An analysis from a Women's Health Initiative researcher at the Fred Hutchinson Cancer Research Center offers the latest good news about the protections against breast cancer that estrogen-only therapy offers women who have had a hysterectomy. But there are still many concerns.

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On average, postmenopausal women who took a particular form of estrogen-only hormone therapy for five to seven years had a significant reduction in invasive breast cancer and death, and the effect carried through for all age groups even after the women stopped taking the pills, according to the latest in-depth look at results from a huge trial begun in 1993.

The analysis, reported Tuesday by The Lancet Oncology, was a reaffirmation and more detailed look at general results reported a year ago from the Women’s Health Initiative (WHI), a landmark study of women’s hormone therapy.

“This provides very clear reassurance for women with a hysterectomy that they can use estrogen alone to treat menopausal symptoms with no real breast-cancer risk,” said lead author Garnet Anderson, a biostatistician at Fred Hutchinson Cancer Research Center in Seattle and principal investigator of the WHI Clinical Coordinating Center.

But because the results were not favorable for women with a family history of breast cancer or who have had benign breast disease, Anderson cautioned: “I wouldn’t take it for breast-cancer prevention.”

Hysterectomy is the second-most-common surgery among women in the U.S., with about a third expected to have the procedure by age 60, though the incidence is declining. Many women turn to hormone therapy — estrogen-only, in the case of those who have had hysterectomies — to ease menopausal symptoms such as hot flashes and sleep disturbances.

The WHI study enrolled more than 27,000 women ages 50 to 79 to study estrogen alone — sold as the pill Premarin — and an estrogen-and-progestin combination pill, Prempro, prescribed for women with a uterus. Both trials were halted abruptly when researchers found those taking hormones had unexpected risks, compared with those on placebo.

Those early results shattered the conventional wisdom that hormone therapy helped protect women from heart attacks, and threw many women and their doctors into confusion.

The combination-pill trial, closed in 2002, found women taking Prempro not only had a higher risk of breast cancer, but also of heart attack, stroke and blood clots. They had less risk of colon cancer and bone breaks.

The estrogen-only trial, shut down in 2004, found a risk of stroke and no protection from heart attacks.

In the mid-1990s, surveys suggested that 38 to 40 percent of women aged 50 to 74 were taking hormone therapy. After the combination-therapy results were announced, numbers dropped drastically; Prempro prescriptions dropped by 66 percent in one year, according to a study reported in the Journal of the American Medical Association (JAMA).

The most recent analysis provides an in-depth follow-up look at 7,645 women in the trial; about half took the estrogen-only pill, and half took only a placebo pill. The data track the health of the women for five years after they stopped taking either estrogen or the placebo.

Anderson’s report showed that for all groups of women — except those with a family history of breast cancer or a history of benign breast disease — use of the estrogen-only pill reduced the risk of invasive breast cancer. Overall, the risk dropped by 23 percent, and prior estrogen use appeared to reduce death from breast cancer and other causes, as well.

That was true for women of all age groups, ethnicities, body mass and other categories, such as their age at menopause or whether they had ever given birth.

The results were very different for women with a family history of breast cancer or those who had had benign breast disease, which the study defined as a finding that had prompted a breast-tissue biopsy. For these women, estrogen appeared to provide no protection or perhaps even an increased risk, Anderson said.

“For breast cancer, the story hasn’t changed, but it has become a little clearer,” Anderson said. “Not only do we see a reduction in breast cancer, now we have data to suggest that mortality is decreased” for the women who took estrogen. Although the mortality data are thin, she said, the differences are statistically significant.

Still, Anderson says she continues to believe women should take estrogen only if they must, to mitigate menopausal symptoms that can make life miserable.

“Stroke is still a concern. If you’re worried about breast cancer, eat right and exercise,” she said. “I don’t think taking this pill would be my first approach.”

For one thing, there appears to be a higher risk of stroke for women while taking estrogen — although the earlier findings showed the increased risk appears to dissipate after they stop.

Also, Anderson said, “we can’t say what would happen if these women stayed on estrogen for 10 or 15 years.”

And finally, the study examines only one form of estrogen therapy: Premarin, which is made up of equine estrogens. “We know a lot about its safety profile and its effects,” Anderson said. “People say that others are ‘more natural,’ but we don’t know what the others do.”

Although the current analysis doesn’t change the big-picture results reported a year ago, Anderson said she and colleagues wanted to look at different subgroups.

The question they were trying to answer: Were the earlier findings that estrogen helped reduce breast-cancer risk generally applicable, or did the overall results mask important differences for women of different ages or medical histories?

Anderson also wanted to look at possible differences in mortality. Although numbers are small, which makes Anderson cautious, the analysis found fewer breast-cancer-related deaths among women who had taken estrogen than in women who took the placebo.

Additionally, fewer women in the estrogen group died from any cause after a breast-cancer diagnosis than those in the control group.

Anderson’s analysis, like last year’s WHI follow-up report in JAMA, runs counter to many observational studies that appear to show an estrogen-breast cancer link.

In the research world, however, randomized studies, such as the WHI, trump observational studies, whose results can be influenced by many uncontrollable factors.

Anderson believes that previous studies suggesting that estrogen increased the risk of breast cancer may have been biased as a result of women on estrogen being more diligent about getting mammograms, which picked up even the tiniest cancers.

“Because estrogen users were more likely to have frequent mammograms, they have more breast cancers detected. This increase was then attributed to estrogen, when in fact it was probably related to how carefully these women were being screened,” she said.

An accompanying commentary in The Lancet Oncology noted the WHI results are modest but significant and raise important questions about why estrogen appears to have a much different effect on breast cancer than does the combination hormone therapy, which the WHI trial found increased breast-cancer risk.

“The biological basis for this difference is unknown,” the researchers wrote.

Carol M. Ostrom: 206-464-2249 or costrom@seattletimes.com. On Twitter @costrom.