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Originally published as JCO Early Release 10.1200/JCO.2009.23.9988 on September 14 2009 © 2009 American Society of Clinical Oncology.
Combined Hormone Therapy at Menopause and Breast Cancer: A Warning—Short-Term Use Increases RiskDivision of Cancer Etiology, Department of Population Sciences, City of Hope Comprehensive Cancer Center and The Beckman Research Institute, Duarte, CA Observational epidemiological studies have repeatedly demonstrated that breast cancer risk is associated with current and long-term use of combined estrogen plus progestagen hormone therapy (HT), with an excess risk of 5% to 9% per year of HT use.1 Yet, it was not until the dissemination of results from the Women's Health Initiative (WHI) clinical trial in 20022 that the medical community began to acknowledge that the risks associated with combined therapy outweighed the benefits. Beginning in 2003, the United States Food and Drug Administration issued draft guidelines for labeling estrogen-containing products suggesting that the only appropriate use of HT was short-term use to relieve menopausal symptoms.3 A number of organizations followed with similar guidelines, further recommending discontinuation of any use of HT for disease prevention.4–10 A major stimulus for these recommendations was the WHI clinical trial results showing that women receiving daily estrogen (E; 0.625 mg conjugated equine estrogen) combined with a progestin (P; 2.5 mg medroxyprogesterone acetate) had greater risk of coronary heart disease than did women receiving a placebo2; yet, the most notable impact of this randomized trial has been the marked decline in United States breast cancer incidence rates beginning in mid-200211–14 after decades of increasing incidence.13,15,16 These reductions in incidence have been observed primarily for estrogen receptor–positive breast cancer11,13 and among non-Hispanic white women age 50 years or older17 living in urban more affluent counties in the United States,18 areas where the prevalence of HT use would have been expected to be high. In parallel with other studies of declining incidence rates, the WHI observational study of more than 41,000 postmenopausal women also showed a marked decline in breast cancer incidence in 2003 among women who had been taking E + P at entry into the cohort.19 The WHI E + P clinical trial, which included more than 16,000 postmenopausal women with an intact uterus who were age 50 to 79 years, found that, overall, women in the treatment arm had 24% greater breast cancer risk over the intervention period, which averaged 5.6 years, than did women in the placebo arm.2,20 Shortly after dissemination of the WHI results for breast cancer and cardiovascular disease, the number of prescriptions for HT dropped by more than 50% in the United States.13,21–23 Although E + P may act as a direct carcinogen, initiating a new tumor, the immediate decline in breast cancer incidence after a decline in E + P prescribing and usage suggests that E + P is a strong promoter of occult, mammographically and clinically nondetectable cancers. Subgroup results published from the WHI E + P clinical trial initially suggested a delay in response. For example, Chlebowski et al19 showed that breast cancer rates did not increase during the first 2 years after random assignment, which suggests that any proliferative impact of E + P on existing occult tumors requires a longer lead period to become detectable. This is consistent with additional analyses showing that the adverse impact of E + P was more evident among women with previous exposure to HT than among women with no prior HT use.24 Further, breast cancer risk did not appear to increase until after 5 years of treatment among women who had no HT exposure before random assignment to the E + P arm.24 Although excess breast cancers were observed on the E + P arm after the clinical trial was halted, the increase in the risk of breast cancer relative to the placebo group during the 2.4 years postintervention phase of the trial was no longer statistically significant and the relative risk gradually declined to 1.0 with increasing time since the end of the trial.19 In total, these results suggest a delay in the increase in breast cancer risk of about 2 years after initial use (when prior users and new users are combined), and a decline in the increased risk that disappears within a 2- to 3-year time period. The former finding is consistent with findings in the Heart and Estrogen/Progestin Replacement Study (HERS), a clinical trial of E + P use among postmenopausal women with established coronary disease, which showed an increase in breast cancer risk in the E + P arm in the first 2 to 5 years after initiation of treatment.25 The latter finding of declining incidence rates within 2 to 3 years of cessation of HT use was also observed in the French E3N cohort26 described in more detail below and in the postintervention phase of HERS.27
A criticism of the WHI that has often been raised is the clinical relevance in relation to cardiovascular risk of a trial in which the majority of recruited women had been menopausal for many years.28–30 An analysis of the WHI in recently postmenopausal women showed no cardioprotective effects of E + P.31,32 This has raised a another important question regarding breast cancer: is short-term E + P use at menopause, when most needed for moderate to severe menopausal symptoms, safe in relation to breast cancer risk? Prentice et al33 attempted to look at this issue, combining data from the WHI E + P clinical trial and the WHI observational study, and comparing women who initiated HT use at menopause (defined as having a zero gap time between menopause and the initiation of first E + P use) with those who had no E + P use. For women on the E + P trial, the hazard ratio (HR) was elevated among those who initiated treatment within 5 years of menopause but not among women with gap times of 5 or more years. For example, among those with no prior E + P exposure before entering the WHI clinical trial, the HR was 1.77 with a 95% CI of 1.07 to 2.93 for a gap time shorter than 5 years, whereas it was 0.99 (95% CI, 0.74 to 1.31) for a gap time
