
- Bonneterre J, Thurlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000;18:3748-57.
- Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596-606.
- Mouridsen H, Sun Y, Gershanovich M, et al. First-line therapy with letrozole (Femera) for advanced breast cancer prolongs time to worsening of Karnofsky Performance Status compared with tamoxifen. Breast Cancer Res Treat 2001;69 Suppl:9:Abs 458.
- Guidelines of Deutsche Krebsgesellschaft eV; 2004.