Cancer gene discoveries have led to important changes in the clinical practice of cancer risk assessment. Genetic tests, in conjunction with family history information, can be used to a) clarify the diagnosis of inherited cancer syndromes in patients with tumors and b) provide information about cancer susceptibility to asymptomatic persons in high-risk families. The promise of cancer gene testing is reduced cancer incidence and mortality through directed prevention and screening.
In addition to the medical and health benefits of cancer gene testing, the power to identify high-risk persons has led to considerable discussion of the implications from consumer, epidemiologic, technologic, ethical, legal, policy, psychological, and genetic counseling perspectives.
Cancer gene testing can include a variety of modalities, including linkage, direct detection when the mutation is known, and mutation analysis, such as protein truncation test or sequencing. In addition, tests for microsatellite instability in colon tumors and gene expression assays may provide indirect evidence supporting a diagnosis of hereditary nonpolyposis colorectal cancer.
Commercial availability of germline cancer gene tests (i.e., BRCA1, BRCA2, APC, hMSH2, hMLH1, p16, NF2) has outpaced the awareness among health professionals of the need for careful implementation of testing algorithms and patient education on the issues.
Surveys of persons at varying risks for cancer show that most persons are interested in having a gene test. The actual uptake of cancer gene testing has been more modest; the decision to undergo gene testing is influenced by psychosocial factors, including perception of cancer risk, perceived ability to cope with gene test results, depression, and fear of insurance discrimination. Among persons who are tested, there appears to be no significant short-term (1–3 months) psychological distress following disclosure of results.
Cancer genetic risk assessment is a multistep process and incorporates medical, psychological, genetic, and counseling dimensions. Clinical indications and a model algorithm for cancer risk assessment and gene testing are provided. For persons who are at risk for cancer, gene test interpretation will depend upon whether the specific germline cancer gene mutation is known for the family. Careful evaluation of the pedigree for characteristic aggregation of tumor types among affected individuals and availability of affected persons for testing are important issues in implementing genetic testing.
Health professionals will need to be aware of the variety of issues that contribute to the process of helping patients to understand their risk, make informed decisions, and appreciate the implications for cancer prevention and risks for other family members. Genetic counseling is an essential component of cancer genetic risk assessment services.
The translation of cancer gene discoveries into the clinical setting by the introduction of genetic testing has undergone a remarkable evolution in a few short years. Cancer genetic testing has become a significant focus from a variety of perspectives because it represents a potentially powerful means to identify high-risk individuals. From a medical and public health perspective, cancer genetic testing provides a more precise way to intervene with measures that may detect cancer at an earlier stage or to prevent cancer altogether. From a patient or consumer perspective, cancer genetic testing offers a new way to learn about individual and family cancer risk but also raises concern about job and insurance discrimination. From an epidemiologic perspective, cancer genetic testing provides a means to better understand the etiology of cancer through the interaction of genetic and environmental factors and to better characterize cancer risk. From the technologic perspective, cancer genetic testing represents an application that mandates development of faster and more cost-effective assays that are clinically valid. From the ethical, legal, and policy perspective, cancer genetic testing reinforces and recasts the basic premise that genetic information is different and requires special protection. Finally, from the psychological and counseling perspective, cancer genetic testing is part of a challenging multidimensional process that involves communication with patients about different types of risk information and requires that patients understand the implications, benefits, and risks.
The confluence of these perspectives and the intensity with which their proponents have addressed genetic testing are due to several factors: the inherent appeal of perceived benefit from cancer genetic knowledge, the potential impact on a broad segment of the population, and the concern that the public and health professional communities are unprepared for this new technology. In this nascent period of gene testing for cancer risk, few of the issues are fully resolved and many continue to arise. This chapter reviews cancer genetic testing from different perspectives and provides an overview of the current status of clinical cancer risk assessment and genetic testing.
Perspectives on Cancer Genetic Testing
Medical and Public Health Perspective
The identification of genes that are responsible for hereditary forms of cancer has resulted in efforts to apply this knowledge clinically, primarily in the form of gene tests. There is no doubt that information derived from genetic testing will lead in many instances to an improvement in cancer risk assessment and clinical management of cancer patients and their families.1,2 In conjunction with family history information, gene tests can be used to clarify the diagnosis of inherited cancer syndromes in patients with tumors and to provide information about cancer susceptibility to asymptomatic persons in high-risk families. Table 49-1 summarizes some hereditary cancer syndromes, detailed elsewhere in this volume, for which genetic testing can potentially improve cancer risk management of patients and their families.
