Purpose
Introduction
Cancer Risk Assessment and Counseling

Genetic Counseling Cancer Risk Assessment Counseling

Components of the Risk Assessment Process

Assessment         Psychosocial assessment         Risk perception Clinical Evaluation         Personal health history         Physical examination         Family history Determining Cancer Risk         Analysis of the family history         Methods of quantifying cancer risk

Education and Counseling About Risk/Risk Communication

Methods of Risk Presentation Risk Communication Communication Strategies

The Option of Genetic Testing

Factors to Take into Consideration in Offering Testing         Indications for testing         Value of testing an affected family member first         Testing in families with evidence of an inherited susceptibility that have not had any genetic testing or in which genetic testing has not identified a mutation         Testing in families with a documented deleterious mutation         Genetic testing and assisted reproductive technology Determining the Test to be Used         Regulation of genetic tests Informed Consent         Core elements of informed consent         Testing in children         Testing in vulnerable populations 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

Ethical, Legal, and Social Implications

Bioethical Issues in Cancer Genetic Testing         Beneficence         Nonmaleficence         Autonomy         Justice Privacy and Confidentiality: Disclosure of Patient’s Genetic Information         Disclosure in research         “Duty to warn”: legal proceedings, federal/state legislation, and recommendations of professional organizations Employment and Insurance Discrimination         Legal proceedings, federal/state legislation, and recommendations of professional organizations         Professional guidelines and other resources

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Changes to This Summary (12/18/2008)
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Purpose

This PDQ cancer information summary for health professionals provides a framework for assessing and counseling clients about their chance of having an inherited susceptibility to cancer. This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board.

Information about the following is included in this summary:

• Components of the risk assessment process.
• Strategies for communicating cancer risk.
• Aspects of genetic testing including considerations about whether genetic testing should be offered, which genetic test should be used, informed consent for genetic testing, and the psychological impact of genetic information or test results on the individual and family.
• Ethical, legal, and social implications of cancer risk assessment and counseling.

This summary does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

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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.]

This summary describes current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Genetic counseling is defined by the National Society of Genetic Counselors as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Several reviews present overviews of the cancer risk assessment, counseling and genetic testing process.[1-4].

Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history in a maternal or paternal lineage with features suggestive of hereditary cancer.[5] These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify families who may benefit from a referral to genetic counseling.[2,6] The introductory sections of the PDQ cancer genetics information summaries on breast, ovarian, colorectal, prostate and medullary thyroid cancers describe the clinical features of hereditary syndromes associated with these cancers.

The following are features that suggest hereditary cancer:

• Unusually early age of cancer onset (e.g., premenopausal breast cancer).
• Multiple primary cancers in a single individual (e.g., colorectal and endometrial cancer).
• Bilateral cancer in paired organs, or multifocal disease (e.g., bilateral breast cancer or multifocal renal cancer).
• Clustering of the same type of cancer in close relatives (e.g., mother, daughter and sisters with breast cancer).
• Cancers occurring in multiple generations of a family (autosomal dominant inheritance).
• Occurrence of rare tumors (e.g., retinoblastoma, adrenocortical carcinoma, granulosa cell tumor of the ovary, ocular melanoma, hepatoma, or duodenal cancer).
• Unusual presentation of cancer (e.g., male breast cancer).
• Uncommon tumor histology (e.g., medullary thyroid carcinoma).
• Rare cancers associated with birth defects (e.g., Wilms tumor and genitourinary abnormalities).
• Geographic or ethnic populations known to be at high risk of hereditary cancers. Genetic testing candidates may be identified based solely on ethnicity when a strong founder effect is present in a given population (e.g., Ashkenazi heritage and BRCA1/BRCA2 mutations).[7,8]

As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:

• An individual's personal history (including ethnicity) and/or family history is suspicious for a genetic predisposition to cancer.
• The genetic test has sufficient sensitivity and specificity to be interpreted.
• The test will impact the individual's diagnosis, cancer management or cancer risk management, and/or help clarify risk for family members.[9]

A candidate for genetic testing receives genetic education and counseling before testing to facilitate informed decision making and adaptation to the risk or condition.[10] Genetic education and counseling gives an individual time to consider the various medical uncertainties, diagnosis, or medical management based on varied test results, and the risks, benefits and limitations of genetic testing.

