Combination hormone therapy doubles breast density and quadruples risk of abnormal mammograms

Postmenopausal women who take combination estrogen-plus-progestin hormone-replacement therapy for one year experience a twofold increase in breast density – a known risk factor for breast cancer – and a quadrupled risk of having an abnormal mammogram, according to new findings from a sub-study of the Women’s Health Initiative, or WHI.

Lead investigator Anne McTiernan, M.D., Ph.D., of Fred Hutchinson Cancer Research Center, presented these findings today at the third annual International Conference on Frontiers in Cancer Prevention Research hosted by the American Association for Cancer Research. “I was surprised by the magnitude of the effect – the doubling of breast density associated with combination-hormone therapy,” said McTiernan, a member of Fred Hutchinson’s Public Health Sciences Division and lead physician of the WHI Clinical Coordinating Center, which is based at Fred Hutchinson.

The effect of HRT on breast density remained consistent throughout the two-year study period and was similar across ethnic and racial groups. The impact was particularly pronounced among women in the highest age bracket; those between 70 and 79 experienced a nearly threefold increase in breast density as compared to younger women, presumably because their breast tissue was less dense to begin with, McTiernan said. “These findings are unique in showing a sustained effect over two years and that even in older postmenpausal women breast density can increase in response to estrogen-plus-progestin therapy,” McTiernan said.

The study involved a randomly selected subgroup of 413 racially and ethnically diverse postmenopausal women, ages 50 to 79, who were participants in the WHI estrogen plus progestin trial, which involved more than 16,500 women nationwide. Half of the women in the sub-study were randomly selected to receive estrogen plus progestin and half received an identical-looking placebo. All received a baseline mammogram at the beginning of the study and a follow-up mammogram after one or two years.

On average, participants were 62 years old and 12 years post-menopause at the beginning of the study. The majority of the women were non-Hispanic white (42 percent) or African-American (35 percent), 16 percent were Hispanic and 6 percent were Asian/Pacific Islander.

Breast density was measured by a computer-aided technique that calculated the amount of dense, or white-appearing, tissue on digitized mammography images. A woman’s risk of breast cancer and her chances of getting an accurate cancer diagnosis depend largely on the density of her breast tissue. Density is measured according to the ratio of connective and epithelial tissue, which appears on a mammogram as white; as compared to fatty tissue, which appears as black. Because cancer also appears as white on a mammogram, a high degree of breast density can make it difficult to spot tumors and other abnormalities.

In addition to being harder to image, dense breast tissue also appears to be more biologically active and susceptible to malignancy. Previous research at Fred Hutchinson has shown that women under 50 with predominantly dense breasts are four times more likely to develop breast cancer than those with little or no breast density. While density is determined largely by age and genetics, this study underscores the fact that other factors can play a part as well. In addition to hormone-replacement therapy, weight and physical activity also have been found to have an impact on breast density.

“By increasing breast density, the use of combination estrogen-plus-progestin hormone therapy may increase breast-cancer risk as well as decrease the sensitivity of screening mammography,” McTiernan said. “Our results suggest that avoiding such hormone therapy may help improve the sensitivity of mammograms for detecting early breast cancers at a stage when they are most treatable.”

In addition, McTiernan and colleagues suggest that health-care providers may want to track breast-density change during regular mammography screenings and use this information as part of the risk-benefit assessment when helping women choose whether to continue hormone therapy.