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© 2000 American Society for Clinical Oncology
The Genetic Testing Process: How Much Counseling Is Needed?From the University of Chicago Medical Center, Chicago, IL. Address reprint requests to Shelly Cummings, MS, University of Chicago Medical Center, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637-1463; email scumming{at}medicine.bsd.uchicago.edu
THE ROLE OF CLINICAL cancer genetic testing for cancer-predisposing syndromes is a rapidly evolving area, and the appropriateness of such testing varies as a function of which disorder is thought to be present and the manner in which a genetic test result would influence clinical management. Several questions arise when health care providers are introduced to the idea of genetic testing for cancer susceptibility genes. Such questions include the following: When is it appropriate to consider genetic testing? What information should patients be told before they elect to undergo genetic testing? Who is the best individual to test in a family? How will learning if there is a cancer-predisposition gene in a patient effect medical management? This last question may be one of the most important to consider. One should take into account whether a test result would change clinical management, and if the answer is no, then testing may not be reasonable. If testing could conceivably alter clinical management, then comprehensive pretest genetic counseling is essential before proceeding with genetic testing. The genetic testing process involves more steps and provider time than many other medical tests because of the complex issues that arise. In fact, a task force was commissioned by the federal government that argued that gene tests are fundamentally different from other clinical tests because of the complexities in assessing and interpreting results and counseling patients.1 None of the currently available cancer susceptibility tests are appropriate for general population screening. Therefore, accurate risk assessment and counseling are considered integral components of genetic screening for cancer predisposition. This article will outline the genetic counseling process and highlight the topics that are essential for genetic counseling and testing for hereditary cancer syndromes.
Risk assessment is a complex process that requires each family to be considered individually. There are a myriad of risk-assessment tools available, but the counselor must understand the strengths and limitations of each model and realize which would be the most appropriate for a particular family. Because cancer is a common occurrence, particularly in some populations, it is not unremarkable to see cancer on both sides of a family. The counselor needs to assess risk on each side of the family separately and devise the most appropriate plan for genetic screening if it is elected by the patient. A general guideline to follow when considering candidates for genetic susceptibility testing, because they are apparently at high risk for having inherited a mutation in a cancer susceptibility gene, is included in Table 1.
Empiric risk models for estimating the risk of breast cancer are based on epidemiologic data and can be useful tools in counseling patients. However, these models underestimate the risk of breast cancer in women from families with inherited breast cancer and overestimate risk in women who are not carriers of mutated genes. The Claus model, based on data derived from the Cancer and Steroid Hormone (CASH) study, may be more accurate for women with inherited breast cancer.2 This model calculated cumulative risk of breast cancer based on family history; however, it is the only factor used in this model. The Gail model, based on data from the Breast Cancer Detection and Demonstration Project, incorporated the patient’s age, reproductive history, history of benign breast disease, and history of breast cancer in first-degree relatives.3 However, it does not account for cancer history in second-degree relatives, the paternal history, or the age at which cancer was diagnosed. The Gail model was used to assess risk in the tamoxifen (Nolvadex; Zeneca Pharmaceuticals, Wilmington, DE) breast cancer prevention trial. Neither model is designed to estimate the probability that a woman has a mutation in BRCA1 or BRCA2. Models are available that may further facilitate risk assessment for complex families by providing more accurate estimates of their chances of carrying alterations in specific susceptibility genes.4-6 Clinical-based genetic testing has allowed families to move beyond pedigree analysis and into individualized genetic testing. Interpretation of genetic test results can be challenging, and the potential impact on future management of the patient is great. In light of this, extensive pretest, posttest, and follow-up genetic counseling needs to be conducted and should include many essential elements.
