Breast cancer prevention

Epidemiological, experimental, and clinical data strongly support the possibility that breast cancer will be prevented by using anti-estrogenic interventions in healthy women. Three trials involving over 20,000 women have so far been reported using tamoxifen 20 mg/day or placebo in healthy women to chemoprevent breast cancer. The American National Surgical Adjuvant Breast and Bowel P-1 Project randomized over 13,000 women to take tamoxifen or placebo and showed a 49% reduction in the early incidence of breast cancer. This was associated with a reduction in osteoporotic fractures but increases in the risks of endometrial cancer, cataract, and thromboembolism. The Royal Marsden tamoxifen trial randomized 2,500 women, and the Italian national trial randomized 5,000 women. Interim analyses from these two trials showed no effect on the early incidence of breast cancer. These results, therefore, have not been able to clearly show an overall clinical benefit of giving tamoxifen to healthy women, nor have they shown which women are likely to benefit. Another selective anti-estrogen (SERM), raloxifene, has been used in a clinical trial to prevent osteoporotic fractures in women with low bone mineral density. Annual mammography in this trial has shown an approximate 80% reduction in the early incidence of breast cancer, and further follow-up of this trial continues. New trials in chemoprevention of breast cancer being started or being proposed use luteinizing-hormone-releasing hormone analogues, aromatase inhibitors, and other SERMs.     

Breast cancer prevention trials

A new option for women at increased risk for breast cancer is chemoprevention—namely, an attempt to decrease breast cancer incidence by means of drug therapy. The efficacy of tamoxifen as a chemopreventive agent has been studied to date in three randomized, controlled trials, with varying results. Investigators with the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial found that tamoxifen reduced the incidence of breast cancer by almost half, whereas British and Italian researchers found no significant benefit. This disparity is due, in part, to differences in the baseline breast cancer risk characteristics among the study populations, differing cohort sizes, variable use of hormone replacement therapy, and other factors. In this article, we review the eligibility criteria, treatment plans, and results from the three published randomized trials of tamoxifen versus placebo. We also review the data on raloxifene and breast cancer incidence. Chemoprevention with tamoxifen, in a non-study setting, is one option for women at increased risk for breast cancer. The ongoing Study of Tamoxifen and Raloxifene (STAR) is a randomized, doubleblinded trial comparing the effectiveness of raloxifene with that of tamoxifen in postmenopausal women at increased risk for developing breast cancer. Until the results of this trial are available, it is premature to use raloxifene for primary breast cancer prevention.     

Breast cancer prevention: present and future

Increased risk of breast cancer may result from modifiable factors such as endogenous hormone levels, obesity, HRT, and non-lactation, or non-modifiable factors such as genetic susceptibility or increasing age. Those factors that are easiest to modify may have a limited impact on the totality of breast cancer. The Gail model, based on known factors may be useful for estimating life-time risk in some individuals. Tamoxifen prevention still remains contentious. In the NSABP-P1 study, there was a 49% reduction in risk of breast cancer in women given tamoxifen but in the Italian and Royal Marsden trials, no effect on breast cancer incidence was detected, possibly because of the different case-mix in these studies. Raloxifene, tested in the MORE trial reduced the incidence of breast cancer by 65%. The effect was restricted to ER positive tumours: no reduction in ER negative cancers was seen. Life-style factors such as diet, obesity, exercise, and age of first full term pregnancy and number of pregnancies have a mild to moderate impact on risk and so may have little effect on the incidence of breast cancer. Reduction of alcohol intake could lead to a modest reduction in the risk of breast cancer but possibly adversely affect other diseases. So far, studies of retinoids have not shown a benefit in terms of breast cancer risk reduction. Fat reduction and GnRH analogues reduce mammographic density but have not yet been shown to affect risk.     

Future possibilities in the prevention of breast cancer: Breast cancer prevention trials

The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been reported. The largest tamoxifen trial showed approximately 50% reduction in breast cancer incidence in the short term, but the two smaller trials did not find any reduction. Greater agreement exists for side effects; incidences of thromboembolic disease and endometrial cancers are raised approximately threefold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a meta-analysis indicates that all results are compatible with a 40% reduction in short-term incidence. Several important questions remain regarding the clinical implications of this result, including the effect on mortality, the appropriate risk groups for chemoprevention and the long-term effects on incidence. Continued follow up of these trials is crucial for resolving these issues.     

National cancer control programs and setting priorities

Although considerable resources are being allocated globally to cancer research, efforts to implement these findings efficiently are lagging behind. Enough is known about the cause of common tumors such as lung, oral, and liver cancer to allow active measures to be taken for their prevention. Effective early detection programs have been developed for cervical, breast, and oral cancer, and treatment methods exist whereby at least one-third of all cancer patients can be cured if their disease is detected early. Unfortunately, however, most cancer activities currently in place were developed haphazardly and lack overall coordination. National cancer control efforts can be more effectively planned and implemented if they follow a systematic stepwise approach of assessing the current situation, setting health objectives, evaluating the possible strategies, and setting priorities using quantitative assessments. Cancer affects both developed and developing countries of the world, and well planned national efforts emphasizing prevention and early detection can significantly reduce the cancer problem.     