References

1. Petersen GM: Genetic testing. Hematol Oncol Clin North Am 14 (4): 939-52, 2000.  [PUBMED Abstract]
   
   
2. Kuschel B, Lux MP, Goecke TO, et al.: Prevention and therapy for BRCA1/2 mutation carriers and women at high risk for breast and ovarian cancer. Eur J Cancer Prev 9 (3): 139-50, 2000.  [PUBMED Abstract]
   
   
3. Schoen RE: Families at risk for colorectal cancer: risk assessment and genetic testing. J Clin Gastroenterol 31 (2): 114-20, 2000.  [PUBMED Abstract]
   
   
4. Trepanier A, Ahrens M, McKinnon W, et al.: Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. J Genet Couns 13 (2): 83-114, 2004.  [PUBMED Abstract]
   
   
5. Weitzel JN, Lagos VI, Cullinane CA, et al.: Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 297 (23): 2587-95, 2007.  [PUBMED Abstract]
   
   
6. Hampel H, Sweet K, Westman JA, et al.: Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 41 (2): 81-91, 2004.  [PUBMED Abstract]
   
   
7. Tobias DH, Eng C, McCurdy LD, et al.: Founder BRCA 1 and 2 mutations among a consecutive series of Ashkenazi Jewish ovarian cancer patients. Gynecol Oncol 78 (2): 148-51, 2000.  [PUBMED Abstract]
   
   
8. Beller U, Halle D, Catane R, et al.: High frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history. Gynecol Oncol 67 (2): 123-6, 1997.  [PUBMED Abstract]
   
   
9. American Society of Clinical Oncology.: American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 21 (12): 2397-406, 2003.  [PUBMED Abstract]
   
   
10. Genetic Counseling as a Profession. Chicago, IL: National Society of Genetic Counselors, 2006 Also available online. Last accessed September 5, 2007. 
    
    

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Cancer Risk Assessment and Counseling

Comprehensive cancer risk assessment is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations, delivered in the context of one or more genetic counseling sessions. Several professional organizations, including the American Society of Clinical Oncology,[1] Oncology Nursing Society, and the International Society of Nurses in Genetics, emphasize the importance of genetic counseling in the cancer risk assessment and genetic testing process.[2]

Genetic counseling informs the consultand about potential cancer risks and the benefits and limitations of genetic testing, and offers an opportunity to consider the potential medical, psychological, familial, and social implications of genetic information.[2-4] Descriptions of genetic counseling and the specialized practice of cancer risk assessment counseling are detailed below.

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.”[5]

In 2006, the National Society of Genetic Counselors further refined the definition of genetic counseling to include the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease including integration of the following:

• Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
• Education about inheritance, testing, management, prevention, resources and research.
• Counseling to promote informed choices and adaptation to the risk or condition.[2]

Additionally, understanding the potential impact of genetic testing facilitates discussion on how information might be transmitted and shared among family members.

Central to the philosophy and practice of genetic counseling 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. This is facilitated through a 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; and other relevant background characteristics.[6,7] The psychosocial assessment is especially important in the genetic counseling process because individuals most vulnerable to adverse effects of genetic information may include those who have had difficulty dealing with stressful life events in the past.[8] Variables that may influence psychosocial adjustment to genetic information include: individual and familial factors, cultural factors, and health system factors, such as the type of test, disease status and risk information.[8] Findings from a psychosocial assessment can be used to help guide the direction of the counseling session.[9] 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 demonstrated to be superior to another. The relationship between the availability of effective medical treatment for mutation carriers and the clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals.[10] Uptake of genetic counseling services among those referred is moderate (30%-40%). Efforts to decrease barriers to service utilization are ongoing (e.g., a patient navigator telephone call may increase utilization of these services by at-risk women).[11] Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.[12-17]

The scope of genetic counseling practice has expanded over the past several years to address risk assessment and genetic testing for hereditary cancer predisposition. Cancer risk assessment counseling has emerged as a specialized practice that requires knowledge of genetics, oncology, and individual and family counseling skills that may be provided by health care providers with this interdisciplinary training.[18,19] Some centers providing cancer risk assessment services involve a multidisciplinary team, which may include a genetic counselor, a genetics advanced practice nurse, a medical geneticist or a physician such as an oncologist, surgeon, or internist, and a mental health professional. The Cancer Genetics Services Directory provides a partial list of individuals involved in cancer risk assessment, genetic counseling, testing, and other related services, and is available on the National Cancer Institute's Web site.

