Journal of Genetic Counseling, Vol. 6, No. 2, 1997

BRCA1 Testing: Genetic Counseling Protocol Development and Counseling Issues Bonnie Jeanne Baty,1-7 Vickie L. Venne,2 Jamie McDonald,3 Robert T. Croyle,4 Corinne Halls,5 Jean E. Nash,6 and Jeffrey R. Botkin1

This article discusses the genetic counseling protocols which were developed and counseling issues that have arisen in the first 2 years of evaluating a large kindred with a BRCA1 mutation. The rationale for the development of the genetic counseling protocols and specific genetic counseling visual aids are presented and discussed. The protocols and counseling aids can serve as models for other programs offering cancer susceptibility testing. The observations of study counselors about study subject concerns and responses to genetic testing at the time of the pretest and posttest counseling sessions are presented. KEYWORDS: cancer susceptibility testing; BRCA1; genetic counseling; cancer predisposition.

INTRODUCTION The first breast cancer predisposition gene (BRCA1) was located to chromosome 17q in 1990 (Hall et al., 1990) and cloned in 1994 (Miki et al., 1994). BRCA1 is a large tumor suppressor gene with 22 exons, and more than 100 mutations have been identified. Mutation analysis is possible in high risk families, but not yet feasible in the general population. Data 1

Department of Pediatrics, University of Utah, Salt Lake City, Utah. Cancer Institute, University of Utah, Salt Lake City, Utah. Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah. 4 Department of Psychology, University of Utah, Salt Lake City, Utah. 5 Department of Psychiatry, University of Utah, Salt Lake City, Utah. 6 Department of Human Genetics, University of Utah, Salt Lake City, Utah. 7 Correspondence should be direct to Bonnie Jeanne Baty, Department of Pediatrics, Room MREB 413, University of Utah Health Sciences Center, Salt Lake City, Utah 84112. 2 Huntsman 3

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from the Breast Cancer Linkage Consortium (BCLC) showed that breast, ovarian, prostate, and colorectal cancers are significantly elevated in BRCA1 families (Ford et al., 1994). The development of techniques for locating and isolating cancer predisposition genes has paved the way for a new area of counseling and testing. This development brings together the two previously separate specialties of oncology and genetic counseling. These two disciplines have been radically changed by new information about cancer predisposition genes and by the possibility of widespread information transfer from research to clinical practice. Liaisons are being forged between genetic, oncological, and mental health care practitioners to provide clinical genetic counseling and testing, to date mostly in research settings. Protocols continue to be developed in many different institutions involved in research and clinical service. Several publications have described cancer risk counseling in general (Kelly, 1991; King et al., 1993; Hoskins et al., 1995; Peters and Stopfer, 1996; Schneider, 1994) and cancer risk counseling and testing protocols (Biesecker et al., 1993; Peters, 1992; Richards et al., 1995), and these articles provide much information about the important issues encountered in the counseling process. The counseling protocols discussed in this article were developed as part of the BRCA1 Counseling and Information Project (BCIP) being conducted at the University of Utah Health Sciences Center (Botkin et al., 1996). This article will present the development of these counseling protocols and discuss important counseling issues that have been identified by three genetic counselors who have counseled the first 175 subjects in the study. This information can help health professionals develop their own cancer predisposition testing protocols.

DESCRIPTION OF BRCA1 COUNSELING AND INFORMATION PROJECT The BCIP involves one large kindred (K2082) descended from Utah pioneers with an identified mutation of the BRCA1 gene (C—>T at codon 1313 resulting in Gln-»Stop) (Goldgar et al., 1994; Miki et al, 1994). Sixtytwo cases of breast and/or ovarian cancer have been identified in descendants of a male born in 1812 and his two wives. The BCIP offers counseling and testing for this mutation to 800 adult men and women in K2082 who are at risk to have this specific BRCA1 mutation. The individual a priori risks vary from 12% to 50%, since some subjects have a parent who has the mutation and other subjects are direct descendants of the progenitor

