Introduction
Cancer Risk Counseling
Taking a Family History
Analysis of the Family History
Risk Perception
Risk Communication
Counseling About Risk Management
The Option of Genetic Testing
        Factors to take into consideration in offering testing
        Determining the test to be used
Informed Consent
Importance of Pretest Counseling
Psychological Impact of Genetic Information/Test Results on the Individual
Psychological Impact of Genetic Information/Test Results on the Family
Exploration of Potential Risks, Benefits, Burdens, and Limitations of Genetic Susceptibility Testing
Posttest Education and Result Notification

Introduction

 [Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

The purpose of this summary is to describe current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Several reviews present good general overviews of the process.[1-3] People are usually considered to be candidates for genetic counseling if they have a strong family history of cancer; in general, this means a family history that includes several affected relatives, with at least some affected at atypically early ages. The definition of a strong family history, however, varies for different cancers. Refer to information available in introductory sections of the PDQ cancer genetics information summaries on specific cancers.

People who have one or more of the following may also be candidates for genetic counseling:

• A diagnosis of cancer at an atypically young age.
• A rare cancer (e.g., childhood adrenocortical carcinoma).
• An unusual presentation.
• Multiple primary cancers.
• Cancers associated with birth defects.
• In some cases, extreme cancer anxiety, even in the absence of heightened risk.
• Unusual or multiple cancers in family members (e.g., sarcoma or retinoblastoma).

Individuals who are candidates for genetic testing receive genetic counseling before testing to facilitate decision making. Genetic counseling gives individuals time to consider both the various medical uncertainties and psychosocial risks and benefits involved in genetic testing.

Components that are common to the genetic counseling process include constructing and evaluating a pedigree, eliciting and evaluating a personal and family medical history, and providing information about genetic risk. When testing occurs, genetic counseling incorporates pretest counseling, testing, posttest counseling, and follow-up. This process may include discussing, ordering, and interpreting clinical genetic laboratory tests. Much preparation time outside the appointment is spent obtaining and reviewing medical records, seeking information about diagnoses in the differential diagnosis list, finding support groups and patient resources, communicating with other specialists, and doing case documentation.[4] In some instances, physical findings may be important in determining whether a cancer syndrome is present; this determination requires a targeted physical examination by a medical professional for physical findings specific to a genetic syndrome.

The genetic consultation begins by addressing the individual’s needs, worries, questions, and concerns, and giving him or her an indication of what to expect. Early in the session, it is essential to establish trust, rapport, and a sense of safety. Other tasks during the early phase of counseling include eliciting beliefs about cancer, exploring questions, and negotiating a mutually agreeable agenda. Later in the session, counseling focuses on obtaining and giving information, promoting autonomy in decision-making, and recommending active coping strategies, while assisting the patient in dealing with practical and emotional issues.

Information about inherited risk of cancer is growing rapidly. Many of the issues discussed in a counseling session may need to be revisited as new information emerges. At the end of the counseling process, individuals are typically reminded of the possibility that future research may provide new options and/or new information on risk. Individuals may be advised to check in with the counselor periodically to determine whether new information is sufficient to merit an additional counseling session. The obligation of health care providers to recontact individuals when new testing or treatment options are available is controversial, and standards have not yet been established.

Genetic counseling may be provided by various health professionals (e.g., genetic counselors, genetic advanced practice nurses, social workers, psychologists, and physicians) who have expertise in this area. Genetic counselors and genetic advanced practice nurses are professionals trained to deliver medical and genetic risk information and to counsel individuals and families about prevention and risk reduction. A Cancer Genetics Services Directory, a partial list of individuals involved in cancer risk assessment, genetic counseling, testing, and other related services, is available on the National Cancer Institute's Web site. A number of professional guidelines on the elements of cancer genetics risk assessment and counseling based on expert opinion are available [5-10] and, except where noted, the discussion below is based on expert opinion.

The need for advanced professional training in cancer genetics for genetics counselors, physicians, nurses, laboratory technicians, and others has been widely reported.[11-14] The National Coalition for Health Professional Education in Genetics was established in 1996 to enhance the level of general professional education about genetics. It has published core competencies for all health professionals.[15] A number of other organizations have also published guidelines.[7,8,16-19]

In a workshop on genetic counseling aspects of heritable cancer syndromes and genetic testing, the American Cancer Society (ACS) reaffirmed that counseling must take place prior to genetic testing and that counseling should be independent of testing.[20] Specific recommendations were made for the ACS to expand its existing scholarships, training programs, and postdoctoral fellowships in cancer genetics and to collaborate with other organizations to develop training programs.

Genetic counseling has been defined by the American Society of Human Genetics as “a communication process which deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family. The process involves an attempt by one or more appropriately trained persons to help the individual or family to:

1. comprehend the medical facts including the diagnosis, probable course of the disorder, and the available management;
2. appreciate the way that heredity contributes to the disorder, and to the risk of recurrence (occurrence), in specific relatives;
3. understand the alternatives for dealing with the risk of recurrence (occurrence);
4. choose a course of action which seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision; and
5. make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence (occurrence) of that disorder.”[21]

Additionally, genetics professionals and other health providers must understand the potential impact of genetic testing on families and discuss how information might be transmitted and shared among family members.