The need for advanced professional training in cancer genetics for genetics counselors, physicians, nurses, laboratory technicians, and others has been widely reported.[20-24] Despite these identified needs, the evidence indicates that competency in genetics and genomics remains limited across all health care disciplines with the exception of genetic specialists.[25] The National Coalition for Health Professional Education in Genetics (NCHPEG) was established in 1996 to enhance the level of general professional education about genetics. NCHPEG has published and updated core competencies for all health professionals. Building on this work, individual health professions such as nursing and physician assistants, have developed and published core competencies specific to their profession.[26,27] A number of other organizations have also published professional guidelines, and scopes and standards of practice.[28-33]

Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies are being explored including group sessions and telephone counseling.[34-38] Additionally, computer programs designed to provide genetics education can be successful adjuncts to personal genetic counseling services in a computer-literate population.[39-41]

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.[42] 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, 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.

Several studies have since shown that the majority of individuals are satisfied with their genetic counseling experience.[43-46] However, one study of 61 women participating in a BRCA1/2 genetic testing program found that satisfaction with genetic counseling was influenced by psychological variables including optimism, family functioning, and general and cancer-specific distress.[47]

A meta-analysis of several controlled studies showed that outcomes of genetic counseling included improvement in cancer genetic knowledge (pooled short term difference – 0.70 U, 95% confidence interval, -0.21– -0.31 U). Overall, no long term increases in general anxiety, cancer specific worry, distress or depression were detected as a consequence of genetic counseling. However, the impact of genetic counseling on risk perception is less clear, with some studies reporting no change in risk perception while others reported significant differences before and after counseling.[48]

Evidence regarding long-term recommendation recall as a consequence of genetic counseling is now emerging. One study of 41 women who underwent genetic education and counseling followed by a written summary of the recommendations found that the majority did not accurately recall the recommendations 4 to 6 months postcounseling.[46] Other data indicate that recall and interpretation of genetic test results may also be inaccurate. In a study of 24 individuals tested from 1998-2006, who were found to have a BRCA variant of uncertain significance (VUS), 29% recalled the result as being a deleterious mutation. In this study there was a difference between factual recall and subjective interpretation of the test results; the majority of those who accurately recalled the VUS as being uninformative still interpreted the result as conferring a predisposition to cancer.[49]

References

1. American Society of Clinical Oncology.: American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 21 (12): 2397-406, 2003.  [PUBMED Abstract]
   
   
2. Resta R, Biesecker BB, Bennett RL, et al.: A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns 15 (2): 77-83, 2006.  [PUBMED Abstract]
   
   
3. Lerman C, Peters JA, Ades T, et al.: Genetic counseling issues. Workshop No. 2. Cancer 80(3): 628-629, 1997. 
   
   
4. Resta RG: Defining and redefining the scope and goals of genetic counseling. Am J Med Genet C Semin Med Genet 142C (4): 269-75, 2006.  [PUBMED Abstract]
   
   
5. Genetic counseling. Am J Hum Genet 27 (2): 240-2, 1975.  [PUBMED Abstract]
   
   
6. Baty BJ, Kinney AY, Ellis SM: Developing culturally sensitive cancer genetics communication aids for African Americans. Am J Med Genet 118A (2): 146-55, 2003.  [PUBMED Abstract]
   
   
7. Jenkins JF, Lea DH: Nursing Care in the Genomic Era: A Case-Based Approach. Sudbury, Mass: Jones and Bartlett Publishers, 2005. 
   
   
8. Meiser B, Gaff C, Julian-Reynier C, et al.: International perspectives on genetic counseling and testing for breast cancer risk. Breast Dis 27: 109-25, 2006-2007.  [PUBMED Abstract]
   
   
9. Trepanier A, Ahrens M, McKinnon W, et al.: Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. J Genet Couns 13 (2): 83-114, 2004.  [PUBMED Abstract]
   
   
10. Burke W, Pinsky LE, Press NA: Categorizing genetic tests to identify their ethical, legal, and social implications. Am J Med Genet 106 (3): 233-40, 2001 Fall.  [PUBMED Abstract]
    
    
11. Rahm AK, Sukhanova A, Ellis J, et al.: Increasing utilization of cancer genetic counseling services using a patient navigator model. J Genet Couns 16 (2): 171-7, 2007.  [PUBMED Abstract]
    
    
12. Walker AP: The practice of genetic counseling. In: Baker DL, Schuette JL, Uhlmann WR, eds.: A Guide to Genetic Counseling. New York, NY: Wiley-Liss, 1998, pp 1-26. 
    