Table 49-1: Hereditary syndromes with increased cancer risk and identified susceptibility genes and chromosomal localizations |Favorite Table|Download (.pdf) Table 49-1: Hereditary syndromes with increased cancer risk and identified susceptibility genes and chromosomal localizations
|Syndrome ||Predominate Tumor Types ||Chromosome ||Gene ||Reference |
|Ataxia telangiectasia ||Breast cancer, chromosome breakage/rearrangement syndrome ||11q22.3 || ATM ||154 |
|Cowden disease ||Multiple hamartomas of skin and mucous membranes, breast cancer, thyroid cancer, renal cell adenocarcinoma, dysplastic cerebellar gangliocytoma ||10q23 || PTEN ||155,156 |
|Familial adenomatous polyposis ||Multiple colorectal adenomas ||5q21 || APC ||157,158 |
|Familial gastric cancer ||Gastric cancer ||16q22.1 || CDH1 ||159 |
|Familial melanoma ||Melanoma, glioblastoma, lung cancer ||9p21 || CDKN2 (p16) ||160 |
|Gorlin syndrome ||Nevoid basal cell carcinoma of skin ||9q || NBCCS ||161–163 |
|Hereditary breast-ovarian cancer syndrome ||Breast, ovarian, prostate carcinoma; increased risk of other tumors ||17q21 13q12–q13 || BRCA1 BRCA2 ||150,151 |
|Hereditary nonpolyposis colorectal cancer ||Colon, endometrial, ovarian, stomach, small bowel, ureteral carcinomas ||2p16 3p21 2q31–q33 7q11.2 2p16 || hMsh2 hMLH1 hPMS1 hPMS2 hMSH6 ||81,83,164 |
|Hereditary prostate cancer ||Prostate carcinoma ||1q24–25 Xq27–28 || HPC1 HPCX ||165,166 |
|Li-Fraumeni syndrome ||Leukemia, soft-tissue sarcoma, osteosarcoma, brain tumor, breast and adrenal cortical carcinoma ||17p13 || TP53 ||167 |
|Multiple endocrine neoplasia type 1 ||Parathyroid, endocrine pancreas, and pituitary tumors ||11q || MEN-1 ||168 |
|Multiple endocrine neoplasia type 2a ||Medullary thyroid carcinoma, pheochromocytoma ||10q11.2 || RET ||169 |
|Multiple endocrine neoplasia type 2b ||Familial medullary thyroid carcinoma ||10q11.2 || RET ||170,171 |
|Neurofibromatosis type 1 ||Multiple peripheral neurofibromas, optic glioma, neurofibrosarcoma ||17q11.2 || NF1 ||172–176 |
|Neurofibromatosis type 2 ||Central schwannomas and meningiomas, acoustic neuromas ||22q11.2 || NF2 ||177 |
|Peutz-Jeghers syndrome ||Multiple gastrointestinal tract polyps hamartomatous and adenomatus cancer of intestinal tract, pancreas, ovary, testis, breast, uterus ||19p13.3 || STK11 ||178,179 |
|Retinoblastoma ||Retinoblastomas, osteosarcomas ||13q14 || RB ||180,181 |
|von Hippel–Lindau syndrome ||Renal cell carcinoma, pheochromocytoma, hemangloblastoma ||3p25–p26 || VHL ||182 |
Genetic testing for cancer holds the promise of reducing cancer mortality through timely screening and early intervention in those with predisposing mutations. The anticipated health benefits of testing rest on the assumption that persons at increased risk for cancer will be given options for preventive screening regimens or other interventions (such as prophylactic surgery or chemoprevention). Several decision analysis studies have evaluated the theoretical health and cost benefits of cancer gene testing for retinoblastoma3 and familial adenomatous polyposis (FAP), 4,5 and those of management decisions (surveillance and prophylactic surgery) for hereditary breast cancer, 6,7 and hereditary colorectal cancer8 and have generally found that the use of genetic test information or targeted interventions in cancer gene mutation carriers can be an improvement over conventional methods of cancer prevention. The parameters and construction of these decision analysis models vary, and some may only approximate the actual clinical situation, but they do appear to support the concept that genetic testing has a valid medical rationale.
It is becoming apparent that gene tests can and will change the way in which cancer risk assessment will be performed.1,2,9-13 Indeed, certain gene tests (APC, RET, RB1, VHL) may now be considered part of the standard management of the respective hereditary cancer syndrome families, while the medical benefit of other gene tests (hMSH2, hMLH1, hPMS1, hPMS2, BRCA1, BRCA2, and p53) is presumed but not established.14 The gene test outcome for an individual patient or at-risk family member can lead to more informed and directed recommendations for preventive interventions. As a general example, Fig. 49-1 illustrates the way in which colon cancer risk assessment has been conventionally performed. That is, health professionals often evaluate family histories of persons at risk for colon cancer who seek to learn their cancer risk but less often assess family histories of patients with colon cancer. Conventional risk assessment is based almost exclusively on evaluation of the family history, after which cancer screening recommendations can be made, tailored according to whether an inherited syndrome can be diagnosed. Fig. 49-2 illustrates a potential scenario in which colon cancer gene tests will alter this process. When gene tests are offered in conjunction with family history evaluation, not only will the two sources of information help make a firmer diagnosis, but clinical management of colon cancer patients may be influenced by this diagnosis. Likewise, more refined follow-up recommendations may be given to at-risk persons, whether they test positive or negative for a colon cancer gene. Genetic testing for cancer risk carries psychosocial implications that should be communicated through careful genetic counseling to persons considering cancer gene tests, both patients and family members. On one hand, genetic counseling will entail directive counseling toward cancer prevention where indicated, but on the other, it will entail communication about complex issues related to heredity, genetic test performance, probabilities, and uncertainty of outcome.
Current view of conventional colon cancer risk assessment.
Future view of colon cancer risk assessment.
From the public health perspective, cancer gene discoveries may potentially be translated into genetic screening programs to identify high-risk groups to whom interventions (lifestyle modification, chemoprevention, or early detection) can be more effectively applied. There is agreement that much research is required prior to implementing any kind of public health program that involves genetic screening for cancer.15-18 There is a need for more research into the issues surrounding technical and policy implications when applied to large-scale screening.19 There is also a need to understand the frequency and attributable risks of cancer susceptibility genes and the efficacy and effectiveness of interventions in susceptible individuals, including examination of the premise that health prevention behaviors would be enhanced by knowledge of one's genetic susceptibility status. The difficulties are underscored by a recent study using decision analysis to investigate the role of genetic screening in cancer prevention. Grann and coworkers found that the theoretical cost-benefit ratio and survival rate would make screening all Ashkenazi Jewish women for specific BRCA1 and BRCA2 mutations cost-effective only if prophylactic surgery were performed on mutation carriers.20
A variety of studies have found that there is great interest in cancer genetic testing across all risk groups, whether for breast, ovarian, prostate, or colon cancers.21-29 Studies among first-degree relatives of cancer patients have found that when presented with the hypothetical possibility of cancer genetic testing, the majority of respondents probably or definitely want genetic testing. Cancer risk perception is increased among those with a positive family history, and these individuals may be more likely to choose genetic testing to learn more about their cancer risk.25-31 Generally, those with a family history of a given disorder are more likely to engage in disease prevention behaviors for that disorder, 32-34 and most persons tend to overestimate their personal risk of cancer25 or probability of carrying a cancer gene mutation.35 Adherence to screening recommendations after genetic testing is likely to be associated with pre-genetic testing screening behavior32-34,36 and with previous symptoms suggestive of cancer.37
In clinical and research experience, the reasons patients give for wanting cancer genetic testing are cancer worry and/or desire to know if more screening tests are needed (personal cancer risk concern), childbearing concerns or need to learn if one's children are at risk (concern for relatives), and wanting to take better care of oneself (general health concern).30,31,38-41 As will be discussed later, there are a number of psychosocial factors that influence the actual decision to have a cancer gene test. Among those that can damp interest are perceived inability to cope with the gene test result and worry about insurance discrimination.
