HRT Study Stopped Due to Increased Risk of Invasive Breast Cancer

BETHESDA, Maryland—Researchers abruptly halted a prevention trial of estrogen/ progestin in healthy menopausal women after an independent monitoring committee found a 26% increase in invasive breast cancer among women taking the hormone replacement therapy (HRT). The committee also found that the HRT group had a greater risk of coronary heart disease, stroke, and pulmonary embolism than the placebo group.

The National Heart, Lung, and Blood Institute (NHLBI) stopped the trial, which is a component of the Women’s Health Initiative (WHI), after 5.2 years of average follow-up. The study was scheduled to run until 2005. It was designed to determine whether postmenopausal estrogen/progestin therapy, given to women with a uterus, could prevent heart disease and hip fractures and to determine its risks.

The study involved 16,608 women ages 50 to 79 who were randomized to receive placebo or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyproges-terone acetate.

"The cardiovascular and cancer risks of estrogen plus progestin outweigh any benefits, and a 26% increase in breast cancer risk is too high a price to pay, even if there were a heart benefit," said NHLBI director Claude Lenfant, MD.

On the positive side, the WHI results show a 37% reduction in colorectal cancer in the treatment group, a 24% decline in hip fractures, and no difference in mortality from all causes.

A separate WHI study of estrogen-only in women who have had a hysterectomy is continuing because the risks and benefits of estrogen alone remain undetermined. According to the data safety and monitoring board, there is no indication of any increased breast cancer risk in the estrogen-only study.

"When the estrogen-only trial is completed, a comparison of the results of these two trials may provide a better idea of the role of estrogen vs estrogen/ progestin, in health and disease," said Marcia Stefanick, PhD, associate professor of medicine, Stanford University, and chair of the WHI Steering Committee.

According to acting WHI director Jacques Rossouw, MD, the adverse effects of HRT applied to all women in the treatment arm, regardless of their age, ethnicity, or prior disease history. About 6 million women in the United States take estrogen plus progestin.

The National Cancer Institute issued a statement re-emphasizing its recommendation that women ages 40 and older get a mammography screening for breast cancer every 1 to 2 years.

Although the increased risk of invasive breast cancer was significant and the risk to the population was large, the absolute number of cases was low. WHI results show that during 1 year, among 10,000 postmenopausal women with a uterus taking the estrogen/progestin combination, there will be 8 more cases of invasive breast cancer than in the 10,000 who do not take HRT. Comparable numbers for other diseases include heart attack, 7; stroke, 8; and blood clots, 18, including 8 in the lungs.

Increased Individual Risk Small

"This is a relatively small annual increase in risk for an individual woman," Dr. Rossouw said. "Individual women who have participated in the trial and women in the population who have been on estrogen and progestin should not be unduly alarmed."

The NHLBI stopped the trial after a review by the study’s data and safety monitoring board on May 31. The review found that the numbers of invasive breast cancer in the treatment group had crossed the boundary established as a signal for increased risk. "We prespecified that the change in cancer rates did not have to be that large to warrant stopping the trial," said biostatistician Garnet Anderson, PhD, of the Fred Hutchinson Cancer Research Center, who led the analysis. "The trial was stopped at the first clear indication of increased risk."