    
13. Bartels DM, LeRoy BS, Caplan AL, eds.: Prescribing Our Future: Ethical Challenges in Genetic Counseling. New York, NY: Aldine De Gruyter, 1993. 
    
    
14. Kenen RH: Genetic counseling: the development of a new interdisciplinary occupational field. Soc Sci Med 18 (7): 541-9, 1984.  [PUBMED Abstract]
    
    
15. Kenen RH, Smith AC: Genetic counseling for the next 25 years: models for the future. J Genet Couns 4(2): 115-124, 1995. 
    
    
16. Biesecker BB: Goals of genetic counseling. Clin Genet 60 (5): 323-30, 2001.  [PUBMED Abstract]
    
    
17. Weil Jon: Psychosocial Genetic Counseling. New York, NY: Oxford University Press, 2000. 
    
    
18. Freedman AN, Wideroff L, Olson L, et al.: US physicians' attitudes toward genetic testing for cancer susceptibility. Am J Med Genet A 120A (1): 63-71, 2003.  [PUBMED Abstract]
    
    
19. Myers MF, Doksum T, Holtzman NA: Genetic services for common complex disorders: surveys of health maintenance organizations and academic genetic centers. Genet Med 1 (6): 272-85, 1999 Sep-Oct.  [PUBMED Abstract]
    
    
20. Cole DE, Gallinger S, McCready DR, et al.: Genetic counselling and testing for susceptibility to breast, ovarian and colon cancer: where are we today? CMAJ 154 (2): 149-55, 1996.  [PUBMED Abstract]
    
    
21. Calzone KA: Predisposition testing for breast and ovarian cancer susceptibility. Semin Oncol Nurs 13 (2): 82-90, 1997.  [PUBMED Abstract]
    
    
22. Mansoura MK, Collins FS: Medical implications of the genetic revolution. Journal of Health Care Law and Policy 1(2): 329-353, 1998. 
    
    
23. Holtzman NA, Watson MS, eds.: Promoting Safe and Effective Genetic Testing in the United States: Final Report of the Task Force on Genetic Testing. Baltimore, Md: Johns Hopkins Press, 1998. Also available online. Last accessed June 28, 2007. 
    
    
24. McInerney JD: Genetics education for health professionals: a context. J Genet Couns 17 (2): 145-51, 2008.  [PUBMED Abstract]
    
    
25. Harvey EK, Fogel CE, Peyrot M, et al.: Providers' knowledge of genetics: A survey of 5915 individuals and families with genetic conditions. Genet Med 9 (5): 259-67, 2007.  [PUBMED Abstract]
    
    
26. Jenkins J, Calzone KA: Establishing the essential nursing competencies for genetics and genomics. J Nurs Scholarsh 39 (1): 10-6, 2007.  [PUBMED Abstract]
    
    
27. Rackover M: Establishing essential physician assistant clinical competencies guidelines for genetics and genomics. The Journal of Physician Assistant Education 18 (2): 47-8, 2007. 
    
    
28. American College of Medical Genetics.: Genetic susceptibility to breast and ovarian cancer: assessment, counseling and testing guidelines. New York: New York State Department of Health, American College of Medical Genetics Foundation, 1999. Also available online. Last accessed March 8, 2007. 
    
    
29. McKinnon WC, Baty BJ, Bennett RL, et al.: Predisposition genetic testing for late-onset disorders in adults. A position paper of the National Society of Genetic Counselors. JAMA 278 (15): 1217-20, 1997.  [PUBMED Abstract]
    
    
30. Resource document for curriculum development in cancer genetics education. American Society of Clinical Oncology. J Clin Oncol 15 (5): 2157-69, 1997.  [PUBMED Abstract]
    
    
31. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995.  [PUBMED Abstract]
    
    
32. ASHG statement. Professional disclosure of familial genetic information. The American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. Am J Hum Genet 62 (2): 474-83, 1998.  [PUBMED Abstract]
    
    
33. The National Action Plan on Breast Cancer (NAPBC) Hereditary Susceptibility Working Group and Education Subgroup.: Hereditary Susceptibility to Breast and Ovarian Cancer: An Outline of Fundamental Knowledge Needed by all Health Care Professionals. Washington D.C.: US Dept. of Health and Human Services, The Office on Women's Health, 2000. 
    
