Breast cancer in patients, 70 years or older

Over 30% of breast cancers are diagnosed after age 70. The incidence of breast cancer in the elderly has increased since 1960. Risk factors for breast cancer are a medical history without pregnancy, a first pregnancy after age 30 and the use of hormonal replacement therapy. The biology of breast cancer at advanced age indicates a relative slow, less aggressive and hormone dependent tumour growth. In spite of these favourable characteristics, the prognosis is not better than at middle age. Over 20% of older patients die from co-existing other diseases within 5 years after the diagnosis of breast cancer. This comorbidity, mostly cardiovascular or pulmonary, affects the possibilities and the outcome of treatment. Treatment of the primary tumour is performed according to the same guidelines as in younger patients. Indication exists for hormonal adjuvant treatment with tamoxifen in patients with oestrogen receptor positive tumours. Hormonal treatment is the treatment of choice in metastatic disease. Chemotherapy is given in patients with oestrogen receptor negative tumours and in patients with progressive hepatic or pulmonary metastases.     

The effects of tamoxifen on the female genital tract

Tamoxifen has both agonistic and antagonistic effects on the female genital tract, depending on the ambient oestradiol concentration and the menopausal status of the patient. In postmenopausal women tamoxifen has an oestrogen agonistic effect on the vaginal epithelium, the uterine myometrium and the endometrium. It may induce benign cystic hyperplasia of the endometrial stroma and cause an increase in poly formation. The risk of endometrial cancer increases 2-3-fold after an exposure of up to 5 years. In asymptomatic tamoxifen users, gynaecological surveillance is not recommended. However, if there is postmenopausal bleeding, then transvaginal ultrasonography and histology of the endometrium are indicated. Tamoxifen can aggravate hot flushes and have a negative effect on sexual function. In premenopausal women, tamoxifen may induce ovarian cysts resulting in high serum-oestradiol levels. Oligomenorrhoea and amenorrhoea will occur in half of the patients. Tamoxifen has an antagonistic effect on the endometrium in premenopausal women and is associated with hot flushes and impaired sexual functioning. Teratogenic effects on the foetus have been described. Despite its gynaecological side effects, the benefits of tamoxifen in breast-cancer treatment outweigh the risks. Patients need to be informed about these side effects. Irregular or postmenopausal blood loss must always be reported to the treating physician.     

Interactions between radiation and hormonal therapy in breast cancer: simultaneous or sequential treatment

BACKGROUND: Combining radiation and hormone therapy (administration of selective estrogen receptor modulators) has become common clinical practice in recent years for receptor positive breast cancer. Little is known about a possible interaction of both treatment modalities if they are given simultaneously. Tamoxifen (antiestrogen molecule, triphenylethylene derivative) may theoretically render cancer cells less responsive to radiotherapy arresting hormone-receptor-positive cells in G0/G1 phase and increase the risk of breast and lung fibrosis stimulating the secretion of transforming growth factor beta in human fibroblasts. PURPOSE: This article reviews the published data to assess the impact of sequencing of hormonal and radiation therapy on outcomes in breast cancer. METHODS: Computerised searches for publications debating the sequencing of hormonal therapy relative to radiation therapy were done using MEDLINE data. RESULTS: Results of tamoxifen experiments with cell culture regarding radioprotection of tumour clonogens are conflicting. In contrast to in vitro results, in animal studies no protective effect of tamoxifen was observed. In one in vitro study, letrozole (non-steroid selective aromatase inhibitor) had a radiosensitizing effect on breast-cancer lines. No randomised clinical trials to date have studied sequencing of tamoxifen or other selective estrogen receptor modulators and radiotherapy. Results from retrospective clinical studies which included treatment arms with and without tamoxifen showed reduction in tumour recurrence with tamoxifen. Some of these studies have noted increased risk of lung and breast fibrosis with tamoxifen with radiotherapy. Results of three articles examined the effect of tamoxifen sequence showed no adverse effect on local control or survival in sequential versus concurrent tamoxifen and radiation patients. One of the three studies also assessed the risk of complications with respect to the timing of tamoxifen with radiotherapy. There was no difference in the rates of complications between the two groups. The association of radiation and selective aromatase inhibitors or aromatase inactivators has not been addressed in clinical studies. CONCLUSIONS: Combined application of tamoxifen and radiotherapy improves survival and local control in breast cancer. Available clinical studies do not indicate that the simultaneous application of tamoxifen and radiotherapy is disadvantageous, as was suggested by some of the in vitro studies. The risk of subcutaneous breast and lung fibrosis might be slightly increased if tamoxifen is given simultaneously with radiotherapy. Both treatment modalities should be started early after surgery. There is no sufficient evidence to withhold tamoxifen administration during irradiation of breast cancer. The issue of optimal sequencing of hormonal and radiotherapy should be addressed in randomised clinical trials.     