Central to genetic counseling philosophy and practice are the principles of voluntary utilization of services, informed decision making, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of patient confidentiality and privacy. An important objective of genetic counseling is to provide an opportunity for shared decision making when the medical benefits of one course of action are not demonstrably superior to another. The relationship between availability of effective medical treatment for mutation carriers and clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals.[22] Genetic counseling generally involves some combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a family’s culture and ethnicity;[23,24] and other relevant background variables. Uptake of genetic counseling services among those referred is moderate (30% - 40%). Efforts to decrease barriers, such as patient navigation programs and increase the utilization of services by at-risk women, are ongoing.[25] Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.[26-31]

In the past decade, genetic counseling has expanded to include discussion of genetic testing for cancer risk as more genes associated with inherited cancer susceptibility have been discovered. Cancer genetic counseling often involves a multidisciplinary team, which may include a genetic counselor, genetic advanced practice nurse, or medical geneticist; a mental health professional; and a medical expert such as an oncologist, surgeon, or internist. The process of counseling may require a number of visits to address the medical, genetic testing, and psychosocial support issues. Even when cancer risk counseling is initiated by an individual, inherited cancer risk has implications for the entire family. Because genetic risk affects biological relatives, contact with these relatives is often essential to collect an accurate family and medical history. Cancer genetic counseling may involve several family members, some of whom may have had cancer.

Certain features of genetic disease susceptibility highlight the importance of genetic counseling. Specifically, an accurate assessment depends on a detailed family history and, conversely, information about one individual has implications for others in the family. The purpose of risk counseling is to provide information about an individual’s empiric risk of cancer. If the assessment indicates an increased cancer risk, counseling includes discussion of cancer risk management strategies and options for genetic testing. Risk counseling may also lead to reassurance if cancer risk is found not to be greater than average or substantially less than the person had anticipated. In some cases, the purpose of counseling includes helping the individual explore feelings about his or her personal risk status and make a healthy adjustment to that risk status. Either alone or in consultation with a mental health provider, professionals offering cancer genetic counseling attempt to assess whether the individual’s expectations of counseling are realistic and whether there are factors suggesting unusual risk of adverse psychological outcomes after disclosure of risk and/or genetic status. Sometimes, referral for psychotherapeutic treatment prior to or in lieu of testing may be recommended.[32]

Some studies of patient satisfaction with cancer genetic counseling services have been published. For example, one survey of participants after the first year of operation of a cancer genetics program reported that the clinical services met the needs and expectations of most people.[33] Patients reported that the best parts of the experience were simply having a chance to talk to someone about cancer concerns, having personalized summary letters and family pedigrees, and learning that cancer risk was lower than expected or realizing that one had been justified in suspecting the inheritance of cancer in one’s family. Additionally, computer programs designed to provide genetics education can be successful adjuncts to personal genetic counseling services in a computer-literate population.[34-37]

Follow-up is often multidisciplinary, with input from and referral to professionals trained in genetic counseling, nursing, social work, psychology, preventive medicine, public health, occupational health, and mental health, as well as referral as needed to medical specialists in fields such as surgery, gastroenterology, gynecology, and oncology. Because inherited cancers affect more than the individual, the entire family may become involved.

In order to estimate an individual's hereditary cancer risk, it is essential to summarize family history information in the form of a pedigree.A pedigree, or family tree, is a standardized graphic representation of family relationships in which patterns of disease transmission are tracked.[38] Family history is an essential tool for cancer risk assessment. Written and interview methods of evaluating family cancer history have been shown to be useful. Assessment can be obtained via interview or written self-report, as both have been found to result in equivalent information in a study that utilized a sample (n = 104) that varied widely in educational attainment.[39] A graphic illustration facilitates identification of patterns of transmission, recognition of specific hereditary cancer syndromes, and determination of the best methods for risk assessment. Factors suggesting inherited cancer risk include the following:

• Clustering of the same type of cancer in close relatives.
• Unusually early age of cancer onset.
• Two or more primary cancers in a single individual.
• Evidence of autosomal dominant inheritance.
• Bilateral cancer in paired organs.
• Multifocal cancer.
• Patterns of cancer in the family that are associated with a known cancer syndrome.

Criteria have been compiled that may help identify families who may benefit from a referral to genetic counseling.[40] Standards of pedigree nomenclature have been established.[38] Refer to Figure 1 for common pedigree symbols.

A cancer family history typically includes the following:

• Both maternal and paternal relatives. Hereditary cancer syndromes can be inherited from either the mother or the father.
• Race, ancestry, and ethnicity information for all grandparents. This may influence decisions about genetic testing because specific mutations (so-called founder mutations) may occur with increased frequency in selected populations.
• Information about seemingly unrelated conditions, such as birth defects or other nonmalignant conditions of children and adults, that may aid in the diagnosis of a cancer susceptibility syndrome.
• A minimum of three generations. This will help identify inheritance patterns, as cancer is often an adult-onset disease.
• Notation of adoption, nonpaternity, consanguinity, and use of assisted reproductive technology (e.g., donor egg or sperm), when appropriate.

A three-generation family history includes the following:

• First-degree relatives (e.g., children, brothers and sisters, and parents).
• Second-degree relatives (e.g., grandparents, aunts and uncles, nieces and nephews, and grandchildren).
• Third-degree relatives (e.g., cousins, great aunts, and great uncles) are included if these individuals have had cancer and/or one of their first-degree relatives has been affected with cancer.

For any relative with cancer, collect the following information:[41]

• Type of each primary cancer.
• Age at diagnosis for each primary cancer.
• Where the relative was diagnosed and/or treated.
• If the individual is still living, current age; if deceased, age at death and cause of death.
• Carcinogenic exposures (e.g., tobacco use, radiation exposure).
• Other significant health problems.

For any relative not affected with cancer, collect the following information:

• Current age or age at death.
• If deceased, cause of death.
• History of any surgeries that reduce the risk for cancer.
• Whether routinely screened for cancer.
• Any nonmalignant features of the syndrome in question.
• Carcinogenic exposures.
• Other significant health problems.