The epidemiologic challenges offered by genetic testing are threefold. First, it is necessary to understand the frequency, attributable risk, and heterogeneity of cancer-associated gene mutations. In general, the mutations in genes that are known to be associated with hereditary forms of cancer (e.g., breast cancer42) are not common, and obtaining estimates is complicated by the logistic difficulties of conducting population-based genetic testing, and by ethnic variation. For example, certain types of BRCA1, BRCA2, and APC mutations are more common in the Ashkenazi Jewish population, 43-45 and certain hMLH1 mutations are more common in the Finnish population, due to a founder effect.46,47 In addition, it is recognized from a number of studies that not all hereditary forms of cancer are accounted for by the currently known genes.48,49
Second, the opportunity to understand genetic and nongenetic contributions to cancer causation is enhanced by the existence of persons, either with or without clinical manifestations of malignancy, who are known to carry cancer gene mutations. The respective roles of genes and environment may be more efficiently addressed in such defined risk groups. While studying more common polymorphisms of genes associated with metabolism of carcinogens has been one strategy to investigate this relationship, it may be increasingly possible to study high-penetrance cancer gene mutations. For example, Brunet and coworkers examined the relationship of smoking to breast cancer risk using only BRCA1 or BRCA2 mutation carriers and found a protective effect of smoking.50 While this result contradicts our widespread understanding of the more typical harmful effect of smoking, this study design yielded an example of the type of knowledge that can be obtained from samples of gene-tested patients.
Third, the necessity to more carefully characterize and communicate cancer risk has been reinforced by cancer genetic testing.51,52 In particular, there are two main ways in which risk associated with cancer gene mutations is usually given to patients: (1) The probability that a person will carry a cancer gene mutation, given information such as age, gender, ethnicity, and family history. A number of studies have investigated ways to estimate these risks and have obtained varying results, depending upon the subjects studied and the factors employed in computing risks.53-56 Predictive models have been developed for hereditary breast and ovarian cancer57-59 and for hereditary nonpolyposis colorectal cancer (HNPCC).60 (2) The probability that a mutation carrier is going to develop cancer (also termed lifetime risk or penetrance of a gene mutation). These studies are more difficult to perform, but estimates have been made, using both high-risk samples and larger population studies.44,61-63 As the volume of gene-tested persons increases, the current methods for computing risks will be refined to more accurately inform the risk assessment process.
Two of the most consistent patterns to emerge from genetic studies of inherited cancer syndromes are that there are many causal mutations in associated loci and that many families have unique mutations. Thus, testing laboratories will have to develop a variety of different strategies for detecting mutations in patients or diagnosing at-risk individuals in cancer-carrying families.64-66 These tests range from linkage analysis67-69 and single-stranded conformational polymorphism analysis70 to protein truncation tests71,72 and direct end-to-end DNA sequencing and allele specific oligonucleotide assays.64 The relative merits and drawbacks of mutation detection approaches have been reviewed elsewhere, 64-66,73,74 and different laboratories vary in their strategies for gene testing. Potential new strategies include DNA chip technology, 64 conversion of diploidy to haploidy, 75 and mass spectrometry, 76 but it is unlikely that there will ever be tests that meet the ideal criteria for DNA-based genetic tests, as set forth by Eng and Vijg:64 100% sensitivity, 100% specificity, cost-effectiveness (<$100 per gene or combination of genes), throughput and speed of testing that fit into clinical laboratory routine, and being user friendly.
Because of the relatively high sophistication of current mutation analysis technology, it is not necessarily a simple process for the clinician to understand and interpret the potential implications of gene test results. The Task Force on Genetic Testing of the National Institutes of Health–Department of Energy Working Group on the Ethical, Legal, and Social Implications of Human Genome Research has set forth general principles on gene testing relative to gene test validation and testing laboratory quality control77 and has proposed revisions to policies regulating laboratories that perform gene tests, which notably mandate the inclusion of clinical validation of tests.78 This group argues that gene tests are different from other clinical tests because of the complexities in assessment and interpretation and that they require more intake information. In addition, it says health care providers must describe the features of the genetic test, including potential consequences, prior to testing. When a clearcut test result is obtained, either because a disease-predisposing mutation is detected (positive gene test) or because a mutation is not detected in an at-risk person from a family where a known mutation is segregating (true negative gene test), the subsequent counseling and management options are more apparent. Inconclusive or uninformative negative gene tests will occur when no mutation is detected in a cancer family but, because of the limitations of the testing method, a mutation in the tested locus (or elsewhere) cannot be ruled out. At-risk members in these families should not reduce their vigilance in cancer screening.
Tissue Sources for Clinical Gene Testing.
The most common tissue source for gene testing is leukocyte DNA; a simple blood sample is often all that is required to perform a gene test. DNA obtained from paraffin-embedded tissue blocks obtained at surgery is also an option, if an affected relative is deceased or obtaining a blood sample is not feasible.
Specific tumor DNA studies may also yield information to aid in the diagnosis of inherited susceptibility to cancer. In the case of HNPCC, a special tumor analysis to identify microsatellite instability (MSI, also known as replication error [RER]) can be performed.79,80 In this analysis, DNA from both normal tissue and tumor tissue is analyzed by highly polymorphic microsatellite DNA markers and their banding patterns compared. Allele alterations (band shifts) seen between tumor and normal DNA suggest that the patient may have an impaired ability to repair DNA, which is an indirect assessment of forms of HNPCC that are due to mutations in mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2).79-83 Because MSI analysis is less time consuming and expensive than gene tests based on mutation analysis, it offers a useful first screening test for HNPCC.55
The utility of gene expression assays in tumors as an adjunct to germline mutation detection in a genetically heterogeneous syndrome has also been evaluated. For example, in the case of a suspected HNPCC mutation carrier whose tumor is MSI-positive, immunohistochemistry expression assays of hMSH2 and hMLH1 may help to identify which gene to sequence.84,85 RNA expression assays of BRCA1 have been investigated as a means of screening for germline mutations.86
Commercial Availability of Testing.
