American Association for Clinical Chemistry
Better health through laboratory medicine
April 27, 2006
1

In This Issue . . .

Assessing Cancer Risk: Beyond the BRCA Test
Why a Negative Result Might Lead to More Testing for Mutations in Cancer Genes
Julie L McDowell


Researchers believe that people with a long family history of cancer could be carrying mutations in BRCA 1 or BRCA 2 genes, which are associated with an increased risk for developing breast or ovarian cancer. To help identify people carrying these gene mutations, the U.S. Preventive Services Task Force (USPSTF) recommended last year that women and men with increased-risk family history should be referred for genetic counseling, where these individuals would be evaluated for the appropriateness of genetic testing for mutations in these genes, which account for a portion of families that are suspected to have an inherited susceptibility to develop breast or ovarian cancer. However, a recent study in the Journal of the American Medical Association found that even though some patients with a family history of cancer consistent with this inherited cancer susceptibility—and where these mutations are likely to be found—test negative for the BRCA mutations, some are still carrying genetic mutations putting them at high risk for developing breast and ovarian cancer. This issue of Strategies analyzes these findings and reveals how they're prompting some clinicians to revise their genetic testing protocol for high-risk patients.

Many patients with a strong family history of cancer, particularly women, base their cancer prevention efforts on the outcome of a test that detects mutations in the BRCA 1 or 2 genes, because of the high risk associated with these mutations and breast and ovarian cancer. Researchers have found that lifetime risks of breast cancer among U.S. women with mutations in these genes can climb as high as 80–85%, while lifetime risks of ovarian cancer are greater than 40% for carriers of the BRCA1 mutation and 20% for carriers of the BRCA2 mutation. Research has also indicated elevated risks for young woman carrying these genetic mutations; among white women in the U.S. , 5%-10% of breast cancer cases and 10% to 15% of ovarian cancer cases are due to inherited mutations in BRCA1 and BRCA2.

There is only one test for the BRCA mutations, and it is performed by Myriad Genetics, Inc. ( Salt Lake City , Utah ), and costs range from about $350 for basic testing to $3,120 for the complete evaluation. If the test result is negative, then there is usually a sense of relief, although screening recommendations dictate that patients should still get regular mammograms. If the result is positive, however, patients must live with the knowledge that they will very likely get cancer, prompting some to take drastic preventative measures, such as prophylactic mastectomies and removal of the ovaries. “The test itself is used in clinical decision making,” said Kathy J. Helzlsouer, MD, MHS, a epidemiologist and cancer researcher, and Director of the Prevention and Research Center, Weinberg Center for Women's Health and Medicine at Mercy Medical Center in Baltimore, Md. “Women will consider whether or not they should take tamoxifen for prevention, or some consider removing their breasts prophylactically because women in the family have died from breast cancer. We see women considering what they should do about their ovaries, whether to screen them or not, or have them removed after they are finished with child bearing.” Men also take the test, she added, because they can be at risk for breast cancer, while both men and women are concerned about passing the genetic mutation on to their children.

If a woman tests positive for the BRCA1 or BRCA2 mutation, Helzlsouer adheres to expert opinions that indicate adding MRI screening, along with mammogram screening of the breast, during annual exams. “MRI has increased sensitivity but a lower specificity, and therefore a higher false positive rate,” she explained. “Other considerations discussed as part of the counseling include chemoprevention or prophylactic surgery.” In terms of ovarian cancer, no screening has been proven effective, according to Helzlsouer. If a woman tests positive and is concerned about an increased susceptibility to ovarian cancer, she may choose prophylactic surgery once child bearing is done or after menopause.

If the genetic test result is a true negative, meaning that there is a known mutation in the family and the individual tests negative, then the screening recommendations follow the general population guidelines. However, if the result is deemed negative but not informative, meaning clinicians cannot determine the reason for the increased family history of cancer, then the screening recommendations depend on the individual's family history and whether there are other genetic—or even environmental—links to the increased risk of cancer.

Missing Genetic Changes and Rearrangements

Despite the role of BRCA mutations in cancer, the accuracy of the current testing has recently been called into question. According to the study in the March 22/29 issue of JAMA (2006;295:1379-1388), approximately 12% of those from high risk families who test negative for the mutations carry cancer-predisposing genomic deletions or duplications in one of these genes. High risk individuals in the study came from families with four or more breast cancer cases on the same side of the family. The study, which was co-authored by geneticist Mary-Claire King, PhD of the University of Washington (Seattle), who first identified the BRCA1 gene and its link with breast cancer, looked for other changes and rearrangements in the genes that might not be picked up by Myriad's test.

“ They also looked at some other genes that have been associated with breast cancer, such as CHEK2 and TP53,” explained Helzlsouer. “What they found is that there are some changes that occur in BRCA 1 or BRCA 2 that are not picked up with the current testing, although while the study was going on, Myriad started adding one gene rearrangement to their testing in the interim, so some of those are picked up now, but not all. However, there were still some patients where they found changes in other genes that could explain the family history such as in CHEK2.” Helzlsouer points out that this study was done on a select group of patients with a strong family history; all of the study's participants had at least four relatives affected by breast cancer on one side of the family. According to the study, inherited mutations of TP53, as well as other genes such as PTEN are rare, but are associated with high risks of early onset breast cancer.

Myriad Genetics officials also emphasize the significance of the patient population analyzed in this study. “Since 2002, the BRCA test has been looking at the five most common large rearrangements, and later this year we will introduce a technology which can find all rearrangements whether they are previously known or not,” explained company spokesman Bill Hockett. “But it's important to realize that the group of severe risk patients in the paper represents about half of 1% of individuals we test at Myriad.”

Based on these findings, King and her co-authors said that for high-risk women with a negative test a result, following up with a diagnostic test called MLPA (multiplex ligation-dependent probe amplification) appears to be the most cost-effective and efficient way to identify BRCA 1 and 2 rearrangements. Unfortunately, the test is typically not available in the U.S. —only in Europe . Genetic testing for mutations in cancer susceptibility genes such as CHEK2, PTEN, and TP53 is available in the U.S. , and is currently being considered by Helzlsouer for follow-up testing. “TP53 and PTEN testing has been considered and is based on family history. However, CHEK2 testing was not routinely considered. Because of this article, we are going back to some of our families and relooking at the family history for those who have tested negative and telling them that this is something we might want to consider,” she said. “This study has caused me to go back and consider additional testing in some select families.”

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Julie McDowell is the Editor of Strategies. She can be reached by email.