Breast Cancer In Healthy Women Research Articles

Associations between lifestyle factors and breast cancer in healthy women and breast cancer survivors and need for ehealth support

Breast cancer is the leading cause of cancer-related mortality amongst women and its’ incidence is highest in Western-Europe. Contributing factors are higher levels of obesity and alcohol consumption, and lower levels of physical activity. Literature suggests a poor compliance to health recommendations in both breast cancer survivors and women without history of breast cancer. In the light of breast cancer prevention it is of great importance to improve this adherence and to integrate health education. Ehealth counselling might be a useful medium to obtain this goal. To gain an insight in women’s needs and requirements regarding an eHealth programme, this study used a qualitative research design based on the iChange Model.

A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women.

Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women.

Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial

SummaryBackgroundFour previously published randomised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first 10 years of follow-up. We report the long-term follow-up of the IBIS-I trial, in which the participants and investigators remain largely masked to treatment allocation.MethodsIn the IBIS-I randomised controlled trial, premenopausal and postmenopausal women 35–70 years of age deemed to be at an increased risk of developing breast cancer were randomly assigned (1:1) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years. Patients were randomly assigned to the two treatment groups by telephone or fax according to a block randomisation schedule (permuted block sizes of six or ten). Patients and investigators were masked to treatment assignment by use of central randomisation and coded drug supply. The primary endpoint was the occurrence of breast cancer (invasive breast cancer and ductal carcinoma in situ), analysed by intention to treat. Cox proportional hazard models were used to assess breast cancer occurrence and mortality. The trial is closed to recruitment and active treatment is completed, but long-term follow-up is ongoing. This trial is registered with controlledtrials.com, number ISRCTN91879928.FindingsBetween April 14, 1992, and March 30, 2001, 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were randomly allocated to the two treatment groups: 3579 to tamoxifen and 3575 to placebo. After a median follow up of 16·0 years (IQR 14·1–17·6), 601 breast cancers have been reported (251 [7·0%] in 3579 patients in the tamoxifen group vs 350 [9·8%] in 3575 women in the placebo group; hazard ratio [HR] 0·71 [95% CI 0·60–0·83], p<0·0001). The risk of developing breast cancer was similar between years 0–10 (226 [6·3%] in 3575 women in the placebo group vs 163 [4·6%] in 3579 women in the tamoxifen group; hazard ratio [HR] 0·72 [95% CI 0·59–0·88], p=0·001) and after 10 years (124 [3·8%] in 3295 women vs 88 [2·6%] in 3343, respectively; HR 0·69 [0·53–0·91], p=0·009). The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer (HR 0·66 [95% CI 0·54–0·81], p<0·0001) and ductal carcinoma in situ (0·65 [0·43–1·00], p=0·05), but no effect was noted for invasive oestrogen receptor-negative breast cancer (HR 1·05 [95% CI 0·71–1·57], p=0·8).InterpretationThese results show that tamoxifen offers a very long period of protection after treatment cessation, and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention.FundingCancer Research UK (UK) and the National Health and Medical Research Council (Australia).

Abstract P2-14-08: Plasma pro-enkephalin and pro-neurotensin for the risk prediction of incident breast cancer in healthy women

