- Open Access
Menopausal hormone therapy after breast cancer
Breast Cancer Research volume 7, Article number: 168 (2005)
The use of postmenopausal hormone therapy after breast cancer remains controversial. Evidence shows variation by study design, and even among three randomized controlled trials there is substantial heterogeneity of results. Two Swedish trials of comparable size show relative risks of recurrence of 3.3 and 0.82 on comparing women receiving postmenopausal hormone therapy with control women. The extent of use of tamoxifen and concomitant use of progestins in combination with estrogen, although raised as one possible explanation for this heterogeneity, are not supported by evidence from trials of high-dose progestins used after breast cancer. Caution is needed when considering the use of postmenopausal hormone therapy after breast cancer.
There is now resounding evidence that use of exogenous hormones by postmenopausal women increases risk for breast cancer [1–3]. Likewise, obesity among postmenopausal women with breast cancer is a major determinant of relapse and mortality [4, 5], being directly related to poor outcomes. On the other hand, tamoxifen provides lasting reduction in risk for recurrence and mortality , an effect that is independent of adjuvant chemotherapy. Despite this evidence relating endogenous and exogenous hormones to breast cancer risk and outcomes, debate continues regarding the use of postmenopausal hormones for symptom relief among women with breast cancer. Col and colleagues , in this issue of Breast Cancer Research, report a systematic review in which they identified eight observational studies and two randomized controlled trials of postmenopausal hormone therapy. They note that the combined results for the two trials show increased risk for recurrence (relative risk [RR] = 3.4, 95% confidence interval [CI] = 1.6 to 7.3), which contrasts with the findings of the observational results, which show a decrease in risk (RR = 0.6, 95% CI = 0.5–0.8). While noting heterogeneity between the results according to study design, Col and colleagues do not explore the data to describe the possible sources of heterogeneity [8, 9] beyond study design. As noted below, the quality of data reporting limits their ability in this regard.
Biologic evidence supports estrogenic exposures being related to incidence and poor outcome among women with breast cancer. Weight after diagnosis is a strong predictor of outcome , and weight gain after diagnosis is associated with increased recurrence and mortality . There are direct positive relations between adiposity and circulating estrogens , and between adult weight gain and postmenopausal breast cancer risk , and circulating endogenous hormones represent the primary explanation for this positive relation between adiposity and postmenopausal breast cancer incidence . Together, these data support an increase in incidence of breast cancer with use of postmenopausal hormone therapy. Should the effect of exogenous postmenopausal hormonal therapy differ after diagnosis, when adiposity and weight gain have adverse effects on recurrence and mortality?
To cloud further the current evidence, a third randomized trial , which has been published since the synthesis by Col and colleagues, found no increase in risk with use of postmenopausal hormone therapy (RR = 0.8, 95% CI = 0.4–1.9), based on 4.1 years of follow up in 434 women (Table 1). The authors raise the intriguing possibility that the choice of hormone regimen may modify the risk for recurrence and account for some of the heterogeneity observed. This trial is of comparable size and design to the HABITS (Hormone Replacement Therapy after Breast Cancer – Is It Safe?) trial, also conducted in Sweden . Clearly, more detailed analysis of this small body of evidence might improve our understanding of the difference between unopposed estrogen and combination estrogen plus progestin therapy among women who have been treated for histologically confirmed breast cancer. Alternatively, we can consider other evidence on use of progestins after diagnosis and breast cancer outcomes.
Several recent studies suggested that, when drug therapies are considered, observational studies give measures of effect comparable to those observed through randomized trials [15, 16]. However, here we have significant heterogeneity of results both within the randomized trials (Stockholm trial  and HABITS trial , both conducted in Sweden) and between the observational and randomized study findings in the systematic review conducted by Col and coworkers . As Col and colleagues note, the observational studies often did not report results separately for women using combination hormone therapy and those using unopposed estrogens. It is noteworthy that the Stockholm trial attempted to minimize the use of progestogen, and the HABITS trial recommended either cyclical estrogen plus progestin for women with uterine bleeding within 2 years of randomization or continuous combined therapy for other women with a uterus. The Stockholm trial recommended 20 mg medroxyprogesterone acetate (MPA) for 14 days every 105 days for women over 55 years of age. The Stockholm trial also included a higher percentage of patients receiving concomitant adjuvant tamoxifen therapy than did the HABITS trial (52% versus 21%), and a lower percentage of patients with node-positive breast cancer (16% versus 26%). Thus, a lower risk population may have been studied in the Stockholm trial, with lower exposure to MPA.
It has been hypothesized that MPA might act through glucocorticoid receptors to reduce metastatic potential . Two trials that used high-dose MPA for 6 months in women with breast cancer and followed them for more than a decade [18, 19] fail to support a reduction in recurrence. A systematic review of trials of MPA in combination with either tamoxifen or combination chemotherapy after breast cancer sheds some light on this possibility. Synthesis of data from randomized trials published through 1996 shows no overall improvement in median survival among women treated with MPA, and no survival advantage for higher versus lower doses of endocrine therapy (including MPA) . Finally, given that estrogen plus progestin clearly increases the incidence of breast cancer, and that the Women's Health Initiative showed that the distribution of tumor stage was comparable in the estrogen plus progestin arm and the placebo arm , treatment with MPA before diagnosis does not appear to reduce metastatic potential. These data combined then do not provide strong evidence that merely the dose or frequency of MPA administration could account for the heterogeneity among the Swedish trials. Furthermore, these data clearly do not support MPA as an agent to reduce recurrence and improve survival.