Interaction between breast cancer, psychosocial stress and the immune response]

Awareness of the interactive relation between psychosocial stressors, neuroendocrine and immunological processes, and tumour progression in patients with breast cancer appears to be important for clinicians. However, it is not established yet how the available knowledge can be applied therapeutically. Hormonal factors play a part in the carcinogenesis of breast cancer. Growth of the breast tumour is influenced by endocrine hormones. Antioestrogen therapy is effective in the treatment of breast cancer. Several components of the immune system are related to the course of disease in breast cancer patients. Psychosocial stressors influence neuroendocrine (corticotrophin-releasing hormone (CRH), cortisol, oestrogen) and immunological functions. Psychosocial stressors may be linked to recurrence or survival. Certain coping mechanisms (even those of a negative nature) and the social network of the patient may have prognostic values. Since recurrence of the disease is still possible many years after curative surgery, multifactorial effects on the course of disease are likely.     

Prospects for the primary prevention of breast cancer.

In this paper, the rationale, stage of development, and known or potential adverse effects of three potential strategies for the prevention of breast cancer are reviewed. Two methods--the use of tamoxifen in postmenopausal women and the use of luteinizing hormone (LH)-releasing hormone agonists in premenopausal women--involve hormonal manipulation. In the premenopausal period, the goal is to reduce the number of ovulatory menstrual cycles a woman experiences in order to reduce her exposure to estrogen and progesterone. Physical activity during adolescence is proposed as a nonhormonal method of accomplishing this. The use of LH-releasing hormone agonists to produce a reversible menopause can also reduce a woman's cumulative exposure to ovarian steroid hormones. Tamoxifen, which is effective in breast cancer therapy, provides endocrine control of estrogen-regulated breast tumor growth. Breast cancer chemoprevention trials using tamoxifen among postmenopausal women have been proposed, and pilot studies are under way.     

Selective estrogen-receptor modulators (SERM's) in postmenopausal women]

Selective oestrogen receptor modulators (SERMs) constitute a group of new drugs which mimic oestrogen in some organs and tissues but have an oestrogen antagonistic mode of action in other tissues. In postmenopausal women these compounds have a favourable effect on lipoprotein cholesterol levels in the blood and bone mineral density, thereby reducing fracture risk, especially in the vertebral column. In contrast to oestrogen therapy SERMs reduce the risk of mammary carcinoma. Currently tamoxifen and raloxifene are the best known SERMs. Tamoxifen increases endometrial hyperplasia and the risk of endometrial carcinoma. Raloxifene inhibits uterine tissue proliferation and does not appear to influence the endometrium directly. Raloxifene appears to be finding a place for itself in the treatment and prevention of osteoporosis in postmenopausal women. At this moment it is not yet possible to foresee what the impact of SERMs will be in the treatment and prevention of cardiovascular diseases and breast cancer.     

