Cancer recurrence and mortality in women using hormone replacement therapy after breast cancer: Meta-analysis

,

Original Research

Cancer recurrence and mortality in women using hormone replacement therapy after breast cancer: Meta-analysis

J Fam Pract. 2002 December;51(12):1056-1062

By

Linda N. Meurer, MD, MPH

PDF Download

References

1. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L. Menopausal estrogen and estrogen–progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91.

2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33.

3. Bluming AZ, Waisman JR, Dosik GM, et al. Hormone replacement therapy (ERT) in women with previously treated primary breast cancer. Update VII. Proc ASCO 2001;20:12b.-

4. DiSaia PJ, Brewster WR. Hormone replacement therapy in breast cancer survivors. Am J Obstet Gynecol 2000;183:517.-

5. Brewster WR, DiSaia PJ, Grosen EA, McGonigle KF, Kuykendall JL, Creasman WT. An experience with estrogen replacement therapy in breast cancer survivors. Int J Fertil Womens Med 1999;44(4):186-92.

6. DiSaia PJ, Odicino F, Grosen EA, Cowan B, Pecorelli S, Wile AG. Hormone replacement therapy in breast cancer. Lancet 1993;342:1232.-

7. Decker D, Cox T, Burdakin J, Jaiyesimi I, Pettinga J, Benitez P. Hormone replacement therapy (ERT) in breast cancer survivors. Proc ASCO 1996;15:208.-

8. Guidozzi F. Estrogen replacement therapy in breast cancer survivors. Int J Gynaecol Obstet 1999;64:59-63.

9. Powles TJ, Hickish T, Casey S, O’Brien M. Hormone replacement after breast cancer. Lancet 1993;342:60-1.

10. Vassilopoulou-Sellin R, Theriault R, Klein MJ. Estrogen replacement therapy in women with prior diagnosis and treatment for breast cancer. Gynecol Oncol 1997;65:89-93.

11. Wile AG, Opfell RW, Margileth DA. Hormone replacement therapy in previously treated breast cancer patients. Am J Surg 1993;165:372-5.

12. DiSaia PJ, Grosen EA, Odicino F, et al. Replacement therapy for breast cancer survivors. A pilot study. Cancer 1995;76(suppl):2075-8.

13. Espie M, Gorins A, Perret F, et al. Hormone replacement therapy (ERT) in patients treated for breast cancer: Analysis of a cohort of 120 patients [abstract]. Proc ASCO 1999;18:586a.-

14. Peters GN, Jones SE. Estrogen replacement therapy in breast cancer patients: a time for change? [abstract]. J Clin Oncol 1996;15:121.-

15. Dew J, Eden J, Beller E, et al. A cohort study of hormone replacement therapy given to women previously treated for breast cancer. Climacteric 1998;1:137-42.

16. DiSaia PJ, Grosen EA, Kurosaki T, Gildea M, Cowan B, Anton-Culver H. Hormone replacement therapy in breast cancer survivors: a cohort study [see comments]. Am J Obstet Gynecol 1996;174:1494-8.

17. DiSaia PJ, Brewster WR, Ziogas A, Anton-Culver H. Breast cancer survival and hormone replacement therapy: a cohort analysis. Am J Clin Oncol 2000;23:541-5.

18. Eden J, Bush T, Natrajan PK, Wren B. A case-control study of combined continuous estrogen–progestin replacement therapy among women with a personal history of breast cancer. Menopause 1995;2:67-72.

19. Marsden J, Whitehead M, A’Hern R, Baum M, Sacks N. Are randomized trials of hormone replacement therapy in symptomatic women with breast cancer feasible? Fertil Steril 2000;73:292-9.

20. Natrajan PK, Soumakis K, Gambrell RD, Jr. Estrogen replacement therapy in women with previous breast cancer. Am J Obstet Gynecol 1999;181:288-95.

21. Vassilopoulou-Sellin R, Asmar L, Hortobagyi GN, et al. Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively. J Clin Oncol 1999;17:1482-7.

22. Wile AG, Opfell RW, Margileth DA, Anton-Culver H. Hormone replacement therapy does not effect breast cancer outcome. Proc ASCO 1991;10:58.-

23. Habel LA, Daling JR, Newcoomb PA, et al. Risk of recurrence after ductal carcinoma in situ of the breast. Cancer Epidemiol Biomarkers Prev 1998;7:689-96.

24. Ursic-Vrscaj M, Bebar S. A case-control study of hormone replacement therapy after primary surgical breast cancer treatment. Eur J Surg Oncol 1999;25:146-51.

25. Beckmann MW, Jap D, Djahansouzi S, et al. Hormone replacement therapy after treatment of breast cancer: effects on postmenopausal symptoms, bone mineral density and recurrence rates. Oncology 2001;60:199-206.

26. Col NF, Hirota LK, Orr RK, Erban JK, Wong JB, Lau J. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol 2001;19:2357-63.

27. Cobleigh MA. Hormone replacement therapy and nonhormonal control of menopausal symptoms in breast cancer survivors. In: Biological and Hormonal Therapies of Cancer. Foon Ka, Muss HB (eds.): Kluwer Academic Publishers, Boston, 1998;209-230.

