Genetic Cancer Risk Assessment
Genetic testing clearly has the potential to benefit carefully selected and counseled families. Education and adequately trained health care professionals are key elements in the successful integration of genetic cancer-risk assessment into clinical practice.
The genetic risk assessment process begins with an evaluation of perceived risk and the impact of cancer on the patient and family. This information forms the framework for counseling.
Comprehensive Personal and Family Histories
Detailed information regarding personal, reproductive, and hormonal risk factors is noted. Family history, including age at disease onset, types of cancer, and current age or age at death, is obtained for all family members going back at least three generations.
Documentation of Cancer Cases
Documentation is crucial to accurate risk estimation. Pathology reports, medical record notes, and death certificates may all be used in determining the exact diagnosis.
Pedigree Construction and Evaluation
The family pedigree is then constructed and analyzed to determine whether a pattern of cancer in the family is consistent with genetic disease. Sometimes, small family structure or lack of information about the family limits assessment of a hereditary trait; other times, clues such as ancestry or early age at diagnosis influence risk assessment and the usefulness of genetic testing.
Individual Risk Assessment
Several models are used to estimate the likelihood that a detectable BRCA1 or BRCA2 mutation is responsible for the disease in the family. The BRCA PRO computer program is a cancer risk–assessment tool that uses a family history of breast or ovarian cancer in first- and second-degree relatives to calculate the probabilities that either a BRCA1 or BRCA2 mutation is responsible for the disease. It includes a Bayesian calculation (of conditional probability) to account for age-specific penetrance differences. If genetic testing is not performed or results are uninformative, the empiric breast cancer risk is estimated by the phenotype as well as the Claus model (derived from the Cancer and Hormone Study, which uses age at onset of breast cancer among first- and second-degree relatives) or Gail model (which uses a combination of family, menstrual, reproductive, and breast pathology information). Personal and family characteristics that are associated with an increased likelihood of a BRCA1 or BRCA2 mutation are summarized in Table 2.
Patients should be given information about the principles of genetics and hereditary cancer patterns and the application of genetic testing (appropriateness, limitations, advantages, and disadvantages).
Genetic Counseling and Testing
Informed consent is obtained before genetic testing is performed. For individuals who decide to undergo testing, a post-test counseling session is scheduled to disclose and explain the results in person.
Customized Screening and Prevention Recommendations
Regardless of whether or not a woman undergoes genetic testing, a customized management plan is delineated, with the goal of preventing or detecting malignancy early, within the context of the patient's personal preferences and degree of risk (Table 3).
Laboratory Methods and Limitations
Several techniques/strategies for detecting mutations in cancer genes have been adopted by different researchers and commercial vendors.
Directed assays are available for specific founder or ancestral mutations that are common in a given population. Among Ashkenazi Jews, 1 in 40 individuals bears one of three founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2); these mutations account for 25% of early-onset breast cancer in this population. Moreover, 95% of Ashkenazi Jews with a BRCA gene mutation will have one of the three founder mutations. However, complete gene sequencing can be performed if a patient does not test positive for a founder mutation.
Large genomic rearrangements of the BRCA genes account for approximately 10% of all deleterious mutations and are not detectable by the standard sequenceing test. The NCCN guidelines recently defined BRCA testing as full sequencing of the translated exons and full screening for large rearrangements (aka BART, per the commercial vendor).
All of the approaches to detecting mutations have limitations. In general, discovery of an inactivating or "deleterious" mutation of either BRCA1 or BRCA2 indicates a high probability that a person will develop breast and/or ovarian cancer.
One of the greatest challenges is the interpretation of missense mutations. These mutations are more likely to be significant if located in an evolutionarily conserved or functionally critical region of the protein. In the absence of a clear disease association, it is often difficult to exclude the possibility that a given missense alteration simply represents a rare polymorphism. Using advanced methods, a recent study was able to characterize 133 of 1,433 variants as likely polymorphisms and 43 as likely deleterious; the majority would still be designated as "genetic variants of uncertain significance."
Although less common, mutations in other genes besides BRCA1 and BRCA2 (eg, CHEK2 and TP53) may predispose patients to breast cancer. Clinical Characteristics such as macrocephaly and/or uterine and thyroid cancer, may direct the diagnostic strategy to the genes such as PTEN associated with Cowden Syndrome.
In general, testing should be initiated with the youngest affected individual in a given family. Even if one is convinced that a family has hereditary breast and ovarian cancers based on clinical criteria, there is only a 50% chance that an offspring or sibling of an affected patient will have inherited the deleterious allele. Therefore, only a positive test result (detection of a known or likely deleterious mutation) is truly informative.
Until the "familial mutation" is known, a negative test result could mean either that the unaffected person being tested did not inherit the cancer-susceptibility mutation or that the person inherited the disease-associated gene but the mutation was not detectable by the methods used.
In many cases, no affected family members are available for testing. In such circumstances, one may proceed with genetic testing of an unaffected person, but only after that individual has been thoroughly counseled regarding the risks, benefits, and limitations of testing.
Unless there is a suggestive family history, cancer-susceptibility testing is not considered appropriate for screening unaffected individuals in the general population. However, it may be reasonable to test unaffected persons who are members of an ethnic group in which specific ancestral mutations are prevalent and whose family structure is limited (ie, the family is small, with few female relatives or no information due to premature death from noncancerous causes).
