Weighing the Evidence: Are Women Who Test True Negative for BRCA at Increased Risk of Cancer?
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by Lisa Rezende, PhD
BRCA tests can produce a few types of negative results (see “New Tools Help Patients with Uncertain or Negative BRCA Results” on page 3). When relatives test negative for a known BRCA mutation in their family, the result is known as a “true negative.” Women with a true negative result are usually advised that their breast and ovarian cancer risk is similar to the risk of women in the general population.
In our Spring 2007 newsletter, we reviewed a paper that questioned the cancer risk in women who test as true negatives. Many experts on our advisory board expressed concerns regarding the study design and analysis, and felt that recommendations for counseling BRCA-negative women should not be changed based on this study.
The issue recently gained media attention when the same researchers reported similar conclusions from their latest small study. Following 238 first-degree relatives of BRCA2 carriers who tested negative for the mutation, researchers found 11 more cases of breast cancer than they would expect in the general population. First-degree relatives of BRCA1 mutation carriers who tested negative did not have a significant increase in risk when compared to the general population, although three more cases of breast cancer developed than would be expected for average-risk women.
In contrast, four separate studies published since 2007 have shown that women who test as true negatives for a familial BRCA mutation are not at significantly increased risk for breast cancer. These studies–which all support the current counseling practice for women who test true negative for a familial BRCA mutation—did not receive as much media attention as the recent study that challenges current practice.
How can several studies produce different results? The lead author of one of these studies, Dr. Allison Kurian of Stanford University School of Medicine, notes that both of the studies that found an increase in breast cancer rates for BRCA-negative family members involved families who were enrolled at a cancer genetics clinic; these women were likely to have a strong history of breast or ovarian cancer and may have had other risk factors in common with their relatives. Studies of women with BRCA mutations who receive care in more of a “real world setting” outside of high-risk clinics provide an assessment of cancer risk that is likely to apply to a broader population of families with BRCA mutations.
What does this mean for the relatives of BRCA1 or BRCA2 carriers who have tested negative for the mutation that runs in their families? Experts still believe that most relatives of BRCA1 or BRCA2 mutation carriers who test true negative are not at significantly heightened risk of breast cancer.
This study and the subsequent media attention highlight the importance of turning to a credible source of information rather than the media for information that affects health care decisions. Unfortunately, sometimes the popular press emphasizes more provocative and controversial research findings, and not all media outlets consult multiple experts to assure that their coverage is balanced and relevant. FORCE works with our Scientific Advisory Board to help translate the latest research findings into credible information. More importantly, people should consult with experts who have advanced training in cancer genetics before and after genetic testing in order to understand how genetic test results affect their personal cancer risk.
Smith A, Moran A, Boyd MC, et al. “Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening.” Journal of Medical Genetics 2007; 44:10-15.
Evans GR, Ingham SL, Buchan I, et al. “Increased rate of phenocopies in all age groups in BRCA1/2 mutation kindred, but increased prospective breast cancer risk is confined to BRCA2 mutation carriers.” Cancer, Epidemiology, Biomarkers, and Prevention 2013; 22:2269-2276.
Kurian AW, Gong GD, John EM, et al. “Breast cancer risk for noncarriers of family-specific BRCA1 and BRCA2 mutations: findings from the Breast Cancer Family Registry.” Journal of Clinical Oncology 2011; 29:4505-4509.
Domchek SM, Gaudet MM, Stopfer JE, et al. “Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2.” Breast Cancer Research and Treatment 2010; 119:409-414.
Korde LA, Mueller CM, Loud JT, et al. “No evidence of excess breast cancer risk among mutation-negative women from BRCA mutation-positive families,” Breast Cancer Research and Treatment 2011; 125:169-173.
Harvey SL, Milne RL, McLanlan SA, et al. “Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 positive families.” Breast Cancer Research and Treatment 2011; 130: 1057-1061.
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