Chemoprevention of Breast Cancer

Epidemiological and experimental evidence indicate that oes-trogenic activity plays an important role in the promotion of human breast cancer. This raises the possibility that anti-oestro-genic intervention could prevent the development of this disease. in order to detect a 25% reduction in incidence of breast cancer between a treatment and control population, at least 300 breast cancers would need to develop. With a high-risk group of women, such as those with a family history, between 40 and 60 years old, 10000 women would be required with a 10-year follow-up for 250-300 cancer to develop. This would indicate that to have a reasonable chance of detecting a significant prevention of breast cancer, by an anti-oestrogenic intervention, 5000 treatment and 5 000 control women with a high risk of developing breast cancer would be needed. However, before such a major trial could be attempted it was essential to evaluate the ethics, logistics, patient and doctor acceptability, acute toxicity, patient accrual and compliance of tamoxifen, in a prevention context, in a small feasibility trial. We have therefore started a double-blind placebo controlled feasibility trial designed to accrual 200 women aged between 35 and 65 with a family history of breast cancer. Between October 1986 and July 1987 a total of 124 patients were randomised to receive either tamoxifen or placebo. With these patients as background the present paper will outline the various problems, including acute toxicity, compliance and patient acceptability for tamoxifen versus placebo in a prevention trial.     

A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer

Epidemiological and experimental evidence indicates that oestrogens are involved in the carcinogenic promotion of human breast cancer. We have undertaken a pilot trial of tamoxifen, an anti-oestrogen, compared to placebo given to 200 women at a high risk of developing breast cancer. The results of this trial show that acute toxicity is low and that accrual and compliance are satisfactory. Furthermore, biochemical monitoring of lipids and clotting factors indicate that tamoxifen may reduce the risk of cardiovascular deaths. At this stage no untoward long-term risks have been identified, and it is therefore proposed that a large multicentre trial should be started.     

A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study

BackgroundPostmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies.MethodsWe conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence.ResultsAfter 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44–1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12–0.86), in HRT users <5 years (RR, 0.35; 95% CI 0.15–0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23–1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen.ConclusionsThe addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study.     

延长辅助内分泌治疗在激素受体阳性早期乳腺癌治疗中的价值

雌激素受体（estrogen receptor,ER）阳性早期乳腺癌的复发风险一直存在。MA.17试验证明,在淋巴结阳性、雌激素受体阳性的乳腺癌患者中,常规应用5年来曲唑治疗后继续应用他莫昔芬治疗,其无病生存期（disease-free survival,DFS）和整体生存期（overall survival,OS）都得到了明显改善。MA.17R试验证明,完成5年芳香化酶抑制剂治疗的患者,继续随机应用来曲唑或安慰剂,来曲唑组的DFS明显改善。在这些研究中,延长内分泌治疗能减少远期复发的绝对益处是适度的,然而其耐受性和依从性的挑战依然存在。对于完成5年常规内分泌治疗的患者,最终是选择他莫昔芬还是来曲唑来延长治疗,主要应该考虑患者的绝经状态、淋巴结情况、耐受性和潜在的利益大小这些因素。     

Chemoprevention Strategies 2006

Opinion statement Several large, prospective trials have evaluated tamoxifen compared with placebo for breast cancer risk reduction in women at increased risk for breast cancer. The risk of developing breast cancer is the primary determinant of net benefit, with greater net benefits accruing to women with the highest risk of breast cancer. Both age and the presence of factors that increase the risk of toxicity have the greatest effect on the net benefit associated with tamoxifen. The greatest clinical benefit with least side effects is derived from the use of tamoxifen in younger, premenopausal women who are less likely to have thromboembolic complications and uterine cancer, in women without a uterus, and in women at higher breast cancer risk such as those with atypical hyperplasia or lobular carcinoma in situ. Tamoxifen may offer benefit to women who are carriers of BRCA2 mutations, although no prospective trials have been conducted. Compared to placebo in postmenopausal women at average risk of breast cancer in published trials of osteoporosis, raloxifene reduces the risk of invasive breast cancer. Among younger postmenopausal women who are at increased risk of breast cancer, raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. Raloxifene appears to be less effective than tamoxifen in reducing the risk of in situ breast cancer. In high-risk, younger, postmenopausal women, raloxifene appears to offer net benefit when comparing reduction of the risk of breast cancer and the prevention of fractures with the risk of stroke, venous thromboembolic events, uterine events, as well as symptomatic side effects.     