HRT and breast cancer

Research on hormone replacement therapy (HRT) in the 21st century has been dominated by the findings of the Women’s Health Initiative (WHI) and Million Women Study (MWS). Clinical practice has changed accordingly. Both studies confirm an increase in the risk of breast cancer among women using combined HRT (oestrogen and progestogen) when compared with women who have never used HRT. The risk among women using oestrogen-only preparations of HRT, according to the MWS, is increased, but to a lesser extent than for women using combined HRT. In contrast the WHI Study suggests that oestrogen alone is not associated with an increased risk of breast cancer. Despite these different findings most evidence-based guidelines from professional organizations still advise use of HRT only for the relief of menopausal symptoms and only short term. Routine use of unopposed oestrogen for women with a uterus is being discussed but is still not recommended. New data have also led to the recommendation that HRT is contraindicated for women who have had breast cancer. More research is needed on the contribution of progestogens to the increased risk of breast cancer and on the safety of different routes of administration of both oestrogen and progestogen.     

Management of Advanced Breast Cancer

Breast cancer is the most common malignancy affecting women and imposes a substantial economic burden on society. Estrogen is thought to play a major role in both the initiation and promotion of hormone dependent breast cancer, and a number of well recognized risk factors for breast cancer reflect increased cumulative estrogen exposure (e.g. early menarche, late menopause).Metastatic breast cancer is an incurable condition and the goals of treatment are to relieve symptoms, improve health-related quality of life and prolong life. Women with hormone receptor-positive disease are candidates for hormonal treatment. In contrast, chemotherapy is traditionally the treatment of choice in those with hormone receptor-negative disease or symptomatic visceral disease.Anastrozole is a highly selective nonsteroidal type II aromatase inhibitor that suppresses plasma and intratumoral estrogen levels. The results of 2 multicenter, randomized, double-blind trials have shown anastrozole to be at least as effective as tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer, although survival data are lacking. In the smaller of these trials, the median time to disease progression was significantly prolonged (p = 0.005) in anastrozole, compared with tamoxifen, recipients (11.1 vs 5.6 months), although combined analysis of the 2 trials revealed no significant difference between an-astrozole and tamoxifen in terms of this end-point.Similarly, anastrozole has been shown to be at least as effective as megestrol in the second-line treatment of postmenopausal women with advanced breast cancer in 2 multicenter randomized studies. Combined analysis of the studies revealed a significant survival advantage (p < 0.025) for anastrozole 1 mg/day, compared with megestrol 40mg 4 times daily, recipients (estimated hazard ratio 0.78; 97.5% confidence interval 0.6 to <1).Tolerability is an important consideration in women with advanced breast cancer. The most common adverse events associated with anastrozole therapy were gastrointestinal disturbance, hot flushes, asthenia and pain. Anastrozole is associated with less vaginal bleeding and thromboembolic disease than tamoxifen and less bodyweight gain than megestrol. Anastrozole also appears to be a cost-effective option in the first- and second-line treatment of advanced breast cancer, although data are limited. Conclusion: Current treatment guidelines support the use of anastrozole in the second-line treatment of postmenopausal women with advanced breast cancer. Although current treatment guidelines do not yet reflect this, data from recent, well designed studies demonstrate that anastrozole is likely to be a viable alternative to tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer.     

Dietary supplements of dehydroepiandrosterone in relation to breast cancer risk

OBJECTIVE: Dietary supplements of the adrernocertical hormone dehydroepiandrosterone (DHEA) are widely taken in the hope of staving off the aging process. Potential dangers have not been fully researched, particularly evidence of a correlation between increased serum concentrations of DHEA and higher breast cancer risk in postmenopausal women. DESIGN: The review examines reports of clinical, epidemiological experimental studies for evidence that DHEA may be a factor in promoting the growth of mammary cancer. Biological mechanisms which might be involved are identified. RESULTS: DHEA is reported to inhibit the growth of human mammary cancer cells in vitro and also the growth of chemically-induced mammary cancer in rats. However, growth inhibition occurs only in the presence of high oestrogen concentrations, and growth stimulation occurs in both models in the presence of a low-level oestrogen milieu. Epidemiological studies report a positive correlation between higher serum concentrations of DHEA and increased breast cancer risk in the case of postmenopausal but not premenopausal women. Postulated mechanisms include a direct effect on mammary cells by androgenic metabolites of DHEA or an indirect effect by an increase in bioavailable oestrogen levels. The increased serum concentration of free insulin-like growth factor 1 which follows prolonged DHEA intake may also have a role by stimulating oestrogen receptor activity in breast tissue. CONCLUSION: Late promotion of breast cancer in postmenopausal women may be stimulated by prolonged intake of DHEA, and the risk may be increased by the endocrine abnormality associated with pre-existing abdominal obesity. Caution is advised in the use of dietary supplements of DHEA particularly by obese postmenopausal women.     