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through deceased ancestors. The overall study goals are to evaluate subjects who are offered genetic testing to identify changes in psychological distress, cancer-related attitudes and beliefs, health-related behaviors, and family and social environments. This paper will focus on the genetic counseling protocols and counseling issues identified by study counselors. The study protocol has been previously described (Botkin et al, 1996). As of August 13, 1996, 720 contact letters were sent and 588 responses were received (82%). Of these, 466 (79% of those who responded; 65% of those sent letters) expressed interest in participating (seven for interviews only, without genetic counseling and testing). Of those participating, 268 (58%) are females and 197 (42%) are males (one is unknown). The first genetic counseling visit has been completed by 229 subjects (60% females and 40% males) and 175 subjects (60% females and 40% males) have received results. Of those who received results, 44 females and 23 males have the family specific mutation; 61 females and 47 males do not. Two subjects were deferred for psychological reasons. Of the estimated 800 at-risk family members, some were not invited to participate because a parent or grandparent tested negative, and some individuals have not responded to the study invitation for the same reason. At the beginning of this study, there were 36 cases of breast cancer, 26 cases of ovarian cancer, 13 cases of prostate cancer, and nine cases of colorectal cancer known in the kindred. Eighty-four percent of the breast and ovarian cases were confirmed by cancer registry records, hospital medical records, or death certificates. Of the cases in which genotype was known through testing or could be inferred from the pedigree, 20 cases of breast cancer occurred in women with the BRCA1 mutation and four cases occurred in mutation negative women. Eighteen cases of ovarian cancer occurred in women who were mutation positive and one case in a woman who was mutation negative. During the course of the study, one new case of ovarian cancer and six new cases of prostate cancer were identified. One case involved a man who had a PSA test as a result of his first genetic counseling session and was found to have prostate cancer. The other cases were previously diagnosed, but not previously known to the study team. There are seven men with prostate cancer who have initiated participation in the study. Of these, two have the BRCA1 mutation, three do not, and two are unknown (one deceased and one decided not to be tested). The cancer risks are different in K2082 from the BCLC data as a whole, with breast cancer risks being lower and ovarian cancer risks being somewhat higher in most decades in K2082. For example, at age 60, cumulative risk for ovarian cancer was 30% in the BCLC data and 41% in K2082, while the risk for breast cancer was 54% in BCLC data and 40% in K2082. At the time this study was initiated, this kindred had accounted

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for about one in seven cases in the BCLC. An analysis of 33 families linked to BRCA1 by Easton et al. (1995) described heterogeneity in the risk for ovarian cancer. The breast and ovarian cancer risks calculated for K2082 classify it as a kindred with high ovarian cancer risk.

COUNSELING PROTOCOLS Since the genetic counseling occurs within a research study and is delivered by three different genetic counselors, we use several strategies to maintain consistency. The first strategy was to develop a checklist of information to cover in pretest and posttest counseling sessions (see Tables I and II). The second strategy is the use of fact sheets to provide background information about each type of cancer (Table III). These fact sheets can be updated, the counselors can review them to refresh their memories without reviewing a quantity of papers, and each counselor has a common set of agreed upon facts to address questions arising in counseling. A third strategy is to use letters which review the information presented in the genetic counseling sessions (Table IV). These documents, developed by the study team and reviewed by our Community Advisory Board, are sent to subjects after each counseling session to ensure that consistent written information is received by all research subjects. Counselors can alter the letters when appropriate. One reason to alter letters is when additional material is covered, for example, when the couple being counseled also has a family member with another genetic condition or a referral is being documented in writing. Another reason is when risks need to be altered, for example, for a subject with cancer. Another example of altered risks is a mutation negative subject with a sister who has breast cancer, but tests negative for the family BRCA1 mutation, leaving the subject with the risk of a first degree relative with breast cancer. A fourth reason is when an unusual plan is needed, for example, a subject whose parent has not yet received their results who is told that their result session will be scheduled after their parent's result session. In addition to letters, subjects receive a copy of the genetic testing consent form, which is separate from the initial consent form to participate in the study. The counselor's discussion of risks and benefits includes information about test accuracy, importance of correct cancer diagnoses, laboratory error rate, physical risks of blood drawing, potential problems with insurance or employment, psychological risks, and benefits of health care planning. The consent form also contains information about free counseling and medical consultation available during the study, confidentiality, options to

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Table I. BRCAl Counseling and Information Project Pretest Genetic Counseling Protocol 1. 2. 3.