With the discovery of specific genes responsible for inherited cancer syndromes, commercial laboratories have been quick to invest in the development of marketable gene tests. Among the cancers that may affect a larger segment of the population, hereditary breast and ovarian cancer (BRCA1, BRCA2), HNPCC (hMSH2, hMLH1), FAP and its variants (APC), hereditary melanoma (p16), and neurofibromatosis type 2 (NF2) now have commercially available gene tests.14,87-89
The widening commercial availability of germline cancer gene tests has outpaced the awareness among health professionals of the need for careful implementation of testing algorithms and patient education on the issues.88,89 There have been calls for caution in moving genetic tests out of the research labs and into the commercial labs87,90-94 until their impact and the effectiveness of cancer prevention strategies can be studied. Specifically, some professional organizations advise that genetic testing and counseling for cancer risk may be safely integrated into clinical practice only after there have been studies of gene frequencies and associated cancer risks, test sensitivity and specificity, the efficacy of interventions for decreasing cancer morbidity and mortality, counseling methods, and genetic discrimination among those found to be at high risk.92-94
Ethical, Legal, and Policy Perspective
The ethical, legal, and policy issues in genetic testing have been discussed in numerous reviews and position statements, 92-103 and certain themes are emerging. Perhaps the most important overarching theme is that genetic information is different from other types of information (whether medical, demographic, or social), because of implications for future risk of disease and because of implications for other relatives. As a result, genetic testing that reveals intrinsic genetic status mandates special consideration.
As with all ethical dilemmas, there are no absolute right or wrong answers to many of the questions raised by cancer genetic testing. Inherent in medical and genetic service is the principle of beneficence. Discussions and decisions related to genetic testing can further be guided by the relevant principles of bioethics identified by the Committee on Assessing Genetic Risks of the National Academy of Sciences and Institute of Medicine, 91 including: respect for autonomy, privacy, confidentiality, and equity. These have implications for shaping how clinicians should approach and manage cancer patients and their families. Some common ethical issues for clinicians to consider are the right to know/not to know, sharing of genetic information, coercion by family members to participate in genetic testing, privacy of medical and genetic information, reproductive decision-making, and testing of minors.
The legal and social ramifications of genetic susceptibility testing for cancer are also taking shape. Some issues that may have legal implications for clinicians are disclosing benefits, risks, and limitations of cancer genetic testing; following up and recontacting patients and family members when new information emerges; maintaining confidentiality of genetic information; and warning of inherited cancer risk (“genetic transferability”) to others.
Privacy of Genetic Information.
Genetic information should be considered confidential, and it is incumbent upon health professionals and laboratories to exercise all means of preventing unauthorized disclosure of gene test results to third parties. In practice, it is recommended that results should be released only to those individuals to whom the patient has consented or requested in writing to have them released, and care should be taken to minimize the likelihood that results will become available to unauthorized persons or organizations.77 Garber and Patenaude point out, however, that physicians may breach confidentiality unintentionally by placing information in medical charts that may be reviewed by insurers or other third parties.96 The dilemma is that omitting this information compromises the patient's future medical care, yet including the information would compromise the ability of the patient or family members to obtain health, life, or disability insurance (and therefore coverage for preventive screening tests or procedures).
Another crucial issue is the revelation of gene test results to family members. As shown in Fig. 49-3, the optimal algorithm for gene testing of at-risk persons is to first test a family member who is affected with cancer; this patient must be willing to have the resulting genetic information shared with relatives. It is an important principle of gene testing that health care providers have an obligation to the person being tested not to inform other family members without the permission of the person tested.77,91 There are also circumstances in which certain individuals may not want their test results known, yet by virtue of the pedigree structure this information will become known (e.g., an identical twin of a gene-positive patient); or family members may refuse to have their gene test results shared. The resolution of these issues may not always be easy, but it will call for careful planning and thorough genetic counseling with the family members involved, well before gene test results are made available.103-105
Basic algorithm for cancer risk assessment that employs gene testing.
Risk of Genetic Discrimination.
Persons at risk for cancer face other risks in the form of genetic discrimination (insurance, employment, educational, or other opportunities). Insurance companies may use genetic information, much as they use any other medical information, to underwrite an insurance policy. In these cases, insurance companies may deny insurance to those whom they consider to be at too great a risk for an illness or to those with pre-existing conditions.106,107 Such denials are predicted to become more commonplace as new predisposition tests are developed.108,109 Billings et al.108 and Lapham et al.107 have identified cases in which insurance or employment discrimination has occurred. They found discrimination against the “asymptomatic ill”—those with a genetic predisposition who remain healthy—who usually lost their insurance after undertaking preventive care. Overall, the problems encountered included difficulty obtaining coverage, finding or retaining employment, and being given permission for adoptions. Insurance problems often arose when people tried to alter existing policies because of relocations or job changes. Information provided by physicians often had little or no influence on the adverse outcomes. Many people dealt with this by giving incomplete or dishonest information.107,108
With respect to discrimination in the workplace, there may be risk of loss of employability if gene status or genetic risk of cancer is known or required by employers.110 Recent attempts to remedy this include laws to protect access to health insurance, including the Health Insurance Portability and Accountability Act, which took effect in July 1997; protection of access to employment by an interpretation of the Americans with Disabilities Act of 1990 to include genetic information, and state laws to prevent genetic information from being used in employment considerations.
Psychological and Genetic Counseling Perspective.
The areas of psychological importance in cancer genetic testing include interest in and uptake of testing, impact of both positive and negative gene test results on cancer prevention behaviors and interventions (e.g., prophylactic surgery), and genetic testing of children.111
Uptake of Cancer Genetic Testing.