Impact of Genetic Cancer Risk Status on Management
Data from the Breast Cancer Linkage Consortium suggest that the cumulative risk of developing a second primary breast cancer is approximately 65% by age 70 among BRCA gene mutation carriers who have already had breast cancer. A large, retrospective cohort study of BRCA mutation carriers with a history of limited-stage breast cancer indicated up to a 40% risk of contralateral breast cancer at 10 years. A subsequent study of the same cohort noted almost a 13% risk for ovarian cancer in the same interval and that ovarian cancer was the cause of cancer death in 25% of stage I breast cancer patients with BRCA mutations.
Thus, knowledge of the genetic status of a woman affected with breast cancer might influence the initial surgical approach (eg, bilateral mastectomy might be recommended for a mutation carrier instead of a more conservative procedure). Moreover, since ovarian cancer risk may be markedly increased in women with BRCA1 mutations (and to a lesser degree with BRCA2 mutations), additional measures, such as surveillance for presymptomatic detection of early-stage tumors or consideration of oophorectomy, may be warranted.
According to data from BRCA-mutated carriers who underwent risk-reduction salpingo-oophorectomy (RRSO), breast cancer risk is also decreased from bilateral oophorectomies.
Rebbeck et al performed a meta-analysis of published studies of RRSO in BRCA-mutation carriers and confirmed the magnitude of breast cancer risk reduction associated with the procedure. Critically, their findings firmly established a significant risk reduction for BRCA1 carriers (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.35–0.64), who are predisposed to ER-negative tumors in particular.
Both retrospective and prospective data have demonstrated the efficacy (> 90% risk reduction) of bilateral mastectomy in women who are at high risk for the disease based upon BRCA genetic status. Women who opt for risk-reduction mastectomy should be offered reconstruction. Skin-sparing mastectomy may enhance the cosmetic results of reconstruction and should be discussed with the patient's surgeon. This procedure entails removing the breast tissue (including the nipple-areolar complex). Women who develop breast cancer despite prophylactic mastectomy may develop it in the locoregional areas such as the chest wall or skin or lymph nodes; in rare instances, it may present as a metastasis at a distant site.
The efficacy of bilateral risk-reduction mastectomy has been confirmed in a large prospective study of 483 women with BRCA mutations. With a mean follow-up of 6.4 years, risk-reduction mastectomy reduced the risk of breast cancer by 90% (95% in women who also underwent RRSO).
Potential Benefits and Risks of Genetic Testing
The ability to identify individuals at highest risk for cancer holds the promise of improved prevention and early detection of cancers. Patients who are not at high risk can be spared anxiety and the need for increased surveillance. Recent studies suggest a better emotional state among at-risk relatives who undergo testing than among those who choose not to know their status. The patient's perception of risk is often much higher than risk estimated by current models.
Potential medical, psychological, and socioeconomic risks must be addressed in the context of obtaining informed consent for genetic testing.
Concerns about insurance. Fear about adverse effects of testing on insurability remains the premier concern among patients. Close behind that is concern about the cost of analyzing large complex genes ($3,600 for full sequencing of BRCA1 and BRCA2 and an additional $800 if the test for genomic rearrangements is ordered a la carte).
Legal and privacy issues. The legal and privacy issues surrounding genetic testing are as complex as the testing technologies. Although several state laws regarding the privacy of medical information, genetic testing, and insurance and employment discrimination have been passed, they vary widely.
The 1996 Health Insurance Portability and Accountability Act (US public law 104-191), governing group medical plans, stipulates that genetic information may not be treated as a preexisting condition in the absence of a diagnosis of the condition related to such information. It further prohibits basing rules for eligibility or costs for coverage on genetic information. However, the law did not address genetic privacy issues and does not cover individual policies. Many states have laws addressing genetic discrimination, but concerns about gaps remain. Recent Federal legislation expanded protection against genetic discrimination to include individual policies. The Genetic Information Nondiscrimination Act of 2008 (GINA) prohibits health insurers and employers from discriminating against individuals on the basis of genetic information.
Recommendations for Genetic Testing
Guidelines from the American Society of Clinical Oncology (ASCO) recommend that cancer predisposition testing be offered only in the following situations: (1) if a person has a strong family history of cancer or early onset of disease; (2) if the test can be adequately interpreted; and (3) if the results will influence the medical management of the patient or family member. ASCO updated its policy statement regarding genetic testing to extend commentary on the lack of documented clinical utility of commercially available genomic tests relying on single nucleotide polymorphism markers with very modest relative risk for breast cancer.
NCCN practice guidelines for genetics/familial high-risk cancer screening are updated annually and published at www.nccn.org.
Weitzel et al characterized the impact of family structure on the prevalence of BRCA gene mutations among 306 women who developed breast cancer before the age of 50 years and who had no first- or second-degree relatives with breast or ovarian cancer. BRCA mutations were detected in 13.7% of women with limited family structure (ie, fewer than two first- or second-degree relatives surviving beyond age 45 years in either lineage) and 5.2% of those having adequate family structure. Family structure, therefore, apparently is a strong predictor of mutation status (odds ratio = 2.8; 95% CI = 1.19–6.73, P = .019). The NCCN genetic testing guidelines are more inclusive for single cases of breast cancer when family structure is limited.