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Tamoxifen's Clinical Applications
Old and New
Aman U. Buzdar, MD
Arch Fam Med. 2000;9:906-912.
ABSTRACT
The American Cancer Society estimates that this year more than 180,000 women in the United States will develop breast cancer and more than 40,000 women will die of the disease. According to a National Cancer Institute model, 5 years of preventive therapy with tamoxifen citrate reduced the risk of invasive breast cancer by 49% (P<.00001) in women at increased risk for breast cancer. The reduction in risk was greater in women with a history of lobular carcinoma in situ (LCIS; 56% relative risk reduction) or atypical hyperplasia (86% relative risk reduction). It should be noted, however, that no benefit was found in 2 European studies using notably different risk evaluation models and entry criteria. Because elevated risks of uterine cancer and thromboembolic disease have been associated with tamoxifen therapy, appropriate counseling should be given to any woman considering tamoxifen as a means of reducing breast cancer risk.
INTRODUCTION
Tamoxifen was first synthesized in 1962 as part of a project to develop an oral contraceptive.1 Although animal studies showed that tamoxifen was devoid of contraceptive properties, its antiestrogenic actions made it a candidate for endocrine treatment of breast cancer. Tamoxifen was first approved in 1977 for the treatment of metastatic breast cancer and subsequently as adjuvant therapy for this disease. A well-defined adverse effect profile and extensive data on secondary benefits have been accumulated from 10 million patient-years of data. Tamoxifen has become the most widely prescribed and extensively studied anticancer agent in the world (data on file, Zeneca Pharmaceuticals, Wilmington, Del, 1999). As a result of recently published long-term clinical trial data, tamoxifen has been approved for reduction of breast cancer risk in healthy women who have an increased risk of developing the disease (Table 1).2-3
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Table 1. Tamoxifen Indications
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Research has shown that tamoxifen therapy may benefit women with all stages of breast cancer, regardless of nodal or menopausal status. Analysis of data collected for more than 20 years has led to a shift in the treatment paradigm for breast cancer. Now, the hormone receptor status of a tumor is generally considered a more important factor in tamoxifen treatment decisions than a patient's age, menopausal status, or cancer staging (Table 2). Other treatment decisions rely on nodal status, tumor size, presence or absence of metastases, and patient prognosis.
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Table 2. Comparison of Selected Trials of Tamoxifen Citrate (20 mg/d) as Adjuvant Therapy*
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Since 1977, the trend has been to use tamoxifen at earlier and earlier stages of disease. Tamoxifen prevents both invasive and noninvasive disease and has been proven to reduce the incidence of invasive disease in women with in situ carcinomas.2-3
Particularly at a time when healthy women may receive a 5-year course of tamoxifen, the issues of long-term safety and secondary effects play an important role in determining which women are likely to benefit from preventive therapy. Tamoxifen has been shown to increase bone density and improve lipid profiles,4-5 but it has also been associated with increased incidence of thromboembolism and endometrial cancer.6-8 Thus, all risks and benefits of tamoxifen must be considered for each individual. Further studies may help to clarify which women are likely to benefit from preventive therapy with tamoxifen.
THE ROLE OF TAMOXIFEN IN THE TREATMENT OF BREAST CANCER
Benefit of Treatment
For hormonal treatment of advanced breast cancer in postmenopausal women, tamoxifen is the treatment of choice. In premenopausal women, physicians may choose between tamoxifen and ovarian ablation as first-line therapy, since the 2 treatments are approximately equivalent in efficacy and safety.9-10
Before breast cancer has progressed to an advanced state, tamoxifen is frequently used as an adjuvant treatment following local therapy. Clinical trials and meta-analyses have demonstrated the benefits of tamoxifen in adjuvant treatment, reporting a 42% reduction in breast cancer recurrence and a 22% reduction in mortality 10 years after treatment in women receiving 5 years of tamoxifen therapy.6 In patients with estrogen-receptor–positive tumors, tamoxifen therapy for 5 years reduced the risk of recurrence by 50% (SE, ± 4%) and reduced the risk of death by 28% (SE, ± 5%).
