HRT studies cut through confusion on breast cancer, coronary heart disease

Risks slightly increase — Should you change your current practice?

Two new studies indicate a modestly increased risk of developing breast cancer among women using estrogen/progestin combination hormone replacement therapy (HRT) compared with those using estrogen-only therapy (ERT).1,2 A preliminary update from the Women’s Health Initiative states that during the first two years of the national study, a small increase in the number of heart attacks, strokes, and blood clots has been noted in women taking active hormones compared with placebo pills.

How should you respond? Stay the course, advise two national professional societies, both of which have issued statements on the HRT/breast cancer issue. The statement by the American College of Obstetricians and Gynecologists in Washington, DC, reads, "Although these new studies add to the existing knowledge regarding this issue, particularly regarding combined estrogen-progestin regimens, ACOG does not recommend a change in clinical practice based on these new studies. Additional research is needed to better define the balance of risks and benefits of HRT use."3

The society continues to recommend that practitioners consider HRT to relieve vasomotor symptoms, genitourinary tract atrophy, and mood and cognitive disturbances associated with menopause, as well as to reduce osteoporosis and cardiovascular disease. ACOG plans publication later this year of a new committee opinion on the issue of breast cancer and HRT.

The American Society for Reproductive Medicine (ASRM) "maintains its current recommendation for use of HRT in healthy post-menopausal women," reads the statement on HRT and breast cancer from the Birmingham, AL-based group.4 "Furthermore, it is imperative that physicians continue to discuss risks and benefits of HRT individually with each woman considering therapy, including the need for regular mammographic screening and preventive health care."

For those who are seeing women enrolled in the Women’s Health Initiative, encourage their continued participation in the clinical trial, advises Leon Speroff, MD, professor of obstetrics and gynecology at Oregon Health Sciences University in Portland.

"Because the events in the Women’s Health Initiative occurred early, followed by a reduction, clinicians should encourage participants in the study to remain enrolled, impressing upon them the importance of this large clinical trial," Speroff says. (See story, p. 68, for information on the Women’s Health Initiative’s preliminary report.)

Examine the JAMA data

In the first study dealing with HRT use and breast cancer, published in The Journal of the American Medical Association (JAMA), researchers from the National Cancer Institute (NCI) in Rockville, MD, analyzed follow-up information from 46,355 post-menopausal women who participated in the Breast Cancer Detection Demonstration Project, a nationwide breast cancer screening program. The scientists compared the new cases of breast cancer with the type of hormone replacement therapy used for this group of women who had no previous evidence nor diagnosis of breast cancer.

Most of the data in the study referred to the sequential regimen where progestins were given for fewer than 15 days per month, says lead author Catherine Schairer, PhD, of the NCI’s Division of Cancer Epidemiology and Genetics. The regimen being tested in the Women’s Health Initiative is the combined continuous regimen where both estrogen and progestin are given daily, she notes. The researchers identified 2,082 cases of breast cancer during the 1980 through 1995 follow-up period.

The JAMA study found that increases in breast cancer risk associated with HRT were primarily among recent users of HRT (current and past use occurring within the previous four years). The relative risks were 1.2 for estrogen-only users and 1.4 for those on a combination regimen. The relative risk refers to the risk of outcome in the exposed population (HRT users) relative to that in the unexposed or control population (non-HRT users). A relative risk greater than 1.0 implies an increased risk.

"Our results suggest that the combined estrogen-progestin regimen is associated with greater increases in breast cancer risk than estrogen alone," the authors write. "Assessing the comparative risk of estrogen alone vs. estrogen-progestin was complicated by the fact that use of estrogen alone was associated with increased risk in lean but not heavy women." The authors found differences between the two regimens (estrogen-only and estrogen-progestin HRTs) among lean women, but they were unable to draw conclusions among heavier women.

According to the ASRM statement, the women included in the study were much more apt to have had a surgical consultation or breast biopsy, characteristics that are risk factors for breast cancer, than were all women in the same age group.4 Also, the study relied on the women for historical recall as to whether they took a progestin, and the dose and type of progestin might be different from those now administered. Moreover, the risk of breast cancer was increased only among thin women with a body mass index of 24.4 kg/m2 or less.

"Is there a slight risk of breast cancer [in lean women] with long exposure to estrogen-progestin, or is this a problem of an imprecise conclusion in a range easily affected by biases and small numbers?" asks Speroff. "I don’t know the right answer, but, in my view, the relative risks are not high enough or precise enough to allow a definitive clinical conclusion."

Review JNCI data

In the second study, published in the Journal of the National Cancer Institute (JNCI), researchers looked at women with incident breast cancers diagnosed over four years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents individually matched to case subjects in age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as HRT use. Information on 1,897 post-menopausal case subjects and on 1,637 post-menopausal control subjects ages 55 to 72 years who had not undergone a simple hysterectomy was analyzed for the report.

The JNCI study findings indicate a greater increased risk of breast cancer associated with the use of estrogen and progestin compared with estrogen alone. Researchers further note that a sequential combination of estrogen and progestin was associated with a greater risk of breast cancer than the risk associated with a daily continuous regimen of estrogen and progestin.

The JNCI study found that any HRT regimen was associated with a 10% higher breast cancer risk for each five years of use (odds ratio of 1.10). Risk was higher for estrogen-progestin use, with an odds ratio of 1.24, than for HRT using estrogen alone (odds ratio of 1.06). The odds ratio indicates the ratio of the odds of being exposed to an agent in the case group (i.e., those who developed breast cancer who used HRT) relative to the odds in the control group.

Ronald Ross, MD, professor and chairman of the department of preventive medicine at the University of Southern California’s Norris Comprehensive Cancer Center in Los Angeles, says the take-home message from the two recent studies should be the need for developing a delivery system that targets progestins directly to the endometrium to diminish risks of endometrial cancer.

"Certainly the cardiovascular system doesn’t want much to do with progestins, [and] this certainly shows you that the breast doesn’t want much to do with progestins post-menopausally," he observes. "Let’s figure out a way to get it to the organ that really needs it and wants it menopausally."

Is there cause for concern about use of hormone therapy when it comes to breast cancer? Not at the present time, states Trudy Bush, PhD, MHS, professor in the department of epidemiology and preventive medicine at the University of Maryland at Baltimore and adjunct professor of epidemiology at Johns Hopkins University, also in Baltimore. Her observations have not changed since she published the following in a JAMA editorial:

"Does ERT increase the risk of breast cancer? After more than five decades of ERT use in the United States and scores of epidemiological studies, this question still cannot be answered definitively," she wrote. "In contrast, the association between ERT and endometrial cancer was clearly established nearly 25 years ago by epidemiological studies. At this time the absence of convincing evidence of an association between ERT and breast cancer risk should be reassuring."5

How can providers address the issue with patients? Stress the benefits of post-menopausal hormone therapy; point out the continuing concern regarding the relationship between estrogen use and breast cancer (particularly long-term use); and emphasize the absence of definitive evidence linking such therapy to an increased risk of breast cancer, as well as the uniform data indicating better outcomes in hormone users who develop breast cancer, Speroff says.


1. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283:485-491.

2. Ross RK, Paganini-Hill A, Wan PC, et al. Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000; 92:328-332.

3. American College of Obstetricians and Gynecologists. ACOG releases statement on recent studies of HRT and breast cancer. ACOG 2000; 44:9.

4. American Society of Reproductive Medicine. Hormone Replacement Therapy and the Risk of Breast Cancer. Web:

5. Bush TL, Whiteman MK. Hormone replacement therapy and risk of breast cancer. JAMA 1999; 281:2,140-2,141.