This Article Abstract Full Text (PDF) Erratum (v20,p1430) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lippman, M. E. Articles by Cummings, S. R. Search for Related Content PubMed PubMed Citation Articles by Lippman, M. E. Articles by Cummings, S. R.

Indicators of Lifetime Estrogen Exposure: Effect on Breast Cancer Incidence and Interaction With Raloxifene Therapy in the Multiple Outcomes of Raloxifene Evaluation Study Participants

From the Osteoporosis Research Program, Women’s College Hospital, Toronto, Ontario, Canada; Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC; Lilly Research Laboratories, Indianapolis, IN; Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA; and Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco, CA.

Address reprint requests to Marc E. Lippman, MD, Department of Internal Medicine, 3101 Taubman Center, University of Michigan Health System, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0368; email: lippmanm{at}umich.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To test the hypothesis that risk factors related to lifetime estrogen exposure predict breast cancer incidence and to test if any subgroups experience enhanced benefit from raloxifene.

PATIENTS AND METHODS: Postmenopausal women with osteoporosis (N = 7,705), enrolled onto the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, were randomly assigned to receive placebo, raloxifene 60 mg/d, or raloxifene 120 mg/d for 4 years. Breast cancer risk was analyzed by the following baseline characteristics indicative of estrogen exposure: previous hormone replacement therapy, prevalent vertebral fractures, family history of breast cancer, estradiol level, bone mineral density (BMD), body mass index, and age at menopause. Therapy-by-subgroup interactions were assessed using a logistic regression model.

RESULTS: Overall, women with the highest one-third estradiol levels ( 12 pmol/L) had a 2.07-fold increased invasive breast cancer risk compared with women with lower levels. Raloxifene significantly reduced breast cancer risk in both the low- and high-estrogen subgroups for all risk factors examined (P < .05 for each comparison). The women with the highest BMD and those with a family history of breast cancer experienced a significantly greater therapy benefit with raloxifene, compared with the two thirds of patients with lower BMD or those without a family history, respectively; the subgroup-by-therapy interactions were significant (P = .005 and P = .015, respectively).

CONCLUSION: The MORE trial confirms that increased lifetime estrogen exposure increases breast cancer risk. Raloxifene therapy reduces breast cancer risk in postmenopausal osteoporotic women regardless of lifetime estrogen exposure, but the reduction is greater in those with higher lifetime exposure to estrogen.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Identification of women who are at increased risk for breast cancer, and thus may benefit more from lifestyle modifications or preventive therapies, is an emerging and growing need. It is also essential to understand any variability in the effect of preventive therapies among patient populations.

Endogenous estrogen exposure has been linked to increased breast cancer risk, both measured directly through serum estradiol levels^1,2 and as assessed through surrogate indicators of lifetime estrogen exposure, such as nulliparity, older age at first birth, early menarche, late menopause,^3,4 and increased breast density.⁵ Other estrogen-related risk factors also have been identified, including other disease states. For example, women with osteoporosis are more likely to have a lower lifetime estrogen exposure and a lower risk for breast cancer,^6,7 Body mass index (BMI), which is negatively correlated with premenopausal breast cancer risk,⁸ is positively correlated with postmenopausal breast cancer risk.^9-11 In addition, obese women have higher endogenous estrogen levels¹¹ and are more likely to develop estrogen receptor–positive (ER+) tumors.¹²

Although the role of endogenous estrogen in breast cancer has been established,¹³ the role of exogenous hormones in the form of estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) seems probable but remains controversial. Two large studies (one prospective study and one literature review) both concluded that HRT increases breast cancer risk.^14,15 Even though the magnitude of increased breast cancer risk caused by exogenous estrogen is unknown, the fear of cancer prevents many women from taking estrogen therapies.¹⁶

