More data emerge from Women's Health Initiative

Results from a long-term follow-up analysis of participants in the Women's Health Initiative (WHI) suggest that among postmenopausal women, use of estrogen plus progestin is associated with an increased incidence of breast cancers that are more advanced, and with a higher risk of deaths attributable to breast cancer.1

In the original WHI study,16,608 U.S. postmenopausal women ages 50-79 who had not undergone hysterectomy were assigned randomly to receive combined conjugated equine estrogens 0.625 mg per day plus medroxyprogesterone acetate 2.5 mg/day, or a placebo. After the original trial completion date, investigators sought reconsent for continued follow-up for breast cancer incidence; 83% (12,788) of the surviving participants complied.

In the new WHI publication, researchers report after an average intervention time of 5.6 years and an average follow-up of 7.9 years, breast cancer incidence was increased among women who received the combined hormone therapy.

The researchers found that in intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up, estrogen plus progestin compared with placebo increased the incidence of invasive breast cancer: 385 cases (0.42% per year) versus 293 cases (0.34% per year). Women in the combined hormone therapy group had more breast cancers with positive lymph nodes compared with women in the placebo group: 81 (23.7%) versus 43 (16.2 %). In addition, more women died of breast cancer in the combined hormone therapy group compared with the placebo group: 25 deaths (0.03% per year) versus 12 deaths (0.01% per year), representing 2.6 versus 1.3 deaths per 10,000 women per year, respectively, the investigators note.1

What does it mean?

So what is the take-home message from the new WHI analysis? According to a response issued by the North American Menopause Society, the primary finding is of one to two extra deaths from breast cancer per 10,000 women per year randomized to combined hormone therapy. For every 10,000 women in the study who were randomized to placebo, there were 1.3 deaths from breast cancer per year. For every 10,000 women randomized to combined hormone therapy, there were 2.6 deaths from breast cancer per year, the response notes.2

"Clinicians can help women put the breast cancer risk into perspective by informing them that the increased risk of breast cancer using estrogen plus progestogen for five years is very similar to the increased risk of breast cancer associated with having menopause five years later," the NAMS response notes. "This increased risk of breast cancer occurs with a woman's own internal, natural estrogen and progesterone."

There are a few things to keep in mind regarding data from the current WHI analysis, says Susan Wysocki, WHNP-BC, FAANP, president and chief executive officer of the National Association of Nurse Practitioners in Women's Health.

"The first is that these data do not relate to women on estrogen alone," notes Wysocki. "Those data appear to have favorable or a null effect on breast cancer." (Editor's note: unopposed estrogen therapy is used for hysterectomized women.)

"One other issue to consider is whether increased breast density, as a result of taking hormones, is part of the problem," Wysocki states. "It is important to note that new technologies such as tomosynthesis (3D mammographic views of the breast) may be something, that in the future, will increase the detection of breast abnormalities in women who take hormones."

Definitions are varied

Current recommendations call for using hormone therapy only when needed to treat moderate to severe symptoms of menopause and using the lowest effective dose for the shortest amount of time.3,4 But what constitutes "lowest" and "shortest"?

"Clinicians who prescribe brief courses of hormone therapy for relief of menopausal symptoms should be aware that this approach has not been proven in rigorous clinical trials and that the downstream negative consequences for their patients are of uncertain magnitude," states an accompanying editorial to the current analysis publication.5

The current "lowest dose" of combined hormone therapy is about half the dosage of the preparation examined in the WHI study, notes Rowan Chlebowski, MD, PhD, an oncologist at the Los Angeles Biomedical Research Institute at Harbor — UCLA Medical Center and principal investigator of the current WHI analysis. However, the Food and Drug Administration continues to use the same labeling for lower-dose preparations because they have not submitted additional data to show in effect that they are indeed safer, he notes. In the same vein, no randomized clinical trial has established parameters for what constitutes the "shortest" duration of time for symptom relief, states Chlebowski.

Additional randomized trials are needed to determine whether lower doses or shorter durations of hormone therapy can safely treat menopausal symptoms without increasing cancer risk, says Chlebowski. Also more information is needed on women who start hormone therapy for the first time between the ages of 50 and 55; the average age in the WHI study was 63. Two randomized trials might provide such information within a few years: the Kronos Early Estrogen Prevention Study and the Early vs. Late Intervention Trial with Estradiol.

References

  1. Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010; 304:1684-1692.
  2. North American Menopause Society. NAMS response to new WHI breast cancer data. Press release. Accessed at http://www.menopause.org/whibreastcancer.aspx .
  3. Utian WH, Archer DF, Bachmann GA, et al. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Menopause 2008;15:584-602.
  4. U.S. Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the US Preventive Services Task Force. Ann Intern Med 2005;142:855-860.
  5. Bach PB. Postmenopausal hormone therapy and breast cancer — an uncertain trade-off. JAMA 2010;304:1719-1720.

Practical tips to ease menopause symptoms

Looking for practical, non-hormonal measures to help patients cope with common menopausal symptoms? Use the following suggestions from Margery Gass, MD, executive director of the North American Menopause Society:

• Hot flashes. Advise women to be sensitive to their environment, says Gass. Avoid anything that increases their sensation of warmth. Sometimes it can be as subtle as avoiding sitting under bright lights. One way to combat environmental elements is to wear clothing that can be removed when it gets too warm in a room, notes Gass. Avoid wearing close-fitting clothing items such as turtlenecks.

Alternative over-the-counter products, such as black cohosh, are available for relief of hot flashes. While such products have not been shown to be highly effective, most of them are safe enough to use if patients want to try them and see if they are one of the lucky women who finds an advantage from using such products, Gass states.

• Vaginal dryness. Counsel women on the use of lubricants and moisturizers designed for the vagina, says Gass. These are different kinds of products, so women need to be aware that they can use both of them, she states. "Women can use a moisturizer regularly that has carryover benefit for sexual activity, and/or they can just use the lubricant at the time of intercourse," says Gass.

• Night sweats. Explain that night sweats are simply hot flashes that occur at night. Avoid allowing the body to get too hot at night, says Gass.

"With winter, it is important for women to know that down comforters are some of the worst offenders because they trap the heat too well," states Gass. "You want something that is not going to be such a good heat trap, something that will allow the air to circulate more."

Some women have tried wearing loosely woven exercise clothing with wicking properties to help keep the skin cool at night, says Gass. An overhead fan on a very low level of oscillation can help keep the body a little bit cooler, she advises. [See menopause patient handout.]