Individual clinical studies have shown the treatment benefits of tamoxifen to be significant for both premenopausal and postmenopausal patients with either node-positive11-16 or node-negative disease.7, 16-21 Furthermore, in the largest study of women with node-negative, estrogen receptor–positive disease, an overall survival benefit from tamoxifen accrued after 10 years (relative risk of death, 0.84; P = .04).17
Duration of Treatment
While various durations of tamoxifen treatment have been instituted in various trials (ranging from 1 year to indefinite periods of time), the most definitive trial of duration of therapy was the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial, which examined the effects of a 5-year vs a 10-year therapeutic span. Results of the study showed no significant differences between 5 and 10 years of therapy in terms of disease-free survival (92% vs 86%) and overall survival (96% vs 94%). The benefit of 5 years of tamoxifen therapy endured the 10 years of follow-up, but no additional benefit from therapy lasting longer than 5 years has yet been shown.6, 22-23
A meta-analysis conducted by the Early Breast Cancer Trialists' Collaborative Group examined data from randomized studies of adjuvant tamoxifen use that began prior to 1990. The latest results were published in 1998. Reductions in breast cancer recurrence and mortality were greater for women receiving 5 years of therapy than for those receiving 1 or 2 years of therapy (Table 3 and Table 4). Five years of tamoxifen therapy was found to reduce 10-year breast cancer recurrence rates in women overall by 42%. The meta-analysis showed that 5 years of tamoxifen therapy is clearly better than 1 or 2 years of therapy with respect to recurrence and overall mortality. After 5 years of therapy, the incidence of endometrial cancer rose (ratio of incidence rates, treated to untreated, 2.58). This was counterbalanced by a 42% decrease in incidence of contralateral breast cancer in women treated for 5 years with tamoxifen.6 To date, there is no convincing evidence of an increased benefit of tamoxifen therapy beyond 5 years.
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Table 3. Reduction in Recurrence of Breast Cancer Found by Meta-Analysis According to Duration of Tamoxifen Therapy and Estrogen-Receptor (ER) Status*
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Table 4. Reduction in Mortality Found by Meta-Analysis According to Duration of Tamoxifen Therapy in Breast Cancer Patients Receiving Tamoxifen as an Adjuvant Treatment*
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Safety
Long-term side effects of tamoxifen have been elucidated in various studies. In the B-14 study, patients in the tamoxifen group were more likely to have hot flashes, vaginal discharge, and irregular menses than were patients in the placebo group, though the difference between the groups decreased among older patients. Endometrial cancer occurred in more women who had received tamoxifen therapy than in women assigned to the placebo group (P<.001). There were no differences between groups in the development of secondary cancer in other sites.7 While 5 years of tamoxifen therapy seems to offer a benefit in many cases, risks should be weighed against benefits in individual patients.
PREVENTION OF BREAST CANCER
Preliminary Evidence
While tamoxifen has historically been used to treat rather than prevent breast cancer, the NSABP B-14 trial provided evidence that, compared with untreated controls, the group given tamoxifen had a substantial decrease in the incidence of contralateral breast cancer (P<.009). Rates of breast cancer in the treated group were less than half of those in the untreated group. Tamoxifen appeared either to treat breast tumors at such an early stage that they were never clinically detected or to prevent the formation of new tumors.7
Evidence from other large trials corroborated the significant effects of tamoxifen on the incidence of new primary breast tumors,8, 19-20 with 1 trial reporting a 40% reduction (P = .008) in the incidence of tumors in the contralateral breast in postmenopausal patients given tamoxifen compared with the incidence in those given a placebo.24 The Early Breast Cancer Trialists' Collaborative Group meta-analysis showed a 47% reduction in contralateral breast cancer among women who received 5 years of tamoxifen therapy (P<.00001). This benefit was independent of age or estrogen-receptor status of the original tumor.25
NSABP P-1 Trial
Because of the finding that tamoxifen reduces the incidence of new tumors in breast cancer patients, a trial was conducted to determine whether tamoxifen reduces the incidence of new breast cancers in healthy women at increased risk of developing the disease. The NSABP conducted the P-1 trial with women whose breast cancer risk was at least equivalent to that of a typical 60-year-old woman, as determined by a modified risk assessment model compiled from breast cancer incidence data by Mitchell Gail and colleagues of the National Cancer Institute.26 Risk factors in this model include the patient's current age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and number of breast biopsies. Modifications were made to account for patient race and benign conditions such as atypical hyperplasia.2, 26 Patients were randomly assigned to receive either 20 mg/d of tamoxifen