People often have incomplete or inaccurate information about the cancer history in their family (e.g., because of adoption, use of donor egg or sperm, uncertain paternity, loss of contact with relatives, small family size, or deaths at an early age from unrelated conditions).[38,41-46] Accuracy may also vary by site of cancer or degree of relatedness.[47] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[45,47,48] A 2004 review suggests that reporting of cancer family histories may be most accurate for breast cancer and less accurate for gynecologic malignancies.[47] Verification of medical diagnoses through medical records, tumor registries, or death certificates may improve the risk assessment and should be considered if significant medical decisions such as risk-reducing surgery will be based on family history. Information collected on prophylactic surgery procedures, such as oophorectomy, could change the constellation of cancers observed in a family resulting in a significant change to prior probability estimation.[49] Additionally, it is important to regularly update pedigrees as family histories change over time and the occurrence of additional cancers may alter the likelihood of a hereditary predisposition to cancer.

The process of taking the family history, recording it in a standardized way in a pedigree, and discussing the patterns of disease with family members has a psychosocial dimension. The process, at least symbolically, brings the family into the session, even when a single person is being counseled. Problems that may be encountered in eliciting a family history and constructing a pedigree include difficulty contacting relatives with whom one has little or no relationship, differing views between family members about the value of genetic information, resistance to discussion of cancer and cancer-related illness, unanticipated discovery of previously unknown medical or family information, and coercion of one relative by another regarding testing decisions. In addition, unexpected emotional distress may be experienced in the process of gathering family history information.

Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes one important aspect of risk assessment. This analysis might be thought of as a series of questions:

1. What is the evidence that a cancer susceptibility syndrome is present in this family?
2. If a syndrome is present, what is the most probable diagnosis?
3. What is the most likely mode of inheritance, regardless of whether a syndrome diagnosis can be established?
4. What could make this family history difficult to interpret?
5. What is the chance of a member of this family developing cancer, if an inherited susceptibility exists?
6. If no recognizable syndrome is present, what are the implications of other epidemiological risk factors?

The following sections relate to the way that each of these questions might be addressed:

1. What is the evidence that a cancer susceptibility syndrome is present in this family?

   The clues to a hereditary syndrome are based on pedigree analysis and physical findings. The index of suspicion should be raised by the following:

   • Multiple cancers in close relatives, particularly in multiple generations.
   • Early age of onset: younger than 40 to 50 years for adult-onset cancers.
   • Multiple cancers in a single individual.
   • Bilateral cancer in paired organs (e.g., breast, kidney).
   • Recognition of the known association between etiologically related cancers in the family.
   • Presence of congenital anomalies or precursor lesions that are known to be associated with increased cancer risk (e.g., presence of atypical nevi and risk of malignant melanoma).
   • Recognizable Mendelian inheritance pattern.



2. If a syndrome is present, what is the most probable diagnosis?

   Hundreds of inherited conditions are associated with an increased risk of cancer. These have been summarized in texts [50-52] and a concise review.[53] Diagnostic criteria for different hereditary syndromes incorporate different features from the list above, depending on the original purpose of defining the syndrome (e.g., for gene mapping, genotype-phenotype studies, epidemiological investigations, population screening, or clinical service). Thus, a syndrome such as Lynch syndrome can be defined for research purposes by the Amsterdam Criteria as having three related individuals with colorectal cancer, spanning two generations, of which one person is younger than 50 years, better known as the 3-2-1 rule. These criteria have limitations in the clinical setting, however, in that they ignore endometrial and other extracolonic tumors known to be important features of Lynch syndrome. Revised published criteria that consider extracolonic cancers in establishing the diagnosis of Lynch syndrome have been subsequently developed and include the Amsterdam criteria II and the revised Bethesda guidelines.




3. What is the most likely mode of inheritance, regardless of whether a syndrome diagnosis can be established?

   The mode of inheritance refers to the way that genetic traits are transmitted in the family. Mendel’s laws of inheritance posit that genetic factors are transmitted from parents to offspring as discrete units known as genes that are inherited independently from each other and are passed on from an older generation to the following generation. The most common forms of Mendelian inheritance are autosomal dominant, autosomal recessive, and X-linked. Non-Mendelian forms of inheritance include chromosomal, multifactorial, and mitochondrial. Researchers have learned from cancer and other inherited diseases that even Mendelian inheritance is modified by environmental and other genetic factors and that there are variations in the ways that the laws of inheritance work.[54-56]

   Most commonly, Mendelian inheritance is established by a combination of clinical diagnosis with a compatible, but not in itself conclusive, pedigree pattern.[57] Below is a list of inheritance patterns with clues to their recognition in the pedigree, followed by a list of situations that may complicate pedigree interpretation.

   Autosomal dominant

   Autosomal dominant inheritance refers to disorders that are expressed in the heterozygote (i.e., the affected person has one copy of a mutated allele and one allele that is functioning normally). Autosomal dominant inheritance is characterized by the following:

   • Vertical occurrence (i.e., seen in successive generations).
   • Usually seen only on one side of the family (i.e., unipaternal or unimaternal).
   • Males and females may inherit and transmit the disorder to offspring.
   • Male-to-male transmission may be seen.
   • Offspring have a 50% chance of inheriting a mutation and a 50% chance of inheriting the normal allele.
   • The condition may appear to skip a generation due to incomplete penetrance, early death due to other causes, delayed age of onset, or paucity of females or males when the target organ is sex-specific.
   • Most currently known cancer susceptibility syndromes follow an autosomal dominant inheritance pattern. Examples include hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis (FAP), and von Hippel Lindau disease.
   • It is possible for an individual to have a mutation in a gene that has not previously been expressed as an autosomal dominant family history of cancer due to a variety of factors discussed below (see question #4).
   • It is possible for an individual to have a de novo (new) mutation. This person would be the first affected member of his or her family but could transmit this trait in the normal autosomal dominant manner.

