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SAN ANTONIO -- Menopausal hormone replacement therapy (HRT) with estrogen alone yielded lasting reductions in breast cancer incidence and death while estrogen plus progestin showed persistent increases in both, long-term data from two Women's Health Initiative (WHI) trials indicated.

At over 16 years of cumulative follow-up, women with prior hysterectomy randomized to estrogen-only HRT had a 23% reduction in breast cancer diagnosis compared to those assigned placebo (HR 0.77, 95% CI 0.62-0.92), driven in large part by fewer diagnoses of estrogen receptor-positive/progesterone receptor-negative disease, reported Rowan Chlebowski, MD, PhD, of Harbor-UCLA Medical Center in West Carlson, California.

And among the more than 10,000 women in the study, those on estrogen alone, in the form of conjugated equine estrogen (CEE), had a 44% reduction in breast cancer deaths (HR 0.56, 95% CI 0.34-0.92).

"After a half-century, the effects of estrogen alone or estrogen plus progestin on breast cancer still remain controversial," Chlebowski said during a press briefing here at the (SABCS).

"Women considering estrogen alone should know it's safer and there may be a breast cancer benefit associated with its use," he said. "I think women considering estrogen plus progestin have a little bit more difficult dilemma, because they have to be willing to accept a maybe 20-year and maybe lifetime increased breast cancer risk."

For this group, a second randomized WHI trial of over 16,000 women who still had their uterus found that those assigned to CEE plus progestin had a 29% higher incidence of breast cancer at over 18 years of cumulative follow-up (HR 1.29, 95% CI 1.14-1.47).

Furthermore, CEE plus progestin, in the form of medroxyprogesterone acetate (MPA), was associated with increased deaths from the disease (HR 1.45, 95% CI 0.98-2.15).

Death from any cause following a breast cancer diagnosis appeared to be improved with estrogen alone (HR 0.75, 95% CI 0.56-1.01) while being significantly increased with the estrogen-progestin combination (HR 1.29, 95% CI 1.02-1.63).

"As soon as the WHI findings were reported, long-term use of hormone replacement therapy (i.e., CEE and MPA, and CEE) decreased greatly," Charles Shapiro, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told 口袋女优 by email. "It is reassuring for women with intractable menopausal symptoms that short-term therapy with CEE alone has decreased risks of breast cancer."

Shapiro said the findings on reduced risk with CEE, and the increased risks with the addition of MPA, have been previously reported, but how far beyond the treatment period these effects persisted was less known.

Given alone, estrogen's benefit showed a reduction in breast cancer incidence during the intervention portion of the trial (median 7.2 years), but the effects appeared to be lasting over the course of the near 20-year follow-up:

• Intervention: HR 0.76, 95% CI 0.58-0.98

• Postintervention I: HR 0.76, 95% CI 0.55-1.05

• Postintervention II: HR 0.83, 95% CI 0.57-1.20

The increased risk of breast cancer with estrogen plus progestin, given for a median of 5.6 years, showed a reverse trend, with harm persisting across the two decades:

• Intervention: HR 1.26, 95% CI 1.02-1.56

• Postintervention I: HR 1.32, 95% CI 1.08-1.61

• Postintervention II: HR 1.30, 95% CI 0.99-1.70

The updated findings from Chlebowski contradict a recent meta-analysis of 58 different studies that said both forms of HRT were linked to a higher risk of breast cancer, and he hoped the results would have an impact on medical guidelines.

"One of the issues is how do you interpret 58 observational studies' findings against a 10,800-patient randomized trial with 20 years follow-up," said Chlebowski, but he emphasized that the two forms of HRT "clearly do not have the same effect."

From 1993 to 1998, postmenopausal women were enrolled onto the WHI trials at 40 centers across the U.S. For those with prior hysterectomy, women were randomized to either CEE alone (n=5,310) or placebo (n=5,429) and treated until the trial was stopped due to a higher observed risk of stroke. Those who still had their uterus received CEE plus MPA (n=8,506) or placebo (n=8,102) until this trial was halted due to the increased risk of breast cancer.

Participants had no history of breast cancer and received a mammogram to confirm this, and then received annual screening during the trial. Patients were followed until 2016. The investigators verified deaths using patients' medical records and death certificates and by querying the National Death Index, which captures 98% of deaths in the U.S.

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