A randomized placebo-controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (National Cancer Institute of Canada—Clinical Trials Group Trial,MA.12)

BackgroundIn the early 1990s, the role of adjuvant tamoxifen in premenopausal women with early breast cancer (EBC) was not established. Similarly, optimum timing relative to adjuvant chemotherapy and efficacy of tamoxifen in hormone receptor-negative tumors were unclear.Patients and methodsPremenopausal women with EBC, any hormone receptor status, after surgery received standard adjuvant chemotherapy [doxorubicin (adriamycin)/cyclophosphamide, cyclophosphamide/methotrexate/5-fluorouracil, or cyclophosphamide/epirubicin/5-fluorouracil] followed by randomization to tamoxifen or placebo for 5 years. Outcomes were overall survival (OS), disease-free survival (DFS), toxicity, and compliance with therapy.ResultsMedian follow-up for 672 women was 9.7 years. Multivariate analysis showed improved DFS [78.2% versus 71.3% at 5 years; hazard ratio (HR) 0.77; P = 0.056] and a trend for improved OS (86.6% versus 82.1% at 5 years; HR 0.78; P = 0.12). There was no evidence of greater benefit for the receptor-positive subgroup. Compliance with treatment was suboptimal in both arms, with 103 (31%) women on tamoxifen and 70 (21%) on placebo-stopping therapy early because of toxicity, refusal, or other choices.ConclusionsAdjuvant tamoxifen, given after chemotherapy to premenopausal women with EBC, improved 5-year DFS. Poor compliance may have reduced treatment efficacy.     

Tamoxifen should be cost-effective in reducing breast cancer risk in high-risk women.

PURPOSE: To estimate the cost-effectiveness of tamoxifen in the prevention of breast cancer. PATIENTS AND METHODS: Clinical trial results of National Surgical Adjuvant Breast Program P-1 compared tamoxifen versus placebo in the prevention of breast cancer, and direct medical care costs were estimated from the Agency for Health Care Policy and Research and local sources. The base estimate of effectiveness included all women on the trial. RESULTS: For every 100 women treated for 5 years, 1.665 expected cancers would not be detected. If breast cancer death is fully prevented by this strategy, then the cost-effectiveness of tamoxifen compared with no intervention is $8,479 per additional year of life gained. If lifetime prevention of the risk of death from breast cancer exceeded 17%, then the cost-effectiveness ratio would be less than $50,000 per year of life gained (a common benchmark). CONCLUSIONS: Tamoxifen for breast cancer prevention should be cost-effective under nearly all circumstances. Its use will require additional resources because it is not cost saving, but it fits within accepted guidelines.     

Prevention of breast cancer using selective oestrogen receptor modulators (SERMs)

Placebo controlled trials in over 25,000 women showed that tamoxifen reduced breast cancer risk by about 40% and osteoporotic fracture risk by about 32%. Similarly placebo controlled trials in nearly 18,000 women showed that raloxifene reduced breast cancer risk by 44–72% and osteoporotic fractures risk by 30–50%. A direct comparison of tamoxifen with raloxifene showed similar risk reduction for breast cancer and osteoporotic fractures with less toxicity for raloxifene.     

Adjuvant aromatase inhibitors following tamoxifen for early-stage breast cancer in postmenopausal women: what do we really know?

