MADIRA KnowledgeBase
Queue Letter
Printed by: Ann Rabuttinio Date printed: 09/15/99 09:32:31 AM
This is a RPI response.
September 10, 1999
T. Richard Smith, M.D. 151 Meadowcrest St. Gretna, LA 70056 Dear Dr. Smith: Joey Englert, your Wyeth Territory Representative, has forwarded your request for information regarding the risk of breast cancer associated with the use of the WyethAyerst products Premarin (conjugated estrogens), Prempro or Premphase (conjugated estrogens and medroxyprogesterone acetate). As stated in the Prempro prescribing information under Warnings:
Some studies have reported a moderately increased risk of breast cancer (relative risk of 1.3 to 2.0) in those women on estrogen replacement therapy taking higher doses, or in those taking lower doses for prolonged periods of time, especially in excess of 10 years. The majority of studies, however, have not shown an association in women who have ever used estrogen replacement therapy. The effect of added progestins on the risk of breast cancer is unknown, although a moderately increased risk in those taking combination estrogen/progestin therapy has been reported. Other studies have not shown this relationship. In a one year clinical trial of PREMPRO, PREMPHASE and Premarin alone, 5 new cases of breast cancer were detected among 1377 women who received the combination treatments, while no new cases were detected among 347 women who received
Premarin alone. The overall incidence of breast cancer in this clinical trial does not exceed that expected in the general population. In the three year clinical Postmenopausal Estrogen Progestin Intervention (PEPI) trial of 875 women to assess differences among placebo, unopposed Premarin, and three different combination hormone therapy regimens, one (1) new case of breast cancer was detected in the placebo group (n=174), one in the Premarin alone group (n=175), none in the continuous Premarin plus continuous medroxyprogesterone acetate group (n=174), and two (2) in the continuous Premarin plus cyclic medroxyprogesterone acetate group (n=174). Women on hormone replacement therapy should have regular breast examinations and should be instructed in breast self-examination, and women over the age of 50 should have regular mammograms.1
Incidence In total, over forty published studies have examined the risk of breast cancer with postmenopausal hormone use. Although the majority of studies to date examined the risk of breast cancer associated with postmenopausal estrogen therapy, studies have also evaluated the risks associated with combination estrogen and progestin therapy.2-13 To put this extensive amount of information into perspective and provide an overall assessment of breast cancer risk with estrogen replacement therapy/hormone replacement therapy (ERT/HRT), seven meta-analyses have been conducted which evaluated data derived from individual studies.14-20 However, these meta-analyses do not include data from the latest studies on this topic.10-12,21,23-27 Additional meta-analyses need to be done to incorporate the latest data into the body of information which already exists on the risk of breast cancer with postmenopausal hormone therapy. Enclosed for your interest are articles by Speroff and Creasman which provides a comprehensive overview of published meta-analyses and key studies regarding the risk of breast cancer associated with postmenopausal hormone use.28,29 Also enclosed for your review are the results of studies conducted in the United States that were recently published and are not included in the review by Speroff along with the results of the most recent metaanalysis.10,20,23,24 Mortality Several studies have found an improved prognosis and reduced or unaltered mortality for women who were diagnosed with breast cancer and took HRT compared to women who were diagnosed with breast cancer and did not use HRT.22,30-34 One possible explanation is that since women on HRT may have mammograms or other medical examinations on a regular basis, the breast cancer may be in an earlier stage at time of detection. Earlier detection, in turn, is associated with improved survival and lower mortality from breast cancer.20,22,30-33 HRT users have better differentiated tumours than non-users when screen-detected, which may explain their reduced mortality.34 A recent study found lower risk for mortality even among women with a family history of breast cancer who used HRT compared to women who never used HRT.33 Estrogens are contraindicated in patients with known or suspected cancer of the breast except in appropriately selected patients being treated for metastatic disease.1
The enclosed information is supplied as a professional courtesy in response to your inquiry. It is intended to provide pertinent data to assist you in forming your own conclusions and making decisions. This information is not intended to advocate any indication, dosage, or other claim that is not covered in the enclosed package insert. We hope this information will be helpful to you. If we may be of further assistance, please do not hesitate to contact us. Sincerely,
Mary Hannon, R.N. Manager, Drug Information
DAL/PREM 437/app 10-94/rr 8-99 SGM References: 1. 2. Prempro – Current prescribing information. Ewertz, M: Breast cancer in Denmark: Incidence, risk factors, and characteristics of survival. Acta Oncologica 32(6): 595-615, 1993. Schairer, C et al: Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States). Cancer Causes and Control 5(6): 491-500, 1994. Newcomb, PA et al: Long-term hormone replacement therapy and risk of breast cancer in postmenopausal women. Am J Epidemiol 142(8): 788-795, 1995. Colditz, GA et al: The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. NEJM 332(24): 1589-1593, 1995. Stanford, JL et al: Combined estrogen and progestin hormone replacement in relation to risk of breast cancer in middle-aged women. JAMA 274(2): 137-142, 1995. Schuurman, AG et al: Exogenous hormone use and the risk of postmenopausal breast cancer: Results from the Netherlands Cohort Study. Cancer Causes and Control 6(5): 416-424, 1995. Folsom, AR et al: Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women. Am J Public Health 85(8): 1128-1132, 1995. La Vecchia, C et al: Hormone replacement treatment and breast cancer risk: A cooperative Italian study. Br J Cancer 72: 244-248, 1995. Longnecker, MP et al: Risk factors for in situ breast cancer. Cancer Epidemiology, Biomarkers, & Prevention 5(12): 961-965, 1996.
