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


Risk for breast cancer after postmenopausal estrogen

ACP J Club. 1992 Nov-Dec;117:93. doi:10.7326/ACPJC-1992-117-3-093

To the Editor

The review of coronary disease and stroke after postmenopausal estrogen in the January/February issue of ACP Journal Club was timely, but one of the comments by Dr. Barrett-Connor (1) was somewhat distressing. She states "long-term estrogen, with or without progestin, may increase the risk for breast cancer by 50%." Dupont and Page (2) indicate that "the combined results from multiple studies provide strong evidence that menopausal therapy consisting of 0.625 mg per day or less with conjugated estrogens does not increase breast cancer risk."

Charles A. Beard, MD
Eureka Springs, Arizona

In response

There have been several meta-analyses of estrogen and breast cancer; each included different studies and came to somewhat different conclusions. For example, the paper by Dupont and Page (3) found no significant excess risk, but the paper by Steinberg and colleagues (4) found that longer estrogen use (more than 5 years) carried a 30% to 60% increased risk. A recent background paper from the Office of Technology Assessment (5) concluded that the risk for breast cancer associated with (long-term) unopposed estrogen use was increased by 30% to 80% (the lack of information on the risk of added progestin was noted). I chose the middle ground of a 50% increased risk because it is included in nearly all reported confidence intervals.

The observational studies may underestimate the risk because women with a family history of breast cancer, for example, may not be prescribed estrogens as frequently as women without such history. They may also overestimate the risk because women who take estrogen have more frequent mammograms and, therefore, more diagnoses.

Meta-analyses of observational studies do not solve these problems; they only merge them to increase the prospect of finding statistically significant differences. Also, the usual weighting procedure may put undue emphasis on a large study with built-in peculiarities. For example, the large Nurses' Health Study found a relative risk of 1.3 or l.4 for breast cancer with postmenopausal estrogen use in women who were aged 35 to 55 years at baseline. In order to be postmenopausal, many of these women must have had either a premature or surgical menopause, factors that are usually found to be protective against breast cancer. Thus, their overall risk could have been lower than that seen in older women.

I believe the estimated 50% increase in breast cancer risk with long-term estrogen use is reasonable and not overly cautious—particularly in view of how common breast cancer is among older women, even in the absence of estrogen.

Elizabeth Barrett-Connor, MD
University of California, San Diego
San Diego, California


1. Barrett-Connor E. Commentary on "Coronary Disease and Stroke after Postmenopausal Estrogen." ACP J Club. 1992 Jan-Feb:29 (Ann Intern Med. vol 116, suppl 1). Comment on: Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses' Health Study. N Engl J Med. 1991;325:756-62.

2. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med. 1991;151:67-72.

1. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med. 1991;151:67-72.

2. Steinberg KK, Thacker SB, Smith SJ, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA. 1991;265: 1985-90.

3. U.S. Congress, Office of Technology Assessment. The Menopause, Hormone Therapy, and Women's Health. Washington, DC: Office of Technology Assessment; 1992:42. OTA-BP-BA-88.