Abstract Experimental settings have indicated that Neurotensin regulates both satiety and breast cancer growth. Proneurotensin 1-117 (pro-NT), which stems from the same precursor as Neurotensin, has been developed as a reliable plasma surrogate biomarker for the unstable Neurotensin and has been shown to be associated with the development of incident breast cancer. Enkephalins and related opioid peptides may negatively regulate carcinogenesis and the growth of breast tumors through stimulation of the immune tumor defense system as well as direct inhibitory effects on breast cancer cells. However, little is known about their role in the development of breast cancer in humans. Enkephalin can be assessed in plasma by measuring a stable surrogate marker, Pro-Enkephalin A 119-159 (pro-ENK). OBJECTIVE: To test if plasma pro-ENK in healthy women is associated with the development of incident breast cancer and if it adds information to pro-NT for the risk prediction. DESIGN, SETTING, AND PARTICIPANTS: We measured pro-ENK and pro-NT in fasting plasma from 1929 women (mean age 58 +/- 5.9 years) of the population based Malmo Diet and Cancer Study (MDCS), who were free from breast cancer prior to the baseline exam. We used Cox proportional hazards models to relate pro-ENK and pro-NT to first breast cancer events (n = 123) within 15 years of follow-up. RESULTS: Decreasing concentrations of pro-ENK were significantly associated with the risk of women to develop breast cancer: Women belonging to quartiles 3, 2 and 1 of pro-ENK compared to those of quartile 4 had Hazard ratios (HR) for breast cancer of 1.41 (0.74-2.69), 2.3 (1.27-4.14) and 3.19 (1.82-5.62). Pro-NT: As compared to women belonging to the 1st quartile of pro-NT, women belonging to quartiles 2, 3 and 4 of pro-NT had HRs for the devlopment of breast cancer of 1.24 (0.69-2.24), 1.61 (0.92-2.82) and 2.37 (1.4-4.01). Pro-ENK significantly added prognostic value to pro-NT (p = 0.00006) and vice versa (p = 0.00002). The HR for women with pro-ENK in the 1st quartile and pro-NT in the 4th quartile (high risk group) was 4.17 (2.48-7.03) as compared to women with pro-ENK in quartiles 2-4 and pro-NT in quartiles 1-3 (low risk group). Women with one of the biomarkers in high risk still had a slightly increased risk (HR 1.71 (1.16-2.52)) as compared to the low risk group. CONCLUSION: Biomarker based risk prediction for the development of breast cancer is significantly improved, when plasma pro-ENK is added to pro-NT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-08.

A pilot chemoprevention study of isopropanolic black cohosh extract in women with ductal carcinoma in situ.

TPS1609 Background: Recent evidence suggests that black cohosh (Cimicifuga racemosa) may be a potential agent for breast cancer prevention. The active ingredients in black cohosh preparations appear to be triterpene glycosides. Recent preclinical data suggest several mechanisms by which triterpenes may prevent and treat breast cancer, including anti-proliferative, pro-apoptotic, anti-estrogenic, and anti-inflammatory effects. Epidemiologic data demonstrate a significant protective effect of black cohosh against the development of breast cancer in healthy women, and prolonged disease-free survival in breast cancer patients. There is also abundant evidence demonstrating the safety and tolerability of black cohosh in several clinical trials studying its use for treatment of hot flashes. We hypothesize that efficacy of black cohosh can be demonstrated in a pilot pre-operative window trial in a cohort of women with ductal carcinoma in situ (DCIS). Methods: In this trial, we treat women with a 2-5 week pre-operative course of commercial standardized isopropanolic black cohosh extract (20 mg orally twice per day). We aim to demonstrate a reduction in breast epithelial cell proliferation as measured by Ki-67 staining in regions of DCIS using traditional IHC staining and AQUA analysis. We also assess safety and tolerability of black cohosh through monitoring of patient adherence, liver function tests and serum hormone levels. 22 patients will be enrolled onto the trial. Sample size is based on power calculations for the specific study aim of determining the mean change in the levels of Ki67, using a targeted effect size. Assuming a 10% drop-out rate, a sample size of 20 patients will achieve 91% power to detect a 0.8 standard deviation of difference with a two-sided significance level at 0.05 using Wilcoxon signed-rank test. Eligible subjects are pre- and post-menopausal women ≥ 18 years of age newly diagnosed with DCIS histologically confirmed on breast core biopsy, prior to definitive excision. Women who have recently taken any agent known to affect Ki67 levels in the breast (e.g. hormone therapy) are excluded. Enrollment is currently ongoing with 10 of 22 patients accrued. Clinical trial registry number NCT01628536. Clinical trial information: NCT01628536.

Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial

BackgroundThe management of hormonal deficiency symptoms in breast cancer survivors is an unsolved problem. While hormone replacement therapy (HRT) may increase the risk of breast cancer in healthy women, its effects on recurrence is unclear. Observational studies have suggested decreased recurrence rates from HRT. The few clinical trials in this field have all been closed preterm. MethodsThe Stockholm trial was started in 1997 and designed to minimise the dose of progestogen in the HRT arm. Disease-free women with a history of breast cancer were randomised to HRT (n=188) or no HRT (n=190). The trial was stopped in 2003 when another Swedish study (HABITS, the Hormonal Replacement After Breast Cancer – Is it Safe?) reported increased recurrence. However the Stockholm material showed no excess risk after 4years of follow-up. A long term follow-up has now been performed. FindingsAfter 10.8years of follow-up, there was no difference in new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio (HR)=1.3; 95% confidence interval (CI)=0.9–1.9). Among women on HRT, 11 had local recurrence and 12 distant metastases versus 15 and 12 for the controls. There were 14 contra-lateral breast cancers in the HRT group and four in the control group (HR=3.6; 95% CI=1.2–10.9; p=0.013). No differences in mortality or new primary malignancies were found. InterpretationThe number of new events did not differ significantly between groups, in contrast to previous reports. The increased recurrence in HABITS has been attributed to higher progestogen exposure. As both trials were prematurely closed, data do not allow firm conclusions. Both studies found no increased mortality from breast cancer or other causes from HRT. Current guidelines typically consider HRT contraindicated in breast cancer survivors. Findings suggest that, in some women symptom relief may outweigh the potential risks of HRT.

Serum enterolactone levels and mortality outcome in women with early breast cancer: a retrospective cohort study

We previously demonstrated that high serum enterolactone levels are associated with a reduced incidence of breast cancer in healthy women. The present study was aimed at investigating whether a similar association might be found between serum enterolactone levels and the mortality of women with early breast cancer. The levels of enterolactone in cryopreserved serum aliquots obtained from 300 patients, operated on for breast cancer, were measured using a time-resolved fluoro-immunoassay. Levels were analyzed in respect to the risk of mortality following surgery. Cox proportional hazard regression models were used to check for prognostic features, to estimate hazard ratios for group comparisons and to test for the interaction on mortality hazards between the variables and enterolactone concentrations. The Fine and Gray competing risk proportional hazard regression model was used to predict the probabilities of breast cancer-related and breast cancer-unrelated mortalities. At a median follow-up time of 23 years (range 0.6-26.1), 180 patients died, 112 of whom died due to breast cancer-related events. An association between a decreased mortality risk and enterolactone levels ≥ 10 nmol/l was found in respect to both all-cause and breast cancer-specific mortality. The difference in mortality hazards was statistically significant, but it appeared to decrease and to lose significance after the first 10 years, though competing risk analysis showed that breast cancer-related mortality risk remained constantly lower in those patients with higher enterolactone levels. Our findings are consistent with those of most recent literature and provide further evidence that mammalian lignans might play an important role in reducing all-cause and cancer-specific mortality of the patients operated on for breast cancer.

Can Oral Bisphosphonates Really Reduce the Risk of Breast Cancer in Healthy Women?

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Fetal microchimerism in normal breast in healthy women and women with breast cancer.