citrate (n = 6681) or a placebo (n = 6707), each for 5 years. After 69 months of follow-up, results showed that tamoxifen reduced the risk of invasive breast cancer by 49% (P<.00001), reducing the cumulative incidence from 43.4 cases per 1000 women in the placebo group to 22.0 cases per 1000 in the tamoxifen group. All age groups experienced decreased risk, though the magnitude of the relative risk reduction increased with increasing age: 44% in women younger than 50 years; 51% in women aged 50 to 59 years; and 55% in women aged 60 years and older. The risk of invasive cancer was also reduced by 56% in women with a history of LCIS and by 86% in women with atypical hyperplasia (Table 5 and Figure 1). Tamoxifen reduced the risk of noninvasive breast cancer by 50% (P<.002). Tamoxifen did not appear to change the incidence of estrogen-receptor–negative tumors but the incidence of estrogen-receptor–positive tumors was reduced by 69%.2
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Table 5. Comparison of Tamoxifen Chemopreventive Studies*
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Reduction in the relative risk of invasive breast cancer among healthy female populations at increased risk, calculated in the NSABP P-1 trial. LCIS indicates lobular carcinoma in situ; AH, atypical hyperplasia; and NSABP, National Surgical Adjuvant Breast and Bowel Project.
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Administration of tamoxifen had both beneficial and detrimental effects unrelated to breast cancer. Tamoxifen therapy was associated with a reduction in fractures of the hip (45%), radius (Colles' fracture, 39%), and spine (26%). The total fracture reduction almost reached statistical significance (relative risk, 0.81; 95% confidence interval, 0.63-1.05). The rate of endometrial stage I cancer increased (risk ratio, 2.53, tamoxifen to placebo); risk was greatest in women aged 50 years and older. In the tamoxifen group, 36 of 6681 women developed stage I endometrial cancer, compared with the placebo group, in which 14 of 6707 patients developed stage I endometrial cancer and 1 patient developed stage IV disease. Tamoxifen was also associated with increased risk of stroke (risk ratio, 1.59), pulmonary embolism (risk ratio, 3.01), and deep vein thrombosis (risk ratio, 1.60). Again, risk was greatest in women aged 50 years or older. These differences were not statistically significant at the traditional level, but the trends are worth consideration.2 Secondary effects of tamoxifen should be considered as part of any treatment decision.
The P-1 trial was stopped when the independent monitoring committee concluded that the benefit of tamoxifen in patients at increased risk for breast cancer had been confirmed and therefore subsequent treatment with placebo would be unethical. This study showed that tamoxifen may be an appropriate prophylactic therapy in women at increased risk for breast cancer.2
Other Prevention Trials
Two trials did not find a significant protective effect of tamoxifen in their respective populations of healthy women (Table 5). The Italian Tamoxifen Prevention Study randomized women who had prior hysterectomies to receive either tamoxifen citrate 20 mg/d or a placebo for 5 years, with 5 years of follow-up planned. Recruitment occurred via national advertising and subjects were not required to have any risk factors for breast cancer. The study was finally stopped because of the high dropout rate, with only 149 (3%) of 5408 subjects having completed 5 years of treatment at the time of analysis, and with 3837 (71%) still receiving the assigned intervention. With a median follow-up of 46 months, there was no difference in breast cancer frequency between the group given placebo and that given tamoxifen. Hormone replacement therapy (HRT) was used by 14% of women during the trial. In these women, there was a statistically significant reduction (P = .0216) in the incidence of breast cancer that was not observed in the overall population. Investigators also noticed higher rates of thrombophlebitis, phlebothrombosis, and embolus (P = .0053) in women taking tamoxifen.27
Overall, the Italian trial had too low a statistical power to detect an effect of tamoxifen, and the participants were at low or average risk of developing breast cancer."27 Furthermore, there were several differences between this trial and the NSABP trial: the lack of breast cancer risk factors among participants, the smaller sample size, recruitment by advertising, the high drop-out rate, the small number of breast cancer events occurring in the placebo group, and the use of HRT among a substantial proportion of the study population, which may be a confounding factor. Another problem with the study protocol was the use of hysterectomy as an entry criterion. Women who had a hysterectomy that included oophorectomy were already at reduced risk for breast cancer because of decreased estrogen levels. The competitive estrogen-binding effects of tamoxifen could not be expected to offer additional preventive effects against the development of breast cancer in these women. Later reports on this study may shed light on whether tamoxifen is a useful agent for breast cancer prevention in low-to-normal-risk populations. The preliminary finding that tamoxifen may offer benefits in populations given HRT may be a subject for further research.
