Predisposition Testing for Inherited Breast Cancer
Predisposition Testing for Inherited Breast Cancer
Physicians and patients have become increasingly aware that women with a personal or family history of early-onset breast and/or ovarian cancer have a significant probability of carrying an altered breast cancer susceptibility gene. The elegant work of many groups, nicely summarized in the article by Ms. Cummings and Dr. Olopade, has begun to provide more specific information for patients and physicians facing medical decisions, such as those illustrated in the cases provided in the article.
The American Society of Clinical Oncology (ASCO) has mandated that medical oncologists be able to recognize inherited cancer syndromes and discuss with patients the advantages and disadvantages of genetic testing, based on their individual circumstances. The article provides much information that should prove useful to oncologists who want to incorporate inherited breast and ovarian cancer and genetic testing issues into patient care--whether they provide the testing and counseling themselves or refer patients to other professionals for those services.
Genetic testing for cancer susceptibility may help specify cancer risk assessment for unaffected individuals. Cancer patients and survivors face a complementary set of issues, which may be more often encountered by medical oncologists.
Importance of Risk Assessment
The high cost of the resources currently necessary to provide genetic testing--the actual tests and the hours of counselor/physician time--have made it reasonable for most programs to offer testing only to individuals who have a sufficient prior probability of carrying a mutation, which is often set at about 10%. This probability is estimated from pedigrees by considering the pattern of breast and ovarian cancers in a family, ages at diagnosis, and ethnic derivation. In addition to the approaches described by Cummings and Olopade, newer models for the personal computer developed at Myriad Genetics or by Berry and colleagues may further facilitate risk assessment for complex families by providing more accurate estimates of their chances of carrying alterations in specific susceptibility genes.[1,2]
Pedigree interpretation and model estimation are the first links in the chain of probabilistic statements that comprise cancer risk estimation. Despite the mathematical complexities, all of the conditional statements in risk estimation--the chance that a particular cancer or second malignancy will occur by a certain age, the chance that a deleterious mutation informing that risk will be found, and, ultimately, the chance that specific interventions will alter these risks--are not fundamentally different from the probabilistic information contained in staging algorithms or treatment trial results. They should, therefore, easily become familiar territory for oncologists.
Communication of these complex statements and the issues that they raise for self-image, family communication, and insurance or employment discrimination is a difficult task. Thus, statements by official bodies recommend the involvement of a trained genetic counselor or nurse geneticist as a required component of genetic testing.
As is true for cancer treatment, cancer risk analysis is only as good as the data on which it is based. Medical documentation of key cancer diagnoses in relatives permits risk assessments to be as accurate as possible. Results of genetic tests may assist in cancer risk estimation. If a genetic test result is not clearly positive, assessment of the risk of cancer reverts to estimation based on family history, the accuracy of which may be especially important if a patient plans prophylactic surgery.
For example, a 35-year-old woman with early-stage breast cancer who is contemplating prophylactic oophorectomy who reports that her mother and sister were diagnosed with breast and ovarian cancer, respectively, by 40 years old has a very high likelihood of carrying a hereditary predisposition, even if BRCA1 and BRCA2 analyses are negative. However, if the mother really developed breast cancer at age 70 and the sister actually had ovarian cysts, the negative test is much more reassuring and prophylactic oophorectomy would not be advised or encouraged.
Small families pose a special challenge since individuals may harbor a germ-line BRCA1 or BRCA2 mutation without a remarkable family cancer history, as when an altered gene has been transmitted through the paternal lineage. The chance that a woman with breast cancer diagnosed before age 30 will have a germ-line BRCA1 or BRCA2 mutation exceeds 10%, even if she has no other affected relatives, and would surpass 20% if she were of Ashkenazi Jewish descent.[4,5] Eventually, rapid inexpensive genetic analysis will replace all of the risk models.