Abstract Abstract #5048 Introduction: A lasting legacy of a fetus to his mother is a small number of stably persistent allogeneic cells, a phenomenon known as fetal microchimerism. We have been testing the hypothesis that fetal microchimerism is protective against cancer in the mother by participation in immune surveillance. Prior studies demonstrated that fetal microchimerism in the peripheral blood is associated with protection from breast cancer (Cancer Res, 67(19):9035-8 and PLoS ONE, 3(3):e1706). Here we examine whether the same association of fetal microchimerism extends to the tissue of interest, the breast.&amp;#x2028; Methods: Total genomic DNA was extracted from frozen normal breast tissue adjacent to invasive disease in women with breast cancer. Control tissues were from reduction mammoplasty procedures performed for women with no prior history of invasive breast cancer. The presence of male DNA, presumably from a prior male fetus, was tested with a quantitative PCR assay for the Y chromosome gene, DYS14. Proportions of tissues harboring fetal microchimerism were compared between women with and without prior history of invasive breast cancer.&amp;#x2028; Results: At present, tissues from 19 women with cancer and 19 without have been tested for the presence and quantity of fetal microchimerism using the DYS14 assay. Fetal microchimerism was detected less frequently in tissues from women with cancer (26%) than without (63%). The odds ratio for this protective association of fetal microchimerism with breast cancer is 0.21 (0.04-1.0 95% confidence interval; p=0.05). A trend towards larger median quantities of fetal microchimerism was noted in control tissues versus normal breast from cancer patients (0.34 versus 0 fetal genomes/million maternal cells, p&amp;gt;0.05).&amp;#x2028; Conclusions: Preliminary results suggest that the negative association of breast cancer and fetal microchimerism observed previously in the blood is also reflected at the level of the tissue of interest. These results merit further investigation in the breast tissue of controls to identify the phenotype of the cells detected. Furthermore, the findings here provide further support to the overall hypothesis that fetal microchimerism may participate in immune surveillance against breast cancer in healthy women. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5048.

Differences and similarities in breast cancer risk assessment models in clinical practice: which model to choose?

To show differences and similarities between risk estimation models for breast cancer in healthy women from BRCA1/2-negative or untested families. After a systematic literature search seven models were selected: Gail-2, Claus Model, Claus Tables, BOADICEA, Jonker Model, Claus-Extended Formula, and Tyrer-Cuzick. Life-time risks (LTRs) for developing breast cancer were estimated for two healthy counsellees, aged 40, with a variety in family histories and personal risk factors. Comparisons were made with guideline thresholds for individual screening. Without a clinically significant family history LTRs varied from 6.7% (Gail-2 Model) to 12.8% (Tyrer-Cuzick Model). Adding more information on personal risk factors increased the LTRs and yearly mammography will be advised in most situations. Older models (i.e. Gail-2 and Claus) are likely to underestimate the LTR for developing breast cancer as their baseline risk for women is too low. When models include personal risk factors, surveillance thresholds have to be reformulated. For current clinical practice, the Tyrer-Cuzick Model and the BOADICEA Model seem good choices.

Increased Risk of Recurrence After Hormone Replacement Therapy in Breast Cancer Survivors

Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up. HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and chi(2) tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone. Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test). After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

Red clover isoflavones are safe and well tolerated in women with a family history of breast cancer

To assess the safety and tolerability of a standardized 40 mg red clover isoflavone dietary supplement (Promensil, Novogen) in women with a family history of breast cancer to evaluate the feasibility of using the supplement for prevention of breast cancer in healthy women. Healthy women aged 35-70 years (n = 401) with at least one first-degree relative with breast cancer received red clover isoflavones or placebo for three years in a randomized, double-blind, placebo-controlled pilot trial. Participants were assessed clinically and blood samples taken for biochemical analysis every six months. In addition, study participants underwent mammography, bone density and transvaginal ultrasound (postmenopausal women only) once per year. No significant differences in breast density, endometrial thickness, serum cholesterol, follicle stimulating hormone levels and bone mineral density were detected between those taking red clover isoflavones and placebo. In postmenopausal women, some significant differences in bone marker levels were seen between active and placebo groups, at six months and at 12 months. The adverse event profile was similar across all red clover isoflavone and placebo groups. This three-year study supports the growing body of evidence that treatment with red clover isoflavones is safe and well tolerated in healthy women. Supplements containing red clover isoflavones did not adversely affect breast density, skeletal strength or cardiovascular status. In postmenopausal women, endometrial status was not adversely affected. The adverse event profile was similar between red clover isoflavones, and placebo and endocrine status did not differ.

