The study raises the possibility that, when such tumors do form, tamoxifen may increase the likelihood that the tumor will be a less-common, hormone-resistant type of breast cancer that has a poorer prognosis than the more common, hormone-sensitive type of breast cancer.

In the population-based study, the women showed a 10% overall reduction in the risk of developing cancer in the opposite breast. Risk dropped more — by 20% — in those women whose initial tumor was the type that needs estrogen to grow, called estrogen receptor (ER) positive.

About two-thirds of breast tumors are ER positive. Tamoxifen is an effective treatment in preventing recurrent cancer in about half of the women with an ER-positive tumor. Tamoxifen works by blocking estrogen from binding with these cancer cells, stopping the tumors’ growth.

But the very small group of women in the study who developed a contralateral tumor (a new breast cancer in the breast opposite from where the first cancer was diagnosed and treated) while taking tamoxifen were almost five times more likely to develop the less-common type of tumor that does not depend on estrogen to grow (estrogen receptor negative, or ER negative) than women who were not taking tamoxifen. Women with these estrogen receptor-negative tumors experience a survival rate that is 8% to 35% lower than women with ER-positive tumors.

However, "this study should not change any current clinical practices," says lead author Christopher Li, MD, speaking at a news conference in Seattle. Li is a postdoctoral fellow in epidemiology at the Fred Hutchinson Cancer Research Center and University of Washington School of Public Health and Community Medicine.

Li acknowledged his concern that, because of this study, women might abandon tamoxifen — though dozens of studies have shown it improves 10-year survival rates, reduces the risk of recurrence, and reduces the risk of tumors developing in the opposite breast. "I’m trying to give women a very explicit message about it," Li emphasizes, "and saying they should not change current clinical practice."

Li says the reason for the higher risk of ER-negative tumors isn’t known. He believes there are two possible explanations. First, in tumors with mixed ER-negative and -positive cells, the ER-negative cells continue growing alongside slow-or-no-growth ER-positive cells. In this circumstance, the tamoxifen works as expected on the ER-positive cells, and only the ER-negative cells grow into a cancer that is discovered by the patient or the doctor. Second, tamoxifen possibly can stimulate the growth of ER-negative cells, and actually make them grow more quickly than if they were not exposed to tamoxifen.

"Our findings are consistent with either one of those explanations," says Li.

Researchers obtained data from the Hutchinson Center’s cancer registry. They studied nearly 9,000 women in western Washington, ages 50 and older, who had been diagnosed with cancer in one breast between 1990 and 1998. About half were tamoxifen users.

Researchers followed the women until cancer developed in the other breast, they died, or the study concluded in December 1999. Among the women who used tamoxifen, 89 developed cancer in the opposite breast. Of those 89 tumors, 17 were ER negative. In the group of women who did not take tamoxifen, 100 women developed cancer in the contralateral breast. Of these women, only three of the tumors were classified as ER negative.

The study results do not suggest that state-of-the-art recommendations for tamoxifen treatment ought to change, says Robert Smith, PhD, director of cancer screening at the American Cancer Society (ACS).

"The impact of tamoxifen on the absolute risk of an ER-negative tumor, while elevated, is still quite, quite small," Smith says. "Furthermore," he adds, "inasmuch as the authors highlight some real limitations to their study, we should view these findings as more provocative than definitive. What the findings suggest is that among the subset of women for whom tamoxifen may actually not be beneficial, there is group that may be adversely affected. If so, we need to better understand how to identify them."

The good part of the study, Smith says, is it will stimulate further research into the complexities of tamoxifen, and potentially help further tailor adjuvant therapy (preventive treatment after all cancer has been removed) based on patient characteristics.

The authors admit a weakness of the study was the lack of information on the length of time women took tamoxifen. Other research has found tamoxifen provides a cumulative benefit for a certain number of years, followed by resistance. Thus the therapy is recommended for five years — longer than most women took it during the course of the Hutchinson Center study. "We plan to do a study on duration of use," Li says.

Li sees this study as a steppingstone to research that will clarify the mechanism of tamoxifen at the cellular level as well as help us understand ER-negative tumor development. Ultimately, Li suggests, the research could lead to a new treatment.

Harmon Eyre, MD, chief medical officer and executive vice president for research and cancer control of the ACS, says the study offers no reason for changing the current use of tamoxifen.

"Tamoxifen now has over 25 years of widespread use throughout the world, and it has clearly been documented as saving many, many thousands of lives from breast cancer," says Eyre. "Additionally, it has been documented to prevent many, many contralateral cancers of the breast in women who have had breast cancer, and it now prevents breast cancer in women who are at high risk from the disease," he emphasizes.

Patients and doctors will continue to benefit from using tamoxifen under appropriate circumstances, Eyre says, while exercising the cautions appropriate to a drug carrying some serious side effects.

"I believe that better drugs that have fewer side effects will eventually replace it," he suggests; "however, the use of tamoxifen should not be changed at the present time based on this one study."