Review study protocol. Answer any questions about study. Take family history from this subject's point of view. Take focused medical history, emphasizing previous cancer and risk factors for cancer. 4. Explore knowledge of breast and ovarian cancer and counsel. 5. Explore knowledge of the genetics of this breast/ovarian cancer susceptibility gene and counsel. Include colon and prostate cancer. Explain concept that some cancers in family are not due to BRCAl. Include differences between susceptibility and actual disease. 6. Explore knowledge of DNA testing and counsel. Cover linkage and direct testing. 7. Explore knowledge of cancer screening and counsel. Explain benefits and limitations of available screening and prophylactic surgery. Explore current cancer screening involvement. 8. Explain subject's a priori risk. Explain how testing might change their risk estimate. Explain residual risk for noncarriers. 9. Explore benefits and drawbacks of knowledge of genotype, and whether individual would like results of DNA testing. The benefits and drawbacks are listed in the consent form for DNA testing and include issues regarding psychological impact. 10. If subject does not want to participate, let them know they can recontact us for duration of study. Request participation in 1-year and 2-year interviews. Refer for cancer screening, if appropriate. If subject is undecided, make arrangements for follow-up contact when they have decided. Refer for cancer screening, if appropriate. If subject does want to participate, explain specifics of how DNA testing is done, accuracy of results and all points in the consent form. For subjects who want to participate in DNA testing 11. Determine what blood samples are needed and arrange. 12. Make arrangements for relaying results. 13. Assess who else is at risk and make preliminary recommendations. 14. Explain availability of consults with oncologist, surgeon, and psychiatrist and how to initiate visit. 15. Answer questions. 16. Arrange to obtain any necessary records from the subject and/or their relatives. 17. Arrange appointment with marriage and family counselor, if not already done. 18. Offer pamphlets. Follow up with letter reviewing counseling.

refuse to participate or withdraw from the study, and compensation for injury. Since insurance discrimination is a particular concern, we developed a list of insurance related topics which are discussed in counseling (Table V). The discussion of psychological risks includes the possibility of sadness, despair, depression, or guilt related to having the gene mutation or relatives having the gene mutation; stress from being at risk for cancer; concerns about being placed in the "caregiver" role in the future; the potential for

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Table II. BRCA1 Counseling and Information Project Posttest Genetic Counseling Protocol 1.

Give increased or decreased risk results with appropriate supportive counseling. (Remember that individuals with cancer still have a risk for other cancers.) Review probability, age specific penetrance. Discuss subject's immediate reaction. 2. Give verbal and written information about options for surveillance and recommendations for preventive measures for both carriers and noncarriers. 3. Provide referral for education about breast self-exam. 4. Explain altered risks in relatives. Make recommendations that high risk relatives be informed of availability of risk information and consider participation in the study. Explain possibilities of transmitting the gene to children. Ask permission to discuss their results with any children who have requested testing. 5. Answer questions. 6. Make follow-up/referral arrangements as requested. Through this study, a psychiatrist, oncologist, and surgeon are available for consultation. Mention tamoxifen trial. 7. Provide verbal and written information about community support groups. 8. Remind client that follow-up genetic counseling and/or individual/family counseling is available for the duration of the study, if needed. Individuals needing more than short-term individual/family therapy will be referred to a selected list of therapists in the community. 9. Explain that if significant new information is discovered in the course of the study, they could be recontacted. 10. Review the subject's plan of action, if possible. 11. Follow session with written results/counseling letter.

Table III. BRCA1 Counseling and Information Project Information Included in Cancer Fact Sheets • • • • • • • • • • • • •

Type of cancer Frequency of cancer in the general population Frequency of known mutations Percentage of cancer type that is genetic Nongenetic risk factors or protective factors Screening recommendations in the general population Screening recommendations in high risk women and men Survival rates Age-related risk of mutation positive women and men to develop cancer Mutation-specific or family-specific information Consortium data Information about the efficacy of cancer screening Risks to mutation negative persons with close relatives who are mutation negative and have cancer • Other information about the gene

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Table IV. BRCA1 Counseling and Information Project Information Included in BRCA1 Genetic Counseling Summary Letters Pretest • • • • • • • • Posttest • • •

letter Overview of BRCA1 Risk of inheriting the family-specific BRCA1 mutation Risk of developing cancer for mutation-positive and mutation-negative men and women Definition of genetic testing Advantages and risks of genetic testing Medical recommendations for high risk women or men (if subject declines testing) Information about the process of receiving test results Glossary of terms letter BRCA1 test result Personal medical recommendations Reminder about available counseling and medical consultation

Table V. Insurance Risks of Genetic Testing • • • • • • • • •

Cancellation of current insurance (health, life, and disability) Inability to obtain insurance in the future Risks may vary depending on type of policy (e.g., large group policy, small group policy, individual policy) Testing may not change risk, since risks due to family history already exist Falsifying information may lead to canceled insurance or lack of payment of claims We do not know magnitude of risks Even though study records are sequestered, insurers may get information if they ask if genetic testing has occurred or the information is given to a medical provider A negative test result may improve the ability to obtain/maintain insurance, but a negative test result could result in insurance problems for a relative Employment discrimination could result due to concerns about future job performance or the expense of future medical bills insured directly by the company

communication or relationship difficulties among relatives due to the testing; and the risk of "survivor guilt" in individuals who do not have the mutation but who have close relatives who do have the mutation. The evaluation performed by the family counselor (described in Botkin et al., 1996) is a standard psychological assessment modified to cover issues specific to BRCA1. Two subjects have been deferred for psychological reasons and in both cases the subject concurred with the decision to defer testing. One subject has never followed through with testing because her mother's results were negative. The other subject did not follow through with counseling referrals. Five other subjects were referred to community resources for counseling but were not deferred. To date, no participant has