A pilot study conducted at the Royal Marsden Hospital (London, England) compared breast cancer incidence in healthy women between the ages of 30 and 70 years who received either tamoxifen or placebo. Eligibility was based on having a family history of breast cancer. Women could enter the study if they had 2 first-degree relatives with breast cancer or 1 first-degree relative with breast cancer who was either younger than 50 years or had bilateral breast cancer. Women were also eligible if they had a first-degree relative with breast cancer and a personal history of benign breast biopsy. Study participants received either tamoxifen citrate 20 mg/d or a placebo for 8 years. After a median of 70 months of follow-up (with more than 40% of women completing therapy to date), the overall frequency of breast cancer was the same for patients receiving tamoxifen (34/1238) as for patients receiving the placebo (36/1233; P = .8). Unlike the Italian trial, this study found no preventive effect of tamoxifen in women using HRT. Breast cancer developed in 12 of 523 patients in the tamoxifen group who were receiving HRT, and in 13 of 507 subjects in the placebo group who were receiving HRT (P = .6). Five cases of endometrial cancer were reported (4 in the tamoxifen group and 1 in the placebo group). Deep vein thrombosis was reported in 6 patients (4 in the tamoxifen group, 2 in the placebo group), and pulmonary embolism was reported in 5 patients (3 in the tamoxifen group, 2 in the placebo group).28
Discrepancies between the results of the British trial and the results of the NSABP P-1 trial are more perplexing because the study enrolled women with at least some risk factors for breast cancer. Royal Marsden investigators estimated the power to detect a 50% reduction in breast cancer frequency at the 5% level to be about 90%.28 The NSABP authors pointed out that the Royal Marsden study population may have been more prone to developing estrogen receptor–negative tumors than the population tested by the NSABP. Since tamoxifen's effects depend on estrogen receptor–positive status and since the study's power was based on a presumed level of prevention, this population difference could result in a significant change in the overall power of the study.2 Another significant difference between the 2 studies is the use of HRT by 26% of the participants of the British trial28 compared with no HRT use among participants in the NSABP trial. Since tamoxifen competes with natural estrogen for tumor receptor sites, concomitant endocrine therapy could confound results.
Finally, because the Royal Marsden trial enrolled women on the basis of family history,the participants were more likely to have a genetic component to their risk. In contrast, the NSABP screening included multiple factors unrelated to family history. The Royal Marsden group estimated that 36% of all study participants and 60% of those who developed breast cancer are in familial clusters with at least an 80% chance of having a gene predisposing them to breast cancer. They pointed out that tumors in women with BRCA1 and BRCA2 genes often lack progesterone receptors and the question was raised as to whether tumors in women with high-risk genes would respond to hormonal therapy in the same way as tumors in the general population.28 (This issue is being studied by the NSABP by analyzing blood samples from trial participants.) While the interim analysis of the Royal Marsden trial offers no evidence to justify the use of tamoxifen for breast cancer prevention in this study population, the study is ongoing in hopes of better defining subgroups of women who might benefit from tamoxifen.
