Researchers have confirmed a previous study's findings that combined estrogen plus progestin hormone replacement therapy (HRT) increased risk of breast cancer and said the decline in rates of the disease following widespread reduction in combined HRT use was unrelated to changes in mammogram screening.

The study was the work of co-author Dr Marcia Stefanick, professor of medicine at Stanford University School of Medicine and other Women's Health Initiative (WHI) investigators, and is published in the 5 February issue of the New England Journal of Medicine, NEJM.

Stefanick and colleagues said that postmenopausal women who take combined estrogen plus progestin HRT for at least five years are doubling their risk of breast cancer. This was their conclusion after re-analysing the WHI data that clearly shows a link between HRT and breast cancer, they said. They also said that women can quickly reduce their risk of breast cancer by stopping HRT.

After the 2002 landmark report from the WHI trial that linked use of estrogen plus progestin HRT to breast cancer and other diseases, there was a dramatic drop in HRT use in the United States, from 60 million prescriptions in 2001 to 20 million in 2005. This was followed by a drop in rates of breast cancer detection, suggesting that stopping HRT reduced breast cancer risk, but the authors wrote that the cause of the decrease remained controversial. Some scientists argued that the drop was linked to changes in mammogram frequency.

According to the authors of this latest study, there is now very strong evidence that estrogen plus progestin HRT causes breast cancer. Stefanick, who chairs the WHI executive committee said:

"You start women on hormones and within five years, their risk for breast cancer is clearly elevated."

"You stop the hormones and within one year, their risk is essentially back to normal. It's reasonably convincing cause-and-effect data," she added.

Stefanick explained that the results do not apply to women taking estrogen only. Another large WHI trial did not find that breast cancer rates went up for the majority of women on estrogen-only therapy.

For the study, Stefanick and colleagues analyzed data from two cohorts. The first cohort comprised 15,000 women in the original WHI landmark study that was stopped three years early by the sponsor, the National Institutes of Health (NIH). These women had been randomly assigned to take either a daily HRT dose comprising 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or a daily dose of placebo. When the results emerged in 2002, the participants were all advised to stop taking the study pills, but the researchers continued to monitor them and note cases of new breast cancers and frequency of mammograms.

The second cohort was from a separate WHI observational study of 41,449 women that started in 1994. This was a study of "the real world" where women made their own choices about whether to have HRT or not. About 40 per cent of them were on HRT at the start of the study and had been taking it for an average of 6.9 years. When the 2002 WHI study results came out linking the combined HRT to breast cancer, this group of women weren't given any special instructions, but they were sent a letter outlining the results. They were also encouraged to go for regular mammogram screening.

The researchers found similar patterns of results in the two cohorts. In the combined HRT clinical trial (the first cohort), the rate of breast cancer was higher in the hormone group in the five years leading up to 2002 and then dropped sharply when they stopped taking the combined HRT (the number of new breast cancers diagnosed in the first year after they stopped taking the HRT dropped by 28 per cent). The rates of mammogram screening remained very similar for all the women.

Although the women in the observation cohort (the "real world" study) were not advised as such to stop the HRT, many of them chose to do so, reflecting the pattern of the population as a whole when the WHI results were published. In this cohort, between 2000 and 2003, there was a 50 per cent drop in use of HRT, which coincided with a 43 per cent drop in breast cancer diagnoses in the same cohort between 2002 and 2003.

The results also showed that a woman who chose to stay on the combined HRT for at least five years doubled her annual risk of developing breast cancer, wrote the researchers, a considerably higher risk than previously thought.

Stefanick and colleagues said the overall results were unaffected by frequency of mammogram screening.

They concluded that:

"The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography."

Critics of the previous WHI study report said that the higher incidence of breast cancers among the women on the combined HRT could have been due to the fact that women on HRT went more frequently to mammogram screening which increases the chances of finding tumors. Stefanick said that while this was true, HRT use can also make it harder to find small tumors because it changes the compostion of the breast.

As Stefanick explained:

"Our data suggest that although you are picking up more tumors in those women, you're probably missing a lot as well because of the problems in using mammography in women taking hormones."

Wyeth, the drug company that makes Prempro, the estrogen plus progestin HRT pill taken by most of the women in the study, disputes the results of this study. Their spokeswoman, Gwendolyn Fisher said in a telephone interview with Reuters that:

"We don't believe the article supports the theory that the decline in use of estrogen plus progesterone caused a one-time abrupt nationwide decline in breast cancer incidence."

If this is was the case, then we should be seeing further reductions in breast cancer rates because the rates of HRT use continue to fall, but we aren't seeing this and the researchers don't offer an explanation for that, she said.

This view appears to have the support of the International Menopause Society. They said that the fall in breast cancer rates started at least 3 years before the WHI trial was stopped. Breast cancer takes years to develop they said in a statement reported by Reuters, adding that:

"If HRT use causes breast cancer, then the drop in breast cancer rates would not be seen for some time yet."

The current advice from the NIH on HRT use includes the following statement (from their WHI trial Questions and Answers page):

"The FDA [US Food and Drug Administration] recommends that hormone therapy be used at the lowest doses for the shortest duration needed to achieve treatment goals. Postmenopausal women who use or are considering using hormone therapy should discuss the possible benefits and risks to them with their physicians."

"Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women."
Chlebowski, Rowan T., Kuller, Lewis H., Prentice, Ross L., Stefanick, Marcia L., Manson, JoAnn E., Gass, Margery, Aragaki, Aaron K., Ockene, Judith K., Lane, Dorothy S., Sarto, Gloria E., Rajkovic, Aleksandar, Schenken, Robert, Hendrix, Susan L., Ravdin, Peter M., Rohan, Thomas E., Yasmeen, Shagufta, Anderson, Garnet, the WHI Investigators.
N Engl J Med Volume 360, Number 6, pages 573-587, February 5, 2009.

Click here for Abstract.

Click here for Questions and Answers about the WHI trial (NIH).

Sources: Journal Abstract, Stanford University Medical Center, Reuters, National Institutes of Health (NIH).

Written by: Catharine Paddock, PhD