Hormone replacement therapy for survivors of breast cancer

Women with breast cancer who undergo therapies beyond the surgical intervention (chemotherapy, hormone therapy) often suffer from the lack of estrogens, manifesting as climacteric symptoms. Hormone replacement therapy (HRT) offers well-established clinical benefits for the relief of menopausal symptoms, improving quality of life, and may reduce the likelihood of osteoporosis and cardiovascular disease. However, HRT is generally considered to be contraindicated in breast cancer patients, as no firm safety data are yet available from randomised clinical trials. After publication of results of Women's Health Initiative (WHI) and One Million Women Study (MWS) randomised controlled trials, a majority of physicians do not find the need to prescribe HRT in breast cancer survivors, despite the fact that only prolonged use of HRT is associated with breast cancer in healthy women and the follow-up periods in these studies were relatively short. Moreover, a randomised trial, Hormone replacement therapy after breast cancer diagnosis, is it safe? (HABITS) was recently stopped because of negative results concerning breast cancer in the group of HRT users. Another randomised controlled trial, the Stockholm Trial, was also stopped preterm because of compliance and recruitment problems. When breast cancer survivors present with severe climacteric complaints and they ask for help, a pragmatic approach is justifiable as current evidence-based medicine fails to give a clear answer. In hysterectomised patients tibolone or low dose estrogen and in not hysterectomised patients tibolone or the combination of a low dose estrogen and a hormonal IUD for a short period of time could be considered.

Chemoprevention of breast cancer among Asian women—its perspective and problems

Chemoprevention of breast cancer employing tamoxifen and others has been demonstrated to be effective in reducing the frequency of developing breast malignancy in Western countries. In Asian countries, the frequency of breast cancer as well as its premalignant lesions has recently increased. Therefore, the possible chemoprevention may benefit those women with potential high risks of developing breast cancer and with premalignant lesions. However, the details of these findings of chemoprevention in Western countries have not been available for women with Asian descendant. In addition, risk factors of developing breast cancer in healthy women have not been established in Asian countries compared to Western countries with relative paucity of familial breast cancer cases. Thus, possible chemoprevention of breast cancer in Asian countries may be targeted toward those with established premalignant breast lesions such as ductal carcinoma in situ and/or atypical ductal hyperplasia. However, due to their recent increment of their incidence, biological and/or clinical features of these premalignant breast lesions have not been extensively characterized in Asian women and further investigations are required for wide spread chemoprevention.

Anti-oestrogenic chemoprevention of breast cancer—the need to progress

Clinical trials of the selective oestrogen receptor modulator (SERM), tamoxifen, have shown an early reduction in risk of breast cancer in healthy women of approximately 40%, but with associated risks and benefits to normal tissues. An overall clinical benefit and the identification of the women at risk of breast cancer who may gain benefit from tamoxifen has not been clearly established. The identification of those women at risk who are most likely to gain benefit, and the development of other SERMs and aromatase inhibitors which might be more active and have a more beneficial spectrum of activity on normal tissues in healthy women is essential, if the aim of preventing breast cancer in healthy women is to be achieved.

Indole-3-carbinol modulation of hepatic monooxygenases CYP1A1, CYP1A2 and FMO1 in guinea pig, mouse and rabbit

Indole-3-carbinol (I3C), a major component of cruciferous vegetables, has been shown to be chemoprotective against cancer in a number of animal models and is being evaluated as a potential agent to prevent breast cancer in healthy women. Some concern has been raised related to the long-term use of I3C, as in some models chronic dietary post-initiation exposures promote cancers. I3C administration to rats marked induces several cytochrome P450s (CYPs), especially CYP1A1 (approx. 25-fold), while at the same time inhibiting the expression of FMO1. The consequence is a marked shift in the metabolic profile of drugs such as nicotine and tamoxifen, that are substrates for both monooxygenases. Such an effect could lead to adverse drug reactions in humans. In order to determine if the effect of I3C was manifest in species other than the rat, we fed 2000-ppm I3C to male guinea pigs, mice and rabbits for a period of 4 weeks. In each species, induction of CYP1A1/1A2 expression was observed in the liver but little or no effect on FMO1 was evident, with the possible exception of the rabbit. These data demonstrate that the ability of I3C to both induce CYP1A1 and inhibit FMO1, as observed in the rat, may not be common to other mammals for which FMO1 is the major isoform in the liver.