Raloxifene is a selective ER modulator with estrogen agonist effects on bone^17,18 and lipids^17,19 and estrogen antagonist effects in the breast and uterus.^20-22 Raloxifene is currently approved in the United States for the prevention and treatment of postmenopausal osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) Study (a double blind, placebo-controlled, randomized clinical trial) evaluated the effect of long-term therapy with raloxifene in the treatment of postmenopausal osteoporosis. The incidence of breast cancer was a secondary end point of the trial, and previous analyses indicated that raloxifene reduced the incidence of invasive breast cancer and ER+ invasive breast cancers compared with placebo after 40 months of follow-up.²⁰

We hypothesized that patients in MORE with the highest exposure to estrogen would have the greatest risk of breast cancer, and correspondingly, that the effect of raloxifene would be greatest in those patients. We confirmed that several risk factors for breast cancer (eg, serum estradiol levels, bone mineral density [BMD], BMI, or family history of breast cancer) predict breast cancer incidence in the MORE trial. We demonstrated that women in subgroups reflecting higher estrogen exposure experience enhanced benefit from raloxifene therapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
This multicenter, randomized trial enrolled 7,705 postmenopausal ( 2 years past menopause) women of up to 80 years of age with osteoporosis, as defined by low BMD (lumbar spine or femoral neck t-score -2.5) or prevalent vertebral fractures.^18,20 Women with a known or suspected history of breast cancer, invasive endometrial cancer, abnormal uterine bleeding, or history of stroke or venous thromboembolic disease during the past 10 years were excluded. Women were also excluded if they had taken systemic estrogen (except estriol 2 mg/d); topical estrogen more often than three times a week; progestins, androgens, or corticosteroids during the previous 6 months; or if they drank more than four alcoholic drinks per day. All women provided written informed consent. There were no therapy-group differences for any baseline characteristic (Table 1).

Breast Cancer Ascertainment
Mammograms or breast ultrasonography were optional at year 1 and required at baseline and at years 2, 3, and 4. At each study visit (every 6 months), women were also asked about any breast cancer, biopsies, or surgeries that had occurred since the last visit. If the investigators suspected breast cancer, they requested records of procedures. Women who were diagnosed with breast cancer stopped study medication, and their therapy assignments were unblinded to both the sponsor and the United States Food and Drug Administration.

All reported cases of breast cancer were reviewed by an independent blinded adjudication committee of five breast cancer specialists and one nonvoting pharmacologic scientist, none of whom were employed by the sponsor.²⁰ The committee reviewed patient history, mammograms, and available pathology reports from each reported case of breast cancer and determined whether the cancer was (1) a confirmed diagnosis of primary breast cancer and (2) invasive or noninvasive. A diagnosis of indeterminate was assigned when data were insufficient for evaluation.

Analysis
All results reported for patients assigned to raloxifene include patients from both the 60-mg and 120-mg dose groups. Baseline demographic variables were assessed for potential therapy differences using one-way analysis of variance for continuous variables and Pearson’s ² test for categorical variables.

We analyzed the relationship between the incidence of breast cancer and demographic and baseline patient characteristics, including the following: serum estradiol level, femoral neck BMD, BMI, age at menopause, previous HRT use, prevalent vertebral fractures, and family history of breast cancer.

Analyses of breast cancer incidence according to baseline indicators of estrogen exposure were accomplished by dichotomizing baseline variables into two categories. For categorical variables, this dichotomization was based on a yes/no characteristic (eg, previous HRT use [yes/no]; family history of breast cancer [yes/no]). For continuous variables such as BMI and BMD, we divided the participants into two categories: the one third of the cohort with highest theoretical exposure to estrogen (eg, the one third with the highest baseline BMI) versus the two thirds with average to low theoretical exposure to estrogen (Table 2).

The relative risk of developing breast cancer during raloxifene therapy versus placebo was estimated for each subgroup of the demographic variables considered. In addition, the relative risk among patients in the high-estradiol exposure versus low-estradiol exposure subgroups was determined within each therapy group. Results were considered statistically significant if P < .05 or if a 95% confidence interval (CI) excluded 1.0. CIs were calculated using the Mantel-Haenszel estimates provided in SAS Version 6.09 (Cary, NC).