TAMOXIFEN FOR IN SITU CARCINOMA OF THE BREAST
Lobular Carcinoma In Situ
Until recently, women with lobular carcinoma in situ (LCIS) and no evidence of invasive disease were prescribed a course of observation. Annual bilateral mammograms and semiannual physical examinations are recommended. Approximately 21% of patients with LCIS will develop invasive disease during the next 15 years, though histologic examinations are generally favorable and deaths are unusual in women with appropriate medical care.29 Any treatment of in situ carcinoma is aimed at preventing invasive disease. Surgical options such as bilateral mastectomy or breast-conserving surgery are considered only in special circumstances. Pharmacologic prophylaxis might be an alternative. Among women in the P-1 study who had a history of LCIS and received a placebo, the annual rate of invasive breast cancer was about 13 per 1000. A 5-year course of tamoxifen reduced the relative risk of invasive cancer by 56% in women with LCIS.2
Ductal Carcinoma In Situ
In the past, ductal carcinoma in situ (DCIS) was often treated with mastectomy. Tumors with negative margins may be treated with lumpectomy and radiotherapy.29 Data from the NSABP showed that, of patients with DCIS undergoing lumpectomy, 25% developed breast tumors during the next 5 years, while only 13% of those undergoing lumpectomy and radiation therapy developed breast cancer during that time. The NSABP B-24 trial demonstrated that the addition of tamoxifen to the lumpectomy and radiation regimen reduced the 5-year rates of all first breast cancer events from 13.4% (placebo) to 8.2% (P<.001). In the tamoxifen group, only 4.1% of DCIS patients had invasive cancer after 5 years, with slightly more than half of these (2.1% of the total) in the ipsilateral breast.5
CURRENT STATUS OF PREVENTION
In the United States, based on the results of the NSABP P-1 trial and the consideration of other data, tamoxifen has been approved to reduce the risk of breast cancer in women who are at increased risk for the disease. Risk of breast cancer is identified by a modified version of the National Cancer Institute method described by Gail and Benichou26 and used in the NSABP trial. In general, the higher the risk of breast cancer, the greater the benefit of preventive therapy. Experts at the National Cancer Institute calculated breast cancer cases prevented in the NSABP P-1 trial based on participants' 5-year projected risks of invasive breast cancer. In women with a 2.0% risk of developing invasive breast cancer in the next 5 years, 97 cases of breast cancer were prevented per 10,000 women receiving a preventive course of tamoxifen. As risk rose to 4.0% during a 5-year period, only 52 women needed to be treated to prevent 1 case of breast cancer, and as risk reached 7.0%, 1 case of breast cancer was prevented for every 30 women at that risk level who were given tamoxifen. If prevention of noninvasive forms of breast cancer were included in the analysis, the results would be even more impressive.30 The relative benefit of tamoxifen in women receiving HRT and in those with specific breast cancer genotypes remains to be determined.
For all women at increased risk for developing breast cancer, the benefit of prophylactic tamoxifen must be weighed against the potential risks. Women with atypical hyperplasia, LCIS, or DCIS may be good candidates for preventive therapy. Women younger than 50 years with increased risk of breast cancer may choose to receive preventive therapy before menopause to lessen thromboembolic and endometrial cancer risks, which increase after menopause. Hysterectomized women older than 50 years with a low risk for embolism or thrombosis are probably also good candidates for preventive therapy. Other women at increased risk for breast cancer should also be considered for a prophylactic course of tamoxifen if the benefits outweigh the risks.
AUTHOR INFORMATION
Accepted for publication June 20, 2000.
Corresponding author: Aman U. Buzdar, MD, Department of Breast Medical Oncology, M. D. Anderson Cancer Center, Box 56, 1515 Holcombe Blvd, Houston, TX 77037 (e-mail: abuzdar{at}mdanderson.org).
From the Department of Breast Medical Oncology, M. D. Anderson Cancer Center, Houston, Tex.
REFERENCES
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1. Jordan VC. The development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole. Breast Cancer Res Treat. 1988;11:197-209.
FULL TEXT
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ISI
| PUBMED
2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90:1371-1388.
FREE FULL TEXT
3. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999;353:1993-2000.
FULL TEXT
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ISI
| PUBMED
4. Love RR, Newcomb PA, Wiebe DA, et al. Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer. J Natl Cancer Inst. 1990;82:1327-1332.
