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Breast Cancer Susceptibility Genes: Current Challenges and Future Promises
- Barbara Weber, MD
- University of Pennsylvania School of Medicine, Philadelphia, PA 19104 Note: Dr. Weber is on the Clinical Advisory Board of and holds financial interest in the Myriad Genetics company. Requests for Reprints: Barbara Weber, MD, Biomedical Research Building, Room 1009, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, PA 19104.
Recent advances in understanding the basis for breast cancer that clusters in families represent a rare combination of spectacular scientific achievements and immediate clinical applications. In the past 5 years, we have moved from skepticism that single genes could be responsible for inherited forms of common adult cancer to the rapid organization of dozens of clinics designed to provide DNA-based susceptibility testing for mutations in several such recently isolated genes. These discoveries provide both critical tools for understanding the molecular events that precede the development of clinical breast cancer and the information necessary to identify women at exceptional risk for developing breast and ovarian cancer. However, they also highlight the profound lack of knowledge that still exists in all facets of breast cancer genetics. The unknowns range from how these genes function at the molecular and cellular levels to the psychosocial, ethical, and legal effects of susceptibility testing. What is clear is that these genetic discoveries are already affecting many patients and practitioners, few of whom are prepared to incorporate genetic testing and counseling into clinical practice.
Overall, inherited breast cancer is thought to account for about 5% to 10% of all cases of breast cancer. BRCA1 was the first major breast cancer susceptibility gene to be identified [1] and isolated [2]. Alterations in BRCA1 are thought to be responsible for approximately half of all inherited breast cancer, 70% of inherited breast cancer in women younger than 45 years of age at diagnosis, and almost all inherited breast-ovarian cancer [3]. Recent studies have begun to define the incidence of BRCA1 mutations outside of recognized breast cancer families, providing evidence that 5% to 10% of women younger than 40 years of age who have received a diagnosis of breast cancer may have BRCA1 alterations [4, 5]. Furthermore, a BRCA1 mutation termed “185delAG” (describing the deletion of two nucleotides, AG, at position 185 in the BRCA1 gene) is found in approximately 1% of the Ashkenazi Jewish population [6] and in 20% of Ashkenazi Jewish women who receive a diagnosis of breast cancer when they are younger than 40 years of age [4]. The risk for breast cancer associated with the presence of a BRCA1 mutation is estimated to be 87% by 80 years of age [3], and such alterations are also associated with a 40% to 60% lifetime risk for ovarian cancer [7]. Although a few cases of breast cancer in men have been identified in association with BRCA1 mutations, this risk appears to be small. Colon and prostate cancer may also be increased in BRCA1 mutation carriers, but BRCA1 mutations appear to confer a lifetime risk of less than 10% [7].
BRCA2 is the most recently isolated breast cancer susceptibility gene and has a risk profile similar, but not identical, to that of BRCA1 [8-10]. Lifetime risk for breast cancer in BRCA2 mutation carriers is also estimated to be 85%, and risk for ovarian cancer is probably between 10% and 20% [8]. Although these risk values are significantly greater than the 1% risk in the general population, BRCA2-associated risk for ovarian cancer is lower than the risk for ovarian cancer that is associated with BRCA1 mutations. Also in contrast to BRCA1 mutations, BRCA2 mutations are associated with a 6% lifetime risk for breast cancer in men [8]. Although this represents a significantly lower cancer risk to men than to women, the relative risk is 100-fold higher than the risk of the general population. Other cancer risks are probably associated with BRCA2 mutations, but they are currently poorly defined.
If DNA-based testing is to be integrated into primary care practice, several issues must be considered before DNA testing is done. Most can be addressed by two questions: Who should be offered DNA testing? What do women need to know to make an informed decision about such testing?
Who Should Be Offered DNA Testing?