Optimal adjuvant hormone therapy in postmenopausal women with hormone-sensitive mammary carcinoma: tamoxifen and the aromatase inhibitors anastrozole, exemestane and letrozole

Postmenopausal patients with hormone-sensitive breast cancer may be eligible for adjuvant hormone therapy. - For years, tamoxifen was the treatment of choice. - However, the side effects associated with tamoxifen, such as endometrial cancer and thromboembolic disorders, and the search for more effective agents have led to the introduction of new hormonal therapies. - The results of randomised trials with the third-generation aromatase inhibitors anastrozole, exemestane and letrozole demonstrate improved efficacy compared to tamoxifen. - Using aromatase inhibitors, the disease-free survival is prolonged and recent data from some studies also show a benefit in overall survival. - Aromatase inhibitors are associated with specific side effects consisting of osteoporosis/increased incidence of fractures and myalgia/arthralgia.     

Nutrients, age and cognitive function

Many nutrients or indices of nutritional status are associated with cognitive functioning, although the size of the effects on cognitive performance may be small. Results from recent studies, however, seem consistently to indicate that supplementation with beta-carotene and alpha-tocopherol, substances that promote antioxidant vitamins A and E, respectively, can be beneficial to cognitive function in elderly people. Folate rather than vitamin B12 appears to be associated with cognitive functioning. Furthermore the daily intake of ginkgo biloba extract can enhance cognitive performance and has been proved to delay cognitive decline in dementia. A proper dietary composition with regard to the ratio of carbohydrates to proteins, as well as the inclusion of sufficient micronutrients, seems to be favourable in the maintenance of cognitive function in the elderly. Glucose can enhance cognitive function, but a rapid decline of glucose levels may impair cognitive function or may induce feelings of lack of energy. Low doses of caffeine may also enhance cognitive function, although most studies on caffeine and cognition, as with studies on glucose and cognition, have not been carried out in elderly individuals. The effects of nutritional supplements are modest but do not seem to be very different from those of medicinal or investigational cognition-enhancing or anti-dementia drugs.     

Potential risks and benefits of phytoestrogen-rich diets

Interest in the physiological role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the class of compounds known as the phytoestrogens, which embody several groups of non-steroidal oestrogens including isoflavones & lignans that are widely distributed within the plant kingdom. Data from animal and in vitro studies provide plausible mechanisms to explain how phytoestrogens may influence hormone dependent states, but although the clinical application of diets rich in these oestrogen mimics is in its infancy, data from preliminary studies suggest potential beneficial effects of importance to health. Phytoestrogens are strikingly similar in chemical structure to the mammalian oestrogen, oestradiol, and bind to oestrogen receptors (ER) with a preference for the more recently described ER beta. This suggests that these compounds may exert tissue specific effects. Numerous other biological effects independent of the ER (e.g. antioxidant capacity, antiproliferative and antiangiogenic effects) have been ascribed to these compounds. Whether phytoestrogens have any biological activity in humans, either hormonal or non hormonal is a contentious issue and there is currently a paucity of data on human exposure. Much of the available data on the absorption and metabolism of dietary phytoestrogens is of a qualitative nature; it is known that dietary phytoestrogens are metabolised by intestinal bacteria, absorbed, conjugated in the liver, circulated in plasma and excreted in urine. Recent studies have addressed quantitatively what happens to isoflavones following ingestion--with pure compound and stable isotope data to compliment recent pharmacokinetic data for soy foods. The limited studies conducted so far in humans clearly confirm that soya isoflavones can exert hormonal effects. These effects may be of benefit in the prevention of many of the common diseases observed in Western populations (such as breast cancer, prostate cancer, menopausal symptoms, osteoporosis) where the diet is typically devoid of these biologically active naturally occurring compounds. However since biological effects are dependent on many factors including dose, duration of use, protein binding affinity, individual metabolism and intrinsic oestrogenic state, further clinical studies are necessary to determine the potential health effects of these compounds in specific population groups. However we currently know little about age related differences in exposure to these compounds and there are few guidelines on optimal dose for specific health outcomes.     