For one of the assessed subgroups (patients with family history of breast cancer), none of the patients assigned to raloxifene developed invasive breast cancer. To obtain the upper confidence limit for this subgroup, we arbitrarily added one breast cancer patient on raloxifene among women with a family history of breast cancer for purposes of calculation. We believe this is a conservative estimate.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
More than 99.97% of the 7,705 postmenopausal women had breast imaging at baseline, and 48% elected to have an optional breast imaging procedure at the 12-month visit; 91% to 94% of women had required annual breast imaging at years 2, 3, and 4. The small proportion of women choosing sonography at each annual visit (approximately 3% of patients with imaging performed) was similar among therapy groups. Approximately 12% of women reported use of any form of estrogen at some point during the trial; there were no treatment-group differences in the use of concomitant estrogens.

Breast Cancer
At the completion of the 4-year trial (mean and median follow-up of 39.4 and 47.4 months, respectively), 79 cases of breast cancer were reported. Of those, 77 were confirmed by the adjudication board to be primary breast cancer, and 61 of those had sufficient data to be categorized as invasive. Raloxifene (pooled 60-mg/d and 120-mg/d doses) reduced the risk of invasive breast cancer by 72% (relative risk, raloxifene v placebo, 0.28; 95% CI, 0.17 to 0.46).²³

Breast Cancer Risk Factor Subgroups
Overall, women with the highest one-third estradiol levels ( 12 pmol/L) had a 2.07-fold increased invasive breast cancer risk (range, 1.26- to 3.41-fold risk) compared with women with lower levels. In the placebo group, women with the highest estradiol levels had a significantly increased risk for invasive breast cancer (relative risk, 2.56; 95% CI, 1.39 to 4.72); in the raloxifene group, the increased risk was 1.48-fold (nonsignificant) (Table 3). The only baseline characteristic to significantly increase the risk for breast cancer in both therapy groups was prevalent vertebral fracture (2.20-fold and 6.61-fold for placebo and raloxifene, respectively) (Table 3).

View larger version (50K): [in this window] [in a new window]   Fig 1. The relative breast cancer risk reduction after 48 months (median) of raloxifene (60 and 120 mg/d combined v placebo) and 95% CI (narrow striped bars). Raloxifene reduced the breast cancer risk in both the low– and high–estrogen exposure subgroups for all risk factors examined. (a) P < .05; (b) P < .01; (c) P .001, within-subgroup therapy comparisons; (d) P = .005 for treatment-by-subgroup interaction for baseline femoral neck BMD; (e) P = .015 for treatment-by-subgroup interaction for family history of breast cancer; and (f) no cases occurred in the raloxifene group. To obtain the upper confidence limit, we arbitrarily added 1 breast cancer case on raloxifene among women with a family history of breast cancer for purposes of calculation. We believe this is a conservative estimate.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this 4-year, placebo-controlled trial in postmenopausal women with osteoporosis, we confirmed that women with higher lifetime exposure to estradiol, as indicated by higher baseline serum-estradiol levels, higher femoral neck BMD, higher BMI, previous HRT use, no prevalent vertebral fractures, and family history of breast cancer tended to have higher risks for invasive breast cancer.

The inverse association between osteoporosis and breast cancer risk has been demonstrated in previous studies, which have described a 30% to 50% increase in breast cancer risk for each SD increase in BMD⁷ and a decreased breast cancer risk in women with previous hip fracture.⁶ We observed similar results in this trial. Women assigned to placebo who had osteoporotic (vertebral) fractures at baseline had about half the incidence of breast cancer as women on the placebo with no baseline fractures (relative risk, 0.45; 95% CI, 0.22 to 0.95). However, other studies have shown that the predictive value of BMD on breast cancer risk may be influenced by family history of breast cancer,²⁴ endogenous estrogen, and other covariates.²⁵ Nonetheless, this effect with BMD on breast cancer risk may be clinically relevant, because BMD measurements may serve as a surrogate for assessing a woman’s lifetime estrogen exposure and breast cancer risk.