To conclude, given the divergent results from the randomized trials, we recommend caution. Symptom management remains a challenge in some postmenopausal women. The consensus statement suggesting that other established means of controlling symptoms or preventing osteoporosis should be utilized before considering estrogen and progestin therapy in these women remains prudent .
Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE: The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 1995, 332: 1589-1593. 10.1056/NEJM199506153322401.
Beral V: Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003, 362: 419-427. 10.1016/S0140-6736(03)14596-5.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, 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. 2002, 288: 321-333. 10.1001/jama.288.3.321.
Coates RJ, Clark WS, Eley JW, Greenberg RS, Huguley CM, Brown RL: Race, nutritional status, and survival from breast cancer. J Natl Cancer Inst. 1990, 82: 1684-1692.
Kroenke CH, Chen WY, Rosner B, Holmes MD: Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol. 2005, 23: 1370-1378. 10.1200/JCO.2005.01.079.
Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised evidence. Lancet. 2005, 365: 1687-1717. 10.1016/S0140-6736(05)66544-0.
Col NF, Kim JA, Chlebowski RT: Menopausal hormone therapy after breast cancer: a meta-analysis and critical appraisal of the evidence. Breast Cancer Res. 2005, 7: R535-R540. 10.1186/bcr1035.
Berlin JA: The benefits of heterogeneity in meta-analysis of data from epidemiologic studies. Invited commentary. Am J Epidemiol. 1995, 142: 383-387.
Colditz G, Burdick E, Mosteller F: Heterogeneity in meta-analysis of data from epidemiologic studies: a commentary. Am J Epidemiol. 1995, 142: 371-382.
Hankinson SE, Willett WC, Manson JE, Hunter DJ, Colditz GA, Stampfer MJ, Longcope C, Speizer FE: Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst. 1995, 87: 1297-1302.
Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, Hennekens CH, Rosner B, Speizer FE, Willett WC: Dual effects of weight and weight gain on breast cancer risk. JAMA. 1997, 278: 1407-1411. 10.1001/jama.278.17.1407.
Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Long-cope C, Stanczyk FZ, Stephenson HE, Falk RT, Miller R, et al: Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003, 95: 1218-1226.
von Schoultz E, Rutqvist LE: Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005, 97: 533-535.
Holmberg L, Anderson H: HABITS (hormonal replacement therapy after breast cancer – is it safe?), a randomised comparison: trial stopped. Lancet. 2004, 363: 453-455. 10.1016/S0140-6736(04)15493-7.
Benson K, Hartz AJ: A comparison of observational studies and randomized, controlled trials. N Engl J Med. 2000, 342: 1878-1886. 10.1056/NEJM200006223422506.
Concato J, Shah N, Horwitz RI: Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med. 2000, 342: 1887-1892. 10.1056/NEJM200006223422507.
Palmieri D, Halverson DO, Ouatas T, Horak CE, Salerno M, Johnson J, Figg WD, Hollingshead M, Hursting S, Berrigan D, et al: Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer. J Natl Cancer Inst. 2005, 97: 632-642.
Focan C, Beauduin M, Salamon E, de Greve J, de Wasch G, Lobelle JP, Majois F, Tagnon A, Tytgat J, van Belle S, et al: Adjuvant high-dose medroxyprogesterone acetate for early breast cancer: 13 years update in a multicentre randomized trial. Br J Cancer. 2001, 85: 1-8. 10.1054/bjoc.2001.1829.
Hupperets PS, Wils JA, Volovics L, Schouten LJ, Fickers MM, Bron HN, Jager JJ, de Jong JM, Blijham GH: Adjuvant chemohormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate (MPA) for node-positive cancer patients, update at 12 years follow up. Breast. 2001, 10: 35-37. 10.1054/brst.2000.0180.
Stockler M, Wilcken NR, Ghersi D, Simes RJ: Systematic reviews of chemotherapy and endocrine therapy in metastatic breast cancer. Cancer Treat Rev. 2000, 26: 151-168. 10.1053/ctrv.1999.0161.
Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, et al: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003, 289: 3243-3253. 10.1001/jama.289.24.3243.
Anonymous: Treatment of estrogen deficiency symptoms in women surviving breast cancer. The Hormone Foundation, Canadian Breast Cancer Research Initiative, National Cancer Institute of Canada, Endocrine Society, and the University of Virginia Cancer Center and Woman's Place. J Clin Endocrinol Metab. 1998, 83: 1993-2000. 10.1210/jc.83.6.1993.
Marsden J, Whitehead M, Hern RA, Baum M, Sacks N: Are randomized trials of hormone replacement therapy in symptomatic women with breast cancer feasible?. Fertil Steril. 2000, 73: 292-199. 10.1016/S0015-0282(99)00510-5.
The author(s) declare that they have no competing interests.
About this article
Cite this article
Colditz, G.A. Menopausal hormone therapy after breast cancer. Breast Cancer Res 7, 168 (2005) doi:10.1186/bcr1272
- Breast Cancer
- Breast Cancer Risk
- Postmenopausal Breast Cancer