The review of hereditary breast and ovarian cancer by Dr. Srivastava et al in this issue of Oncology represents an excellent attempt to summarize the state of an increasingly complex field. The authors have an active program in cancer risk assessment and genetics at the University of Vermont in Burlington, and their experience is apparent as they organize the burgeoning data on risk assessment and management of carriers of BRCA1 and BRCA2 mutations.
Testing an Affected Family Member
The full set of issues facing women with hereditary breast or ovarian cancers could not be addressed in detail in such an overview. A cancer diagnosis is often the event that prompts the recognition that a hereditary predisposition might be present in a family. Until all genes and their risk-conferring mutations are known, the preferred strategy for evaluating a kindred for a possible hereditary predisposition remains the initial genetic testing of an affected family member. Ideally, this would be the affected family member who is most likely to carry a mutation based on age at diagnosis (younger rather than older), precise diagnosis (medullary breast cancer or papillary serous ovarian cancer), and position in the pedigree. These characteristics are considered because of the possibility of phenocopies for a common disease like breast cancer.
Even in a family with a documented mutation, sporadic breast and ovarian cancers can occur. Available models consider this troubling issue by assigning higher prior probabilities of carrying a mutation to women diagnosed at younger ages, men with breast cancer, and women diagnosed with both breast and ovarian primary malignancies. A negative genetic analysis in a woman diagnosed with breast cancer at age 55 should not necessarily be the end of the evaluation of a kindred in whom early-onset breast and ovarian cancers cluster elsewhere.
Effect of BRCA1/2 Findings on Management
As noted by Srivastava et al, knowledge of a deleterious BRCA1 or BRCA2 mutation is beginning to influence the management of newly diagnosed breast cancers in mutation carriers. Demonstration of the increased risk of second primary cancers in mutation carriers, and the effectiveness of prophylactic mastectomy, have led women and their physicians to more carefully consider the risks and benefits of breast-conserving therapy compared to bilateral mastectomy for primary treatment. Factors that must also influence these decisions include the age of the woman at diagnosis (since younger women stand to gain more life expectancy) and overall prognosis (as women must survive their first tumor in order to benefit from preventing a second cancer.) The model by Schrag et al also emphasizes the importance of an accurate genetic analysis for women with cancer, in its estimation of additional survival benefits from prophylactic contralateral mastectomy of only 2 to 4 weeks for women without predisposing mutations.
Similar clinical considerations influence decisions for women who recognize their hereditary risk after completion of initial cancer treatment. For many breast cancer survivors, the identification of an increased risk of ovarian cancer associated with a BRCA1 or BRCA2 mutation is an important consideration in the decision to undergo genetic testing. Given mounting concerns about the insensitivity of available ovarian screening methods, and the growing evidence of the effectiveness and comparatively low complexity of laparoscopic ovarian surgery, prophylactic oophorectomy is frequently the first action taken by women learning of their mutation carrier status. Women who have had breast cancer are generally precluded from using hormone replacement therapy, a factor that may influence their decisions about the timing of oophorectomy.
Ovarian cancers that occur among mutation carriers have been shown to carry better prognoses than similar sporadic tumors. Whether BRCA1/2-associated breast cancers respond differently to standard treatments than sporadic tumors remains a controversial issue. The recent demonstration that the microarray appearances of BRCA1/2-associated breast cancers differ not only from sporadic cancers, but also from each other, may have important implications for future tailored therapies, as well as upcoming analyses of risk and outcome data for the two genes.
Breast and ovarian cancer survivors often underestimate the potential impact of learning that they carry a predisposing mutation that may account for their malignancy. Women who have had cancer are therefore likely to benefit from genetic counseling as they consider not only whether to have testing, but also when such information would be most useful to them and their families. Many insurers have begun to pay for genetic testing for women who meet specific criteria, and to cover prophylactic surgical procedures as well. However, fewer insurers are willing to pay for testing in women with metastatic disease, whose information may have a more direct application in the management of risk in their relatives, rather than their own cancer care.
Srivastava et al have provided a comprehensive review of issues in the recognition and management of hereditary breast and ovarian cancer risk. Similar efforts to provide data for other strong cancer predisposition genes will be necessary as new genes continue to be identified for these and other malignancies. The paradigms highlighted in this article are likely to be applied repeatedly as the clinical implications of these genes are elucidated.