Overall, 4 years of raloxifene therapy significantly reduced the risk of invasive breast cancer by 72% in this clinical trial of postmenopausal osteoporotic women.²³ Although the effect remained significant across subgroups representing different degrees of lifetime estrogen exposure, the therapeutic effect of raloxifene was greatest among women with evidence of higher lifetime estrogen exposure. Women with higher femoral neck BMD or a family history of breast cancer experienced significantly greater risk reduction on raloxifene compared with women who had lower BMD or who had no family history of the disease, based on significant therapy-by-subgroup interactions.

Although baseline serum estradiol levels did not significantly alter the therapeutic effect of raloxifene, the higher estradiol subgroup experienced a somewhat greater protective effect with therapy. BMD or family history of breast cancer may serve as surrogates of estrogenicity, because increased BMD and positive family history predicted enhanced invasive breast cancer risk reduction with raloxifene in the MORE trial. The variable strengths of the associations between these estrogenicity surrogates and therapeutic effect may suggest that parameters such as BMD or family history of breast cancer may more accurately reflect lifetime estrogen exposure than a more recent snapshot of estrogen exposure provided by a single estradiol measurement.

This differential effect of raloxifene on breast cancer risk reduction may be due to an increase in ER+ tumors with higher estrogen exposure and an ER-antagonistic effect of raloxifene that suppress ER+ tumor growth. Raloxifene may suppress the growth of subclinical tumors,²⁰ opposing the stimulatory effects of increased estrogen exposure. The idea that the effect of a therapy can be modified by patient characteristics or even concomitant therapy has been demonstrated with another selective ER modulator: both ERT and obesity substantially increase the association between tamoxifen use and endometrial cancer risk among patients with breast cancer.²⁶

The effect of raloxifene to reduce the risk of breast cancer differentiates it from ERT and HRT, which may increase the risk of breast cancer^14,27,28 and which are associated with increased breast pain²⁹ and increased breast density.³⁰ In contrast, raloxifene does not cause breast pain³¹ or increase breast density in postmenopausal women.³²

A limitation of this analysis is the level of detail of information available on previous HRT use. Because the type or duration of previous HRT use were not uniformly collected, no conclusions about different HRT regimens can be made. In addition, the majority of MORE patients were white. Although this is consistent with a population screened for osteoporosis, it may limit the extrapolation of these breast cancer findings to the general population. Finally, because women were selected for this trial based on their osteoporosis rather than their breast cancer risk, the only breast cancer risk factors collected were age and family history.

Another limitation may be that women in our study had lower estradiol levels (with two thirds of the cohort having levels less than 12 pmol/L) compared with other published studies in postmenopausal women. For example, in an analysis from the Nurses’ Health Study (217 postmenopausal women, on average 61.5 years of age, 13.3 years past menopause, with BMI of 26.1), mean serum estradiol was 25.3 pmol/L (using a conversion of 3.671 to convert pg/mL to pmol/L).² In the Study of Osteoporosis Fractures,¹ women were, on average, 71 years of age, about 15 years past menopause, had BMI of about 27, and mean estradiol levels of 22 to 29 pmol/L. However, the breast cancer incidence in the MORE trial is consistent with the incidence expected for women over 65 years of age in the Surveillance, Epidemiology, and End-Results database.³² The relatively higher-than-expected incidence in the MORE population may be due, in part, to increased detection by regular mammography.

Although the postmenopausal, osteoporotic women enrolled in MORE may have had low⁷ to normal³³ baseline risk for breast cancer, raloxifene significantly reduced this risk during 4 years of therapy. Although the risk reduction rate was maintained in every subgroup related to lifetime estradiol, raloxifene may cause a greater breast cancer risk reduction rate in women with higher lifetime estrogen exposure. The definition of higher lifetime estrogen exposure could be based on higher BMD ( 0.649 g/cm²) and family history of breast cancer compared with those who have low to normal BMD or who have no family history. Other baseline patient characteristics could also be predictive.

