Current as well as long-term users of hormone replacement therapy (HRT) have an increased risk of developing breast cancer, said researchers in the Feb. 13 issue of the Journal of the American Medical Association (Vol. 287, No. 6: 734-740).

The researchers, from the Fred Hutchinson Cancer Research Center in Seattle, found that use of HRT increased the overall risk of breast cancer by up to 70% —a conclusion that other studies have also reached.

But when they looked further to find out if a specific type of breast cancer was especially associated with HRT use, the researchers detected a surprisingly high association with lobular cancer, a less common form of breast cancer which develops in the milk-producing lobules of the breast.

The risk of developing lobular breast cancer was four times higher in women who currently use combination therapy (estrogen and progestin) and three times higher in women who have used HRT for five or more years.

Lobular cancer accounts for about 10% of all breast cancer cases. The more common form of breast cancer, called ductal cancer because it starts in the milk ducts of the breast, is responsible for up to 85% of all breast cancer. Ductal cancer risk was increased 50% in women who had a history of recent HRT use.

According to an American Cancer Society (ACS) expert, this study raises an interesting hypothesis that HRT may be more strongly associated with lobular breast cancer than with ductal breast cancer.

But more studies need to confirm the link between HRT and lobular cancer, said Eugenia Calle, PhD, ACS director of analytic epidemiology.

"These are early days in the research, and the study contains only small numbers of women with lobular cancer," she said. "It's an important finding, but more work needs to be done."

Even though the figures seem high, they must be taken in the right context, said Emily White, PhD, the lead researcher and a professor of epidemiology.

"Finding a large risk for lobular cancer doesn't impact a woman's overall risk," because so few women develop that kind of cancer, she said.

"What the study really tells us is that the link between HRT use and breast cancer is becoming stronger," she said. "It may be time to re-evaluate the risk versus the benefit," said White.

She added that more research is needed on estrogen's influence on lobular cancer.

"Lobular tumors are more frequently estrogen- and progesterone-receptor positive than ductal cancers, and thus might be particularly influenced by HRT use," White said.

In this study, researchers examined computerized medical and pharmacy records of 705 postmenopausal women who had been diagnosed with invasive breast cancer, as well as 692 postmenopausal women who did not develop the cancer. The women were all followed at a regional health maintenance organization for several years.

Using records instead of a patient's recall of whether and when they used medications, "is a much more accurate way to do a study of this kind," said White.

White and her colleagues found an increased risk of cancer in women who had used estrogen alone or in combination with progestin, and that risk increased the longer a woman used the therapy.

For example, if a women used HRT for 57 months or more over the previous five years, her risk of developing breast cancer was increased 70% compared to a woman who didn't use HRT. Even using HRT for only 18 to 40 months over the preceding five years increased the risk of breast cancer 43%.

That rate stayed the same in the 600-plus women diagnosed with ductal cancer in the study. But what was surprising was how much HRT influenced the risk of developing lobular breast cancer.

Of the 91 women in the study who had been treated for lobular cancer, current use (defined as six months or more) of either estrogen or combination therapy was associated with a 400% increase of lobular cancer. Using HRT for five or more years increased their risk by about 300%.

The authors wrote, "If our results are correct, then nonusers of HRT would have an incidence rate of ductal cancer of about 230 per 100,000 women per year, whereas women with five years of recent HRT use would have a rate of 349 per 100,000 women per year.

In contrast, the authors continued, non-HRT users would have an incidence rate of lobular cancer of "23 per 100,000 women per year and 70 per 100,000 women per year among women with five years of recent HRT use."