It has been observed in a number of studies that while interest in a hypothetical cancer gene test may be high, the actual uptake rates are more modest, even when persons are offered the gene test at no monetary cost. A person's decision to have a gene test is affected by a number of factors, including demographic, psychological, social, and personality.38-41,112,113 Indeed, research suggests that psychological rather than medical factors appear to predominate in decisions about genetic testing. For example, Codori and coworkers38 found that strength of cancer family history did not predict a patient's decision to be tested for HNPCC. Instead, tested persons had greater perceived confidence in their ability to cope with a positive test, thought more frequently about cancer, and had greater perceived risk for developing colorectal cancer. Of some concern was the fact that gene test decliners also were less likely to have had a colonoscopy, leading the authors to posit that those who choose not to take cancer gene tests may also be those who are unlikely to undertake the surveillance interventions. Bowen et al. suggest that while clinicians may think of the benefit of genetic testing as a medical decision, the predominance of emotion and self-perception of risk may lead to difficulties in patient-provider communication.114 To overcome this barrier, some at-risk persons may need more psychological support and counseling to increase perceived ability to handle unfavorable medical information. One lesson from the research thus far is that recognition of psychologically vulnerable persons may require different or tailored genetic counseling to prompt appropriate screening behaviors in those persons who might otherwise avoid screening.
Psychological Consequences of Positive Gene Tests.
A favorable balance of health benefits versus costs depends on determining whether the medical benefits will outweigh any psychological “side effects.” For at-risk persons, cancer gene testing is not without potential side effects, as it may pose risks to psychological well-being and to the very cancer prevention practices it is meant to promote. These risks derive from several factors, including the predictable stress reaction that can follow the delivery of unfavorable medical information.
Surveys of persons at risk for cancer have shown that they expect significant distress in the face of a positive cancer gene test. Eighty percent of 121 female first-degree relatives of ovarian cancer patients reported that they would become depressed if they tested positive for a breast cancer mutation; 77 percent reported that they would become anxious.30 Similarly, 60 percent of male and female first-degree relatives of colon cancer patients reportedly expected to become depressed and 52 percent anxious upon receiving a positive gene test.31 It is possible that distress caused by a positive gene test may interfere with subsequent preventive health behavior. This has been shown in other situations: Of women notified of an abnormal mammogram, those who experienced high levels of psychological distress after notification were less likely to perform subsequent breast self-exam than those with moderate levels of distress;115 persons psychologically distressed after having been notified of their risk for hypertension adhered less to their medication regimens;116 and distressed persons delay seeking medical attention for possible cancer symptoms117
There is concern that persons distressed by their cancer risk will make irrevocable decisions to have unproven prophylactic surgeries.118 This prediction has some support from a study of first-degree relatives of breast cancer patients. Those who subsequently chose prophylactic mastectomy were more anxious and had higher levels of cancer worry than women who later chose continued screening or a chemoprevention trial.119 The finding suggests that women undertake prophylactic surgery to more fully eliminate their cancer risk. However, prophylactic mastectomy, while effective, 120 does not eliminate breast cancer risk, 121,122 and some of the women studied may never develop cancer. Moreover, basing decisions on probabilistic genetic information means that short-term relief from cancer worry could be followed by regret if later, more definitive information reveals that the surgery was unnecessary.
A positive genetic test can have favorable psychological consequences, including removal of uncertainty and being better able to prepare for future events, as has been seen in Huntington disease123,124 and FAP.10 Surveys of persons at risk for cancer suggest that they anticipate benefits from “bad news.” For example, 68 percent of first-degree relatives of ovarian cancer patients reported that they would feel more “in control” of their lives even if they tested positive.125 Several studies that measured psychological parameters at baseline and 1 to 3 months following gene testing have found no adverse reactions in persons who received positive test results: Lerman et al. studied 279 male and female members of BRCA1-linked hereditary breast and ovarian cancer families and found no short-term increased depression or functional impairment in those who tested gene positive.112 Croyle and coworkers found that distress declines after gene testing but that women who are mutation positive for BRCA1 experience more distress than noncarriers in followup.126 In a study of 42 children at risk for FAP and their parents, Codori et al. also did not observe any significant increase in distress or behavioral problems in the gene-positive children.127 The response to genetic testing is likely complex, 128 and research to examine these observations in the context of longer-term impact are ongoing.
Psychological Consequences of Negative Gene Tests.
Those whose receive negative gene tests often experience relief at removal of uncertainty and doubt.10,112,127 These persons are likely to be spared anxiety-provoking, 10,129 costly, and sometimes invasive screening procedures and to be relieved to know that their children's and their own personal risk for cancer is no greater than in the general population.
It is possible that some proportion of those who learn that they do not carry the cancer gene mutation in their family are at risk for psychological distress. In Huntington disease, “survivor guilt” was reported in 25 percent of people who tested negative, 130 and individual cases of depression and marital disruption have been reported.130,131 Twenty-five percent of persons at risk for colon cancer predict feeling guilty, and 50 percent expect to continue worrying about cancer even after learning that they are noncarriers.31 Similar rates were reported by women at risk for breast and ovarian cancer.125
Genetic Testing of Children.
There has been debate on the appropriateness of genetic testing of minors, particularly for cancers that have their onset later in adulthood or for which there is no intervention to change the outcome. The medical and legal ramifications need to be explored and the interests of the children and their parents weighed.91,132 Issues to consider include assessment of the significance of the potential benefits and harms of the gene test, determination of the decision-making capacity of the child, and advocacy on behalf of the child.132,133 Certainly, the medical benefit to the child should be the primary justification for gene testing of children.