   Autosomal recessive

   Autosomal recessive inheritance refers to an inheritance pattern in which an affected person must be homozygous (i.e., carry two copies of a mutant gene, one from each parent). Autosomal recessive inheritance is characterized by the following:

   • Horizontal occurrence (i.e., seen in one generation only); these conditions generally are not seen in successive generations.
   • Affected individuals usually cluster within one sibship.
   • Mutated genes must come from both sides of the family (i.e., biparental inheritance).
   • Parents are heterozygous carriers; each carries one mutated copy of the gene and one functional copy.
   • Parents usually do not express the trait or the full syndrome; in some cases, parents may show a mild version of some features.
   • Heterozygous parents have a 25% recurrence risk for future offspring being affected.
   • Some well-defined cancer susceptibility syndromes with an autosomal recessive inheritance pattern include Bloom syndrome, ataxia telangiectasia, and Fanconi anemia.

   X-linked

   X-linked inheritance refers to inheritance of genes located on the X chromosome. Because males carry one Y and one X chromosome, genes on their X chromosome are hemizygous and may be expressed, regardless of whether dominant or recessive. X-linked recessive inheritance is more common than X-linked dominant and is characterized by the following:

   • Male and female offspring have a 50% chance of inheriting the mutated allele from the carrier.
   • Males in the maternal lineage (brothers and maternal uncles) are affected.
   • Females are rarely affected, and when they are, the effects are usually milder than they are in males.
   • No father-to-son transmission of the mutation occurs (i.e., a father cannot transmit an X-linked condition to his son because he gives the son his Y chromosome and not his X).
   • It is unusual for a cancer susceptibility syndrome to show X-linked transmission. One rare example is X-linked lymphoproliferative disorder.

   Chromosomal

   Chromosomal disorders generally are not inherited conditions. Rather, they occur as a de novo error in meiosis at the time of conception of a given individual. Certain chromosomal anomalies confer a risk of malignancy; thus, inquiries about birth defects and mental retardation are worthwhile in taking a pedigree. Examples of chromosomal disorders with increased risk of malignancy include leukemia associated with Down syndrome (trisomy 21) and breast cancer associated with Klinefelter syndrome (47,XXY karyotype).

   Multifactorial

   Multifactorial or complex disease inheritance is used to describe conditions caused by genetic and environmental factors. Thus, a condition may be caused by the expression of multiple genes or by the interaction of genes and environmental factors. Therefore, a single genetic locus is not responsible for the condition. Rather, the net effect of genetic, lifestyle, and environmental factors determines a person’s liability to be affected with a condition, such as cancer.

   Susceptibility or resistance shows a more or less normal distribution in the population. Most people have an intermediate susceptibility, with those at the tails of the distribution curve having unusually low or unusually high susceptibility. Affected individuals are presumably those who are past a point of threshold for being affected due to their particular combination of risk factors. Outside of the few known Mendelian syndromes that predispose to a high incidence of specific cancer, most cancers are probably multifactorial in etiology.

   Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. In some types of cancer susceptibility, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are now seen as being due to combinations of exposures to known carcinogens such as tobacco smoke as well as to mutations in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.

   The general practitioner is likely to encounter some families with a strong genetic predisposition to breast cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual's health. Although mutations in major cancer susceptibility genes lead to recognizable Mendelian inheritance patterns, they are uncommon, and any given gene accounts for no more than 1% to 5% of cases of a particular cancer type. Mutations in these genes confer high relative risk as well as high absolute risk. The attributable risk is low, however, because they are so rare.

   In contrast, scientists now know of polymorphisms or alterations in deoxyribonucleic acid (DNA) which are very common in the general population. Each polymorphism may confer low relative and absolute risks, but collectively they may account for high attributable risk because they are so common. Development of clinically significant disease in the presence of certain polymorphic types is highly dependent on environmental exposure to a potent carcinogen. People carrying polymorphisms associated with weak disease susceptibility may constitute a target group for whom avoidance of carcinogen exposure may be highly useful in preventing full-blown disease from occurring.

   For more information about specific low-penetrance genes, please refer to the summaries on genetics of specific types of cancer.

   In a pedigree showing multifactorial inheritance, one might see the following:

   • Males and females affected (unless the target organ is sex-specific).
   • A few cancers, without clearcut vertical transmission or sibship clusters.
   • No set pattern of inheritance.
   • May appear to skip generations.
   • Risks to immediate family members of affected individuals are usually twofold to fourfold greater than the general population risk.




4. What could make family history difficult to interpret?

   Other factors may complicate recognition of basic inheritance patterns or represent different types of disease etiology. These include the following:

   • Small family.
   • Deaths at particularly early ages.
   • Removal of target organ, either as prevention or as a result of a medical condition (e.g., total abdominal hysterectomy and bilateral salpingo-oophorectomy due to history of uterine fibroids or endometriosis).
   • Misidentified parentage.
   • Late or variable onset.
   • Nonpenetrance.
   • Variable expression.
   • Genetic heterogeneity.
   • Genomic imprinting.
   • De novo mutation.
   • Mosaicism.
   • Mitochondrial inheritance.
   • Consanguinity.
   • Assisted reproductive technology (e.g., donor egg or sperm).



5. What is the chance of developing cancer if an inherited susceptibility exists?

   These probabilities vary by syndrome, family, gene, and mutation, with different mutations in the same gene sometimes conferring different cancer risks, or the same mutation being associated with different clinical manifestations in different families. These phenomena relate to issues such as penetrance and expressivity discussed elsewhere.




6. If no recognizable syndrome is present, what are the implications of other epidemiological risk factors?

   A positive family history may sometimes provide risk information in the absence of a specific genetically determined cancer syndrome. For example, the risk associated with having a single affected relative with breast or colorectal cancer can be estimated from data derived from epidemiologic and family studies. Examples of empiric risk estimates of this kind are provided in the PDQ summaries on Genetics of Breast and Ovarian Cancer and Genetics of Colorectal Cancer.