Selective Estrogen Receptor Modulation: The Search for an Ideal Hormonal Therapy for Breast Cancer

Female hormones, especially estrogens, play an important role in the pathogenesis of breast neoplasms and are a principal determinant of their biological behavior. Endocrine manipulation through medical or surgical means can often lead to objective shrinkage of breast tumors. Tamoxifen, a triphenylethylene estrogen receptor modulator, is currently the most widely used hormonal treatment for breast cancer. It has been conclusively demonstrated to reduce the risk of relapse following definitive local therapy (and systemic chemotherapy, when indicated) of invasive or noninvasive breast cancer. Recently, it has also been shown to reduce the incidence of breast cancer in healthy women who are at high risk of developing the disease. In addition, it can prevent osteoporosis and reduce the risk of fractures in postmenopausal women. However, its use is also complicated by an increased incidence of endometrial hyperplasia/carcinoma, venous thromboembolism, cataracts, and in some cases, emergence of tamoxifen-dependent clones of breast cancer. These side effects (except cataracts) are believed to be related to estrogen-agonist effects of tamoxifen. Newer drugs, which are “pure antiestrogens” or inhibitors of estrogen biosynthesis, are devoid of such estrogen-agonist activity and may not have the liability of many of these side effects. However, these agents would also be expected to lack the potentially beneficial effects of tamoxifen on lipids and skeletal system. The ability of tamoxifen to act as an estrogen-agonist or estrogen-antagonist in a tissue-specific fashion has led to the concept of selective estrogen-receptor modulation. Selective estrogen receptor modulators (SERMs), which are devoid of estrogenagonist effects on the uterus or breast cancer cells but retain potentially beneficial effects on bones and lipids, have been described as “ideal” SERMs. A number of such compounds are currently being tested. Raloxifene is already approved for prevention of osteoporosis and has potential efficacy for prevention and treatment of breast cancer. An analogue of raloxifene, LY353381, is currently in Phase II clinical trials for treatment of breast cancer, with promising early results. EM800 and CP336156 are other promising ideal SERMs in clinical trials. These compounds may provide better treatment and chemoprevention alternatives for breast cancer as compared to tamoxifen, aromatase inhibitors, and pure antiestrogens. In addition, they may also prove to be useful for the treatment and prevention of prostate cancer as well as for treating benign gynecological diseases such as fibroids and endometriosis. Future laboratory efforts should focus on further broadening the efficacy profile of SERMs (e.g., prevention of Alzheimer's disease and elevation of high-density lipoproteins to improve the likelihood of cardiovascular benefit) and narrowing their side-effect profile (e.g., risk of thromboembolism and hot flashes).

Risk and prognosis of endometrial cancer after tamoxifen for breast cancer

Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. We did a nationwide case-control study on the risk and prognosis of endometrial cancer after tamoxifen use for breast cancer. Information on tamoxifen use and other risk factors for endometrial cancer was obtained from 309 women with endometrial cancer after breast cancer (cases), and 860 matched controls with breast cancer but without endometrial cancer. For 276 cases, we obtained tissue blocks of endometrial cancer to review the diagnosis, and used immunohistochemistry to examine hormone-receptor status and overexpression of p53. Tamoxifen had been used by 108 (36.1%) of 299 cases and 245 (28.5%) controls (relative risk 1.5 [95% CI 1.1-2.0]). Risk of endometrial cancer increased with longer duration of tamoxifen use (p < 0.001), with relative risks of 2.0 (1.2-3.2) for 2-5 years and 6.9 (2.4-19.4) for at least 5 years compared with non-users. Endometrial cancers of stage III and IV occurred more frequently in long-term tamoxifen users (> or = 2 years) than in non-users (17.4% vs 5.4%, p=0.006). Long-term users were more likely than non-users to have had malignant mixed mesodermal tumours or sarcomas of the endometrium (15.4% vs 2.9%, p < or = 0.02), p53-positive tumours (31.4% vs 18.2%, p=0.05), and negative oestrogen-receptor concentrations (60.8% vs 26.2%, p < or = 0.001). 3-year endometrial-cancer-specific survival was significantly worse for long-term tamoxifen users than for non-users (76% for > or = 5 years, 85% for 2-5 years vs 94% for non-users, p=0.02). Long-term tamoxifen users have a worse prognosis of endometrial cancers, which seems to be due to less favourable histology and higher stage. However, the benefit of tamoxifen on breast-cancer survival far outweighs the increased mortality from endometrial cancer. Nevertheless, we seriously question widespread use of tamoxifen as a preventive agent against breast cancer in healthy women.