    
34. Ormond K: Recommendations for telephone counseling. J Genet Couns 9 (1): 63-71, 2000. 
    
    
35. Sangha K: Assessment of the effectiveness of genetic counseling by telephone compared to a clinic visit. J Genet Couns 12 (2): 171-84, 2003. 
    
    
36. Calzone KA, Prindiville SA, Jourkiv O, et al.: Randomized comparison of group versus individual genetic education and counseling for familial breast and/or ovarian cancer. J Clin Oncol 23 (15): 3455-64, 2005.  [PUBMED Abstract]
    
    
37. Jenkins J, Calzone KA, Dimond E, et al.: Randomized comparison of phone versus in-person BRCA1/2 predisposition genetic test result disclosure counseling. Genet Med 9 (8): 487-95, 2007.  [PUBMED Abstract]
    
    
38. Peshkin BN, Demarco TA, Graves KD, et al.: Telephone genetic counseling for high-risk women undergoing BRCA1 and BRCA2 testing: rationale and development of a randomized controlled trial. Genet Test 12 (1): 37-52, 2008.  [PUBMED Abstract]
    
    
39. Green MJ, Biesecker BB, McInerney AM, et al.: An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility. Am J Med Genet 103 (1): 16-23, 2001.  [PUBMED Abstract]
    
    
40. Green MJ, McInerney AM, Biesecker BB, et al.: Education about genetic testing for breast cancer susceptibility: patient preferences for a computer program or genetic counselor. Am J Med Genet 103 (1): 24-31, 2001.  [PUBMED Abstract]
    
    
41. Wang C, Gonzalez R, Milliron KJ, et al.: Genetic counseling for BRCA1/2: a randomized controlled trial of two strategies to facilitate the education and counseling process. Am J Med Genet A 134 (1): 66-73, 2005.  [PUBMED Abstract]
    
    
42. Stadler MP, Mulvihill JJ: Cancer risk assessment and genetic counseling in an academic medical center: consultands' satisfaction, knowledge, and behavior in the first year. J Genet Couns 7(3): 279-297, 1998. 
    
    
43. Chen WY, Garber JE, Higham S, et al.: BRCA1/2 genetic testing in the community setting. J Clin Oncol 20 (22): 4485-92, 2002.  [PUBMED Abstract]
    
    
44. Nordin K, Lidén A, Hansson M, et al.: Coping style, psychological distress, risk perception, and satisfaction in subjects attending genetic counselling for hereditary cancer. J Med Genet 39 (9): 689-94, 2002.  [PUBMED Abstract]
    
    
45. Klemp JR, O'Dea A, Chamberlain C, et al.: Patient satisfaction of BRCA1/2 genetic testing by women at high risk for breast cancer participating in a prevention trial. Fam Cancer 4 (4): 279-84, 2005.  [PUBMED Abstract]
    
    
46. Bober SL, Hoke LA, Duda RB, et al.: Recommendation recall and satisfaction after attending breast/ovarian cancer risk counseling. J Genet Couns 16 (6): 755-62, 2007.  [PUBMED Abstract]
    
    
47. Tercyak KP, Demarco TA, Mars BD, et al.: Women's satisfaction with genetic counseling for hereditary breast-ovarian cancer: psychological aspects. Am J Med Genet A 131 (1): 36-41, 2004.  [PUBMED Abstract]
    
    
48. Braithwaite D, Emery J, Walter F, et al.: Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis. J Natl Cancer Inst 96 (2): 122-33, 2004.  [PUBMED Abstract]
    
    
49. Vos J, Otten W, van Asperen C, et al.: The counsellees' view of an unclassified variant in BRCA1/2: recall, interpretation, and impact on life. Psychooncology 17 (8): 822-30, 2008.  [PUBMED Abstract]
    
    

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Components of the Risk Assessment Process

This section provides an overview of critical elements in the cancer risk assessment process.

A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available, such as the National Cancer Network Practice Guidelines for Genetic/Familial High Risk Assessment: Breast and Ovarian Cancer.[1-7] Except where noted, the discussion below is based on these guidelines.