The first step in the genetic counseling process is to assess the patient’s concerns and reasons for seeking counseling and to guarantee that their personal needs and priorities will be met. Studies have revealed a highly exaggerated perception of risk among women with a family history of breast cancer who seek cancer risk assessment; this has the potential to interfere with appropriate screening behaviors.7 A positive, supportive interaction with the counselor is an important determinant of ultimate satisfaction with the counseling process and adherence to surveillance recommendations. After eliciting the patient’s concerns, a careful and thorough evaluation of the family history should be conducted, looking for patterns suggestive of an inherited cancer syndrome (Table 1). This initial assessment is broad and flexible so as not to exclude from further evaluation individuals whose knowledge of the medical details of their family are incomplete or inaccurate (Fig 1). Affected and unaffected individuals who are likely to carry cancer-predisposing mutations should be considered. In affected persons, genetic testing can be used for molecular diagnosis of an inherited cancer syndrome, such as familial adenomatous polyposis and Li-Fraumeni syndrome. In individuals without a cancer diagnosis, genetic testing may be used to determine whether they have inherited a cancer-predisposing mutation that puts them at greater risk of developing cancer. In all cases, genetic counseling is an essential component of the testing process, from start to finish. Collection of medical records should be conducted to confirm the verbally reported cancer diagnosis in the family. It has been found that individuals report the primary site of cancer accurately only 83% of the time in first-degree relatives and 67% and 60% of the time in second- and third-degree relatives, respectively.8 Confirmation of diagnosis is important, because subtle differences in cancer diagnosis may lead to the suggestion of a different cancer syndrome and therefore necessitate a different genetic test. This point is evident by a 1997 study that demonstrated that among familial adenomatous polyposis patients with unconventional indications for testing, the rate of positive results was only 2.3%. In addition, this study discovered that only 18.6% received genetic counseling before the test, and only 16.9% provided written informed consent. However, the most glaring finding was that in 31.6% of the cases, the physicians misinterpreted the test results.9
One component of pretest education and counseling is known as the informed consent process and is composed of a careful explanation of the scientific aspects of genetic testing, addressing test sensitivity, specificity, possibility of indeterminate test results, actions the patient may take given a positive or negative test result (anticipatory guidance), and the cost of testing (Table 2). Discussion of the elements of informed consent should be performed before the individual has elected to have genetic testing, not when a result is available. The informed consent discussion should emphasize that the process of disclosure makes the individual considering testing completely aware of what is known and unknown about cancer risk assessment and risk reduction strategies. Counselors may use a technique to facilitate decision making called anticipatory guidance. In this form of nondirective counseling, the counselor walks the patient through several "what if" scenarios that encourage the patient to consider how they would respond to the possible test results. Anticipatory guidance can help patients anticipate their reactions to genetic testing and allow them to consider how and when they will share the results with family members. Because the decision to proceed with genetic testing is voluntary, all discussions should include the option of not being tested. Alternative forms of estimating cancer risk, such as Mendelian risk estimates, empiric risk tables, and models, should be provided to all patients, but particularly those who decline testing.
Genetic counseling involves more than just communicating complex medical information to families. One of the biggest challenges of genetic counseling is helping families cope with the emotional, psychologic, medical, social, and economic consequences of genetic disease. The genetic counselor needs to address the psychosocial aspects of testing, which can be very powerful and in some cases may require a consultation with a mental health professional.10 Learning about a personal or reproductive risk is likely to invoke powerful emotional responses that must be acknowledged and dealt with to allow assimilation of the information. Patients can react in unexpected ways when they learn their genetic risk status. Some people take the information in stride, whereas others react with anger, shock, denial, grief, depression, confusion, and guilt. Genetic counselors try to help families cope with the many ramifications of hereditary cancer syndromes and genetic testing. The counselor needs to explain the institutional policies regarding confidentiality of test results, specifically, who will have access to results and under what circumstances and with what possible ramifications. Patients’ perception that insurance companies may use information from the pedigree to deny health or life insurance to an at-risk person seems to be greatly exaggerated compared with what actually takes place. However, until legislative and public policies are in place to safeguard this sensitive information, extreme care must be taken to maintain confidentiality.11,12
The results of genetic testing are more easily interpretable when an individual who has been diagnosed with cancer is the first person tested in the family. If a particular predisposing mutation is identified in an affected person, genetic testing may then be offered to anyone else in the family whether they have had cancer or not. The size and complexity of most genes responsible for hereditary cancer syndromes are reasons to begin testing with an affected individual. The case example in Fig 2 illustrates the difficulty in interpreting a negative test result in someone who has not had cancer but has a family history suggestive of a hereditary cancer syndrome. Susan is a 35-year-old Ashkenazi Jewish woman who desired genetic testing for breast cancer susceptibility. Her family history is consistent with a hereditary breast/ovarian cancer syndrome and she had extensive genetic counseling. She was not found to carry a mutation in either the BRCA1 or BRCA2 genes. However, this negative result did not exclude a genetic predisposition in the family. This result is considered inconclusive because we do not know whether she is a true negative. That is, a mutation could be present in the family but she did not inherit it (50:50 chance). It is also possible that there is a mutation in the family, but it is in a region of BRCA1 or BRCA2 that is not detectable by current testing technology or is due to another cancer susceptibility gene.