Menopause and hormone replacement therapy

Due to the improving life expectancy of women spend third of their active life after the menopause. Estrogen deficiency can be caused by both natural and artificial menopause. The lack of estrogen can directly worsen the quality of life and epidemiological evidence suggests association with development of certain diseased states. Hormone replacement with natural estrogens has been proven to be successful for various indications: it reduces the menopausal vasomotor and psychological symptoms thus improving quality of life. It can also be used to prevent harmful effects of estrogen deficiency in various organs. Literature review supports the role of estrogen in atherosclerosis and osteoporosis prevention. Further evidence required establishing the role of estrogens in secondary prevention of coronary artery disease. Also needs to be explained why the beneficial effects of estrogen therapy in osteoporosis seem to disappear soon after cessation of therapy. Currently the relative risk increase of breast cancer during long-term hormone replacement therapy cannot be exactly measured. Nevertheless, substantial reduction of mortality in estrogen receptor positive breast cancer can also be seen with women on hormone replacement as compared to controls. Some data support the negative correlation of residual but still detectable, endogen estrogen and atherosclerosis and similarly to osteoporosis. The same residual estrogen levels seem to correlate positively with breast cancer. The recognition (and further acceptance) of the role of the residual estrogens might have influence on the indication, choice and dosage of preparation and duration of hormone replacement therapy. Overall evidence is in favor of the need medical attention for menopause: which ranges from preventive screening to long term hormone replacement therapy. The decision to treat requires the risks and benefits taken into consideration. This highly specialized care is provided in menopause clinics in Hungary. New oestrogen like agents are being developed like the selective estrogen receptor modulators, the tibolone and the phyto-estrogens. They provide tissue-specific effect acting as estrogen agonistics, sustaining the beneficial preventive and therapeutic effects of the estrogens, but in the breast and endometrial tissue they behave like estrogen antagonists avoiding the side effects of the current used oestrogens. They might play a significant role in the treatment of menopause in the future.     

Antiestrogen chemoprevention of breast cancer: critical issues and research

Estrogenic hormones play critical roles in many aspects of women's health. Therefore, the impact of any hormonal manipulation must be carefully considered. While the evidence is good that chemoprevention, or more accurately chemosuppression, of breast cancer with tamoxifen is possible, further data are needed to support the case that hormone replacement with tamoxifen in healthy postmenopausal women would provide overall health benefits. Specifically, further data are needed regarding the biological effects of tamoxifen on risk factors for cardiovascular disease, on bone, on the liver, on the uterus, and on the coagulation system. Frequency, severity, and predictors for vasomotor, gynecologic, and depressant side effects also need to be well described. These data will allow rigorous cost-effectiveness analysis of hormone replacement therapies with tamoxifen and estrogen, as well as an analysis of the cost effectiveness of a clinical trial to prove definitively critical health benefits.     

Adjuvant therapy for breast cancer

Adjuvant therapy for breast cancer, a rapidly changing area of management, has made the difference to the breast cancer mortality figures over the last ten years. Initial treatments used hormonal manipulation such as ovarian ablation. This was followed by the development of tamoxifen, an oestrogen receptor antagonist. This has been followed by other hormonal regimes such as aromatase inhibitors, which have been used initially in the metastatic setting but are now being transferred to the adjuvant setting for post-menopausal women. Chemotherapy is used routinely for many breast cancers and is now well tolerated. Newer treatments include the use of taxanes and an antibody against HER-2 receptors; both of these are currently being evaluated in the adjuvant setting. Radiotherapy is a local adjuvant treatment that is given after breast conservation treatment surgery and in some cases is required after a mastectomy to decrease the risk of local recurrence.     