A person’s subjective view of risk may differ from his or her estimated statistical risk.[58,59] The individual’s perception of his or her cancer risk, however, may be the most important factor in determining decisions about screening or other risk-reduction strategies. Thus, it is important to begin a risk assessment process by eliciting the person’s perception of his or her risk as well as how concerned he or she is about the risk and how this has affected his or her day-to-day life (e.g., “What do you think your chances are at this point of getting cancer?” and “Does your thinking about this affect your life?”). As the risk assessment process proceeds, the provider assesses understanding of what is being discussed, how an individual qualitatively and quantitatively views the risk information provided (e.g., “Is your risk higher, lower, or about the same as you expected?”), and the individual's level of distress.

Perceptions of risk are affected by the manner in which risk information is presented, difficulty understanding probability and heredity,[60,61] and other psychological processes on the part of both patients and physicians.[62] The presence of a personal stressor (e.g., “my sister just developed breast cancer”) and the media publicity surrounding a disease, however, can lead to distortions in one’s personal risk assessment. In fact, among women from high-risk families participating in research studies, a large proportion overestimated their chances of having a genetic mutation and their likelihood of developing breast cancer.[63,64] An individual’s perception of cancer risk may not match the risk calculated by statistical models.[65] Individuals tend to pay more attention to personal experience than to baseline cancer rates when making judgments.[66] Hence, a case of cancer in a close relative may make an individual more likely to think of himself or herself as having an increased genetic risk of cancer rather than attributing this event to base rates with which the cancer occurs in the general population or taking into account the fact that overall rates of cancer in his or her family may be relatively low when the entire family is considered.[67] In families with many cases of cancer among young relatives, individuals often feel certain that they too will develop cancer.

Perceived risk can play an important role in an individual’s decision to participate in counseling,[68] despite the fact that perceived risk often varies substantially from statistical risk estimates.[69-71]

The purpose of risk counseling is to provide people with accurate information about their risk, help them understand and interpret their risk, assist them as they use this information to make important health care decisions, and help them make the best possible adjustment to their situation. More research is needed on the best methods of communicating risk in order to help people develop an accurate understanding of their risk. Risk may be communicated in many ways (e.g., with numbers, words, or graphics; alone or in relation to other risks; as the probability of having or not having an adverse event; in relative or in absolute terms; and through combinations of these methods). The way in which risk information is communicated may affect the individual’s perception of the magnitude of that risk. In general, relative risk estimates (e.g., "You have a threefold increased risk of colorectal cancer") are perceived as less informative than absolute risk (e.g., "You have a 25% risk of colorectal cancer") [72] or risk information presented as a ratio (e.g., one in four).[61] A strong preference for having BRCA1/2 mutation risk estimates expressed numerically is reported by women considering testing.[73] People associate widely differing quantitative risks with qualitative descriptors of risk such as “rare” or “common.”[74]

Specific clinical programs for risk management may be offered to persons with an increased genetic risk of cancer. These programs may differ from those offered to persons of average risk in several ways: screening may be initiated at an earlier age or involve shorter screening intervals; screening strategies not in routine use, such as screening for ovarian cancer, may be offered; and interventions to reduce cancer risk, such as risk-reducing surgery, may be offered. Such programs are generally based on expert opinion. Current recommendations are summarized in the PDQ summaries addressing genetics of specific cancers.

Optimally, counseling about cancer risk includes information about options available for risk management, including data (or lack of data) on the efficacy of different measures for reducing risk. The strategies available for risk management (including their efficacy, risk, and psychological implications) may be an important factor in decisions about pursuing genetic testing.

1. Risk assessment suggesting an inherited cancer syndrome.

Experts recommend offering genetic testing when a risk assessment suggests the presence of an inherited cancer syndrome for which specific genes have been identified. American Society of Clinical Oncology (ASCO) policy states that genetic testing should be offered when the following conditions apply:

• An individual has a personal or family history suggestive of a genetic cancer susceptibility syndrome.
• The results of the test can be interpreted.
• Testing will influence medical management.[75]

Characteristics used in making this determination are discussed in the PDQ summaries on specific cancers. Even when individual and family history characteristics indicate a possible inherited cancer syndrome, individuals may elect not to proceed with testing after discussion of potential risks and benefits, as discussed below. Conversely, individuals whose pedigrees are incomplete or uninformative due to very small family size, early deaths, or incomplete data on key family members may elect to pursue genetic testing in an attempt to better define their risk status. In these situations, it is particularly important that the pretest counseling fully explore the limitations of the testing process.

2. Value of testing an affected family member first.

Genetic susceptibility testing generally yields the most useful information when a living family member affected with the cancer of concern is tested first to determine whether a genetic basis for the cancer in the family can be established. If a mutation previously associated with cancer risk is demonstrated in the affected family member, other family members may be tested for the presence or absence of this specific mutation. If no mutation is found in an affected family member, testing is considered uninformative regarding the possible inherited basis for cancer in that family, and thus there is no basis for testing unaffected relatives.

Where there is no close, living, affected relative, other options may be discussed with the patient and the testing laboratory. These generally involve weighing a decision to test the stored tissue of a deceased relative or to test an unaffected person without prior testing of an affected family member. Tests done on stored tissue are technically difficult and may not yield a definitive result. Testing an unaffected person without prior testing of an affected relative often is uninformative because a negative test does not rule out the presence of a cancer susceptibility gene in the family or the subject. In addition, counseling needs to take into account the consequences for a patient receiving a test result of variants of unknown clinical significance. (Refer to the PDQ Cancer Genetics Overview summary for more information.)

Enlarge

This genetic testing algorithm depicts the multi-step process of testing for cancer susceptibility.