28. Steinberg KK, Smith SJ, Thacker SB, Stroup DF. Breast cancer risk and duration of estrogen use: the role of study design in meta-analysis. Epidemiology 1994;5:415-21.

KEY POINTS FOR CLINICIANS

This meta-analysis of observational studies found no increased risk of breast cancer recurrence and a statistically significant reduction in mortality for breast cancer survivors who take hormone replacement therapy compared with those who do not.
Because of biases inherent in the designs of these studies, randomized controlled trials are warranted.
There is no compelling evidence to support universal withholding of estrogen from well-informed women who have survived low-stage breast cancer and who suffer from symptomatic menopause.

ABSTRACT

OBJECTIVES: We compared the risk of cancer recurrence and all-cause mortality among users and nonusers of estrogen replacement therapy (ERT) after the diagnosis of breast cancer.
STUDY DESIGN: This was a systematic review of original research. Eligible studies were reviewed by 2 investigators who independently extracted data from each study according to a predetermined form and assessed each study for validity on standard characteristics. Meta-analyses were performed with Review Manager 4.1 to provide a summary of relative risks of cancer recurrence and mortality.
POPULATION: Studies included 717 subjects who used hormone replacement therapy (HRT) at some time after their diagnosis of breast cancer, as well as 2545 subjects who did not use HRT.
OUTCOMES MEASURED: Outcomes included breast cancer recurrence and all-cause mortality.
RESULTS: Nine independent cohort studies and one 6-month pilot randomized controlled trial were identified. Studies were of variable quality. Breast cancer survivors using ERT experienced no increase in the risk of recurrence compared with controls (relative risk, 0.72; 95% confidence interval, 0.47–1.10) and had significantly fewer deaths (3.0%) than did the nonusers (11.4%) over the combined study periods (relative risk, 0.18; 95% confidence interval, 0.10–0.31). All tests for heterogeneity were nonsignificant.
CONCLUSIONS: Although limited by observational design, existing research does not support the universal withholding of ERT from well-informed women with a previous diagnosis of low-stage breast cancer. Long-term randomized controlled trials are needed.

Estrogen-containing hormone replacement therapy (ERT) after menopause has been implicated as a causal factor in the development of primary breast cancer.^1,2 Fearing cancer recurrence, most physicians do not offer ERT to postmenopausal women with a history of breast cancer. However, estrogen deficiency, which is especially common in women after chemotherapy, can be associated with severe symptoms, reduced quality of life, and increased risk of osteoporosis and possibly coronary artery disease. Although there are theoretical justifications to discourage the use of ERT by women at high risk for breast cancer, there is little objective evidence that hormone replacement increases the likelihood of breast cancer recurrence or of mortality among survivors of primary breast cancer. It is difficult for clinicians and patients to make rational decisions regarding ERT in these patients, given the paucity of studies and the difficulty of interpreting the few studies available.

Several observational studies have been published on the use of estrogen and/or combined estrogen–progesterone hormone replacement therapy in women who have had breast cancer. Many of these studies have reported single-institution series of outcomes among survivors who opted to take ERT for their menopausal symptoms. These studies tend to demonstrate rather unimpressive incidences of recurrence and mortality events. However, it is possible that such studies underestimate the risks because patients who are given ERT may represent a subgroup with a better prognosis than other patients (bias by indication). A smaller number of studies has used comparison groups and attempted to control for disease severity and other factors associated with recurrence.

We conducted a meta-analysis of studies comparing women who used ERT after the diagnosis of breast cancer with a control group of non-ERT users to determine whether ERT is associated with an increased risk of cancer recurrence or all-cause mortality among breast cancer survivors.

Methods

Search strategy

We identified relevant studies through independent literature searches of Medline (from 1966 to August 2001) and Cancerlit (from 1986 to August 2001) with the use of OVID software and the following search terms: estrogen replacement therapy, hormone replacement therapy, breast neoplasms, neoplasm recurrence, survivors. No language restriction was imposed. A careful review of titles and abstracts was done to identify relevant articles, and for these, the full articles were retrieved for review. Bibliographies of identified studies and review articles were examined for additional citations. Medline and Cancerlit databases were also searched by the names of authors of relevant studies to identify any missed articles. The authors of large studies and experts from our institution were asked to review the reference list for completeness and to suggest sources of unpublished data.

Inclusion criteria

Studies were considered for inclusion into the meta-analysis if they met the following criteria: (1) the population studied was women with a previous diagnosis of breast cancer, (2) the risk factor considered was the use of systemic estrogen or any combination hormone replacement therapy that included estrogen, (3) the outcome measured included the recurrence of breast cancer (whether a new or recurring primary cancer) and/or mortality, and (4) the study design was a randomized controlled trial or cohort study comparing women who used ERT after their breast cancer diagnosis with a concurrent, historical, or population-based control group of women who did not. Single-arm cohort studies were retrieved and summarized qualitatively but not included in the statistical analysis. If more than 1 publication was identified which reported the same data, the study with the most recent or complete data was selected for the analysis. We independently reviewed all studies for inclusion, and any differences were resolved through consensus.