Breast feeding and future health

PURPOSE OF REVIEW: This review discusses the long-term health effects of breast feeding, based on the most relevant publications from the second half of 2004 and 2005. RECENT FINDINGS: The positive effect of breast feeding on later cognitive function continues to be the most consistent and important effect. Also, breast feeding is likely to protect against some immune-related diseases later in life, such as type 1 diabetes, coeliac disease, inflammatory bowel diseases and perhaps cancer. The evidence for an effect on allergic disease continues to be inconclusive. Furthermore, breast feeding seems to be associated with a lower blood pressure and serum cholesterol, but there is no clear association with cardiovascular disease or death. Most new studies and meta-analyses show a protective effect against later obesity, but this seems to be small. A new hypothesis suggests that breast feeding programmes the insulin-like growth factor axis and results in higher growth velocity later in childhood. SUMMARY: Evidence is increasing that breast feeding, beyond its well-established beneficial effects during the breast-feeding period, also confers long-term benefits. These effects are not strong at the individual level, but are likely to be of importance at the population level. Since the majority of the studies are observational, however, it is difficult to prove causality.     

HRT and dementia

The role of HRT and/or oestrogens in the aetiology, progression and prevention of neurodegenerative disorders is unclear. Various studies have been conducted in cells, animals and humans to better define these relationships. The following is a presentation of data on the role of oestrogens in the two most common dementia syndromes Alzheimer's Disease and vascular dementia. This review examines whether there is support for the hypothesis that the use of oestrogens reduces the risk for dementia and cognitive decline in a variety of experimental models. A literature search was performed using the following key words: oestrogen and dementia, oestrogen and Alzheimer, oestrogen and cognition, oestrogen and learning, and oestrogen and memory. The reference lists for the articles identified using these search strategies were examined. The strongest evidence for a beneficial effect comes from cell and animal studies. These suggest that treatment with oestrogens may influence the pathogenetic processes of AD, mainly by affecting the beta-amyloid metabolism, by promoting the activity of the cholinergic system, by reducing oxidative stress or cardiovascular risk. Observational studies give some support to the hypothesis that HRT may be protective for cognitive decline and dementia in the elderly, but the inherited methodological problems in these studies preclude any conclusions. The treatment trials published thus far have methodological problems that prohibit definite conclusions on the relationship between HRT and cognitive decline and dementia.     

Management of Hormone-Responsive Postmenopausal Breast Cancer

Postmenopausal breast cancer is frequently hormone responsive and may be treated with agents that prevent estrogen activity. Tamoxifen is the most widely used of these agents, proving effective in both early and advanced disease. However, the role of tamoxifen has been challenged by the development of newer agents which have demonstrated at least equivalent activity and better tolerability, notably the nonsteroidal third-generation aromatase inhibitor anastrozole, which is currently the only other agent approved for primary adjuvant treatment of early disease and first-line treatment of advanced disease.In postmenopausal women with early breast cancer, anastrozole was associated with a significantly higher rate of disease-free survival (86.9% vs 84.5%) and a lower incidence of contralateral breast cancer than tamoxifen. Furthermore, the incidences of thromboembolic events and endometrial cancer were significantly lower with anastrozole. However, anastrozole was associated with an increase in musculoskeletal events (including fractures) and further evaluation of the clinical significance of this finding is warranted. Pharmacoeconomic analyses based on the results of this trial and conducted from different healthcare perspectives have all found anastrozole to be a cost-effective adjuvant therapy for early postmenopausal breast cancer. Clinical trial data indicate that switching patients who have already received 2 years’ tamoxifen treatment to anastrozole reduces the risk of relapse and death compared with continuing treatment with tamoxifen. Further studies are warranted to determine the optimum sequence of agents and duration of adjuvant therapy.Large well designed trials have also shown first-line anastrozole therapy is at least as effective as tamoxifen in prolonging time to disease progression and overall survival in patients with advanced disease. Current data indicate that the drug is more effective than tamoxifen in patients whose tumors are known to express the estrogen receptor. Pharmacoeconomic analyses conducted from various healthcare perspectives support the use of anastrozole as a cost-effective treatment in this indication.Anastrozole has demonstrated similar efficacy to that of other approved agents, including letrozole and fulvestrant, as second-line therapy for patients who have failed first-line therapy (in most cases with tamoxifen).In conclusion, clinical and pharmacoeconomic data support the role of anastrozole as a primary adjuvant treatment for use across the entire spectrum of breast cancer encompassing early disease through to advanced metastatic disease, and reflect current treatment guidelines. Anastrozole has also proven effective in clinical trials in the neoadjuvant setting, though its use in this setting and in breast cancer prevention remains to be fully elucidated.     