Very careful counseling needs to take place to ensure that the patient does not mistakenly assume they are no longer at risk for hereditary cancer and abandon cancer surveillance practices. This would cause more harm than good and is one of the biggest arguments against genetic testing for certain hereditary conditions. To avoid this dilemma, testing should be offered first, whenever possible, to the person in the family who is most likely to be found to have an altered gene and who is less likely to have a sporadic cancer. Once a mutation has been discovered in an affected individual, the results of testing will be more informative in other family members.13 This approach may not be possible for some families, either because everyone who has had cancer has died or is not willing to have testing. Testing may be done on individuals who have not had cancer, but a detailed explanation about the limitations of a negative result must be conducted. There are three possible outcomes to genetic testing: a cancer-predisposing mutation is detected (positive result), a cancer-predisposing mutation is not detected (negative result), or a variant of uncertain significance (inconclusive) is discovered. A positive result can have a profound impact on an individual. It may provide important psychologic benefits by relieving uncertainty and anxiety over their risk of cancer. In addition, it may provide a sense of empowerment and a clearer understanding of their risk of developing cancer. Many families have been living with a black cloud over their heads, and members of these families are waiting for the time when cancer will strike them. For some individuals, finding a disease-associated mutation provides them with something concrete to help them make a decision about whether to have prophylactic surgery. Once a mutation is found within a family, it now allows other family members to consider testing for themselves and provide a more informative result. Typically, a negative test result is usually good news in most areas of medicine. However, studies have shown that those who experience the most behavioral and psychologic effects from genetic testing are those who tested negative.14 The most common response is a phenomenon known as survivor guilt, which occurs when the individual learns that they do not carry a predisposing mutation that is present in the family, but other family members do. Survivor guilt was seen extensively in the families who were originally counseled during the early linkage studies for BRCA1.14 Appropriate pre- and posttest counseling should address the possibility of adverse psychologic effects in all individuals who are tested, but particularly those who have not had cancer. The clinical significance of most variants in cancer susceptibility genes is unknown at present and poses a particular challenge to the health care provider conducting genetic testing and to the family. Indeterminate results (usually missense mutations) arise when a change is identified in the DNA but the effect on protein function is unknown. Because the cancer risk associated with this finding is unknown, individuals are treated as high risk and given the same screening recommendations as before testing. In some cases, further testing may need to be performed on other family members to determine whether the mutation segregates with the cancer observed in the family. This finding can create confusion and disappointment for those who are desperately searching for a reason for their cancer or the many cancers in their family. Studies conducted on patients with Huntington’s disease demonstrated that ambiguous results caused more stress than positive results.15 Reactions to inconclusive results include distress, disappointment, and greater anxiety about cancer risk and management. In some cases, individuals interpret this as good news, because they were not found to have a deleterious mutation. However, they fail to understand that a variant of uncertain significance does not rule out the possibility that it increases the risk for cancer. These individuals experience a false sense of reassurance related to their risk and assume that the results mean they are not at risk for cancer. Because of the clinical challenge that this type of result creates, pretest counseling must address the possibility of finding variants of uncertain significance, particularly when the first individual being tested has not had cancer.
