Monday March 28 2011
Women with a 4-8% 10-year risk should receive preventative drugs
“Breast cancer could be curbed by preventative drug treatment,” reported The Independent. Many newspapers reported suggestions by experts that women at higher risk of breast cancer should be offered preventative drugs in the same way that statins are given to people at greater risk of cardiovascular disease. Most newspapers also report that these drugs are associated with side effects, including a small increased risk of endometrial cancer for some women.
The news stories are based on an article by 12 international cancer experts, representing their consensus opinions on the state of the evidence for preventative therapy for breast cancer. This is an important area of study, and previous research has produced good evidence that the drugs tamoxifen and raloxifene can prevent breast cancer in some groups.
This is a well-structured article, clearly presenting the authors’ arguments for the prevention of breast cancer using drugs such as tamoxifen and raloxifene. In the US, these drugs are recommended as preventatives, although these experts say they are not widely used because of side effects. They are currently not licensed to be used in this way in the UK, however, and must be prescribed off-label. As the researchers say, if these drugs are to be used for prevention in this country, it would be important to identify women who are at the highest risk for breast cancer and who would be most likely to benefit when these side effects are taken into account.
Where did the story come from?
This consensus statement was prepared by experts from Queen Mary University of London, Oncologia Medica in Genoa, Italy, The European Institute of Oncology in Milan, and several other research institutions around the world.
While the publication itself did not appear to have received funding, several of the authors declare potential conflicts of interest largely relating to institutional funding or honoraria from pharmaceutical companies. The statement was published in the peer-reviewed medical journal The Lancet.
This story is widely covered in the newspapers and the reporting is balanced and fair.
What kind of research was this?
The newspaper stories are not based on new research, but on the publication of an opinion piece written by an international group of cancer experts. The group of 12 experts met in March 2010 in Switzerland to discuss breast cancer prevention strategies. This document represents the consensus opinion of these experts on the use of drugs for prevention.
The document discusses the global burden of breast cancer and they mention the current strategies for preventing the disease. These include a range of lifestyle choices, such as avoiding obesity, maintaining physical activity and moderating alcohol intake. There are also surgical and medical options for preventing breast cancer, but the experts limit their discussion to the use of drugs.
The researchers discuss what lessons could be learnt from the current methods of preventing cardiovascular disease, including the ways that women are currently assessed for high disease risk. Some high risk gene mutations for breast cancer (BRCA1, BRCA2, TP53, PTEN) have been identified, although these are rare in the population. The authors say that risk assessment needs to improve so that therapy can be more appropriately targeted.
One approach would be to identify physical markers, such as the density of breast tissue on mammography. This is a promising approach because studies show that a density of more than 75% increases risk of disease by about five times. They say it may be a way of identifying which women might respond best to preventative treatment, although more work is needed to establish this.
The authors go on to discuss the current state of the evidence for different drugs at preventing breast cancer. They say that the traditional approach to licensing drug treatments is not appropriate for preventative treatments. When drugs are approved as treatments, regulatory agencies require them to demonstrate effectiveness in one particular outcome, e.g. mortality, response, etc. The experts say that multiple endpoints are important when considering prevention, and the approach to regulating drugs for this usage needs to change.
What drugs can be considered?
Several drugs can be considered for preventative therapy. Some, including tamoxifen and raloxifene are from the class of drugs known as selective oestrogen-receptor modulators (SERMs). The researchers have the following to say about these drugs:
Tamoxifen has proven effectiveness as a preventative treatment. It is the ‘treatment of choice’ for preventing breast cancer in high-risk women, especially premenopausal women. Studies have shown that it reduces oestrogen-receptor positive invasive breast cancer by 43%. However, it does not affect the incidence of oestrogen-receptor negative cancer. It remains to be seen what the long-term benefits are of taking the drug, such as after 10 years. There are other unknowns, including tamoxifen's effectiveness on postmenopausal women receiving hormone-replacement therapy.
The drug is associated with several side effects, such as an increased risk of endometrial problems, including endometrial cancer. The greatest net benefit in post-menopausal women appears to be in women who have already had a hysterectomy and are therefore not affected by the potential increase in risk of endometrial cancer. In Europe, tamoxifen is only licensed to treat breast cancer. In the US, however, tamoxifen and raloxifene (see below) are explicitly approved for preventing breast cancer.
