By Susan Okie
Washington Post Staff Writer
Tuesday, April 7, 1998; Page Z07

The discovery that taking the drug tamoxifen can help prevent breast cancer in women at high risk of the disease is an historic milestone, marking the beginning of a new strategy of using drugs to prevent cancer as well as treat it.

But the results of a new study, presented by scientists and government officials at a press conference yesterday, also pose new dilemmas for women and their doctors. For many women, the benefits of tamoxifen may not outweigh the dangers, which can include an increased risk of uterine cancer and of potentially fatal blood clots.

Richard Klausner, director of the National Cancer Institute, who called the findings "remarkable," cautioned that "they are complex. There is not a simple take-home message."

In the study of more than 13,000 high-risk women, daily tamoxifen treatment reduced the incidence of invasive breast cancer by 45 percent. There were 85 cases of invasive breast cancer in the tamoxifen group, compared with 154 in the placebo group. Women on tamoxifen also had about a 50 percent lower frequency of noninvasive breast cancer, as well as a lower frequency of fractures of the spine, hip and wrist.

But those benefits came at a price. There were 33 cases of cancer of the endometrium (the lining of the uterus) in the tamoxifen group, compared with 14 in the placebo group. All but one were detected early, and were treated with hysterectomy. One woman in the placebo group died of the disease.

Women taking tamoxifen also had more blood clots in the lung (17, versus 6 in the placebo group) and more blood clots in large leg veins (30 cases, versus 19 in the placebo group). Two women in the tamoxifen group died from blood clots in the lungs.

In addition, researchers said they are uncertain how long tamoxifen's protective effect against breast cancer lasts, how long a high-risk woman should stay on the drug, or at what age tamoxifen treatment would be most effective as preventive therapy. "We really don't know," said Klausner, adding that those questions will have to be answered by further studies.

An estimated 29 million U.S. women -- 21 percent of the adult female population -- might be considered candidates for preventive treatment with tamoxifen because they are at high risk for breast cancer, said Leslie Ford, associate NCI director in the Division of Cancer Prevention. Most of them are high-risk because they are over 59 years old, since breast cancer incidence increases with age. Others have a strong family history of the disease or a combination of other risk factors.

But for some high-risk women, Ford cautioned, "tamoxifen may not be an appropriate choice."

Tamoxifen, marketed by Zeneca Pharmaceuticals under the brand name Nolvadex, has been used to treat breast cancer for two decades. The company's stock closed at $147 yesterday, up $9.75 from Friday's close of $137.25.

Word of the new findings was first reported Sunday, and doctors said they immediately began getting inquiries about the drug from patients. The cost of treatment is $80 to $100 per month.

"My phone has not stopped ringing," said Patrick Borgan, chief breast surgeon at Memorial Sloan-Kettering Cancer Center in New York. "I think it's going to be a national, immediate trend towards getting women on tamoxifen. But I think it's going to have to be a case-by-case analysis."

The multi-hospital study, sponsored by the Pittsburgh-based National Surgical Adjuvant Breast and Bowel Project (NSABP), enrolled 13,388 women who were at high risk of breast cancer. Women were eligible if they were at least 60 years old, or if they were younger but had a combination of risk factors that raised their risk of the disease to that of a 60-year-old. Such factors could include a strong family history of breast cancer, early age at first menstruation, late age at first pregnancy (or no pregnancies), and a history of multiple breast biopsies for suspicious lesions.

About 40 percent of participants were aged 35 to 49; 30 percent were aged 50 to 59, and 30 percent were 60 or older.

The women were divided into two groups. Half took 20 milligrams of tamoxifen daily and the other half took a placebo pill. Neither the women nor their doctors knew who was receiving what. Treatment was to continue for five years, but the study was halted early, when participants had been treated for an average of four years.

All age groups showed similar reductions in breast cancer incidence from tamoxifen. However, in this study, serious side effects such as blood clots and endometrial cancer only occurred in women who were 50 or older, researchers said.

Ford said this suggests that for younger women at high risk of breast cancer, the benefits of tamoxifen seem to outweigh the risks. But only 2.7 percent of U.S. women in their forties and 7.1 percent of women in their fifties would fall into this category.

For women over 50, the risks of the drug need to be carefully weighed. Based on the study's findings, Ford estimated that if 1,000 high-risk women aged 50 or older were treated with tamoxifen for five years, the drug would prevent 17 cases of invasive breast cancer (out of 33 expected) but would cause 10 cases of serious blood clots or strokes and 12 cases of endometrial cancer.

"Those are major life events," said Cindy Pearson, executive director of the National Women's Health Network, a consumer group that has been critical of the study. "If I were a woman with [very high breast cancer risk], I might feel very good about that trade. But for the average woman . . . this is not a breakthrough."

Researchers said yesterday they intend to analyze the study's findings in more detail to determine whether women in certain high-risk categories benefit more than others from tamoxifen. A subgroup of study participants are also undergoing genetic testing to look for mutations in the BRCA1 and BRCA2 genes, which have been associated with an elevated breast cancer risk. Scientists may be able to use this information to find out whether tamoxifen prevents breast cancer in women who have these mutations, Klausner said.

Researchers also hope to conduct a comparative study in postmenopausal women of tamoxifen and raloxifene, a related drug recently marketed to treat osteoporosis, to find out whether raloxifene can also prevent breast cancer, perhaps with a lower incidence of side effects, said Norman Wolmark, chairman of the NSABP.

Because only 3 percent of participants in the tamoxifen study were minorities, the results may not be completely generalizable to women who are African American, Hispanic or members of other ethnic groups, Wolmark said. "That was one of the major shortcomings of the trial," he said.

Government officials and researchers yesterday praised the courage and commitment of the thousands of women who volunteered for the study. "This is their trial and the credit should go to them," Klausner said.

Helene Wilson, 48, of North Wales, Pa., said she volunteered because she had a strong family history of breast cancer. She found out yesterday morning that she'd been in the tamoxifen group.

"I was just elated" at the findings, Wilson said. "It's like winning the Super Bowl. We did it! Our study did it!"

For more information, call the National Cancer Institute's Cancer Information Service at 800-4-CANCER.