*Refer to the Analysis of the Family History section of this summary for more information.

Genetic testing is highly specialized. Any given test is usually performed in only a small number of laboratories. There are also multiple molecular testing methods available, each with its own costs, strengths, and weaknesses. Depending on the method employed and the extent of the analysis, different tests for the same gene will have varying levels of sensitivity and specificity. Even assuming high analytic validity, genetic heterogeneity makes test selection challenging. A number of different genetic syndromes may underlie the development of a particular cancer type. For example, hereditary colon cancer may be due to FAP, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, or other syndromes. Each of these has a different genetic basis. In addition, different genes may be responsible for the same condition (e.g., Lynch syndrome can be due to mutations in one of several mismatch repair genes). Also, allelic heterogeneity (i.e., different mutations within the same gene) can confer different risks or be associated with a different phenotype. For example, though the general rule is that adenomatous polyposis coli (APC) gene mutations are associated with hundreds or thousands of colonic polyps and colon cancer of the classical FAP syndrome, some APC mutations cause a milder clinical picture, with fewer polyps and lower colorectal cancer risk. In addition, other disorders may be part of the FAP spectrum. Mutations in a certain portion of the APC gene also predispose to retinal changes, for example, whereas mutations in a different region of APC predispose to desmoid tumors. Thus, selection of the appropriate genetic test for a given individual requires considerable knowledge of genetic diagnostic methods, correlation between clinical and molecular findings, and access to information about rapidly changing testing options. These issues are addressed in detail in PDQ summaries on the genetics of specific cancers.

Consensus exists among experts that a process of informed consent should be an integral part of the pretest counseling process.[76] This view is driven by several ethical dilemmas that can arise in genetic susceptibility testing that, taken together, constitute a difference in kind from other noninvasive, diagnostic, or screening tests. The most commonly cited concern is the possibility of insurance or employment discrimination if a test result, or even the fact that an individual has sought or is seeking testing, is disclosed. Although many states have legislated against inappropriate use of genetic information, it is not clear whether or how such legislation will apply to underwriting based on family history or genetic test results, or to self-insured health care plans. Existing federal legislation leaves many loopholes. A related issue involves stigmatization that may occur when an individual who may never develop the condition in question, or may not do so for decades, receives genetic information and is labeled or labels himself or herself as ill. Finally, in the case of genetic susceptibility testing, medical information given to one individual has immediate implications for biologic relatives. These implications include not only the medical risks, but also disruptions in familial relationships. The possibility for coercion exists when one family member wants to be tested but, to do so optimally, must first obtain genetic material or information from other family members.

Inclusion of an informed consent process in counseling, including the signing of an informed consent document prior to genetic testing, helps support patient autonomy.[77] It may also reduce the potential for misunderstanding between patient and provider. Many protocols provide opportunities for individuals to review their informed consent during the genetic testing and counseling process. The initial informed consent document provides a comprehensive overview of the process, but relevant issues are raised again at strategic points, for instance, prior to notification of results.

Some programs use a second informed consent process prior to disclosure to the individual of his or her genetic test results. This process allows for the possibility that a person may change his or her mind about receiving test results. After the test result has been disclosed, a third informed consent discussion often occurs. This discussion concerns issues regarding sharing of the genetic test result with health providers and/or interested family members either currently or, potentially, in the future. Obtaining written permission to provide the result to others at risk in the family can avoid vexing problems in the future should the individual not be available to release his or her results.

Meaningful informed consent can enhance preparedness for testing, including careful weighing of benefits and limitations of testing, minimization of adverse psychosocial outcomes, appropriate use of medical options, and a strengthened provider-patient relationship based on honesty, support, trust, and beneficence.

Major elements of an informed consent discussion can be inferred from the preceding discussion. The critical elements, as described in the literature,[5,7,8] include the following:

• Elicitation and discussion of a person’s expectations, beliefs, goals, and motivation.
• Explanation of how inheritance of genetic factors may affect cancer susceptibility.
• Clarification of a person’s increased risk status.
• Discussion of potential benefits, risks, and limitations of testing.
• Discussion of costs and logistics of testing and follow-up.
• Discussion of possible outcomes of testing (e.g., positive, negative, inconclusive, uninterpretable, true positive, false positive).
• Discussion of medical options available for those who choose to test, for those who choose not to test, and for those who have positive, negative, or inconclusive results.
• Data on efficacy of methods of cancer prevention and early detection.
• Discussion of possible psychological, social, economic, and family ramifications of testing or not testing.
• Consideration of how the person’s screening or other behaviors might change depending on the test result.
• Discussion of alternatives to genetic testing (e.g., tissue banking, risk assessment).
• Attainment of verbal and written informed consent or clarification of the decision to decline testing.
• Consideration of personal acceptability of screening and risk reduction options.

All individuals considering genetic testing should be informed that they have several options even after the genetic testing has been completed. They may decide to receive the results at the posttest meeting, delay result notification, or less commonly, not to receive the results of testing. They should be informed that their interest in receiving results will be addressed at the beginning of the posttest meeting (see below), and time will be available to review their concerns and thoughts on notification. It is important that individuals receive this information during the pretest counseling to ensure added comfort with the decision to decline or defer result notification even when testing results become available.

The complexity of genetic testing for cancer susceptibility has led experts to suggest that careful, in-depth counseling should precede any decision about the use of testing in keeping with the accepted principles for the use of genetic testing.[6] For example, New York State guidelines specify that “When an increased risk for hereditary susceptibility is identified through the individual or family history, the clinician should initiate discussion or refer the patient for information concerning genetic testing and its potential benefits and burdens. The clinician who opts to take on this responsibility must provide the depth of content and time required to ensure that the patient can make an informed testing choice.”[7]

Qualitative and quantitative research studies indicate that families hold a variety of beliefs about the inheritance of characteristics within families; some of these beliefs are congruent with current scientific understanding whereas others are not.[78-80] These beliefs may be influenced by education, personal and family experiences, and cultural background. Because behavior is likely to be influenced by these beliefs, the usefulness of genetic information may depend on recognizing and addressing the individual’s pre-existing cognitions. This process begins with initial discussion and continues throughout the genetic counseling process.