Setting priorities for cancer control programs

This paper describes a simple method for comparing the effectiveness and costs of different cancer control activities and illustrates use of the method by evaluating priorities for controlling oral cancer in developing countries. The method estimates the long-term effect of prevention, screening, detection, treatment, and support activities (e.g., pain control) on morbidity, mortality, measures of quality of life, and cost for a specified population. It can be used to compare the cost effectiveness of various combinations of activities for one or more cancers and to help set priorities for cancer control programs. An analysis of two primary prevention activities, two screening activities, and three treatment activities to control oral cancer in Sri Lanka indicates that highest priority should be given to primary prevention activities such as anti-tobacco education and to screening.     

Breast cancer prevention based on gene-environment interaction

Breast cancer, the most common cancer in women, results from combined effects of genetic and environmental factors. Although a number of preventive measures have been suggested to reduce the risk of breast cancer, only a few (e.g., regular mammogram, etc.) proved to be efficient preventive modalities. Among many potential reasons, differences in individual susceptibility factors may complicate the efficacy of the intervention. A growing body of evidence shows that the strength of association between various dietary, behavioral (exercise and obesity), and environmental exposures, and breast cancer risk may be modified by individual genetic factors. Preventive strategies against breast cancer will be discussed considering the findings of the gene-environment interaction of breast cancer. These include behavior modification for high-risk subjects (primary prevention), early detection and extensive monitoring of genetically susceptible subjects and noninvasive treatment of early stage cancer cases (secondary prevention), and finally prophylactic and therapeutic intervention to slow the progression of diseases (tertiary prevention). The accumulating evidences of the gene-environment interactions provide a better understanding of the breast cancer development and enable us to adopt individualized preventive strategies for personalized health care.     

Epidemiology of Breast Cancer in Malaysia

Data from the National Cancer Registry of Malaysia for 2004 provide an age-standardised incidence rate (ASR)of 46.2 per 100,000 women. This means that approximately 1 in 20 women in the country develop breast cancer intheir lifetime. However, the rate differs between the three main races, the Malays, Chinese and Indians. The agestandardized incidence in Chinese is the highest, with 59.7 per 100,000, followed by the Indians at 55.8 per 100,000.The Malays have the lowest incidence of 33.9 per 100,000. This translates into 1 in 16 Chinese, 1 in 16 Indian and 1in 28 Malay women developing breast cancer at some stage in their lives. The commonest age at presentation isbetween 40-49 years, with just over 50% of the cases under the age of 50 years, 16.8% below 40, and 2% under 30.Some 55.7% of all cases were found to be ER positive. The commonest presenting symptom was a lump in the breastin over 90% of cases, generally felt by the woman herself. The mean size of the lump was 4.2 cm, and on average, thewomen waited 3 months before seeking medical attention. Over the 12-year period from 1993 to 2004, about 60-70%of women presented with early stage (Stages 1- 2) while 30-40% presented with late breast cancer (Stages 3-4).Especially Malays present at later stages and with larger tumours. Consequently their survival is worse than withChinese and Indian women. The challenge in Malaysia is to be able to provide a comprehensive service in the diagnosisand treatment of breast cancer, and this requires training of a team of health professionals dedicated to breasthealth, such as breast surgeons, radiologists specializing in breast imaging, breast pathologists, plastic surgeonsspecializing in breast reconstruction, medical and radiation oncologists, psycho-oncologists, counselors, and breastnurses. Advocacy can play a role here in galvanizing the political will to meet this challenge.     

Breast cancer in Sub-Saharan Africa: opportunities for prevention

Although breast cancer is a growing health problem in sub-Saharan Africa, reasons for its increased occurrence remain unclear. We reviewed the published literature to determine the magnitude of the increase in breast cancer, associated risk factors (including for breast cancer subtypes), and ways to reduce incidence and mortality. Some of the increased breast cancer occurrence likely reflects that women are living longer and adopting lifestyles that favor higher incidence rates. However, a greater proportion of breast cancers occur among premenopausal women as compared to elsewhere, which may reflect unique risk factors. Breast cancers diagnosed among African women reportedly include a disproportionate number of poor prognosis tumors, including hormone receptor negative, triple negative, and core basal phenotype tumors. However, it is unclear how lack of standardized methods for tissue collection, fixation, and classification contribute to these rates. Given appropriate classifications, it will be of interest to compare rates with other populations and to identify risk factors that relate to specific tumor subtypes. This includes not only risk factors that have been recognized in other populations but also some that may play unique roles among African women, such as genetic factors, microbiomata, xenoestrogens, hair relaxers, and skin lighteners. With limited opportunities for effective treatment, a focus is needed on identifying etiologic factors that may be amenable to intervention. It will also be essential to understand reasons why women delay seeking care after the onset of symptoms and for there to be educational campaigns about the importance of early detection.