Adjuvant hormonal therapy in the treatment of women with early-stage, hormone receptor (HR)-positive breast cancer is now considered the standard of care. Adjuvant tamoxifen decreases the risk of breast cancer recurrence and death in women with early-stage breast cancer when taken for 5 years. The benefits of tamoxifen are counterbalanced by toxicities including an increased risk of endometrial cancer and thromboembolic events. The selective aromatase inhibitors (AIs)--including anastrozole, letrozole, and exemestane--are challenging the role of tamoxifen as the adjuvant hormonal therapy of choice in postmenopausal women. Results of the Arimidex and Tamoxifen Alone or in Combination trial favor the use of anastrozole over tamoxifen as initial adjuvant hormonal therapy, with improvement in disease-free survival (DFS) and a favorable toxicity profile. The results of 2 large adjuvant trials using AIs sequentially with tamoxifen in postmenopausal women with early-stage, HR-positive breast cancer have been reported. The MA-17 study randomized women to placebo or letrozole for 5 years after completion of 4.5-6 years of initial tamoxifen. The Intergroup Exemestane Study (IES) randomized women following 2-3 years of adjuvant tamoxifen to continue to receive tamoxifen or switch to exemestane for a total of 5 years of adjuvant hormonal therapy. The MA-17 and IES trials demonstrated superior DFS with the AI and corroborated the smaller GROCTA-4B and Italian Tamoxifen Arimidex trials, which studied sequential therapy with aminoglutethamide or anastrozole. There is now substantial medical evidence supporting the use of AIs in postmenopausal women with early-stage, HR-positive breast cancer.     

Symptoms associated with oophorectomy and tamoxifen treatment for breast cancer in premenopausal Vietnamese women

There are very few data about the efficacy and toxicity of adjuvant systemic therapies for breast cancer in non-western populations. In 1993 in Vietnam we began a randomized controlled clinical trial on premenopausal women with operable breast cancer comparing adjuvant surgical oophorectomy plus tamoxifen with observation and this same combined hormonal treatment on recurrence. We evaluated the symptoms reported at regular follow-up visits by the first 482 premenopausal women entered in this clinical trial and treated with surgical oophorectomy plus tamoxifen or observation. Hot flash frequency and intensity, vaginal discharge, and genital pruritus were the only symptoms to occur more frequently in oophorectomy and tamoxifen-treated subjects. Seventy-seven percent of oophorectomy/tamoxifen subjects reported grade 1 or more and 44% grade 2 or more hot flash frequency symptoms in the first 12 months, versus 9% and 1% of observation subjects, respectively. Twenty percent of oophorectomy/tamoxifen subjects had grade 2 or greater intensity of hot flashes some time in the first 12 months versus 0% in observation subjects. Through three years, vasomotor symptoms were reported more frequently in oophorectomy/tamoxifen-treated women (in 23% vs. 3% at three years, mostly grade I toxicities). While noted and persistent vasomotor symptoms were found with oophorectomy plus tamoxifen in this population of Vietnamese women, these were of lower grades and tolerable. This adjuvant treatment may be widely accepted if it is demonstrated to be effective in this population.     

Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a controlled randomised trial

BackgroundAdjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial.Patients and methodsPremenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years.ResultsIn the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients <40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40–49 years of age or ?50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time.ConclusionIn this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women <40 years of age. The effect of tamoxifen was not significantly dependent on time.     

Cardiovascular effects of tamoxifen in women with and without heart disease: breast cancer prevention trial. National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial Investigators