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requested psychological counseling from our study team after genetic test results were received. The questionnaires will allow us to collect data about follow-up counseling either with our study team or with other professionals. Although the extended family history is well known to the research team, a policy decision was made not to use it or laboratory results of other family members to calculate an a priori risk for each subject prior to the first genetic counseling session. This decision was based on a desire to maintain confidentiality for each family member and the availability of direct testing for a family specific mutation (i.e., other family members' results were not necessary to give an accurate result to each subject). Therefore, the family history is obtained from the subject's perspective and includes knowledge of family members, their medical diagnoses with a focus on cancers and knowledge of which family members have been tested and their results. The a priori risk is calculated based on the information that is specifically known by the consultand. We are not aware of any subjects who declined testing based on an inaccurate risk figure, and the genetic counselors were prepared to seek permission for disclosure from appropriate relatives if such a situation occurred. One subject who was estranged from his father requested testing after his father's test was negative. After failing to obtain permission from the father to discuss his results with his son, the decision was made to offer testing to the son. Although we anticipate that most parents would reveal their test results to their adult children, we ask subjects with adult offspring to sign a release giving permission to discuss their test results should that information not be communicated or be misunderstood by adult offspring who subsequently come for genetic counseling. Occasionally we obtain permission to discuss a subject's result with adult siblings, especially if the result alters the siblings' risks of developing cancer. The most striking example for this need occurs when a woman who had breast or ovarian cancer does not have the family-specific mutation. If her sisters also do not have the family specific mutation, they still have a two- to threefold increased risk over the general population for developing breast cancer because they have a firstdegree relative with breast cancer unexplained by the family mutation. In this case, we obtain the subject's permission to discuss this issue with siblings to provide them with a more accurate risk calculation. At the beginning of the study, we used two sets of data to explain age-related risk for breast and ovarian cancer in females in K2082, one set derived from the Breast Cancer Linkage Consortium (BCLC) and the other set specific for K2082. Initially, we tried using both sets of data because both sets have shortcomings. Specifically, the consortium data include women with many different mutations, and the family specific data are based on much smaller numbers of affected individuals. However, the coun-

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selors found that using two datasets was confusing, and so we have decided to use the family-specific data, which we feel has fewer sources of bias, especially after the discovery 4 months into our study that there are many different BRCAl mutations (Shattuck-Eidens et al, 1995). The risk data are organized in two ways. The first is in tabular form (not shown), with sections for background risk for breast cancer in the general female population of Utah (Utah Cancer Registry) and risks for breast cancer, ovarian cancer, and either breast and/or ovarian cancer in women who have a BRCAl mutation. We do not have decade by decade data for the general population risk for ovarian cancer, so we use a single figure of 1% at age 70 (Utah Cancer Registry). The tables separate risk by decade, so that a risk for any number of decades from age 20 to 70 can be easily located. For example, a mutation-positive woman can be told the risk in her current decade, the risk for the following decade, or her cumulative risk. Figure 1 shows an example of the table which uses data from the BCLC. These data were published previously (Ford et al., 1994; Easton et al., 1995), but are updated for this table. Although we usually use family specific data, we present the BCLC data in this article because they are more useful to other genetic counselors. The cumulative risk data are also organized into figures which were drawn by our hospital medical illustrations department, based on the data in the tables, and utilizing the approach of Puck and Fleming (1986). These figures have greater visual impact than the tables and relay information more succinctly. The figures can also be used to discuss many issues associated with risk, such as the earliest age at which cancer was diagnosed in the family, the cancer rates compared to the general population and the comparative rates between breast and ovarian cancer. Figure 2 shows the background risk in Utah and Fig. 3 shows the risk in the BCLC data. We use family specific data in our study, but again we are presenting the more general BCLC data here. Other visual aids used by the genetic counselors include pictures of cells, chromosomes, DNA structure, transcription, translation, chromosomes, multifactorial model of cancer mutations (Cavenee and White, 1995), a schematic drawing of a stop codon inserted in a chain of amino acids, the amino acid sequence in this family (Miki et al., 1994), a photograph of a BRCAl gel, and the family specific risk tables converted to percentages. These visual aids were not consistently used by all three counselors or with every subject, but were commonly used resources. One advantage of three different genetic counselors participating in this project is that we have an opportunity to observe and learn from each other's counseling sessions. One example of this involves the semantics used to describe the word mutation. Although the word 'mutation' was defined orally

