Advanced Breast Cancers, Higher Death Rate Seen in HRT Study

Advanced Breast Cancers, Higher Death Rate Seen in HRT Study
Article date: October 20, 2010

By Karen Patterson
New findings about the link between breast cancer and combined hormone replacement therapy strengthen the argument that estrogen and progestin should be used only conservatively to treat symptoms of menopause.

A study published this week in the Journal of the American Medical Association bolsters earlier research from the Women’s Health Initiative that found women ages 50 to 79 who received the hormones face an elevated risk of breast cancer. The Women’s Health Initiative is a massive clinical trial evaluating various health factors in postmenopausal women.

Longer follow-up finds higher death rate

The new study from the initiative — with a longer patient follow-up period (an average of 11 years) than previous studies — reported 385 cases of invasive breast cancer among women given the combined hormone therapy, versus 293 among women given a dummy pill, or placebo. The study also found that death rates from breast cancer were higher among the women on the hormones, compared with placebo.

“It’s a very strong paper. It clearly takes advantage of a well-conducted clinical trial,” says Susan Gapstur, PhD, vice president of the American Cancer Society’s Epidemiology Research Program. “These findings are adding to the growing evidence and concern about long-term effects of estrogen plus progestin.”

Gapstur, who was not involved in the research, notes that much of the previous data on the link between combined hormone therapy and breast cancer mortality have come from observational studies, where real-world outcomes are noted but direct cause-and-effect links cannot be established scientifically. “The major strengths of the new study are that it allows the investigators to look at the effects, in a randomized trial, of combined hormone therapy.”

The increased death rate reported in the latest research directly challenges findings from the observational studies, which had suggested that cancers that develop after use of combined hormone therapy tend to be more readily treated, says Rowan Chlebowski, MD, PhD, lead author of the new study. “Instead we see that mortality is increased,” he says.

Total number of deaths still small

The new research, based on data from 16,608 women, found that compared with patients on the placebo, those who took estrogen plus progestin (in a formulation known commercially as Prempro):

. had a 25 percent higher risk of invasive breast cancers
. were 78 percent more likely, if diagnosed with breast cancer, to have more advanced cancers, which had spread to the lymph nodes
. faced about double the risk of dying of breast cancer, and for those with breast cancer, a higher risk of dying of any cause.

While those percentages may sound high, the absolute risk that women face is quite low. For instance, 2.6 deaths were calculated a year per 10,000 women on the hormones, compared with 1.3 deaths per 10,000 women on the placebo. The study found 25 deaths among the thousands of women on the hormones, compared with 12 among those on placebo. The researchers were not able to compare the treatments women received for their cancer to see if those might have had any effect.

Gapstur notes that further follow-up may better clarify the long-term impact of combined therapy on breast cancer death rates.

Breast cancer cases fell after hormone use decreased
Still, because estrogen plus progestin has been commonly prescribed, the number of breast cancer cases and deaths that could be prevented by minimizing its use is striking, says Chlebowski, a medical oncologist at Los Angeles Biomedical Research Institute, at Harbor-UCLA Medical Center in Torrance, Calif.

Chlebowski cites research, published in 2007 but reflecting 2003 figures, showing a one-year drop of almost 7 percent in breast cancer incidence among U.S. women age 50 and older. The drop came on the heels of data from the Women’s Health Initiative that first raised the alarm about dangers from combined hormone therapy; prescriptions plummeted by the millions. Since then, annual breast cancer incidence has remained lower, research has found.

“When you see there are 20,000 fewer cases [in 2006 than 2002], and that would fill up a whole basketball arena with people who didn’t have cancers, then that’s serious,” Chlebowski says. “If you said the absolute risk is very, very low, that’s correct. But it looks like now we’re identifying a life-threatening risk of a therapy taken very, very commonly just for symptom management.”

The new research also suggests that breast cancer cases increased across tumor types, Chlebowski said, listing estrogen receptor-positive, progesterone receptor-positive, HER2-positive, triple negative and estrogen receptor-negative cancers. “That really wasn’t known before,” he said, and helps dispel the notion that the cancers that were arising in women who used hormone therapy were less aggressive.

He also noted another report from the Women’s Health Initiative, published in 2009 in The Lancet, indicating that deaths from lung cancer were 71 percent higher among women on combination hormone therapy than among those on placebo. Considering the lung cancer findings, too, “You’re talking about thousands of women being at risk for these diseases when millions of prescriptions are being taken.”

Consider carefully whether to use HRT

Together, the findings argue that women should pay careful attention to drug labeling for combined hormone therapy, which calls for the lowest dose for the shortest duration necessary, he said. Patients often don’t stop to evaluate how they feel after a year or two of therapy to determine whether the hormones are still needed to manage menopause symptoms. Participants in the Women’s Health Initiative took combination hormone therapy an average of 5.6 years.

Chlebowski notes that the study’s findings apply only to one dosing schedule of the hormones — although that was the one used by the vast majority of women at the time the research was undertaken. “The dose is lower now, but we don’t know if simply lowering the dose will result in any difference in findings, because no safety study has been done.”

All of this means women need to think carefully about the potential risks and benefits of combined hormone therapy, Gapstur says.

“Women should have a very, very careful conversation with their physicians about combined hormone therapy, because the evidence is growing that it has clear adverse effects.”


Reviewed by members of the ACS Medical Content Staff
ACS Medical Content and News Staff

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Citation: "Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in Postmenopausal Women." Published in the Oct. 20 issue of JAMA (Vol. 304, No. 15). First author: Rowan T. Chlebowski, MD, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

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Advanced Breast Cancers, Higher Death Rate Seen in HRT Study