Certain hereditary cancer syndromes (e.g., multiple endocrine neoplasia type 2, FAP, retinoblastoma) involve onset of tumors in childhood and warrant genetic testing of children10,12,134,135 because interventions are feasible.91 Genetic testing of children requires special counseling adjusted to their age level, taking into consideration their awareness of cancer risk and perceptions of family attitudes toward cancer.10 While screening and prophylactic surgery for gene-positive persons are currently available modalities, there is potential for chemoprevention or other interventions for which initiation in childhood would be most effective.136 This would reopen the issue of performing gene tests in childhood for cancer syndromes that have their onset in adulthood.9
In summary, the available data suggest that interest in cancer gene testing may be high but that actual uptake may be more modest, being affected by psychological factors. The data also suggest that there may be psychological risks from cancer genetic testing, including emotional distress from positive and negative test results, unintended and inappropriate decreases in cancer screening behavior, irrevocable decisions made in a state of anxiety, false reassurances about cancer risk, distressing and unwanted genetic knowledge, and insurance and employment discrimination. These issues warrant carefully planned implementation of testing protocols. These factors, in large measure, call for sensitive, thorough preparation and follow-up, including education and psychological evaluation and support.
Current Status of Cancer Risk Assessment and Genetic Testing
Cancer Risk Assessment Clinical Services
Within the last several years, there have been numerous clinical initiatives to provide cancer genetic risk assessment and genetic testing services.137-140 Many are located in major medical university or comprehensive cancer center settings, but an increasing number of health professionals in health maintenance organization and private practice settings have begun to offer cancer genetic testing. While clinical geneticists and genetic counselors can provide this service, it is more often the case that the medical specialties that are generally associated with treatment of cancer have begun to recognize the importance of providing this component of a comprehensive service to their patients. In particular, professional societies of clinical oncologists, surgeons, and oncology nurses have initiated educational programs to keep their members current.141-144
The cancer risk assessment service is interdisciplinary (medicine, genetics, genetic counseling) and at a minimum should include a physician (oncologist or clinical geneticist), and genetic counselor, or nurse/nurse practitioner with cancer genetics experience. The service should have access to resource support personnel, including social workers, psychologists, specialists in cancer treatment and management, and ethicists, and to genetic testing laboratories certified under Clinical Laboratory Improvement Act (CLIA) regulations.
Indications for Cancer Risk Assessment
The increased understanding of the relationship of clinical features, epidemiology, and aggregation of cancers in families has allowed the compilation of guidelines to clues for clinicians that would warrant further evaluation for familial or hereditary cancer:1,13,137
A cancer occurring at an unusually young age compared with the usual presentation of that type of cancer
Multifocal development of cancer in a single organ or bilateral development of cancer in paired organs
Development of more than one primary tumor of any type in a single individual
Family history of cancer of the same type in a close relative(s)
High rate of cancer within a family
Occurrence of cancer in an individual or a family exhibiting congenital anomalies or birth defects
Ashkenazi Jewish heritage
Family known to segregate a hereditary gene mutation
More recently, resources for clinical cancer genetics have become available, in the form of both textbooks1,13 and handbooks, 137 Internet-based resources and government-sponsored programs, such as the National Cancer Institute's Cancer Genetics Network, Cancer Information Service, and the Physician Data Query (PDQ) database, are other emerging new resources (Table 49-2).
Table 49-2: Internet-Based Cancer Genetics Resources |Favorite Table|Download (.pdf) Table 49-2: Internet-Based Cancer Genetics Resources
| Resource || Internet (Web Page) Address || Description |
|Alliance of Genetic Support Group ||http://www.geneticalliance.org/index.html ||Nonprofit organization that addresses the concerns of people with, and at risk for, genetic conditions. |
|American Cancer Society || http://www.cancer.org/ ||Nationally recognized non profit organization site contains a variety of information on cancer. |
|Association of Cancer Online Resources - Breast Cancer Information Clearinghouse || http://www.acor.org/ ||Established in 1994, this contains a directory of organizations that provide information and support for breast cancer patients and their families and access to online discussion groups. |
|Avon Breast Cancer Awareness Crusade || http://www.avoncrusade.com/ ||Avon's Internet crusade to provide more women, particularly low-income, minority, and older women, with access to breast cancer education and early detection screening services. |
|Cancer and Genetics ||http://www.cancergenetics.org/ ||The Robert H. Lurie Comprehensive Cancer Center of Northwestern University site contains information for the genral public, primary care physician, nurse practitioners, and other health care professionals. |
|Cancer Genetics Network ||http://www.-dccps.ims.nci.nih.gov/CGN/ ||Newly established network sponsored by the National Cancer Institute. |
|Cancer Information Network ||http://www.cancernetwork.com/ ||Containing separate sections for professional and patients, this site is a good source of facts and news on various cancers. |
|Cancer information Service ||http://cis.nih.gov/ ||Sponsored by the National Cancer Institute, this site is the home of the national information and education network, available at 1-800-4-CANCER, that provides the most up-to-date and accurate information on cancer. |
|CancerNet || http://cancernet.nci.nih.gov/ ||Sponsored by the National Cancer Institute, this site provides access to several NCI databases, including the PDQ (Physician Data Query) and Cancerlit. |
|Clinical Genetics: Information for Genetic Professionals || http://www.kumc.edu/gec/geneinfo.html ||University of Kansas Medical Center site contains clinical, research, and educational resources for genetics professionals. |
|Division of Cancer Epidemiology and Genetics ||http://www-dceg.ims.nci.nih.gov/index.html ||Part of the National Cancer Institute, this site contains information on population-based research on environmental and genetic determinants of cancer. |
|ELSI || http://www.nhgri.nih.gov/ELSI/ ||The Ethical, Legal, and Social Implications program is a branch of the National Human Genome Research Institute, established in 1990 to address issues related to human gene mapping research. |
|Healthfinder || http://www.healthfinder.gov/ ||Developed by the U.S. Department of Health and Human Services, this site contains links to over 1400 health-related sites. |
|Human Genome Project || http://www.nhgri.nih.gov/HGP/ ||Home of the international effort to determine the DNA sequence of the entire human genome. |
|InteliHealth || http://www.intelihealth.com/lH/ihtlH ||Developed by Aetna U.S. Healthcare and the Johns Hopkins University Hospital and Health System, this comprehensive site contains information for both consumers and professional. |