An accurate assessment of psychosocial functioning and of emotional factors related to testing motivation and potential impact and utilization is an important part of pretest counseling.[32,81-84] Generally, a provider inquires about a person’s emotional response to the family history of cancer and also about a person’s response to his or her own risk of developing cancer. People have various coping strategies for dealing with stressful circumstances such as genetic risk. Identifying these strategies and ascertaining how well or how poorly they work will have implications for the support necessary during posttest counseling and will help personalize the discussion of anticipated risks and benefits of testing. Taking a brief history of past and current psychiatric symptoms (depression, extreme anxiety, suicidality) will allow for an assessment of whether this individual is at particular risk of adverse effects following disclosure of results. In such cases, further psychological assessment may be indicated.

In addition, cognitive deficits in the person being counseled may significantly limit understanding of the genetic information provided and hinder the ability to give informed consent, and may also require further psychological assessment. Emotional responses to cancer risk may also affect overall mood and functioning in other areas of life such as home, work, and personal health management, including cancer screening practices.[85] Education and genetic counseling sessions provide an opportunity for ongoing informal assessment of the affective as well as cognitive aspects of the health communication process. A meta-analysis of studies related to the psychological impact of genetic counseling for familial cancer suggests that the counseling process may improve knowledge about cancer risk, but may not alter long-term impact on cancer risk perception in counseled individuals.[86] Since behavioral factors influence adherence to screening and surveillance recommendations, consideration of emotional barriers is important in helping a person choose prevention strategies as well as in discussing the potential utility of genetic testing.[87,88]

The discussion of issues such as history of depression, anxiety, and suicidal thoughts or tendencies requires sensitivity to the individual. The individual must be assured that the counseling process is a collaborative effort to minimize intrusiveness while maximizing benefits. It should be determined whether the individual is currently receiving treatment for major psychiatric illness. Consultation with a mental health professional familiar with psychological assessments may be useful to help the provider develop the strategies for these discussions. It also may be beneficial for the individual to be given standard psychological self-report instruments that assess levels of depression, anxiety, and other psychiatric difficulties that he or she may be experiencing. This step provides objective comparisons with already established normative data.

In addition to the clinical assessment of psychological functioning, several instruments for cancer patients and people at increased risk of cancer have been utilized to assess psychological status. These include the Center for Epidemiological Studies-Depression (CES-D),[89] the Profile of Mood States,[90] the Hospital Anxiety and Depression Scale,[91] and the Brief Symptom Inventory (BSI). Research programs have included one or more of these instruments as a way of helping refine the selection of people at increased risk of adverse psychosocial consequences of genetic testing. Psychological assessments should be ongoing as part of genetic counseling. Some individuals with symptoms of increased distress, extreme avoidance of affect, or marked psychiatric symptomatology should have a discussion with, or evaluated by, a mental health professional. It may be suggested to some people (generally a very small percentage of any population) that postponement of testing until greater emotional stability can be established might be preferable.

In addition to making an assessment of the family history of cancer, the family as a social system may also be assessed as part of the process of cancer genetic counseling. Hereditary susceptibility to cancer may affect social interactions and attitudes toward the family.[92]

In assessing families, characteristics that may be relevant are the organization of the family (including recognition of individuals who propose to speak for or motivate other family members), patterns of communication within the family, cohesion or closeness of family members (or lack thereof), and the family beliefs and values that affect health behaviors. Cultural factors may also play an important role in guiding behavior in some families.

Assessment should also evaluate the impact of the family’s prior experience with illness on their attitudes and behaviors related to genetic counseling and testing. Prior experience with cancer diagnosis and treatment, family experiences related to cancer and loss,[93] and the family members’ interaction with the medical community may heavily influence attitudes toward receiving genetic information and may play a major role in the emotional state of individuals presenting for genetic services.

The practitioner may use the above framework to guide inquiries about the relationship of the individual to (1) the affected members of the family or (2) others who are considering or deciding against the consideration of genetic counseling or testing. Inquiries about how the family shares (or does not share) information about health, illness, and genetic susceptibility may establish whether the individual feels under pressure from other family members or anticipates difficulty in sharing genetic information obtained from counseling or testing. Inquiries about the present health (new diagnoses or deaths from cancer) or relationship status (divorce, marriage, grieving) of family members may inform the provider about the timing of the individual’s participation in counseling or testing and may also reveal possible contraindications for testing at present.

In addition to using a pedigree to evaluate family health history, tools such as the genogram and ecomap can provide specific information regarding the nature of interpersonal relationships within the family as well as the connections with social networks outside of the family.[94]

More specific information about family functioning in coping with hereditary cancers can be found in the psychosocial or counseling sections of PDQ summaries on the genetics of specific types of cancer.

There is substantial evidence that many people do not understand the potential limitations of genetic testing and may give too much weight to the potential benefits.[63,64,95] Counseling provides the opportunity to present a balanced view of the potential risks and benefits of testing and to correct misconceptions. It may be helpful to ask individuals to identify their perceptions about the pros and cons of testing as part of this discussion.

1. Potential burdens of a test result that is uninformative or of uncertain significance.

   In the absence of a known mutation in the family, a negative test result is not informative. In this situation, the tested person’s risk status remains the same as it was prior to testing. One study of 183 women with an uninformative BRCA test result found that most women understood the implications of the test result, and it did not alter their intention to undergo a high-risk screening regimen.[96] If the test identifies a new mutation of unknown clinical significance, the test result is of uncertain significance and cannot be used to revise the tested person’s risk estimate. Subsequent research, however, may provide information about the mutation’s effect (or lack of effect) on cancer risk.