Raloxifene has also been assessed for use in prevention, although the evidence base is a little more complicated. The effectiveness of the drug at preventing breast cancer has only been indirectly compared to tamoxifen using statistical techniques. Raloxifene appears to reduce the risk of all invasive breast cancers by about 23%. The drug is not associated with the effects on the endometrium that may limit the use of tamoxifen, therefore it may be a preferable option for post-menopausal women.
Lasofoxifene was studied in a large trial, which found that the highest daily dose taken reduced the risk of oestrogen-receptor positive breast cancer by 81%. There were benefits too in terms of reducing vertebral and non-vertebral fractures, strokes and other cardiac events.
Another drug called arzoxifene shows similar promise for reducing ER positive breast cancer. However, it seems to raise the risk of venous thromboembolisms. The experts say that more research is needed for this one.
Another class of drugs that have demonstrated potential as preventative treatments are the aromatase inhibitors. When women with early cancer in one breast are given adjuvant treatment (i.e. alongside other treatments such as surgery) with an aromatase inhibitor, their risk of developing a tumour in the other breast is significantly reduced compared to women who receive adjuvant tamoxifen.
Researchers have estimated that aromatase inhibitors can reduce the risk of new ER-positive tumours by 75%. Two large studies are testing these effects in women who are at high risk of disease but are currently cancer-free. While aromatase inhibitors are not associated with the gynaecological and other side effects seen with tamoxifen, they can lead to a reduction in bone mineral density. This means a potential increase in risk of skeletal problems, including fractures.
Other drugs of apparent benefit
There are other drugs that were developed initially for other purposes, but which appear to have a beneficial effect on reducing the incidence (new cases) of breast cancer. These include:
- Bisphosophonates - cohort studies have shown that these drugs, which are used to limit cancer spreading to the bone, can reduce both ER-positive and ER-negative breast cancer incidence by about 30%.
- Metformin, which is used to treat type 2 diabetes and polycystic ovarian syndrome, may be linked to a reduction in breast cancer risk. However, previous studies have not been of a high quality and the researchers say that it ‘deserves to be given high priority for further clinical research’.
- Aspirin appears to reduce the incidence of breast cancer by about 10%, but only after taking it for a long time (about 20 years). The experts say this is a small effect which, on its own, doesn’t justify recommending aspirin for preventing breast cancer.
- Statins are often used to prevent coronary heart disease. Some observational studies suggest they are linked to a reduction in the risk of breast cancer, but the evidence is inconsistent and more evidence is needed.
The researchers also discuss other options that are being developed.
What do the experts conclude?
The experts say that research into the effects of certain drugs to prevent breast cancer is ongoing. Tamoxifen and raloxifene are licensed in the US specifically for this use, but are not widely used as there is some concern about their side effects. It is also difficult to identify women at high risk of the disease who may benefit most from this approach. This is an important area of research, and the experts say that more accurate tools are needed to identify women who are most likely to benefit from preventative therapy. Mammographic breast density shows some promise as a marker of risk for the disease.
Overall, they conclude that to reduce the devastating impact of breast cancer, particularly in developed countries where prevalence is high, preventative therapy should be integrated into ‘wider strategies of risk reduction, including avoidance of obesity and increase in physical activity’.
The panel agreed that an appropriate threshold for offering women preventive therapy would be a 10-year risk of breast cancer of 4–8%. They recommend that advice on how to reduce risk of disease is integrated into screening procedures.
This is a clear and well-structured article in which experts have discussed the current state of the evidence for particular drugs and their role as preventative therapies for breast cancer. The drugs that are currently recommended for this use are associated with side effects and appear only to prevent one type of breast cancer – oestrogen-positive receptor tumours. Therefore, an important aspect in prevention is to identify those women who are at high risk of breast cancer and who would be most likely to receive a net benefit from the drug when the side effects and benefits are taken into account.
This panel of experts agreed that a 4–8% 10-year risk of developing breast cancer is an appropriate level at which preventive therapy could be considered. If breast density is to be used to predict breast cancer risk, then more research is needed into the accuracy of the test and patient’s understanding of exactly what risk means.
Importantly, though tamoxifen and raloxifene are licensed in the US for prevention of breast cancer, they are not often used in this context because of the associated side effects and the difficulty in identifying the women who would benefit. The researchers say that trials are currently underway that will help to direct preventative therapies better.
Further, high quality research is needed for a clearer idea of whether the other drugs mentioned by the authors are of benefit. Some of this is already underway.