We conclude that raloxifene therapy reduces the risk of breast cancer in postmenopausal osteoporotic women regardless of lifetime estrogen exposure but that the reduction is greater in those with higher lifetime exposure to exogenous or endogenous estrogen. This differentiated treatment effect, greater efficacy in women with greater risk of breast cancer, enhances the safety and efficacy profile of raloxifene. The larger ongoing Ralifene for Use in the Heart³⁴ and Study of Tamoxifen and Raloxifene³⁵ trials will provide additional information on the effect of raloxifene on breast cancer risk.

	ACKNOWLEDGMENTS

 
We thank Evelyn Park, MSc, for statistical programming.

	NOTES

 
Supported by Eli Lilly and Company, Indianapolis, IN.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Cauley JA, Lucas FL, Kuller LH, et al: Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer: Study of Osteoporotic Fractures Research Group. Ann Intern Med 130: 270-277, 1999

2. Hankinson SE, Willett WC, Manson JE, et al: Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90: 1292-1299, 1998[Abstract/Free Full Text]

3. Colditz GA: Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 90: 814-823, 1998[Abstract/Free Full Text]

4. Monninkhof EM, van der Schouw YT, Peeters PH: Early age at menopause and breast cancer: Are leaner women more protected? A prospective analysis of the Dutch DOM cohort. Breast Cancer Res Treat 55: 285-291, 1999[Medline]

5. Boyd NF, Byng JW, Jong RA, et al: Quantitative classification of mammographic densities and breast cancer risk: Results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87: 670-675, 1995[Abstract/Free Full Text]

6. Ganry O, Peng J, Dubreuil A: Is there a reduced risk of breast cancer among women with hip fractures? Eur J Epidemiol 15: 313-315, 1999[Medline]

7. Cauley JA, Lucas FL, Kuller LH, et al: Bone mineral density and risk of breast cancer in older women: The study of osteoporotic fractures—Study of Osteoporotic Fractures Research Group. J Am Med Assoc 276: 1404-1408, 1996[Abstract]

8. Vatten LJ, Kvinnsland S: Body mass index and risk of breast cancer: A prospective study of 23,826 Norwegian women. Int J Cancer 45: 440-444, 1990[Medline]

9. Hall HI, Coates RJ, Uhler RJ, et al: Stage of breast cancer in relation to body mass index and bra cup size. Int J Cancer 82: 23-27, 1999[Medline]

10. La Vecchia C, Negri E, Franceschi S, et al: Body mass index and post-menopausal breast cancer: An age-specific analysis. Br J Cancer 75: 441-444, 1997[Medline]

11. Cauley JA, Gutai JP, Kuller LH, et al: The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol 129: 1120-1131, 1989[Abstract/Free Full Text]

12. Maehle BO, Tretli S: Pre-morbid body-mass-index in breast cancer: Reversed effect on survival in hormone receptor negative patients. Breast Cancer Res Treat 41: 123-130, 1996[Medline]

13. Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, et al: A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 87: 190-197, 1995[Abstract/Free Full Text]

14. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52705 women with breast cancer and 108411 women without breast cancer. Lancet 350: 1047-1059, 1997[Medline]

15. Colditz GA, Stampfer MJ, Willett WC, et al: Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women [published erratum appears in JAMA 265: 1828, 1991]. JAMA 264: 2648-2653, 1990[Abstract]

16. Jamieson MA, Reid RL: Compliance with Menopausal Hormone Replacement Therapy, in Lorrain J, Plouffe L, Ravnikar V, et al (eds): Comprehensive Management of Menopause. New York, NY: Springer-Verlag, 1994, pp 309-317