FREE FULL TEXT
5. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med. 1992;326:852-856.
ABSTRACT
6. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet. 1998;351:1451-1467.
FULL TEXT
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ISI
| PUBMED
7. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor–positive tumors. N Engl J Med. 1989;320:479-484.
ABSTRACT
8. Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen: the Stockholm Breast Cancer Study Group. J Natl Cancer Inst. 1993;85:1398-1406.
FREE FULL TEXT
9. Crump M, Sawka CA, DeBoer G, et al. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat. 1997;44:201-210.
FULL TEXT
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ISI
| PUBMED
10. Sawka CA, Pritchard KI, Shelley W, et al. A randomized crossover trial of tamoxifen versus ovarian ablation for metastatic breast cancer in premenopausal women: a report of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA1. Breast Cancer Res Treat. 1997;44:211-215.
FULL TEXT
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ISI
| PUBMED
11. Fisher B, Redmond C, Brown A, et al. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project trial. J Clin Oncol. 1986;4:459-471.
FREE FULL TEXT
12. Marshall JS, Gordon NH, Hubay CA, Pearson OH. Assessment of tamoxifen as adjuvant therapy in stage II breast cancer: a long-term follow-up. J Lab Clin Med. 1987;109:300-307.
ISI
| PUBMED
13. Cummings FJ, Gray R, Tormey DC, et al. Adjuvant tamoxifen versus placebo in elderly women with node-positive breast cancer: long-term follow-up and causes of death. J Clin Oncol. 1993;11:29-35.
ABSTRACT
14. Pritchard KI, Sutherland DJ. The use of endocrine therapy [review]. Hematol Oncol Clin North Am. 1989;3:765-805.
ISI
| PUBMED
15. Pritchard KI, Sutherland DJA. Diagnosis and therapy of breast cancer: the use of endocrine therapy. Hematol Oncol Clin North Am. 1989;3:765-805.
16. Nolvadex Adjuvant Trial Organisation. Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer: analysis at eight years. Eur J Cancer. 1988;57:608-611.
17. Fisher B, Costantino J. Highlights of the NSABP breast cancer prevention trial. Cancer Control. 1997;4:78-86.
PUBMED
18. Breast Cancer Trials Committee. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish trial. Lancet. 1987;2:171-175.
PUBMED
19. Stewart HJ for the Scottish Cancer Trials Breast Group. The Scottish trial of adjuvant tamoxifen in node-negative breast cancer. J Natl Cancer Inst Monogr. 1992;11:117-120.
20. Baum M, Houghton J, Riley D. Results of the Cancer Research Campaign Adjuvant Trial for Perioperative Cyclophosphamide and Long-Term Tamoxifen in Early Breast Cancer reported at the tenth year of follow-up: Cancer Research Campaign Breast Cancer Trials Group. Acta Oncol. 1992;31:251-257.
ISI
| PUBMED
21. Rutqvist LE, Cedermark B, Glas U, et al. Randomized trial of adjuvant tamoxifen in node negative postmenopausal breast cancer. Acta Oncol. 1992;31:265-270.
ISI
| PUBMED
22. Fisher B, Costantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst. 1994;86:527-537.
FREE FULL TEXT
23. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst. 1996;88:1529-1542.
FREE FULL TEXT
24. Rutqvist LE, Johansson H, Signomklao T, et al. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Natl Cancer Inst. 1995;87:645-651.
FREE FULL TEXT
25. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet. 1998;352:930-942.
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ISI
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26. Gail MH, Benichou J. Epidemiology and biostatistics program of the National Cancer Institute. J Natl Cancer Inst. 1994;86:573-575.
FREE FULL TEXT
27. Veronesi U, Maisonneuve P, Costa A, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Lancet. 1998;352:93-97.
ISI
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28. Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998;352:98-101.
ISI
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29. Carlson RW, Goldstein LJ, Gradishar WJ, et al. Update of the NCCN guidelines for treatment of breast cancer. Oncology. 1997;11:199-220.
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30. Gail MH, Constantino JP, Bryant J, Crayle R, Freedman L, Helzlsouer K, Vogel V. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst. 1999;91:1829-1846.
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