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  • Posted: 10/20/2010

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Hormone Therapy Linked to Modest Increase in Breast Cancer Deaths

Women who used a combination of the hormones estrogen and progestin to treat menopausal symptoms during the Women’s Health Initiative (WHI) study had more cases of invasive breast cancer than non-users, and these cancers tended to involve the lymph nodes, according to an 11-year follow-up report on the participants. In addition, women who received the combined-hormone therapy had a slightly higher death rate from breast cancer and from other causes than women who received a placebo, researchers reported in the October 19, 2010, Journal of the American Medical Association (JAMA).

This report is the first from the WHI to include mortality data as well as breast cancer incidence by cancer subtype. “The surprising result was that breast cancer incidence seemed to be increased for all categories of the cancer,” said lead investigator Rowan T. Chlebowski, M.D., Ph.D., of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.

The original study included more than 16,600 postmenopausal women age 50 to 79 years who were randomly assigned to receive combined hormone therapy or placebo. For the current analysis, the researchers obtained re-consent for additional follow-up from more than 12,700 (83 percent) of the surviving participants. With the longer follow-up, the researchers were able to address some unanswered questions, such as whether hormone use increases breast cancer deaths or influences the type of breast cancer a woman develops.

“This analysis confirms that there is an effect on mortality associated with the hormones,” said Peter B. Bach, M.D., of Memorial Sloan-Kettering Cancer Center, who wrote an accompanying editorial. “It also does away with an assumption suggested by some observational studies that hormones are associated with less aggressive cancers.”

Some but not all observational studies have found that although hormone therapy may cause more breast cancers, these cancers, on average, tend to have favorable characteristics and are associated with a lower stage and longer survival than breast cancers in women who did not use hormones. But the findings from the WHI—a randomized controlled trial that is not subject to the same potential biases as an observational study—contradict this idea.

“The WHI results have always suggested that there are elevations in risk for all tumor subtypes,” said co-author Garnet Anderson, Ph.D., of the Fred Hutchinson Cancer Research Center in an e-mail message. “And now the data are increasingly saying that tumors under the influence of estrogen plus progestin are likely to be more advanced and possibly even lethal.”

Compared with placebo, the use of estrogen plus progestin was associated with a statistically significant increase in the incidence of invasive breast cancer overall (295 cases versus 385 cases, respectively). In addition, increased incidence was found among hormone users across all categories of breast cancer examined, but the association was statistically significant only for the presence of positive lymph nodes (43 versus 81, respectively).

In terms of mortality, there were more deaths attributable to breast cancer (2.6 versus 1.3 per 10,000 women per year) and more deaths due to all causes following a diagnosis of breast cancer (5.3 versus 3.4 per 10,000 women per year) in the combined hormone therapy group compared with the placebo group.

“The mortality effects are what we all expected—namely, that they would fall in line with the effects we have seen on incidence,” said Dr. Bach. 

Although the increase in breast cancer mortality among hormone users was modest, it is still an increase, noted Leslie Ford, M.D., of NCI’s Division of Cancer Prevention and the Institute’s WHI liaison. “These are real tumors; they are significant tumors. And now the data confirm that you can die from them.”

Last year, WHI investigators reported that, although combined hormone therapy did not increase the incidence of lung cancer, it increased the number of deaths from lung cancer. Together with the current results, it appears that a therapy designed to help women manage menopausal symptoms may increase deaths from the two leading causes of cancer death in women, said Dr. Chlebowski.

“If combined hormone therapy were a new drug, it’s hard to see how you could get it approved,” he added.

Unless the mortality risks of lung cancer and breast cancer can be mitigated, the use of combined hormone therapy except as short-term therapy in women with symptoms that are not improved by other therapies seems unwarranted, the study authors wrote. They went on to say that it was not possible to reliably define a safe interval for combined hormone therapy.

Dr. Bach echoed this idea in his editorial. Doctors who prescribe brief courses of hormone therapy should be aware that this strategy has not been proven in rigorous clinical trials and that the future negative effects for their patients are unknown, he wrote. So while doctors might discuss the risks and benefits of hormone therapy with patients to help a patient reach an informed decision, the underlying information for making the decision would be speculative.

“The view that these drugs are safe for short periods of time is just not based on evidence or data,” Dr. Bach said in an interview.

Although the potential harms of this treatment have been known since 2002, tens of millions of prescriptions for combined hormone therapy are written for women in the United States each year. Women who are already taking the drugs, Dr. Chlebowski noted, could potentially talk with their doctors about stopping the hormones for a period of time to see if symptoms have improved, as sometimes happens over time.

Meanwhile, non-hormonal treatments for menopausal symptoms are in development. In 2008, NIH established a research network to conduct clinical trials of promising therapies. Preliminary results from the group’s first trial, which tested escitalopram, were presented recently at a scientific meeting and are being submitted for publication, according to Dr. Anderson. Two additional trials are being planned.

After the initial WHI results were reported in 2002, there was a substantial decrease in breast cancer incidence in the United States, which researchers attributed to declines in combined hormone therapy use. Based on the updated findings, the study authors predicted that there would also be a reduction in breast cancer mortality in the United States in the future.

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