In this issue of Journal of Clinical Oncology, Fournier et al34 use data from the E3N cohort, one of the contributing cohorts to the European Prospective Investigation into Cancer and Nutrition, to focus more closely on use of estrogen and progestagen at menopause, addressing with greater statistical power than was available in the Prentice et al report33 the question of use shortly after menopause, and also whether duration of estrogen and progestagen use near menopause matters. This is a carefully designed analysis of data collected at cohort formation and supplemented by data collected approximately every 2 years over the follow-up period from 1992 through 2005. Onset of natural menopause (defined as having at least 12 months elapse since a woman's last menstrual period), surgical menopause and use of combined estrogen and progestagen therapy, were collected prospectively permitting analyses of gap times since menopause that were This report contributes significantly to our knowledge about the potential hazards associated with current clinical practice guidelines indicating that E + P can be used as needed for a limited time period to ameliorate vasomotor and other symptoms of menopause. An immediate 50% increase in breast cancer risk observed within the first 2 years of use is alarming. But, the results are not completely generalizable to other populations as the estrogen plus progestagen regimens used in France as studied in the E3N cohort differ from the most commonly used regimens in the United States, such as the E + P regimen studied in the WHI clinical trial. Women in the E3N study cohort used mainly transdermal or percutaneous estradiol combined with synthetic progestagens including dydrogesterone, nomegestrol acetate, promegestone, chlormadinone acetate, medrogestone, and cyproterone acetate.26 Few women took oral estrogens combined with medroxyprogesterone acetate.26 Thus, it will be important for other cohorts that focus on use of HT in United States populations to evaluate breast cancer risk associated use immediately after menopause. An important issue is the complexity of clinical management of patients. A segment of the medical community has remained skeptical of the WHI clinical trial results30,35–37 and hence is likely to remain unconvinced by the current report by Fournier et al. One view that has been advanced is that the adverse effects of combined E + P therapy as identified in the WHI have been blown out of proportion, do not consider the usual context of HT use at menopause in relation to coronary heart disease risk, and have not been presented fairly in the context of other potential breast cancer risk factors.38 One commentary has taken a controversial view, arguing that E + P therapy has a beneficial impact because it promotes early detection of pre-existing nondetected tumors, thereby leading to better outcomes after breast cancer diagnosis.39 Finally, we must be aware that some women may turn to so-called natural hormones in the belief that because these hormones are not synthetic, chemically formulated hormones, they are safe. This belief is fostered by the increasing promotion of the use of bioidentical hormone replacement therapy, a regimen of so-called natural hormones being recommended by several influential entertainers,40–42 but criticized in the news media40,41 and in an US Food and Drug Administration news release, dated January 10, 2008,43 that warns health care providers and patients that claims made about bio-identical hormone replacement therapy are not supported by medical evidence and are considered false and misleading. A number of factors come into play in the decision as to whether a woman will or will not use combined E + P therapy in the period immediately after menopause. The increase in risk of breast cancer shown in the current report by Fournier and colleagues in this issue, may influence some decisions about use immediately after menopause. But, further data are needed to confirm these results and generalize them to other formulations such as E + P. In the meantime, it would seem that a conservative approach regarding use of combined HT at menopause is warranted, using hormones briefly and only when menopausal symptoms are so intense that no other approach will work. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
Acknowledgment Supported by grant No. CA CA77398 from the National Institutes of Health. NOTES See accompanying article on page 5138 REFERENCES 1. Lee S, Ross RK, Pike MC: An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Br J Cancer 92:2049–2058, 2005.[CrossRef][Medline] 2. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321–333, 2002. 3. U.S. Food and Drug Administration. Draft Guidance for Industry on Labeling for Noncontraceptive Estrogen Drug Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms-Prescribing Information for Health Care Providers and Patient Labeling; Availability. http://www.fda.gov/OHRMS/DOCKETS/98fr/98d-0834-nad0004.pdf. 4. Practice Committee of the American Society for Reproductive Medicine: Estrogen and progestogen therapy in postmenopausal women. Fertil Steril 90:S88–S102, 2008 (suppl 3.[Medline] 5. North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 14:168–182, 2007.[CrossRef][Medline] 6. AACE Menopause Guidelines Revision Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocr Pract 12:315–337, 2006.[Medline] 7. U.S. Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: Recommendations from the U.S. Preventive Services Task Force. Ann Intern Med 142:855–860, 2005. 8. North American Menopause Society. 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Glass AG, Lacey JV Jr, Carreon D, et al: Breast cancer incidence, 1980-2006: Combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst 99:1152–1161, 2007. 