17. Delmas PD, Bjarnason NH, Mitlak BH, et al: Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337: 1641-1647, 1997[Abstract/Free Full Text]

18. Ettinger B, Black DM, Mitlak BH, et al: Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. JAMA 282: 637-645, 1999[Abstract/Free Full Text]

19. Walsh BW, Kuller LH, Wild RA, et al: Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 279: 1445-1451, 1998[Abstract/Free Full Text]

20. Cummings S, Eckert S, Krueger K, et al: The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 281: 2189-2197, 1999[Abstract/Free Full Text]

21. Goldstein SR, Scheele WH, Rajagopalan SK, et al: A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet Gynecol 95: 95-103, 2000[Abstract/Free Full Text]

22. Cohen FJ, Watts S, Shah A, et al: Uterine effects of three-year raloxifene therapy in postmenopausal women under age 60. Obstet Gynecol 95: 104-110, 2000[Abstract/Free Full Text]

23. Cauley JA, Norton L, Lippman ME, et al: Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-Year results from the MORE trial. Breast Cancer Res Treat 65: 125-134, 2001[Medline]

24. Lucas FL, Cauley JA, Stone RA, et al: Bone mineral density and risk of breast cancer: Differences by family history of breast cancer: Study of Osteoporotic Fractures Research Group. Am J Epidemiol 148: 22-29, 1998[Abstract/Free Full Text]

25. Buist DSM, LaCroix AZ, White E, et al: Bone mineral density (BMD), endogenous hormones, and risk in postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 9: 235, 2000

26. Bernstein L, Deapen D, Cerhan JR, et al: Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 91: 1654-1662, 1999[Abstract/Free Full Text]

27. Schairer C, Lubin J, Troisi R, et al: Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 283: 485-491, 2000[Abstract/Free Full Text]

28. Ross RK, Paganini-Hill A, Wan PC, et al: Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst 92: 328-332, 2000[Abstract/Free Full Text]

29. Rozenberg S, Vandromme J, Kroll M, et al: Compliance to hormone replacement therapy. Int J Fertil Menopausal Stud 40: 23-32, 1995

30. Greendale GA, Reboussin BA, Sie A, et al: Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Ann Intern Med 130: 262-269, 1999

31. Davies GC, Huster WJ, Lu Y, et al: Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol 93: 558-565, 1999[Abstract/Free Full Text]

32. Freedman M, Martin JS, O’Gorman J, et al: Digitized mammography: A clinical trial of postmenopausal women randomly assigned to receive raloxifene, estrogen, or placebo. J Natl Cancer Inst 93: 51-56, 2001[Abstract/Free Full Text]

33. Ries LAG, Kosary CL, Hankey BF, et al: SEER Cancer Statistics Review. Bethesda, MD: National Cancer Institute, 1999

34. Barrett-Connor E, Wenger NK, Grady D, et al: Hormone and nonhormone therapy for the maintenance of postmenopausal health: The need for randomized controlled trials of estrogen and raloxifene. J Womens Health 7: 839-847, 1998[Medline]

35. National Cancer Institute: Publication of the MORE Trial Results Support Study of Tamoxifen and Raloxifene (STAR). Bethesda MD: Press Release of National Cancer Institute, National Institutes of Health, Office of Cancer Communications, June 15, 1999

Submitted November 9, 2000; accepted March 31, 2001.

This article has been cited by other articles:

				H. Kennecke, I. Olivotto, C Speers, B Norris, S. Chia, C Bryce, and K. Gelmon Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen Ann. Onc., January 1, 2007; 18(1): 45 - 51. [Abstract] [Full Text] [PDF]

				A. Hirbe, E. A. Morgan, O. Uluckan, and K. Weilbaecher Skeletal complications of breast cancer therapies. Clin. Cancer Res., October 15, 2006; 12(20): 6309s - 6314s. [Abstract] [Full Text] [PDF]