   Potential burdens

   • Need to evaluate other family members to determine the significance of mutations not known to be disease related.
   • Persistent uncertainty about risk status, which may result in a recommendation for intensive monitoring if a hereditary predisposition cannot be ruled out with certainty.
   • Lack of evidence-based guidance regarding prevention or surveillance strategies.
   • Continuing anxiety, frustration, and other adverse psychological sequelae associated with uncertainty because no definitive answer has been provided.
   • High monetary cost of testing.



2. Potential benefits and burdens of a positive test in an unaffected, at-risk individual when a disease-related mutation has been identified in the family.

   Potential benefits

   • Elimination of uncertainty about inherited susceptibility for an individual.
   • Potential for reduction in future morbidity and mortality through enhanced cancer risk management strategies (i.e., increased surveillance, adoption of a healthy lifestyle, and avoidance of risk factors).
   • Opportunity to reduce cancer risk through chemoprevention and risk-reducing surgery.
   • Opportunity to inform relatives about the likelihood that they have the family mutation and about the availability of genetic testing, cancer risk assessment, and management services.

   Potential burdens

   • Neglect of screening and surveillance resulting from increased anxiety about being a mutation carrier.
   • Psychological distress, including anxiety, depression, reduced self-esteem.
   • Increased worry about cancer due to unproven effectiveness of current interventions to reduce risk.
   • Risks and costs of increased screening or prophylaxis.
   • Strained/altered relationships within family.
   • Guilt about possible transmission of genetic risk to children.
   • Potential insurance, employment, or social discrimination.



3. Potential benefits and burdens of a negative test result when a disease-related mutation has been identified in the family.

   Potential benefits

   • Reassurance and reduction of anxiety about personal cancer risk due to heredity.
   • Avoidance of unnecessary intensive monitoring and prevention strategies.
   • Avoidance of aggressive interventions such as risk-reducing surgery.
   • Relief that children are not at increased risk.

   Potential burdens

   • Neglect of routine surveillance resulting from misunderstanding of a negative test result. The patient remains at the general population risk and may be at increased risk depending on his or her personal risk factors and any risk associated with the other branch of the family.
   • Adjustment to the change in expected life course.
   • Survivor guilt.
   • Strained relationship with others in family.
   • Regret over previous decisions (e.g., having had risk-reducing surgery prior to being tested).



4. Potential benefits and burdens of a positive test result in an individual who is the first identified mutation carrier in a family.[97]

   Potential benefits

   • No need to rely on other family members for informative test results.
   • Potentially satisfying altruistic role by providing information to family members by clarifying their risk.

   Potential burdens

   • Confronting ethical dilemmas about who should receive the information, what should be conveyed, and when it should be conveyed to specific family members.
   • Coping with potential personal distress in conveying the information.
   • Coping with family members' potential distress and reaction to the information.
   • Feeling unprepared for the tasks associated with disseminating genetic information through the family.
   • Loss of privacy.

The primary component of the posttest session is result notification. An individual may change his or her mind about receiving results, however, until the moment of results disclosure. Therefore, one should always begin the disclosure session by confirming that test results are still desired. Some people may decline or delay receipt of test results. The percentage who will make this decision is unknown. Such people need ongoing follow-up and the opportunity to receive test results in the future.

Once confirmed, people appreciate direct, immediate reporting of the results; they often describe the wait for results as one of the most stressful aspects of undergoing testing.[98] Often, people need a few minutes of privacy to gather their composure after hearing their test results. Sometimes this precludes all but the briefest discussion at the initial posttest visit. Usually, individuals who have been properly prepared through the pretest counseling process do not exhibit disabling distress. Although it is rare that an acute psychological reaction will occur at disclosure, it is useful for providers of genetic test results to establish a relationship with a mental health provider who can be consulted should extreme reactions occur or be available by referral for people seeking further exploration of emotional issues.

Either at the time of disclosure or shortly thereafter, a session for the provider and the individual to consider the genetic, medical, psychological, and social ramifications of the test result is advisable. Despite having extensive pretest education, people may still be confused about the implications and meaning of the test results. Examples of frequently documented misconceptions include the belief that a positive result means that cancer is present or certain to develop; the belief that a negative result means that cancer will never occur; and failure to understand the uncertainty inherent in certain test results, as when only a limited mutation panel was examined. Regarding medical implications, it is important to inform the person of risk implications and management options for all of the cancer types in an inherited syndrome and to revisit options for risk management.

Posttest counseling may include consideration of the implications of the test results for other family members. Some experts have suggested that if a test result is positive, plans should be made at this time for the notification, education, and counseling of other relatives based on the test result of the individual. Written materials, brochures, or personal letters may aid people in informing the appropriate relatives about genetic risk.

When a test result is negative, the posttest session may be briefer. It is important, however, to discuss genetic, medical, and psychological implications of a negative result in a family with a known mutation as well. For example, it is essential that the person understand that the general population risks for relevant cancer types still apply and that the person’s individual risk of cancer may still be influenced by other risk factors as well as family history from the other side of the family. Furthermore, people are often surprised to feel distress even when a test is negative. This outcome has been documented in a variety of hereditary conditions and should be anticipated in cancer susceptibility testing as well. Postresults discussion of such distress may lead to referral for additional counseling in some cases.

Many individuals benefit from follow-up counseling and consultation with medical specialists after disclosure of test results to allow an opportunity for further discussion of their feelings about their risk status, their options for risk management to incorporate screening and detection procedures, and implications of the test results for other family members.

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