The cancer risk assessment and counseling process, which may vary among providers, requires one or more consultative sessions and generally includes the following:

• A detailed, multifaceted assessment.
• A determination of the risk of cancer and/or indication for genetic testing based on evidence of an inherited cancer syndrome.
• Education and counseling.
• Establishment of a cancer risk management plan.

At the outset of the initial counseling session, eliciting and addressing the consultand's perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues, and guides the focus of counseling and strategies for risk assessment.

The counseling process that takes place as part of cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing, and can identify potential psychological issues that may need to be addressed during or beyond the session. Information collected before and/or during the session may include the following:

• Motivations for seeking cancer risk assessment.
• Beliefs about the causes of cancer.
• Experiences with cancer and feelings, perceptions, concerns, or fears related to those experiences.
• The influence of cancer experiences and perceptions on health behaviors and cancer screening practices.
• Cultural, religious, and socioeconomic background.
• General psychological issues, such as depression or anxiety.
• Coping mechanisms.
• Support systems.

Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether the individual's expectations of counseling are realistic and whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status. In some cases, referral for psychotherapeutic treatment may be recommended prior to or in lieu of testing.[8]

One study has shown that the addition of a colored ecogenetic relationship map (CEGRM) to the psychosocial assessment is feasible for assessing the social milieu in which an individual resides.[9] The CEGRM is a psychosocial assessment tool that expands the family pedigree to include a family systems genogram and ecomap.[10]

The communication of risk involves the delivery of quantitative information regarding what the data indicate about the likelihood of developing illness given various preventive actions. More broadly, however, risk communication is an interactive process regarding the individual’s knowledge, beliefs, emotions, and behaviors associated with risk, as well as the risk message conveyed. Accordingly, the goal of risk communication may impact the individual’s knowledge of risk factors, risk likelihoods, potential consequences of risk, and the benefits and drawbacks of preventive actions.

Even before the provision of risk information, the provider may anticipate that the individual already has some sense of his or her own risk of cancer. The individual may have derived this information from multiple sources, including physicians, family members and the media.[11] This information may be more salient or emotional if a family member has recently died from cancer, or if there is a new family diagnosis.[12,13] Additionally, individuals may have beliefs about how genetic susceptibility works in their family.[14,15] The social-ecological context through which risk beliefs develop and are maintained are important as potential moderators of individuals’ receptivity to the cancer risk communication process, and also represent the context in which individuals will return to continue ongoing decision-making about how to manage their risk.[16,17] As such, individuals’ beliefs, and the social context of risk, are important to discuss in education and genetic risk counseling.

Perceived risk can play an important role in an individual’s decision to participate in counseling,[18] despite the fact that perceived risk often varies substantially from statistical risk estimates.[19-21]

Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:

• Current age.
• Race and ethnicity.
• History of benign or malignant tumors, surgeries, biopsies, major illnesses, medications, and reproductive history (for women, this includes age at menarche, parity, age at first live birth, age at menopause, and history of exogenous hormone use).
• Environmental exposures.
• Diet and exercise practices.
• Past and current alcohol intake and tobacco use.
• Screening practices and date of last screening exams, including imaging and/or physical examinations to identify any problems with compliance.[4,6]

For consultands with a history of cancer, additional information collected includes the following:

• Site of primary tumor.
• Age at diagnosis.
• Tumor pathology.
• Treatment (surgery, chemotherapy, radiation therapy).
• Bilaterality of disease, if applicable.
• Current surveillance plan.[4]

In some cases a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and lymph node exam on a woman undergoing a breast cancer risk assessment.

The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both have been found to result in equivalent information in a study that utilized a sample (n = 104) that varied widely in educational attainment.[22] Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.[23] Factors suggesting inherited cancer risk were previously discussed.

Standards of pedigree nomenclature have been established.[23] Refer to Figure 1 for common pedigree symbols.

Enlarge

Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.

Documentation of a family cancer history typically includes the following:

• A minimum of three generations of relatives on both the maternal and paternal sides of the family. Information on multiple generations helps to demonstrate inheritance patterns. Hereditary cancer can be inherited from either the maternal or paternal side of the family, and is often an adult-onset disease.
• Race, ancestry, and ethnicity of all grandparents. This may influence decisions about genetic testing because specific mutations in some genes are known to occur with increased frequency in some populations (founder effect).
• Information about seemingly unrelated conditions, such as birth defects, atypical skin bumps, or other nonmalignant conditions of children and adults that may aid in the diagnosis of a cancer susceptibility syndrome.
• Notation of adoption, nonpaternity, consanguinity, and use of assisted reproductive technology (e.g., donor egg or sperm), when available.

