Application of Genetic Susceptibility Information

A comprehensive genetics evaluation is important for any individual who is seeking information about a breast cancer susceptibility. In addition to potentially important clinical implications, this information has significant psychological, social, reproductive, ethical and legal ramifications. Furthermore, the clinical information resulting from an evaluation usually has important health and reproductive implications for multiple family members. Primary care providers are not accustomed to addressing these genetic issues and they are lacking in knowledge of basic genetic principles (28,29). Furthermore, they lack the time it takes to provide such a service (30). Clinical genetics professionals deal with these issues routinely and can support the primary care provider or specialist in a consultative way.

The elements of a genetics evaluation include: 1) determination of a genetic diagnosis and/or risk estimate; 2) presentation of the management and prevention options; and, 3) communication of the medical and genetic facts in a genetic counseling session. This process typically involves personnel from various disciplines, including a medical geneticist, genetic counselor, clinical social worker or psychologist.

A genetic diagnosis is arrived at using methods which are similar to those used by other clinicians. Sociodemographics, the personal history, family history, review of medical records of affected family members, the physical examination, and specialized tests, including DNA-based tests are typically employed. Accurate genetic diagnosis requires the expertise of a genetics professional who is familiar with the multiple genetic syndromes that may be considered for an inherited form of breast cancer. This is an important initial step in the genetics consultative process, as distinguishing different forms of a hereditary breast cancer may have important clinical consequences. In addition, co-morbid conditions and lifestyle choices should be considered that may influence management recommendations.

Genetic testing may be helpful in refining a clinical diagnosis and should only be offered after discussion of its potential benefits, risks and limitations. It involves providing a blood sample from which the DNA from white blood cells is isolated. Most commercial laboratories utilize PCR-based (polymerase chain reaction) methods to amplify the genomic DNA in the sample to be followed by sequencing. Additional methodologies include RFLP, DGGE, PTT, SSCP or ASO mutation detection (for detailed description see ref. 31). The accuracy of sequencing is generally very high, however, potential false negative or false positive results may occur with errors made in sample handling, contamination by airborne particles in the laboratory, or failure to amplify a particular allele with the PCR technique. Furthermore, because regulatory regions and introns of genes are not usually screened, mutations in these regions may be missed. Prior to participating in DNA-based testing, subjects should be informed of the testing process, including the methodology, accuracy, cost, turn-around time, possible outcomes (positive, negative, and uncertain), the possible psychological and social impact the test results may have, and the potential clinical consequences which may result from such information.

Ideally genetic testing should occur in an individual who is affected with cancer, as it is suspected that if an inherited mutation exists it should be found in their DNA. This is not always possible, as often times affected family members are deceased and therefore unable to provide a blood sample. Currently, germline mutation analysis of BRCA1 and BRCA2 from archived, non-cancerous tissue from a deceased affected relative is not technically feasible in most cases. Current guidelines suggest that BRCA1 and BRCA2 testing should be limited to those individuals with a family history of breast or ovarian cancer (32).

General recommendations for cancer prevention in BRCA1 and BRCA2 have been provided by several experts in the field of cancer genetics (25,26). Those individuals who test negative for a known familial mutation have essentially a background risk for cancer development which is similar to the general population. These individuals should be offered population screening guidelines. Individuals with a moderate family history not suggestive of a genetic syndrome and in whom a deleterious mutation has not been identified may follow an increased level of surveillance and chemoprevention with standard agents, such as antioxidants and aspirin. Individuals may be classified as high risk based on pedigree analysis consistent with a known hereditary cancer syndrome, carrier status of a mutation in a cancer susceptibility gene, or because of large empiric or relative risks. For these individuals, enhanced surveillance, prophylactic surgery and chemoprevention with standard agents may be discussed, as well as opportunities for available investigational chemotherapeutic agents.

Genetic counseling services should be provided to anyone entering into the process of genetic diagnosis, risk assessment and testing. Genetic counseling is a communication process that deals with the human problems associated with a genetic disorder or the risk of a genetic disorder occurring within a family (33). Through the process of genetic counseling, a genetics professional will help an individual and his/her family members to: 1) understand the medical information available about the genetic diagnosis, including the probable course of the disorder (penetrance and variable expressivity), and treatment and management options available, including genetic testing; 2) appreciate the contribution of heredity to the disorder and the risk of occurrence in other family members and to future offspring; 3) understand the options for dealing with the risk of occurrence and recurrence, and choose the course of action that is most appropriate to the individual or family in view of each members risk, and the family's goals and values; 4) support decisions made by the individual or family; 5) aid the family members in adjustment to the disorder by discussing potential emotional concerns, helping them recognize and understand their emotions including anxiety, fear, and guilt, thereby facilitating their coping and adaptation process; and, 6) identify potential societal concerns that may arise as a consequence of participating in genetic risk assessment and/or testing, including possible stigmatization by friends and employers, potential discrimination by insurers and employers, and the financial costs resulting from testing, and consequent prevention and management strategies.