There have been many debates on whether genetic testing should be offered in light of the limited data available on clinical management after testing.16,17 Despite the earlier controversy, commercial testing is available and widely advertised by multiple enterprises. The public is becoming increasingly more savvy to the technologies that are available and is requesting them more often. This public demand is forcing clinicians to stay abreast of the latest discoveries in cancer prevention and genetic testing. For centuries, clinicians have been basing medical management decisions on what they see occurring in families. Recent advances in molecular genetics have identified a number of genes associated with inherited susceptibility to cancer and have provided a means to begin identifying individuals and families with an increased risk for cancer. Genetic testing may now allow health care providers to home in on their patient’s risk more precisely and allows patients to make decisions based on whether they actually carry a mutation. The rapid expansion of knowledge about cancer genetics has implications for all aspects of management, including prevention, screening, and treatment. The National Comprehensive Cancer Network has composed practice guidelines for the management of hereditary breast cancer syndromes.18 The guidelines were developed with an acute awareness of the preliminary nature of our knowledge on the clinical application of molecular genetics for cancer. The experts who devised these guidelines also appreciate the need for flexibility when applying their recommendations to individual families. The health care provider conducts a delicate balancing act of individual risk management and the implementation of long-term follow-up for at-risk individuals. These challenging decisions can only be made when the patient is fully informed of the psychologic and medical pros and cons of genetic testing and clinical management strategies currently available. The challenge for health care providers will be to combine their own education of genetics with the principles of patient autonomy, informed consent, confidentiality, and the constantly emerging field of molecular genetics. The power of this information must be harnessed to increase patients’ awareness of their genetic inheritance so that genetic counseling becomes the gold standard of care in the next millennium. Genetics will be all-too pervasive in medicine for it to be an optional extra for oncology and other specialties and too ethically charged to be conducted inappropriately. Genetic counselors can meet these challenges by helping patients and their families cope with the sequelae of genetic testing.
1. Holtzman NA , Watson MS, (eds): Promoting Safe and Effective Genetic Testing in the United States: Final Report of the Task Force on Genetic Testing. Bethesda, MD, National Institutes of Health, 1997 2. Claus EB, Risch NJ, Thompson WD: Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 48: 232-242, 1991[Medline] 3. Gail MH, Benichou J: Assessing the risk of breast cancer in individuals, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer Prevention. Philadelphia, PA, JB Lippincott, 1992, pp 12-15 4. Frank TS, Manley S, Thomas A, et al: Sequence analysis of BRCA1and BRCA2: Correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 61: 2417-2425, 1998 5. 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[Medline]
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Couch F, Weber B, DeShano M, et al: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336: 1409-1415, 1997
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Bluman LF, Rimer BK, Berry DA, et al: Attitudes, knowledge, and risk perceptions of women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2. J Clin Oncol 17: 1040-1046, 1999 8. Love RR, Evan AM, Josten DM: The accuracy of patient reports of a family history of cancer. J Chron Dis 338: 289-293, 1985
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Giardiello FM, Brensinger JD, Petersen GM, et al: The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med 336: 823-827, 1997
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Dorval M, Patenaude AF, Schneider KA, et al: Anticipated versus actual emotional reactions to disclosure of results of genetic tests for cancer susceptibility: Findings from p53 and BRCA1 testing programs. J Clin Oncol 18: 2135-2142, 2000
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Hudson KL, Rothenberg KH, Andrews LB, et al: Genetic discrimination and health insurance: An urgent need for reform. Science 270: 391-352, 1995 12. Rothenberg KH: Genetic discrimination and health insurance: A call for legislative action. J Am Med Womens Assoc 52: 43-44, 1997 13. Lerman C, Rimer B, Trock B, et al: Factors associated with repeat adherence to breast cancer screening. Prev Med 119: 279-290, 1990
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Botkin JR, Croyle RT, Smith KR, et al: A model protocol for evaluating the behavior and psychosocial effects of BRCA1 testing. J Natl Cancer Inst 88: 872-881, 1996 15. Wiggins PA, Whyte P, Huggins M, et al: The psychological consequences of predictive testing for Huntington disease: Canadian collaborative study of predictive testing. N Engl J Med 327: 1401-1405, 1992[Abstract] 16. O’Malley MS, Klabunde CN, McKinley ED, et al: Should we test women for inherited susceptibility to breast cancer? N C Med J 58: 1176-1180, 1997 17. Burke W, Daly M, Garber J, et al: Recommendations for follow-up care of individuals with an inherited predisposition to cancer: BRCA1 and BRCA2. JAMA 277: 997-1003, 1997[Abstract] 18. Daly M: NCCN Practice guidelines: Genetics/familial high-risk cancer screening—The National Comprehensive Cancer Network. Oncology 13: 161-183, 1999 This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
IDENTIFYING AT-RISK INDIVIDUALS
, healthy female; 
, healthy male; •, living female with cancer; 
, living male with cancer; • with slash, deceased female with cancer; 