|International Collaborative Group on Hereditary Non-polyposis Colorectal Cancer ||http://www.nfdht.nl/ ||Mainly for physicians and researchers, this site contains a mutation database and a set of clinical guidelines. |
|Johns Hopkins Breast Center ||http://www.med.jhu.edu/breastcenter/ ||This site is the Internet link to the Johns Hopkins Oncology Center, a National Cancer institute-designated Comprehensive Cancer Center. |
|Johns Hopkins Colon Cancer Center ||http://www.hopkins-coloncancer.org/ ||This site is the Internet link to the Johns Hopkins Breast Cancer Center, part of the Johns Hopkins Oncology Center, a National Cancer Institute-designated Comprehensive Cancer Center |
|Medscape Oncology || http://oncology.medscape.com/Home/Topics//oncology.html ||A commercial, comprehensive web service for both clinicians and consumers. |
|National Cancer Institute || http://www.nci.nih.gov/ ||The U.S. goverment's primary agency for cancer research and training. |
|National Institutes of Health || http://www.nih.gov/ ||One of eight agencies that make up the Public Health Service in the Department of Health and Human Services. |
|Office of Genetics and Disease Prevention || http://www.cdc.gov/genetics/ ||Maintained by the Centers for Disease Control and Prevention, this site contains information on the impact of human genetic research and the Human Genome Project on public health and disease prevention, including HuGE Net. |
|OncoLink: Genetics and Cancer ||http://Oncolink.upenn.edu/causeprevent/genetics/ ||Part of the University of Pennsylvania Cancer Center OncoLink site. |
|Principles and Recommendation: Task Force on Genetic Testing ||http://www.med.jhu.edu/tfgtelsi/promoting/ ||Final report of the Task Force on Genetic Testing, a workiong group of the National Institutes of Health and Department of Energy human genome programs. |
|The Susen G. Komen Foundation ||http://www.komen.org ||For both patients and professionals, this site contains information on breast cancer detection and coping as well as grant and funding opportunities. |
|US TOO International, Inc. ||http://www..ustoo.com/ ||Home to the largest prostate cancer support group in the world, this site provides access to information on prostate cancer and to counseling and educational meetings. |
Indications for Cancer Gene Tests
At this time, cancer gene tests have two primary clinical applications. When affected individuals are tested, gene tests may be used to molecularly diagnose an inherited cancer syndrome. When asymptomatic persons are tested, gene tests may be used to identify whether or not they are at increased risk because they carry a known predisposing mutation. The appropriate use of gene tests, particularly in determining who should be tested, is relatively straightforward in clearcut hereditary cancer syndrome families. However, this distinction is rapidly becoming blurred as further characterization of cancer gene loci appears to indicate that gene tests may be used for familial cancers due to mutations associated with lower penetrance in families that do not fit known criteria for hereditary syndromes, or for screening specific populations in which cancer susceptibility genes occur at high frequency.
Testing Affected Individuals to Clarify the Diagnosis.
A patient with cancer might be offered gene testing to rule in or out a suspected inherited syndrome. In this case, there may be indications from family history or from clustering of specific tumors in family members suggestive of a hereditary syndrome (such as leukemia, soft-tissue sarcoma, brain tumors, or breast cancer in Li-Fraumeni syndrome145). Table 49-1 lists some of the tumor types that are associated with known cancer syndromes. Gene tests may also be offered to patients with apparently sporadic cancer if the cancer occurs at an unusually young age or if the patient has other stigmata suggestive of a hereditary syndrome. For example, FAP might be suspected in a patient who has multiple colonic adenomas, congenital hypertrophy of the retinal pigment epithelium, and desmoid tumor146 but no family history of colon polyps or cancer. APC gene testing is an indicated diagnostic test, as such a patient could have a de novo mutation in the APC gene.147 If the APC gene test is positive, the patient can be presumed to have FAP and his or her children to be at 50 percent risk for inheriting the mutation.
Because genetic heterogeneity is seen in some hereditary cancer phenotypes, gene tests may be used help to identify the specific locus that is involved. For example, Turcot syndrome, a rare colon polyposis/cancer syndrome associated with central nervous system malignancies, has been shown to be genetically heterogeneous, with at least three loci (APC, hMLH1, and hPMS2) that independently produce a similar clinical picture.148 Patients from suspected hereditary breast cancer families may need to be tested for at least two genes, BRCA1 and BRCA2, because both genes may produce similar family histories.149-151
Testing at-Risk Individuals for Inherited Susceptibility to Cancer.
Asymptomatic at-risk persons from known hereditary cancer syndrome families may benefit from gene testing. In particular, when a mutation in a cancer gene is known to be segregating in the family, at-risk persons who test negative for the mutation may be relieved of years of surveillance, while persons who test positive for the mutation may approach the screening regimen with greater willingness to adhere to the recommendations.
When a mutation is not known to segregate in a cancer family, or if the diagnosis of a cancer syndrome is less clearcut, gene testing of at-risk persons in these families is more problematic. Often there is not a living family member with cancer who can undergo gene testing to identify the mutation. In such instances a negative gene test result in an at-risk person is not a “true” negative result that places him or her at the general population's risk for that cancer. Rather, this person has an “inconclusive” or “uninformative” negative test result that does not rule out other cancer gene loci, or even other mutations in the tested locus that the gene test was not able to detect. A person receiving an inconclusive test result should continue to maintain a cancer surveillance regimen as though no gene test was ever done.
Cancer Genetic Risk Assessment Process
The risk assessment process has multiple steps and incorporates multiple dimensions: medicine, psychology, genetics, and counseling. Health professionals trained in cancer genetics will need to have an awareness of the variety of issues that contribute to the process of helping patients to understand their risk, make informed decisions, and appreciate the implications for cancer prevention and risks for other family members.
Algorithm for Genetic Testing.
With due consideration given to the issues surrounding cancer gene testing, a basic algorithm for integrating gene tests in cancer risk assessment can be constructed (Fig. 49-3). In this algorithm, eligible persons might include patients with a diagnosis of a known hereditary cancer syndrome and/or family members, patients with a positive family history, and patients with young onset of cancer (generally before age 50). Such patients should receive initial face-to-face counseling about cancer risk, with an educational component that includes a review of the genetics of the specific cancer(s) relevant to the patient, factors influencing increased cancer risk, and preventive intervention options, all adjusted to each patient's level of understanding. If it has not already been done, a detailed family history should be elicited and follow-up confirmation of cancer diagnoses in family members obtained, if possible.