Using multiple risk models with preventive interventions

An ideal preventive intervention would have negligible side effects and could be applied to the entire population, thus achieving maximal preventive impact. Unfortunately, many interventions have adverse effects and beneficial effects. For example, tamoxifen reduces the risk of breast cancer by about 50% and the risk of hip fracture by 45%, but increases the risk of stroke by about 60%; other serious adverse effects include endometrial cancer and pulmonary embolus. Hence, tamoxifen should only be given to the subset of the population with high enough risks of breast cancer and hip fracture such that the preventive benefits outweigh the risks. Recommendations for preventive use of tamoxifen have been based primarily on breast cancer risk. Age-specific and race-specific rates were considered for other health outcomes, but not risk models. In this paper, we investigate the extent to which modeling not only the risk of breast cancer, but also the risk of stroke, can improve the decision to take tamoxifen. These calculations also give insight into the relative benefits of improving the discriminatory accuracy of such risk models versus improving the preventive effectiveness or reducing the adverse risks of the intervention. Depending on the discriminatory accuracies of the risk models, there may be considerable advantage to modeling the risks of more than one health outcome. Published 2012. This article is a US Government work and is in the public domain in the USA.     

Use of HRT and the subsequent risk of cancer

At least 20 million women in developed countries are estimated to be currently using hormone replacement therapy (HRT). Almost 100 epidemiological studies have reported on the relationship between the use of HRT and the risk of cancer of female reproductive organs, namely the breast, uterus or ovary. Cancer at these sites is common and there are a priori reasons why the use of hormonal therapy to 'replace' the endogenous production of ovarian hormones after the menopause might increase the risk of these cancers. The available evidence indicates that the risk of breast cancer or endometrial cancer is increased while women are using HRT, the risk increasing with increasing duration of use. Most of the evidence about these cancers relates to use of HRT preparations containing oestrogens alone. The limited evidence about combination therapy, with oestrogens and progestogens, suggests that, compared to oestrogens alone, the effect on the breast is similar, but the effect on the endometrium is diminished, the diminution in risk being greater the more days each month that progestogens are used. The effect of HRT on breast cancer wears off after use ceases and has disappeared largely, if not wholly, within 5 years, whereas the effects on endometrial cancer take longer to wear off, if at all. The breast and endometrial cancers that are diagnosed in HRT users are less aggressive clinically than cancers in never-users but, as yet, there is little reliable information about the relationship between use of HRT and mortality from these cancers. For other cancer sites, the existing data about the effects of HRT are inconclusive. The longer the period of use of HRT, the greater the excess incidence of cancer of the breast and endometrium is likely to be. Use of HRT for short periods of time should have little effect on the incidence of these cancers. The cumulative excess incidence in 1000 women who used HRT for 10 years, beginning at age 50, is estimated to be six for breast cancer, 42 for endometrial cancer in women with an intact uterus using oestrogen therapy alone and about 20 for endometrial cancer in women with an intact uterus using oestrogen-progestogen combinations. The estimate for combined therapy is based on small numbers and may well vary with the type of preparation used. The overall balance between the excess incidence of these cancers and other effects of HRT needs to be evaluated carefully and will require more reliable data than exist at present.