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Fred Hutchinson Cancer Research Center Reports Findings From The Largest Study To Date of BRCA1 in Breast Cancer Patients

Many women with breast cancer who may fear they carry a mutation in BRCA1 probably do not carry such a mutation.

SEATTLE -- In the largest study conducted to date of breast cancer patients drawn from the general population, researchers at the Fred Hutchinson Cancer Research Center found that the majority of women diagnosed with breast cancer before age 45 who have a first-degree family history of breast cancer (involving an affected mother or sister) and the majority of those diagnosed before age 35 did not carry a mutation in the breast and ovarian cancer susceptibility gene, BRCA1. The report was published in the March 25 issue of the Journal of the American Medical Association. This study was funded by the National Cancer Institute.

"Women with relatively modest family history profiles or with no family history have not had information to guide them regarding their likelihood of carrying mutations in BRCA1," says Kathleen Malone, Ph.D., epidemiologist at the Hutchinson Center. "Previous research has focused on rare high risk families with many members affected with breast or ovarian cancer."

The findings of this study confirm earlier predictions that mutations are considerably less frequent in women with minimal to modest family histories than has been seen in women with four or more affected relatives. Many women who may believe they are at high risk for carrying a BRCA1 mutation on the basis of their family history or early age of breast cancer diagnosis are unlikely to have such a mutation. However, they may carry mutations in other known, or as yet unknown, breast cancer related genes.

In addition, researchers believe that the proportion of all breast cancer cases in the general population, including those with a later age of diagnosis and those with no affected relatives, who carry BRCA1 mutations is likely to be even smaller than the proportions seen in this study.

The research team, led by Malone and Elaine Ostrander, Ph.D., a molecular biologist at the Hutchinson Center, found that the women with breast cancer who had BRCA1 mutations lacked a common family history profile.

The study showed a large proportion (more than 92%) of the women diagnosed with breast cancer before age 45 who had a first-degree family history of breast cancer and a similar proportion of the women diagnosed with breast cancer before age 35 did not carry BRCA1 mutations.

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There were a few women with little or no family history of breast cancer who were BRCA1 mutation carriers, suggesting that all women and their health care providers need to be vigilant with regard to cancer prevention and surveillance efforts.

According to the researchers, while early onset of the disease and a strong family history of breast cancer may be useful as broad guidelines for checking BRCA1 status and risk, these findings suggest that it may be difficult to develop specific recommendations regarding BRCA1 mutation screening among women who have little or no family history of breast cancer.

Study Design and Results

The study was designed to assess the frequency of BRCA1 mutations in women believed to be at increased risk for having an inherited form of breast cancer and to identify any specific features of family history that characterize women who are mutation carriers. Two groups of breast cancer patients drawn from two population-based studies of breast cancer in young women were targeted for molecular analysis: those diagnosed with breast cancer before age 45 who had a first-degree family history and those diagnosed with breast cancer before age 35 regardless of the family history. These two groups were selected because they represent the women in the general population thought to be at the highest risk of carrying mutations, except for the few women with extreme family histories.

Among the 208 women diagnosed with breast cancer before age 45 who had a first-degree family history of breast cancer, 7.2 percent carried a BRCA1 mutation. Of the 193 women diagnosed with breast cancer before age 35, 6.2 percent carried a BRCA1 mutation. Mutations were more common in patients diagnosed at a younger age, in those with at least one relative with breast cancer diagnosed before age 45, in those with greater numbers of affected relatives, and in those with a family history of ovarian cancer.

The family history profiles seen in this study are considerably less pronounced than those in studies of high-risk families and thus, the BRCA1 frequency is much lower. It has been suggested that cancer in most families with less than four affected members and no ovarian cancer is not due to BRCA1. In this study, the mean number of relatives affected with breast cancer was 1.7, and the mean number with breast and ovarian cancers was 1.85. Although the number of families in this study with four or more affected women were small, the study did find that mutation frequency varied by combination of four or more relatives with breast and ovarian cancers.

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This report was published in the March 25 issue of JAMA along with a report from another population-based study conducted by researchers at the University of North Carolina and the University of Washington.

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