				M. E. Lippman, S. R. Cummings, D. P. Disch, J. L. Mershon, S. A. Dowsett, J. A. Cauley, and S. Martino Effect of Raloxifene on the Incidence of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis Categorized by Breast Cancer Risk Clin. Cancer Res., September 1, 2006; 12(17): 5242 - 5247. [Abstract] [Full Text] [PDF]

				A. D.-Y. Lin, A. Mannikarottu, B. A Kogan, C. Whitbeck, P. Chichester, R. E Leggett, and R. M Levin Estrogen induces angiogenesis of the female rabbit bladder. J. Endocrinol., August 1, 2006; 190(2): 241 - 246. [Abstract] [Full Text] [PDF]

				V. G. Vogel, J. P. Costantino, D. L. Wickerham, W. M. Cronin, R. S. Cecchini, J. N. Atkins, T. B. Bevers, L. Fehrenbacher, E. R. Pajon Jr, J. L. Wade III, et al. Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial JAMA, June 21, 2006; 295(23): 2727 - 2741. [Abstract] [Full Text] [PDF]

				V. G. Vogel and E. Taioli Have We Found the Ultimate Risk Factor for Breast Cancer? J. Clin. Oncol., April 20, 2006; 24(12): 1791 - 1794. [Full Text] [PDF]

				S R Davis, I Dinatale, L Rivera-Woll, and S Davison Postmenopausal hormone therapy: from monkey glands to transdermal patches J. Endocrinol., May 1, 2005; 185(2): 207 - 222. [Abstract] [Full Text] [PDF]

				S. Wang, F. Paris, C. S. Sultan, R. X.-D. Song, L. M. Demers, B. Sundaram, J. Settlage, S. Ohorodnik, and R. J. Santen Recombinant Cell Ultrasensitive Bioassay for Measurement of Estrogens in Postmenopausal Women J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1407 - 1413. [Abstract] [Full Text] [PDF]

				C. C. Benz, C. A. Clarke, and D. H. Moore II Geographic Excess of Estrogen Receptor-Positive Breast Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2003; 12(12): 1523 - 1527. [Abstract] [Full Text] [PDF]

				J. J. Dignam, K. Wieand, K. A. Johnson, B. Fisher, L. Xu, and E. P. Mamounas Obesity, Tamoxifen Use, and Outcomes in Women With Estrogen Receptor-Positive Early-Stage Breast Cancer J Natl Cancer Inst, October 1, 2003; 95(19): 1467 - 1476. [Abstract] [Full Text] [PDF]

				N. F. Col The Use of Gene Tests to Detect Hereditary Predisposition to Chronic Disease: Is Cost-Effectiveness Analysis Relevant? Med Decis Making, September 1, 2003; 23(5): 441 - 448. [Abstract] [PDF]

				S P Tuck and R M Francis Osteoporosis Postgrad. Med. J., September 1, 2002; 78(923): 526 - 532. [Abstract] [Full Text] [PDF]

				R. T. Chlebowski, N. Col, E. P. Winer, D. E. Collyar, S. R. Cummings, V. G. Vogel III, H. J. Burstein, A. Eisen, I. Lipkus, and D. G. Pfister American Society of Clinical Oncology Technology Assessment of Pharmacologic Interventions for Breast Cancer Risk Reduction Including Tamoxifen, Raloxifene, and Aromatase Inhibition J. Clin. Oncol., August 1, 2002; 20(15): 3328 - 3343. [Abstract] [Full Text] [PDF]

				S. R. Cummings, T. Duong, E. Kenyon, J. A. Cauley, M. Whitehead, K. A. Krueger, and for the Multiple Outcomes of Raloxifene Evaluation Serum Estradiol Level and Risk of Breast Cancer During Treatment With Raloxifene JAMA, January 9, 2002; 287(2): 216 - 220. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Erratum (v20,p1430) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lippman, M. E. Articles by Cummings, S. R. Search for Related Content PubMed PubMed Citation Articles by Lippman, M. E. Articles by Cummings, S. R.