BACKGROUND: The overall effect of prophylactic tamoxifen in women depends on the balance between the effects of the drug, which include preventing breast cancer and altering cardiovascular risk. In a recent clinical trial, postmenopausal estrogen-progestin therapy was shown to increase the risk of early cardiovascular events among women with a history of coronary heart disease (CHD). The cardiovascular effects of tamoxifen in women with and without CHD are not known. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT) is the only clinical trial that provides data to assess the cardiovascular effects of tamoxifen in women with and without CHD. METHODS: A total of 13 388 women at increased risk for breast cancer were randomly assigned in the BCPT to receive either tamoxifen (20 mg/day) or placebo. Cardiovascular follow-up was available for 13 194 women, 1048 of whom had prior clinical CHD. Fatal and nonfatal myocardial infarction, unstable angina, and severe angina were tabulated (mean follow-up: 49 months). All statistical tests were two-sided. RESULTS: Cardiovascular event rates were not statistically significantly different between women assigned to receive tamoxifen and those assigned to receive placebo, independent of pre-existing CHD. Among women without CHD (6074 on tamoxifen versus 6072 on placebo), risk ratios (95% confidence intervals [CIs]) for tamoxifen users were 1.75 (0.44 to 8.13) for fatal myocardial infarction, 1.11 (0.55 to 2.28) for nonfatal myocardial infarction, 0.69 (0.29 to 1.57) for unstable angina, and 0.83 (0.32 to 2.10) for severe angina. In women with CHD (516 on tamoxifen versus 532 on placebo), risk ratios (95% CIs) for tamoxifen users were 0.00 (0 to 1.58) for fatal myocardial infarction, 1.25 (0.32 to 5.18) for nonfatal myocardial infarction, 2.26 (0.87 to 6.55) for unstable angina, and 1.39 (0.23 to 9.47) for severe angina. There was no evidence that the lack of association between tamoxifen and cardiovascular events was related to an early increase in risk that may have been offset by a late decrease in risk. CONCLUSION: When used for breast cancer prevention in women with or without heart disease, tamoxifen is not associated with beneficial or adverse cardiovascular effects.     

Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among postmenopausal patients with early stage breast cancer

The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. A total of 2,738 postmenopausal women with invasive, early stage disease were randomised between tamoxifen for 2 or 5 years, or no adjuvant endocrine therapy. Among high-risk patients the treatment was given against a background of either postoperative, locoregional radiation or CMF-type chemotherapy. The median follow up was 18 years (range 11-25 years). There was a statistically significant (p =0.001) interaction between ER status and tamoxifen with no treatment benefit among receptor negatives. PgR-status had little additional predictive value. Among ER-positive patients tamoxifen reduced locoregional recurrences by 48%, contralateral breast cancers by 54%, distant metastases by 28%, and all events by 24% (p <0.001). On the other hand, there was a substantial increase of endometrial cancer associated with tamoxifen. There was no effect of tamoxifen on intercurrent mortality whereas breast cancer deaths were reduced by 31% (p <0.001) and overall mortality by 15% (p =0.01). Tamoxifen produced long-term benefits among estrogen receptor positive patients in terms of breast cancer-related events, but also an increased incidence of endometrial cancer. Despite long-term follow-up we observed no benefit with tamoxifen in terms of cardiovascular mortality.     

Haemostatic changes and thromboembolic risk during tamoxifen therapy in normal women.

Tamoxifen has been implicated as a risk factor for venous thrombosis in advanced breast cancer although the evidence for increased arterial or venous thrombosis with tamoxifen in early breast cancer is less clear. The effect of tamoxifen on haemostasis, and thereby possible thromboembolic risk, was investigated in normal women enrolled in a placebo controlled trial of tamoxifen as a chemopreventative agent for breast cancer. There was an initial reduction in fibrinogen levels in all women on tamoxifen over the first year of follow-up and a marginal reduction in antithrombin III and Protein S in postmenopausal women at 6 months. There were no changes in cross linked fibrinogen degradation products or Protein C for pre or post-menopausal women. There was no increase in the incidence of thromboembolic events on tamoxifen. This study demonstrates that tamoxifen has only marginal effects on factors involved in haemostasis reported to affect the incidence of arterial or venous thromboembolic disease. The follow-up time is relatively short (maximum 36 months) and careful long term follow-up is necessary to detect clinically significant morbidity.     

Effects of tamoxifen on benign breast disease in women at high risk for breast cancer

