NCI Breast Cancer Trial Raises Genetic Testing Questions

By Lisa Seachrist

Washington Editor

WASHINGTON — Last week women were met with the stunning news that results from the National Cancer Institute-sponsored Breast Cancer Prevention Trial (BCPT) showed the drug tamoxifen could reduce the incidence of breast cancer by 45 percent in the short term.

However encouraging the results of the trial, women who are at higher risk for breast cancer are faced with difficult choices over whether to take tamoxifen as a preventive measure against breast cancer. The drug carries with it significant side effects, including increased risk for uterine cancer and life-threatening blood clots.

In this atmosphere, Peter Meldrum, president and CEO at Myriad Genetics Inc., in Salt Lake City, noted there may be a role for testing women who are contemplating tamoxifen to determine if they have BRCA-1 and BRCA-2 gene mutations.

Myriad Genetics and OncorMed Inc., of Gaithersburg, Md., market tests for the BRCA-1 and BRCA-2 genes, which are linked to breast cancer.

"The risks associated with tamoxifen are quite high and you wouldn't want to use this drug in the general population," Meldrum said. "A woman in a breast cancer family would have a 50-50 chance of inheriting a defective gene. If a woman didn't inherit the gene, she would have the risk found in the general population and would probably not be a candidate for tamoxifen."

The anti-estrogen drug is one of the most widely prescribed cancer therapeutics and is sold by Zeneca Inc., of Wilmington, Del., a subsidiary of London-based Zeneca Group plc.

Trial Looks At Cancer Prevention

The BCPT was a randomized, double-blind, placebo controlled taxomifen trial that enrolled 13,000 women who were at high risk for developing breast cancer. Risk was established using a statistical model that included a women's age, age at first menses, age at first delivery, number of breast biopsies and diagnosis of lobular carcinoma in situ. Women over the age of 60 were considered high risk by virtue of the fact that breast cancer risk increases as women age. Younger women, however, had to have a combination of risk factors that would place them over the defined threshold for the study.

Most of the youngest women in the trial, those between the ages of 35 to 49, had two or more first-degree relatives who had developed breast cancer.

Because 90 percent of familial early-onset breast cancers can be linked to mutations in BRCA-1 and BRCA-2, Meldrum said genetic testing may provide valuable information to young women considering tamoxifen

In applying genetic tests for BRCA-1 and BRCA-2 mutations, Myriad uses a protocol that tests women who have one first-degree relative with ovarian cancer or two first degree relatives with breast cancer.

Under that protocol, the company finds 20 percent of the women tested show a mutation in one of the two genes. Meldrum pointed out the criteria fall well within the American Society of Clinical Oncology's guidelines, which consider a 10 percent positive rate as the threshold for conducting genetic tests for a predisposition for cancer.

"Knowing your genetic risk is important information that a woman could use in making the decision to go on tamoxifen," Meldrum said. "In making a decision about the trade-offs between breast cancer prevention and the risk of uterine cancer and blood clots, you want as much information as possible."

Leslie Alexandre, vice president of corporate affairs and marketing at OncorMed, noted that because the BCPT hasn't yet assessed the genetic risks of the women who participated in the trial, it remains to be seen what role genetic testing will play in making such a decision.

"We have always felt there is a role for BRCA-1 and BRCA-2 testing in high risk families as a means for potentially saving lives through increased monitoring or even prophylactic mastectomy," Alexandre said. "The tamoxifen study showed there is a potential to reduce the incidence of breast cancer by 45 percent, which is certainly a more attractive option than prophylactic surgery. But we don't yet know how that will apply to those women with genetic susceptibility."

Leslie Ford, assistant director of Early Detection and Community Oncology in the Division of Cancer Prevention at NCI in Bethesda, Md., said the institute is conducting a case-controlled study to assess the incidence of BRCA-1 and BRCA-2 genes in patients who got cancer and those who didn't in the study. With the results of that study likely to come out in the next year or two, Ford called efforts to use genetic testing in making a decision on whether to take tamoxifen "premature."

"Until we have the results from the case controlled study, we can't really say how genetic susceptibility fits into the decision about tamoxifen," Ford said. "The other part is that women who test negative for genetic mutations may still be good candidates for tamoxifen. We suspect the majority of the women don't have a mutation, yet many of the younger women in the study had two first-degree relatives with breast cancer."

Study Highlights Practice Of Genetic Medicine

Meldrum agreed results of the NCI genetic study will offer a more complete picture of tamoxifen's role for patients with genetic mutations. But, he noted, in the absence of better data, knowing their genetic status is information that will assist women in making such a decision.

David Stone, managing director with Cowen & Co., in Boston, said the most important part of the study was that it showed chemoprevention is possible. Stone observed as more information comes out and more specific anti-estrogens are developed that have fewer side effects than tamoxifen, genetic testing is likely to become commonplace.

"This study is an important beginning in molecular medicine," Stone said. "The trend will actually be to do genetic analysis to determine the exact therapies or chemopreventives to use."

Both Stone and Alexandre said that promise of molecular medicine will not be realized until issues surrounding genetic discrimination, privacy and health coverage are resolved.

Myriad's and OncorMed's genetic tests both run between $400 and $2700, depending on the extent of the analysis required. Both companies require that patients undergo informed consent and counseling about the risks and benefits of the test. *