The current availability of genetic testing has not resulted in uniformly high demand for its use, even among cancer patients. There have been serious concerns about insurance discrimination, personal coping, and familial relationships. Ultimately, an individual may decide to learn her genetic status if the information would influence medical decisions about cancer treatment, surveillance, or prevention; provide risk information to other family members; or just for the sake of knowing about her risk or the "reason" for her own cancer (see the authors Table 7).
Should Inherited Breast Cancers Be Managed Differently?
Whether the management of inherited cancers should differ from that of the more common sporadic tumors remains to be determined. Comparison of the pathologic features of BRCA1- and BRCA2-related breast cancers with those of sporadic controls have revealed that high nuclear grade and medullary subtype--features generally more common in younger women--occur more frequently among BRCA1-related tumors. Population-based series comparing survival in patients with hereditary vs sporadic breast cancers have generally shown no significant differences, stage for stage.[7,8]
The interaction of the BRCA1 and BRCA2 gene products with proteins involved in the repair of radiation-induced DNA errors have raised concerns that adjuvant radiation therapy may increase the rates of local recurrence, radiation-induced second primary cancers, or treatment-related complications in mutation carriers. Since early data do not confirm increased radiation-related toxicities in women with inherited breast cancer, these concerns remain hypothetical at present.[10,11] Nevertheless, physicians may want to discuss these issues, as well as the increased rate of contralateral breast cancers in mutation carriers, when making primary therapy recommendations at diagnosis. No data regarding differential efficacy of chemotherapy or tamoxifen (Nolvadex) in inherited vs sporadic breast cancers have yet appeared.
Breast or Ovarian Cancer Survivors
Given the limitations of current analytic technologies, a woman who has survived breast or ovarian cancer is often the family member whose genetic test results would be most informative for other relatives. In our experience, cancer survivors are often less surprised to learn of positive results and have more difficulty coping with negative results. The existence of other genes that confer breast cancer susceptibility leaves open the possibility that their cancer has an inherited component, and does not completely eliminate the possibility that the survivor has passed on an increased risk to her offspring.
Contrary to expectation, women found to carry a predisposing mutation may find themselves somewhat isolated within their families if, despite earlier conversations, relatives do not eagerly opt for testing. Certainly, many families are supportive and open with each other, but others bring their particular difficulties in communication to the issues raised by testing. Individuals who provide psychosocial and emotional support services for patients at high risk of developing cancer may benefit from some targeted education about the issues raised by this emerging approach to cancer risk assessment.
1. Frank TS, Manley S, Thomas A, et al: Sequence analysis of BRCA1 and BRCA2: Correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 61:2417-2425, 1998.
2. Parmigiani G, Berry DA, Aguilar O: Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62:145-158, 1998.
3. Statement of the American Societ of Clinical Oncology: Genetic testing for cancer susceptibility. J Clin Oncol 14(5):1730-1736, 1996.
4. Fitzgerald MG, MacDonald DJ, Krainer M, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early onset breast cancer. N Engl J Med 334:143-149, 1996.
5. Rao BB, Boyd AA, Volick K, et al: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14:185-187, 1996.
6. Breast Cancer Linkage Consortium: Pathology of familial breast cancer: Differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349:1505-1510, 1997.
7. Verhoog L, Brekelmans C, Seynaeve C, et al: Survival and tumor characteristics of breast cancer patients with germline mutations of BRCA1. Lancet 351:316-321, 1998.
8. Johannasson OT, Ranstam J, Borg A, et al: Survival of BRCA1 breast and ovarian cancer patients: A population-based study from southern Sweden. J Clin Oncol 16: 397-404, 1998.
9. Scully R, Chen J, Plug A, et al: Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88:265-275, 1997.
10. Chabner E, Nixon A, Gelman R, et al: Family history and treatment outcome in young women after breast-conserving surgery and radiation therapy for early stage breast cancer. J Clin Oncol 16:2045-1051, 1998.
11. Robson ME, Gilewski T, Hass B, et al: BRCA-associated breast cancer in young Jewish women. J Clin Oncol 61:1642-1649, 1998