BACKGROUND: In 1998 the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated that tamoxifen treatment reduced the incidence of both invasive and noninvasive breast cancer in women at high risk for the disease. We examined the effect of tamoxifen treatment on the incidence of benign breast disease and the number of breast biopsies in the same group of women. METHODS: We examined the medical records of 13 203 women with follow-up who participated in the NSABP Breast Cancer Prevention Trial. Included in this analysis were women who had undergone a breast biopsy and who had histologic diagnoses of adenosis, cyst, duct ectasia, fibrocystic disease, fibroadenoma, fibrosis, hyperplasia, or metaplasia. The relative risk (RR) for each histologic diagnosis was estimated for women who received tamoxifen and for women who received placebo. We also tallied the number of biopsies that women in the placebo and tamoxifen groups underwent. RESULTS: Overall, tamoxifen treatment reduced the risk of benign breast disease by 28% (RR = 0.72, 95% confidence interval [CI] = 0.65 to 0.79). Tamoxifen therapy resulted in statistically significant reductions in the risk of adenosis (RR = 0.59, 95% CI = 0.47 to 0.73), cyst (RR = 0.66, 95% CI = 0.58 to 0.75), duct ectasia (RR = 0.72, 95% CI = 0.53 to 0.97), fibrocystic disease (RR = 0.67, 95% CI = 0.58 to 0.77), hyperplasia (RR = 0.60, 95% CI = 0.50 to 0.71), and metaplasia (RR = 0.51, 95% CI = 0.41 to 0.62). Tamoxifen therapy also reduced the risk for fibroadenoma (RR = 0.77, 95% CI = 0.56 to 1.04) and fibrosis (RR = 0.86, 95% CI = 0.72 to 1.03). Compared with the placebo group, the tamoxifen group had 29% (95% CI = 23% to 34%) fewer biopsies (1048 versus 1469) and 19% fewer women who underwent a biopsy (811 versus 1019). This resulted in a 29% reduction in the risk of biopsy in women treated with tamoxifen (RR = 0.71, 95% CI = 0.66 to 0.77). This risk reduction occurred predominantly in women younger than 50 years. CONCLUSION: Women in this study who received tamoxifen, especially younger women (i.e., <50 years), had a reduced incidence of clinically detected benign breast disease and underwent fewer breast biopsies.     

Tamoxifen in ductal carcinoma in situ

The widespread adoption of screening mammography has resulted in an increased incidence of ductal carcinoma in situ (DCIS), which now accounts for 20% to 30% of new breast cancer diagnoses. Despite treatment with combined lumpectomy and radiation therapy, up to 15% of women will experience an ipsilateral breast recurrence, with 50% of these recurrences containing invasive disease. There is also a 6% incidence of contralateral breast cancers in women treated for DCIS. The recognition that adjuvant tamoxifen reduces local, regional, and distant disease in women diagnosed with invasive breast cancer led to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 study, which randomized more than 1,800 women undergoing breast-sparing surgery and radiation for DCIS to adjuvant tamoxifen versus placebo for 5 years. At 7 years of follow-up, there was a statistically significant 27% reduction in the annual incidence rate of all breast cancer-related events for those women receiving tamoxifen, including a 48% reduction in invasive breast cancer. The benefit attributable to tamoxifen was confined to those tumors that were estrogen receptor (ER)-positive. However, adverse events, including endometrial cancer, thromboembolic events, and cataracts, are more common in older women. Tamoxifen should be considered as an adjunct to treatment for women undergoing breast-conserving surgery for ER-positive DCIS.     

The Extended Adjuvant Treatment Strategy in Early Breast Cancer

Adjuvant tamoxifen has a significant survival benefit in early breast cancer but current data suggest that there is no further benefit beyond 5 years’ treatment. Extended adjuvant therapy with oral letrozole 2.5mg daily following 5 years of tamoxifen in postmenopausal women with hormone receptor-positive breast cancer was shown to significantly reduce the risk of recurrence compared with placebo in the MA-17 trial (predicted 4-year disease-free survival 95% vs 90%). A small but significant overall survival benefit has also emerged in the subset of patients with node-positive disease. Side effects were generally mild with letrozole, with a slight increase in the incidence of hot flushes, arthralgia, and muscle pain and a reduction in vaginal bleeding. Newly diagnosed osteoporosis was recorded in 8% of patients receiving letrozole compared with 6% of patients receiving placebo (p = 0.003). There was no significant difference in the incidence of cardiovascular events or hypercholesterolemia. Extended adjuvant therapy with letrozole should now be offered to all but the lowest risk postmenopausal women with hormone receptor-positive disease who are still in remission after 5 years of tamoxifen.     