Similarities and distinctions in the mode of action of different classes of antioestrogens.

Since the description of the first antioestrogen, MER 25, more than four decades ago (Lerner et al. 1958), and of tamoxifen ten years later (Harper & Walpole 1967a,b), a large number of antioestrogens with diverse chemical structures have been described in the literature. The high level of interest in the synthesis and testing of new antioestrogens has been sustained by the therapeutic and commercial success of tamoxifen in the treatment of breast cancer. More recently, the first demonstration that tamoxifen can reduce the incidence of breast cancer in healthy women at high risk of developing the disease (Fisher et al. 1998) and that raloxifene can prevent osteoporosis (Bryant & Dere 1998) have provided a new impetus for drug discovery. Of the many analogues of tamoxifen described, only one other, chlorotamoxifen (toremiphene, Kangas 1990), has been marketed for breast cancer whilst several others are in various stages of clinical evaluation (e.g. idoxifene, Coombes et al. 1995; droloxifene, Bruning 1992). These molecules have very similar chemical and pharmacological properties: they are all non-steroidal, triphenylethylene-derived structures and all are partial agonists (mixed agonist/antagonist activities). A number of other non-steroidal structures with antioestrogenic activity have been reported, including substituted tetrahydronaphthalenes (e.g. nafoxidene, Duncan et al. 1963; trioxifene, Jones et al. 1979), indole derivatives (e.g. zindoxifene, Stein et al. 1990; ZK 119010, von Angerer 1990), benzothiophenes (e.g. LY117018, Black & Good 1980; LY156758 (keoxifene), Clemens et al. 1983) and benzopyrans (Sharma et al. 1990, Grese et al. 1996). All of these antioestrogens share with tamoxifen the pharmacological characteristic of partial-agonist activity; thus, whilst they antagonise the trophic action of oestrogens, this activity is incomplete because each compound has intrinsic oestrogen-like stimulatory (agonist) activity in vivo. The effect of drug treatment is a balance between agonist and antagonist activity. Whilst the term ‘partial-agonist’ accurately conveys the idea that all of these antioestrogens have some oestrogenic activity, it does not adequately describe their complex organ, cell and

Risks versus benefits in the clinical application of aromatase inhibitors.

Third-generation aromatase inhibitors are able to reduce circulating plasma estrogen concentrations in postmenopausal women to below detectable limits and significantly inhibit aromatase, the enzyme responsible for estrogen synthesis, in normal breast tissue and breast tumors. Their role in the treatment of advanced breast cancer is well established and their use in adjuvant therapy is currently being explored. On the basis of these trials, evaluation of these inhibitors in the prevention of breast cancer may be appropriate. Aromatase inhibitors have non-specific toxic side effects including (but not limited to): asthenia, headache, nausea, peripheral edema, fatigue, vomiting and dyspepsia. In addition, certain endocrinological side effects in postmenopausal women are notable, namely hot flushes and vaginal dryness. In advanced breast cancer, these side effects result in treatment withdrawal in few (<4%) women. Of concern, however, are the potential long-term endocrinological side effects in women receiving treatment as first-line adjuvant therapy or in sequence or combination with tamoxifen or other selective estrogen receptor modulators (SERMs). Current studies of adjuvant treatments for breast cancer in healthy women are carefully evaluating, in addition to general toxicities, the effects on bone, lipid metabolism, cardiovascular risk, quality of life and menopausal symptoms. Careful evaluation of all-cause morbidity and mortality is necessary to plan trials and justify long-term use of aromatase inhibitors in the treatment or prevention of breast cancer in healthy women.