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, grandchildren).
• Third-degree relatives (e.g., first cousins, great aunts, and great uncles).
• Additional distant relatives are included if information is available, especially when there are known cancer histories among them.

For any relative with cancer, collect the following information:[24]

• Primary site of each cancer, with supportive documentation of key cancers to confirm primary site and histology (e.g., pathology reports, clinical documents, death certificates).
• Age at diagnosis for each primary cancer.
• Where the relative was diagnosed and/or treated.
• History of surgery or treatments that may have reduced the risk of cancer. For example, bilateral salpingo-oophorectomy in a premenopausal woman significantly reduces the risk of ovarian and breast cancers. This may mask underlying hereditary predisposition to these cancers since breast and ovarian cancer risk is substantially reduced following prophylactic surgery.
• Current age (if the individual is living).
• Age at death and cause of death (if the individual is deceased).
• Carcinogenic exposures (e.g., tobacco use, radiation exposure).
• Other significant health problems.

For relatives not affected with cancer, collect the following information:

• Current age or age at death.
• Cause of death (if deceased).
• History of any surgeries or treatments that may have reduced the risk of cancer.
• Cancer screening practices.
• Any nonmalignant features associated with the syndrome in question.
• Carcinogenic exposures.
• Other significant health problems.

The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting and interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. However, people often have incomplete or inaccurate information about the cancer history in their family.[23-29] Accuracy may also vary by site of cancer or degree of relatedness.[30] A 2004 review suggests that reporting of cancer family histories may be most accurate for breast cancer and less accurate for gynecologic malignancies.[31] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[28,31,32] It is important to confirm the primary site of cancers in the family that will effect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks, especially if decisions such as risk-reducing surgery will be based on family history.[32] The most reliable documentation of cancer etiology and histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates.

It is also important to consider limited, missing or questionable information when reviewing a pedigree for cancer risk assessment. It is more difficult to identify features of hereditary disease in families with a truncated family structure due to loss of contact with relatives, small family size, deaths at an early age from unrelated conditions, or when there are few family members of the at-risk sex in a syndrome with primarily male or female specific disease manifestations such as prostate or ovarian cancer (e.g., few female members in a family at risk for hereditary breast and ovarian cancer syndrome). In addition, information collected on risk-reducing surgical procedures, such as oophorectomy, could significantly change prior probability estimation and the constellation of cancers observed in a family.[33] Other factors to clarify and document whenever possible are adoptions, use of donor egg or sperm, consanguinity, and uncertain paternity.

Additionally, family histories are dynamic. The occurrence of additional cancers may alter the likelihood of a hereditary predisposition to cancer, and consideration of differential diagnoses or empiric cancer risk estimates may change if additional cancers arise in the family. It is important to advise the consultand to take note of, confirm, and report cancer diagnoses or other pertinent family health history that occurs after completion of the initial risk assessment process. This is especially important if genetic testing was not performed or was uninformative.

Finally, the process of taking the family history has a psychosocial dimension. Discussing and documenting discrete aspects of family relationships and health brings the family into the session symbolically, 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 by the consultand 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 the following 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 could make this family history difficult to interpret?
4. What is the most likely mode of inheritance, regardless of whether a syndrome diagnosis can be established?
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 is raised by the following:

   • Multiple cancers in close relatives, particularly in multiple generations.
   • Early age of cancer onset (younger than age 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.

   Clinical characteristics associated with distinctive risk ranges for different cancer genetic syndromes have been clarified by the Society of Gynecologic Oncologists Education Committee.[34]

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 [35-37] and a concise review.[38] 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 (also called hereditary nonpolyposis colorectal cancer [HNPCC]) 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 could make the family history difficult to interpret?

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

   • Small family size.
   • Deaths at particularly early ages.
   • Removal of the 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).
4. 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.[39-41]

   Most commonly, Mendelian inheritance is established by a combination of clinical diagnosis with a compatible, but not in itself conclusive, pedigree pattern.[42] 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, 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 #3).
     • 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 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 clear-cut 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.
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