Commercial Tests Don't Find All Breast Cancer-Related Genetic Abnormalities in Families at Very High Risk

Reviewed study: "Commercial Tests Don't Find All Breast Cancer-Related Genetic Abnormalities in Families at Very High Risk" by M. King and others, Journal of the American Medical Association, March 22, 2006

Is this for me? If you have a family history of breast cancer, you might want to read this article.

Background and importance of the study: Some families seem to be particularly afflicted by breast cancer. When an abnormal gene is inherited and passed down through a family, and that gene increases the risk of developing breast cancer, cancer that results is called hereditary.

Two genes have been identified as causing most cases of hereditary breast cancer. They are BRCA1 and BRCA2. BR stands for BReast, and CA stands for Cancer. Abnormal BRCA1 and BRCA2 genes account for about 5% to 10% of all breast cancers. Women who have an abnormal BRCA1 or BRCA2 gene have about a 60% risk of being diagnosed with breast cancer during their lifetimes, according to the National Cancer Institute. In the United States, women without an inherited abnormal breast cancer gene have about a 12% risk of developing breast cancer over a 90-year life span.

Women with BRCA1 or BRCA2 abnormalities are also at increased risk of developing ovarian cancer. The lifetime risk for ovarian cancer is about 55% for women with BRCA1 mutations and about 25% for women with BRCA2 mutations. By comparison, about 1.8% of women without an inherited BRCA gene abnormality develop ovarian cancer.

Abnormalities in other genes also affect the risk of breast cancer. One such gene is called CHEK2 (CHEK2 stands for cell-cycle checkpoint kinase 2). Women with an abnormal CHEK2 gene (and without an abnormal BRCA1 or BRCA2 gene) may have double the risk they would otherwise have for breast cancer. This means, for example, that if your risk of breast cancer based on your age is 7% and you have the abnormal CHEK2 gene, your risk may go up to 14%.

Other, even more rare genetic mutations have been identified that may increase the risk of cancer, including breast cancer.

Abnormalities in the TP53 gene can cause Li-Fraumeni syndrome. Abnormalities in the PTEN gene are a part of Cowden syndrome. (A syndrome is a set of symptoms or conditions that happen at the same time and suggest the presence of a certain disease or an increased chance of developing the disease.) Both of these syndromes are rare, but they are associated with an increased risk of developing several types of cancer, including breast cancer.

A genetic test can determine if a woman has an abnormal BRCA1 or BRCA2 gene. The test has been available for about 10 years, but it has some drawbacks. Normal test results don't guarantee healthy genes. In some families, many women have had breast cancer, yet they all test normal for the known breast cancer mutations. Other gene abnormalities haven't been identified yet, so we don't know at this time what they look like and therefore how to find them.

In the study reviewed here, the researchers wanted to see how many abnormalities in BRCA1, BRCA2, CHEK2, TP53, and PTEN genes were missed by commercial genetic testing in families that were at high risk for breast cancer.

Study design: The researchers looked at 300 people from families in the United States that had four or more cases of breast or ovarian cancer. All of the participants tested negative for abnormal BRCA1 and BRCA2 genes in commercial tests. A negative test result means that the gene was normal.

The 300 participants had the following characteristics:

• 291 were women with breast cancer, of whom 204 (68%) were diagnosed between the ages of 30 and 49.
• 6 were women with ovarian cancer.
• 3 were men with breast cancer.
• 31 (15.5%) were of Ashkenazi Jewish heritage.

Researchers also wanted to know about the families of the participants. Families were defined as immediate and extended family members. The families had the following cancer-related histories:

• 140 (47%) had female breast cancer only.
• 135 (45%) had female breast cancer and ovarian cancer.
• 13 (4%) had female and male breast cancer.
• 12 (4%) had female and male breast cancer and ovarian cancer.
• 10 (3%) had Li-Fraumeni or Li-Fraumeni-like syndrome.
• 8 (3%) had Cowden syndrome.

The researchers performed special genetic tests, done as part of commercial genetic testing, to determine if any of the participants had genetic abnormalities in BRCA1, BRCA2, CHEK2, TP53, and PTEN genes that had been missed by commercial genetic testing.

The study was funded by the National Institutes of Health; the European Program for Cooperation in Scientific and Technical Research and the Ministry of Education, Youth, and Sports of the Czech Republic; the Ministry of Health of the Czech Republic; and the Breast Cancer Research Foundation.

Results: The researchers found that 52 participants (17%) had abnormal BRCA1, BRCA2, CHEK2, or TP53 genes that had been missed by commercial genetic testing. No abnormal PTEN genes were detected.

Specifically:

• 31 had an abnormal BRCA1 gene.
• 4 had an abnormal BRCA2 gene.
• 14 had an abnormal CHEK2 gene.
• 3 had an abnormal TP53 gene.

The range of abnormalities was very broad. The 52 participants with abnormal genes had 28 different abnormalities.

Abnormal BRCA1 genes were found in more women diagnosed with breast cancer at 40 or younger (15 of 91 women, or 16%) than in women who were older than 40 at the time of diagnosis (13 of 200 women, or 6.5%). This difference was statistically significant, meaning that the BRCA1 abnormality likely contributed to the fact that the women developed cancer at such a relatively young age. It wasn't just due to chance.

Abnormal BRCA1 and BRCA2 genes were found in more participants with ovarian cancer, male breast cancer, or both in their families (29 of 160 people, or 18%) than in people with only female breast cancer in their families (6 of 140 people, or 4.2%). This difference was also statistically significant.

Abnormal CHEK2 genes were not significantly associated with age at breast cancer diagnosis, family history of male breast cancer, or ovarian cancer. A new type of CHEK2 abnormality was found in two women of Czechoslovakian ancestry. In each of their families, the CHEK2 abnormality appeared in women with breast cancer and women with ovarian cancer.

Abnormal TP53 genes were found in 3 of 10 families with Li-Fraumeni or Li-Fraumeni-like syndrome.

Conclusions: The researchers concluded that abnormalities in BRCA1 and BRCA2 genes can take many forms. They found many genetic mutations that were previously unknown. Because many of these genetic mutations are rare, developing a full list of all possible genetic mutations will take a long time.

Among women and men with breast cancer who have a strong family history of breast or ovarian cancer and who test negative for abnormal BRCA1 or BRCA2 genes in commercial tests:

• About 12% can expect to have an undetected BRCA1 or BRCA2 abnormality.
• About 5% can expect to have an undetected CHEK2 or TP53 abnormality.

The researchers also concluded that these new, more effective genetic tests should be made available to women at high risk for breast cancer.