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Tzingounis, V et al: Incidence of benign and malignant breast disorders in women taking hormones (contraceptive pill or hormonal replacement therapy). Anticancer Research 16(6C): 3997-4000, 1996. Persson, I et al: Cancer incidence and mortality in women receiving estrogen and estrogenprogestin replacement therapy – Long-term follow-up of a Swedish cohort. Int J Cancer 67(3): 327-332, 1996. Risch, HA and Howe, GR: Menopausal hormone usage and breast cancer in Saskatchewan: A record-linkage cohort study. Am J Epidemiol 139(7): 670-683, 1994. Grady, D et al: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 117: 1016-1037, 1992. Dupont, WD and Page, DL: Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 151: 67-72, 1991. Steinberg, KK et al: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265(15): 1985-1990, 1991. Colditz, GA et al: Hormone replacement therapy and risk of breast cancer: Results from epidemiologic studies. Am J Obstet Gynecol 168(5): 1473-1480, 1993. Armstrong, BK: Oestrogen therapy after the menopause – boon or bane? Med J Aust 148: 213214, 1988. Delgado-Rodriguez, M et al: Menopause hormone replacement therapy and breast cancer risk. A meta-analysis. Prog Obst Gin 37(10): 601-614, 1994. Beral, V et al: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350: 1047-1059, 1997. Persson, I et al: Trends in breast cancer incidence in Sweden 1958-1988 by time period and birth cohort. Br J Cancer 68(6): 1247-1253, 1993. Willis, DB et al: Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes and Control 7: 449-457, 1996. Ettinger, B et al: Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstet Gynecol 87(1): 6-12, 1996. Grodstein, F et al: Postmenopausal hormone therapy and mortality. NEJM 336(25): 1769-1775, 1997. Tavani, A et al: Hormone replacement therapy and breast cancer risk: An age-specific analysis. Cancer Epidemiology, Biomarkers, & Prevention 6(1): 11-14, 1997. Sourander, L et al: Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on estrogen replacement therapy (ERT). Lancet 352: 1965-1969, 1998. Gapstur, SM et al: Hormone replacement therapy and risk of breast cancer with favorable histology: Results of the Iowa Women’s Health Study. JAMA 281: 2091-2097, 1999.
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Speroff, L: Postmenopausal hormone therapy and breast cancer. Obstet Gynecol 87 (2, suppl.): 44S-54S, 1996. Creasman, WT: Is there an association between hormone replacement therapy and breast cancer. Journal of Women’s Health 7(10): 1231-1246, 1998. Bergkvist, L et al: Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 130(2): 221-228, 1989. Strickland, DM et al: The relationship between breast cancer survival and prior postmenopausal estrogen use. Obstet Gynecol 80(3, Part 1): 400-404, 1992. Bonnier, P et al: Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstet Gynecol 85(1): 11-17, 1995. Sellers, TA et al: The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 127(11): 973-980, 1997. Harding, C et al: Hormone replacement therapy and tumour grade in breast cancer: Prospective study in screening unit. BMJ 312: 1646-1647, 1996.
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Enclosures: References # 10, 20, 23, 24, 28
RE: Inquiry # TG-62499-16015