Current issues of ACP Journal Club are published in Annals of Internal Medicine


Breast cancer was not associated with combined estrogen-progestin hormone replacement therapy

ACP J Club. 1996 Jan-Feb;124:21. doi:10.7326/ACPJC-1996-124-1-021

Source Citation

Stanford JL, Weiss NS, Voigt LF, et al. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA. 1995 Jul 12;274:137-42. [PubMed ID: 7596001]



To determine the risk for breast cancer from use of combined estrogen-progestin hormone replacement therapy (HRT).


Population-based case-control study.


Community-based study in a county in the western United States.


660 women who were 50 to 64 years of age and had histologically confirmed incident invasive or in situ breast cancer that was diagnosed between 1988 and 1990. 537 women (81%) were interviewed. Control participants were women aged 50 to 64 years who resided in the study county. 492 women had never had breast cancer and were included in the analysis.

Assessment of Risk Factors

Duration, type, and dosage of HRT; age; ages at menarche and menopause; reproductive and contraceptive history; height and weight; family history of breast cancer; previous benign breast disease; previous mammography; alcohol use; and socioeconomic status. Hormone exposure, assessed by unblinded interviewers, was limited to use that occurred ≥ 3 months before the date of diagnosis of breast cancer in women with breast cancer and a similar date for women without breast cancer.

Main Outcome Measures

Relative odds (RO) of breast cancer associated with HRT use adjusted for age, age at first full-term pregnancy, and family history of breast cancer.

Main Results

Postmenopausal HRT use was reported by 57.6% of women with breast cancer and 61.0% of women without breast cancer. Compared with non-users of HRT, the RO of breast cancer in HRT users of estrogen alone was 0.9 (95% CI 0.6 to 1.1) and in users of combined estrogen-progestin was 0.9 (CI 0.7 to 1.3). Long-term use of estrogen alone (≥ 20 y) and of combined estrogen-progestin (≥ 8 y) did not contribute to increased risk for breast cancer (RO 1.0, CI 0.5 to 2.0; and RO 0.4, CI 0.2 to 1.0, respectively). The RO of breast cancer was not substantially affected by the type, dose, or regimen of estrogen or progestin, nor was it affected by family history of breast cancer, previous benign breast disease, parity, alcohol use, or oral contraceptive use. Users of HRT who had had a hysterectomy with bilateral oophorectomy had an RO of breast cancer of 19.0 (CI 1.8 to 199.4).


In women aged 50 to 64 years, no association was found between use of combined estrogen-progestin hormone replacement therapy and breast cancer.

Source of funding: In part, National Cancer Institute.

For article reprint: Dr. J. Stanford, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, MP-474, Seattle, WA 98104, USA. FAX 206-667-2717.


Breast cancer was associated with postmenopausal estrogen and progestin hormone therapy

Although clinicians may despair at the seemingly contradictory conclusions of the studies by Colditz and Stanford and their colleagues, these studies provide important new information. In keeping with previous research, both studies support the conclusion that short-term HRT (< 5 years) has no important effect on the risk for breast cancer. Similarly, neither study found evidence that progestins either protect against or dramatically increase the effects of estrogen on the breast. The former claim was made on the basis of an earlier study that has since been discounted because of methodologic problems; the latter concern, raised in a large study done in Sweden, has diminished with longer follow-up from the study (1). Still in dispute are the effects of long-term HRT, which are now commonly prescribed to protect against osteoporosis and coronary heart disease. An increase in breast cancer was shown only among current users in the Nurses' Health Study but not in any group of HRT users in the study by Stanford and colleagues. Several considerations lend greater weight to the findings of the Nurses' Health Study: Hormone exposure data, collected prospectively from medically knowledgeable persons, appear more reliable; analyses excluded in situ disease (present in 16% of women with cancer in the study by Stanford and colleagues); and fewer eligible persons were lost to follow-up. Could the associations be caused by confounding (underlying differences in cancer risk between users and nonusers) or bias (i.e., closer surveillance of hormone users)? Confounding is unlikely because many characteristics that are more common among women taking HRT (lower body mass index, early or surgical menopause, favorable family history) place these women at lower risk for cancer. Also, evidence of detection bias was not found in the Nurses' Health Study and probably cannot explain observed increases in breast cancer mortality.

Nonetheless, the clinical implications of these findings are less dire than they might first appear. In the Nurses' Health Study, risk was confined to current users, even among women who had taken HRT for extended periods, and mortality was not significantly increased among current users as a group. Also, the increase in death from breast cancer among a subgroup of current, long-term users (≥ 5 y; RR 1.45, CI 1.01 to 2.09) was offset by a trend toward decreased risk among former users (RR 0.80, CI 0.60 to 1.07). These findings are consistent with the hypothesis that current use of HRT promotes the growth of existing cancers rather than initiating new cancers. Other reports have documented that most women who develop cancer while taking HRT have a favorable prognosis (2).

These studies reinforce several recommendations. First, clinicians should feel comfortable recommending short-term HRT to relieve perimenopausal symptoms (e.g., hot flashes). Second, combination therapy (estrogen plus progestin) should be limited to women with an intact uterus, to protect against endometrial cancer. Third, a possible increase in the risk for breast cancer must be considered along with the expected benefits of long-term HRT and the preference of each patient. The absolute increases in breast cancer (if real) from HRT seem modest: an increase of 1 to 2 cases of breast cancer per 1000 patient-years of treatment, or a 1% absolute increase in the lifetime risk for dying from breast cancer (i.e., from 3% to 4%). Because CHD and fractures account for more morbidity and mortality than does breast cancer in older women, the benefits of hormone therapy are still likely to exceed the risks for most women, especially those at increased risk for CHD or osteoporosis (3).

It may be many years before the Women's Health Initiative provides more reliable data about the risks and benefits of long-term HRT. Until then, clinicians should engage their perimenopausal patients in an open discussion of symptoms attributable to menopause, the potential benefits and risks of HRT (including effects on the quality of life), and individual concerns and health priorities. Clinicians can offer cautious reassurance to those with indications for long-term HRT, recommend alternative preventive measures for women reluctant to take HRT, and make sure all women taking postmenopausal estrogen receive regular mammograms.

David Atkins, MD, MPH
U.S. Preventive Services Task ForceWashington, DC, USA


1. Persson I, Yuen J, Bergkvist L, et al. Combined oestrogen-progestogen replacement and breast cancer risk [letter]. Lancet. 1992;340:1044.

2. Strickland DM, Gambrell RD Jr, Butzin CA, Strickland K. The relationship between breast cancer survival and prior postmenopausal estrogen use. Obstet Gynecol. 1992;80:400-4.

3. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-37.