The novel aspect of cancer risk assessment is genetic testing. The gene test may consist of mutation analysis or of tumor analysis for microsatellite instability (in the case of colorectal cancer). Following initial counseling, a careful explanation of the risks and benefits of the gene test should be given to the patient, with ample opportunity to check understanding and to answer questions or concerns. Genetic testing may not necessarily be the best option for some patients or families and should be entered into voluntarily, after careful deliberation on the implications.
If a specific causal gene mutation cannot be identified, then genetic testing of at-risk family members should not be pursued. Conventional screening guidelines and interventions as reviewed in the initial counseling session apply. If a specific causal gene mutation is identified, then the diagnosis of the corresponding hereditary cancer syndrome can be confirmed. In this instance, genetic counseling and predictive gene testing may be offered to at-risk family members who may wish to have this test done.
If an at-risk person tests positive for the gene, then he or she will be encouraged to adhere to preventive screening recommendations specific to the hereditary syndrome and counseled regarding other options, such as prophylactic surgery or chemoprevention, if applicable. In the case of FAP, hereditary breast and ovarian cancer, and HNPCC, recommendations have been developed, mostly based on expert opinion.1,122,147,152
If an at-risk person from a family in which the mutation in the cancer gene is known to segregate tests negative for the mutation, then he or she will be encouraged to adhere to cancer screening guidelines for the general population.
Genetic Counseling in Cancer Gene Testing.
Genetic counseling must accompany genetic testing, because of the implications for family members and for reproductive decision-making. While a conventional, non genetic diagnostic test pertains primarily to the health of the person who has been tested, a genetic test often has implications for the health of other relatives, such as offspring, parents, and siblings. For example, a person who learns that he or she has a gene for an autosomal dominant form of cancer immediately knows that all of his or her offspring have a 50 percent risk of having inherited the mutation and his or her grandchildren a 25 percent risk. When an affected person tests positive, without prior evidence that the cancer was hereditary, the entire family may be suddenly suspected to be at increased risk for cancer. An identical twin cannot be tested without automatically revealing the co-twin's status, whether or not she or he wants the information. Similarly, a person at 25 percent risk for cancer (i.e., with an affected grandparent and healthy at-risk parent) who tests positive for the mutation automatically reveals a genetic diagnosis to the at-risk parent. Thus, genetic information may have serious implications for many persons who were not even tested.
Genetic counseling accompanying gene tests for inherited cancer risk should include:
Educating the family about the clinical and management aspects of hereditary cancer, the risks of cancer within the syndrome, and the consequences of receiving gene-positive or gene-negative test results, including the recommended screening guidelines for each possible test outcome.
Exploration of the issues related to the family history and experiences with cancer. These experiences can be multigenerational and include quite personal involvement with relatives who have died from cancer and/or who had oncologic or surgical interventions. Family relationships can be profoundly marked by issues such as guilt and blame, and personal and familial identity may be strongly linked with cancer status. Other issues include the denial of disease risk or stigmatization of cancer within the family and the acceptability, convenience, and affordability of screening regimens. Thus, genetic testing is imbued with meaning for certain patients far beyond its function as a simple determiner of genetic status. The at-risk patient may have pre-formed, well-entrenched conceptions of what having cancer entails, and family relationships and identity may be strongly linked with disease or gene status. Understanding of the patient's perspective is crucial so that it can be taken into account in assisting her or him to adjust to genetic test results.
Exploration of the perception of risk and its meaning and anticipated meaning of any test results. With parents of at-risk minor children, time should also be devoted to discussing how and when the test results and risk will be communicated to the children. In certain countries, employability or loss of insurability (life or health) is a risk, although the magnitude of this risk is at present unknown.
Informed Consent for Gene Testing.
The decision to move forward with the gene test should be freely made by the at-risk person after carefully considering the consequences of genetic testing. It is strongly recommended that a consent form that outlines the meaning of test results and the consequences of the gene test be utilized.14,77,91,153 If patients are to make fully informed decisions about gene testing, the informed consent process must include discussions of several complex issues, listed below. This is a time-consuming process and can require at least an hour of counseling time. The genetic counseling process that accompanies gene testing should incorporate the basic elements of informed consent, including:14,153
Information on the specific test being performed
Implications of a positive and a negative result
Possibility that the test will not be informative
Options for risk estimation without genetic testing
Risk of passing a mutation to children
Technical accuracy of the test
Fees involved in testing and counseling
Risks of psychological distress
Risks of insurance or employer discrimination
Options for and limitations of medical surveillance and screening following testing
Disclosure and Post-Disclosure Counseling.
Disclosure of gene test results, which can occur 2 weeks to 2 months later, depending upon the laboratory, provides another opportunity to meet again with the at-risk family member, explore the meaning of the test, and discuss in a more substantial way the likely follow-up regimen and cancer risks to future offspring.
For persons who test positive for the tested cancer gene, we recommend a third, follow-up session (either by telephone or in person), in which the patient is allowed a second opportunity, free from the initial emotional reaction to the test result, to ask questions about clinical management and the clinician can determine if referral to a mental health professional for additional support is indicated.
In summary, new research developments in the molecular genetics of cancer have led to the feasibility of cancer genetic testing for many patients and family members. Gene tests have the potential to identify high-risk persons, and gene tests results will have clinical implications for cancer risk management: Conventional preventive recommendations can be modified in light of gene test results such that those at higher risk for cancer (gene positive) will be identified for increased cancer surveillance, while those at lower risk (true gene negative) may be reassured. There is a very real potential for misinterpretation of inconclusive gene test results. The new genetic technology also has psychosocial consequences for patients and families and ethical, legal, and policy implications for health care providers. Genetic counseling is an important added component in cancer risk assessment and management, particularly in helping those at risk to understand the variety of implications gene test results have in the context of their experience with cancer and intervention options.
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