Importantly, offering a DNA test is not synonymous with recommending testing; persons should be provided with the pros and cons of testing and should be allowed to decide themselves. Current data suggest that the likelihood of a person having a BRCA1 mutation can be estimated on the basis of family history of breast and ovarian cancers and the age of onset of these cancers [11]. Table 1 lists the probabilities that a woman with breast cancer will harbor a BRCA1 mutation. As a general rule, we offer DNA testing to women with at least a 10% to 15% likelihood of carrying a BRCA1 mutation. At present, there is broad agreement that if genetic testing is to be done, the first person tested in the family should be a clinically affected member (a woman with breast or ovarian cancer or both); this approach maximizes the information obtained from testing. If that clinically affected woman has a mutation, any blood relative older than 18 years of age, either male or female, can then be tested. This is because an unaffected member of a family with apparent autosomal transmission of breast cancer susceptibility has a roughly equal likelihood of being a carrier and not being a carrier (ignoring the adjustment for age, which is done because the older a family member gets without receiving a diagnosis of cancer, the lower her likelihood of being a carrier). Thus, negative DNA test results in unaffected family members do not allow discrimination between noncarriers in a family with genetic susceptibility and noninformative test results. When a disease-associated DNA mutation has been identified in the family, women in the family who have negative genetic test results can be reassured that their risk for breast cancer is roughly equal to the risk of the population (assuming that no significant history exists in the other parent's family). In contrast, no explanation for the pattern of cancer in the family is elucidated by a negative DNA test result in a family without a documented mutation; thus, refinement of risk estimates beyond those made by epidemiologic models is not possible [12].
Although the restrictions currently limiting initial genetic testing of unaffected family members are likely to be relaxed as commercial testing becomes more common, these realities will remain; whenever possible, the policy of testing an affected family member first should be retained. This testing, like all medical diagnostic testing, is most appropriately used on the basis of professional judgment rather than patient request—anxious patients without a significant family history may be reassured more effectively by education than by testing. At present, there are no subpopulations in which widespread DNA testing in the absence of a significant family history is recommended—studies are currently attempting to assess the benefits of and drawbacks to such an approach in the Ashkenazi Jewish population.
What Do Women Need To Know To Make an Informed Decision about Testing?
A detailed list of what constitutes informed consent was described by the American Society of Clinical Oncology [13] and is summarized in Table 2. Most importantly, women need to be educated about the lack of information provided by a negative test result in the absence of a known mutation in the family, the lack of knowledge surrounding recommendations for either intensive screening for disease or prophylactic surgery for mutation carriers, and the potential risk for loss of health insurance associated with genetic testing. Although physicians have traditionally used a somewhat directive approach in making treatment recommendations for existing disease, the incorporation of genetic testing into clinical practice requires a modified paradigm. For example, women need to know that few data are available with which to estimate risk reduction associated with prophylactic mastectomy or oophorectomy or to determine whether any survival benefit is associated with frequent surveillance. Unfortunately, many high-risk women are told to have surgery or intensive screening on the basis of physician bias rather than fact. As studies examining various options are completed, we should be able to offer more definitive information and perhaps make recommendations; at present, however, the necessary data do not exist.
BRCA1 accounts for approximately 50% of all inherited breast cancer, and BRCA2 probably accounts for another 30% to 40%; therefore, it is clear that other breast cancer susceptibility genes remain to be isolated. Nonetheless, a clinical test that detects a mutation in one of these two genes may define risk for as many as 90% of women with a very strong family history of breast cancer. Commercial testing for BRCA1 mutations is already a reality, and testing for BRCA2 mutations will follow shortly. Clinical use of these two tests requires understanding a wide range of issues, including 1) the ability to distinguish a true mutation associated with a marked increase in cancer risk from a rare sequence change of no significance; 2) the inheritance pattern that allows for equal likelihood of transmission from either parent in a family; 3) the need for a patient's full understanding of the risks, benefits, and limitations of testing before testing takes place; 4) the risk for psychological harm to both carrier and relatives; and 5) the possibility of insurance discrimination and subsequent loss of health care coverage after detection of a disease-associated mutation in a healthy person. Genetic susceptibility testing for breast cancer and numerous other adult onset disorders is here—we can rise to the challenge and use this powerful new information wisely and to great benefit only if all physicians seriously heed calls to educate themselves in this very new arena of clinical medicine.
- Copyright ©2004 by the American College of Physicians
