PhD FRCR FRCP
Global Clinical Research (Oncology) Pharmacia Corporation
Professor of Cancer Medicine Hammersmith Hospital
Breast cancer is common and now affects one in 12 women. There have been radical changes in societal attitudes to this disease, leading to increased openness, a plethora of information sources, patient empowerment and increased medical resources.
Breast cancer has also triggered considerable political interest, as doing something about the disease can be persuasive to middle-aged women, who are often floating voters with profound effects on election outcomes in an increasingly centrist Europe.
There have been major changes in the management of breast cancer patients over the last 20 years. Surgery has become more conservative. Wide excision of a tumour after an initial diagnostic biopsy is now by far the most common procedure. This has resulted in a reduced need to perform mastectomies, which in turn has lowered the demand for surgical beds and shifted care increasingly to a daycare setting. This trend is likely to continue with the advent of routine screening programmes (which will increase the proportion of patients presenting with early disease) and neoadjuvant chemotherapy (given before surgery essentially to shrink the tumour).
Conservative surgery is usually followed by radical radiotherapy to the breast and, on occasion, the axillary lymph nodes. The shift to breast-sparing management has dramatically increased the workload of radiotherapy services, often without any forward planning. Modern treatment involves the use of computerised planning techniques and linear accelerators to deliver precise high-energy beams. Further developments in radiotherapy are likely to lead to increasingly precise dose delivery.
Local treatment by surgery or radiotherapy cannot be curative if the disease has spread. Systemic treatment with drugs or hormones will, if effective, deal with metastases wherever they are located. The two main areas of investigation are:
- Looking for novel drugs.
- Working out how best to maximise the benefit of existing drugs by escalating their dose or by giving them early in the natural history of the illness.
Chemotherapy has been used for over 40 years. There are many agents available, of which the most active are adriamycin, cyclophosphamide, docetaxel, epirubicin, paclitaxel and 5-fluorouracil. These drugs act on different components in cancer cells and are able to destroy the cells more effectively than their normal counterparts. However, they are toxic, causing hair loss, gastrointestinal upset, skin changes and, in some patients, bone marrow suppression, leading to life-threatening infections. Although many patients show good responses to such drugs, in that their disease rapidly shrinks, few are actually cured. Most develop recurrences which are resistant to further attack. Chemotherapy prolongs life but its cost, in terms of both drug budgets and toxicity, is high. Health economic analyses have been performed on the cost of prolonging life by six months – for the taxanes this is currently around GBP£10,000 (e16,035.25) for each patient.
Enhancing the effectiveness of current drugs
It was recognised several years ago that increasing the dose of individual cytotoxic drugs led to better response rates. As new bone marrow support technology was developed (such as bone marrow transplantation), the ability to give very high doses of conventional drugs became possible. The majority of randomised studies in this field were, however, disappointing. In 1999, one of the key studies was found to be falsified.(1) This shook the oncological world and led to a far more conservative stance. It is likely that as innovative drugs emerge the need to revisit this strategy will disappear.
Another way of enhancing the effectiveness of existing drugs is to use them in the adjuvant setting – immediately after surgery or radiotherapy. There is a good theoretical base for this strategy, and mature trial data now suggest that it provides reasonable survival benefit in certain subgroups of patients, such as younger women with a small number of axillary lymph nodes infiltrated with cancer. A more recent approach has been to give chemotherapy before surgery – neoadjuvant therapy. This provides information about the effectiveness of the drugs chosen as the tumour response can be easily measured.
Finding new drugs
Drug discovery for breast cancer is now shifting away from nonspecific cell-killing agents to far more sophisticated drugs that target specific molecules. Herceptin is a humanised monoclonal antibody that binds to an oncogene, c-erb B(2), that is overexpressed on the surface of up to one-third of breast cancer cells. This agent enhances sensitivity to taxol and adriamycin. There are many more targeted agents in the pipeline, for instance:
- Small molecules that specifically block the intracellular enzymes involved in growth control.
- Drugs that block the growth of blood vessels into tumours.
- Drugs that prevent metastasis formation.
The human genome project has resulted in a plethora of novel targets for drug design. It is likely that within ten years we will enter an era of “personalised medicine” for breast cancer. A small sample will be analysed using gene-chip technology and the optimal combination of new agents chosen. Molecular pathology will revolutionise the choice of cancer therapy. The drugs will be simple to administer, mostly as tablets, and will be given for several years to control tumour growth.
Hormonal treatments for cancer are very effective in many patients. Oophorectomy or pelvic irradiation to remove ovarian function has now mainly been replaced by drug therapy. Tamoxifen is the world’s oldest and most used anticancer agent, but there are now several other agents with which to suppress female hormone production. The aromatase inhibitors anastrazole, letrozole and exemestane are all extremely effective at reducing oestrogen levels in postmenopausal women. All are licensed in Europe for firstline use in women who have relapsed. It is likely that these drugs will also be of benefit in the adjuvant setting, and pivotal trials are in progress.
A holistic approach
The holistic aspects of breast cancer care are receiving far more attention. The disease has the potential to cause serious psychological problems unless good psychosocial care is provided.(2) Counselling, complementary medicine and information provision are increasingly used to enhance coping strategies.
It is likely that over the next decade we will move to an era of simpler surgery and radiotherapy and to a more complex regimen of individually tailored drugs mostly given orally to achieve long-term control of breast cancer. Clearly, providing the right clinical, physical and emotional environment for this will require close interaction between many professional groups.
- Weiss R, Rifkin R, Stewart M, et al. High dose chemotherapy for high risk primary breast cancer. Lancet 2000;355:999-1003.
- Watson M, Haviland J, Greer S, et al. Influence of psychological response on survival in breast cancer. Lancet 1999;354:1331-6.
Federation of European Cancer Societies