The role of aromatase inhibitors as adjuvant therapy for early breast cancer in postmenopausal women

For endocrine therapy of hormone-sensitive advanced breast cancer in postmenopausal women, the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, are effective both as alternatives to tamoxifen in first-line treatment and following first-line tamoxifen failure. These three agents are currently being evaluated as adjuvant therapy of early breast cancer, again relative to the standard, tamoxifen. Three treatment strategies are under investigation: replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy); sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy); or following 5 years of tamoxifen (extended adjuvant therapy). Results of the first early adjuvant trial (Arimidex, Tamoxifen Alone or in Combination [ATAC]) demonstrated that anastrozole was significantly more effective than tamoxifen in reducing the risk of disease recurrence. Two trials sequencing 2-3 years of an aromatase inhibitor after 2-3 years of tamoxifen have also reported results. A large trial (International Collaborative Cancer Group [ICCG] trial 96) found switching to exemestane to be significantly superior to continuing on tamoxifen in disease-free survival, and in a small study (Italian Tamoxifen Arimidex [ITA] trial), similarly sequencing anastrozole after tamoxifen significantly reduced the hazard of recurrence compared with remaining on tamoxifen. Extended adjuvant therapy with 5 years of letrozole versus placebo following 5 years of tamoxifen was evaluated in the MA.17 trial. Compared with placebo, letrozole resulted in a significant improvement in disease-free survival that was irrespective of whether patients had lymph node-positive or -negative tumours. Results of these four trials emphasise the important role of aromatase inhibitors in the adjuvant setting, yet the optimal approach still needs to be defined. A number of trials further evaluating the three adjuvant treatment strategies are ongoing.     

Tamoxifen – An Update on Current Data and Where it Can Now be Used

Over the past 30 years, data from a large number of clinical trials have confirmed the efficacy of tamoxifen in estrogen receptor (ER)-positive breast cancer, both as adjuvant therapy and for advanced disease. The 1995 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview of randomized trials of adjuvant tamoxifen versus no tamoxifen showed that during approximately 10 years of follow-up, the proportional reductions in mortality for 1, 2 and ～5 years of adjuvant tamoxifen were 12, 17 and 26%, respectively. Tamoxifen is also effective for the prevention of breast cancer. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) breast cancer prevention study (P-1), 5 years of tamoxifen therapy reduced the incidence of invasive and non-invasive breast cancers by 49 and 50%, respectively. In a randomized NSABP trial in women with ductal carcinoma in situ (DCIS), tamoxifen brought about a significant 47% reduction in ipsilateral invasive breast cancers and a 15% reduction in non-invasive breast cancers, compared with placebo. In trials performed by the Swedish Breast Cancer Co-operative Group and the NSABP, the optimal duration of adjuvant tamoxifen therapy appears to be 5 years, although this is equivocal and not yet conclusively defined.     

Ovarian cancer risk in premenopausal and perimenopausal women treated with Tamoxifen: a case-control study

As tamoxifen stimulates ovarian steroidogenesis in premenopausal women, induces ovulation and increases the incidence of benign ovarian cysts, there has been concern that it might also increase ovarian cancer risk in women treated premenopausally. In a national case-control study in Britain, treatment histories were collected for 158 cases of ovarian cancer after breast cancer diagnosed at ages under 55 years and 464 controls who had breast cancer at these ages without subsequent ovarian cancer. Risk of ovarian cancer was not raised for women overall who had taken tamoxifen (odds ratio (OR)=0.9, 95% confidence interval (CI) 0.6-1.3) or for those treated when premenopausal (OR=1.0, 95% CI 0.6-1.6) or perimenopausal (OR=0.7, 95% CI 0.2-2.4). There was also no relation of risk to daily dose, duration or cumulative dose of tamoxifen, or time since last use. There was, however, a significantly raised risk in relation to non-hormonal chemotherapy. The results suggest that tamoxifen treatment of premenopausal or perimenopausal women does not materially affect ovarian cancer risk, but that non-hormonal chemotherapy might increase risk.