14. Clarke CA, Glaser SL, Uratsu SL, et al: Recent declines in hormone therapy utilization and breast cancer incidence: Clinical and population-based evidence. J Clin Oncol 24:e49–e50, 2006. 15. Horner MJ, Ries LAG, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2006, National Cancer Institute. Bethesda, MD: National Cancer Institute, 2009. 16. Glass A, Hoover RN: Changing incidence of breast cancer. J Natl Cancer Inst 80:1076–1077, 1988. 17. Pfeiffer RM, Mitani A, Matsuno RK, et al: Racial differences in breast cancer trends in the United States (2000-2004). J Natl Cancer Inst 100:751–752, 2008. 18. Hausauer AK, Keegan TH, Chang ET, et al. Recent trends in breast cancer incidence in US white women by urban/rural and poverty status. 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Anderson GL, Chlebowski RT, Rossouw JE, et al: Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas 55:103–115, 2006.[CrossRef][Medline] 25. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605–613, 1998. 26. Fournier A, Berrino F, Clavel Chapelon F: Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study. Breast Cancer Res Treat 107:103–111, 2008.[CrossRef][Medline] 27. Hulley S, Furberg C, Barrett-Connor E, et al: Noncardiovascular disease outcomes during 6.8 Years of hormone therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA 288:58–64, 2002. 28. Tannen RL, Weiner MG, Xie D, et al: Perspectives on hormone replacement therapy: The Women's Health Initiative and new observational studies sampling the overall population. Fertil Steril 90:258–264, 2008.[CrossRef][Medline] 29. Speroff L: The future of postmenopausal hormone therapy: It's time to move forward. Maturitas 57:103–106, 2007.[CrossRef][Medline] 30. Phillips LS, Langer RD: Postmenopausal hormone therapy: Critical reappraisal and a unified hypothesis. Fertil Steril 83:558–566, 2005.[CrossRef][Medline] 31. Prentice RL, Manson JE, Langer RD, et al: Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 170:12–23, 2009. 32. Banks E, Canfell K: Invited commentary: Hormone therapy risks and benefits–The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 170:24–28, 2009. 33. Prentice RL, Chlebowski RT, Stefanick ML, et al: Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 167:1207–1216, 2008. 34. Fournier A, Mesrine S, Boutron-Ruault M-C, et al: Estrogen-progestagen menopausal hormone therapy and breast cancer: Does delay from menopause onset to treatment initiation influence risks? J Clin Oncol 27:5138–5143, 2009. 35. Power ML, Anderson BL, Schulkin J: Attitudes of obstetrician-gynecologists toward the evidence from the Women's Health Initiative hormone therapy trials remain generally skeptical. Menopause 16:500–508, 2009.[CrossRef][Medline] 36. Power ML, Schulkin J, Rossouw JE: Evolving practice patterns and attitudes toward hormone therapy of obstetrician-gynecologists. Menopause 14:20–28, 2007.[CrossRef][Medline] 37. Brett AS, Carney PI, McKeown RE: Brief report: Attitudes toward hormone therapy after the Women's Health Initiative: A comparison of internists and gynecologists. J Gen Intern Med 20:416–418, 2005.[CrossRef][Medline] 38. Bluming AZ, Tavris C: Hormone replacement therapy: Real concerns and false alarms. Cancer J 15:93–104, 2009.[Medline] 39. Speroff L: Postmenopausal hormone therapy and the risk of breast cancer: A contrary thought. Menopause 15:393–400, 2008.[CrossRef][Medline] 40. Wingert P, Kantrowitz B. Uh, O! Why medical experts were shocked by Oprah Winfrey's take on hormone replacement and Suzanne Somers's controversial theories on aging. Newsweek. http://www.newsweek.com/id/200025. 41. Wingert P, Kantrowitz B. Are bio-identical hormones safe? Why the FDA is cracking down on these ‘natural’ menopausal therapies. Newsweek. 2008 2 7. http://www.newsweek.com/id/108727. 42. Sommers S. Health and hormones. http://www.suzannesomers.com/HealthAndHormones/Default.aspx. 43. US Food and Drug Administration. Compounded menopause hormone therapy drugs. January 09, 2008 News Release. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm110239.htm.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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5 years. In the combined trial and observational study analysis, breast cancer risk was statistically significantly elevated by more than two-fold in the intervals 2 to 5 years after first use and 5+ years after first use among women with no gap between menopause and first E + P use. Risk estimates did not appear elevated during the first 2 years of E + P use at menopause, although too few cases occurred in the clinical trial (n = 20) or the observational study (n = 6) to make the results meaningful. 
3 years and more than 3 years. Importantly, 60% of the more than 32,000 users of estrogen-progestagen therapy had gap times of 1 year or less. The bottom line: women who initiated HT close to menopause had, approximately, a 50% increased breast cancer risk relative to nonusers, even when they had used use this regimen for 2 years or less. Although late initiators of HT (gap time > 3 years) did not have an increased risk of breast cancer for durations of use of 2 years or less, their risk was elevated for longer durations of use, and was similar to that of women who initiated use close to menopause. The overall results are fairly stable and based on 1,726 breast cancers occurring among more than 53,000 postmenopausal women during an average follow-up of 8.1 years. These patterns of elevated risk with a short gap time and short durations of HT use were not observed among women on an estrogen plus progesterone regimen (as opposed to women receiving estrogen combined with other progestagens); however, the number of events among women starting this regimen within 3 years of last menstrual period and using this regimen for no more than 2 years was small (n = 23). Although these authors have previously reported no increase in risk for women using estrogen plus progesterone,