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Fig. 1. (A) Breast cancer risks (i.e., cumulative penetrance) by age in BCLC data; (B) ovarian cancer risks by age in BCLC data; (C) breast and ovarian cancer risks by age in BCLC data.

during the genetic counseling session, the letter included the phrases "having the gene" and "not having the gene" with the understanding that they meant "having the mutation" and "not having the mutation." When we recognized that this is technically incorrect, we had considerable discussion regarding the appropriateness of changing the letters as opposed to compromising the study by virtue of having subjects seen halfway through the study receive a different letter. Ultimately, the letters were reviewed and changed minimally to include the correct terminology. In addition, the various words that were used to describe the concept of mutation were discussed in detail. As a result, an additional study is being conducted to evaluate the use of the word mutation as well as some of the other variations currently used by counselors.

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Fig. 2. (A) Breast cancer risks in females (i.e., cumulative penetrance) by age in the Utah general population; (B) ovarian cancer risks in females in the Utah general population.

DISCUSSION OF PROTOCOLS This study benefits from the existence of a very large family and many well documented cases of cancer as well as a family-specific mutation. The

Fig. 3. (A) Breast cancer risks (i.e., cumulative penetrance) by age in females who have a BRCA1 mutation in BCLC data; (B) ovarian cancer risks by age in females who have a BRCA1 mutation in BCLC data; (C) breast and/or ovarian cancer risks by age in females who have a BRCA1 mutation in BCLC data.

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laboratory analysis in this family is limited to evaluation of the specific mutation rather than a sequence of the complete gene. Additional clinical and counseling activities if a family-specific mutation is not known include developing a more extensive family history with careful documentation of all known cancers in the extended family. In addition, features of known cancer syndromes must be assessed. When linkage analysis is being done, it is important to identify a mechanism for all family members to be adequately educated and counseled. With the availability of sequencing for more cancer susceptibility genes, linkage analysis will be used less frequently. In cases involving mutation analysis, it is important to obtain DNA results from affected family members first so DNA gene status information can be appropriately interpreted. We started the BCIP study with strong linkage (LOD = 8.5) to the region on chromosome 17q designated as BRCA1, and this family's mutation was identified soon after the beginning of our study. An extensive pedigree was documented and many cases of cancer in older generations in the family had been identified and confirmed, either through medical records or the Utah Cancer Registry. Therefore, our focus with respect to collecting family history information from each consultand is to concentrate on the knowledge each consultand has about his or her relatives, their cancer status, and their BRCA1 test results. Collecting that information early in the counseling session makes it easier for the counselors to maintain confidentiality among family members. Obtaining family history information also allows the counselors to establish rapport, obtain psychosocial histories about the consultand and their immediate family, and to learn more about participants' personal experiences with cancer. In addition, since the master pedigree was developed mostly from information obtained from older relatives, collecting family history information from each subject can add new data about that subject's descendants. It is notable that there is a wealth of conflicting information from various relatives. This inconsistency has been reported many times, and emphasizes the importance of carefully documenting medical histories in studies of genetic linkage or genotype/phenotype correlation. Early in the study, we developed visual aids to help explain cancer susceptibility and risk information. The figures used to explain risk (Figs. 2 and 3) seemed to have more impact than verbal information or tables. The figures enable a subject to quickly understand the relative risk of carriers and noncarriers of the familial gene mutation. This probably has both positive and negative effects. For some subjects, the visual image of risk may be more disturbing than a verbal discussion. An advantage of using the tables is the ability to look at the decade by decade risk. For instance, a 40-year-old woman may want to know her risk of developing breast cancer

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in the next decade. The three genetic counselors in this study use different combinations of visual aids. The effects of using various types of counseling aids on patient comprehension and attitude toward risk and genetic testing is an interesting topic for further study. One element of our protocol is to elicit the subject's cancer screening history. Individuals are quite variable in their compliance with and knowledge of age appropriate cancer screening. Our study does not provide direct services for cancer screening. However, individual screening practices and strategies to improve participation in cancer screening are discussed, referrals are made, and medical recommendations are provided when results are given. Cancer risk counseling should include active health promotion by the health care team. Based on previous studies (Peters, 1992; Schneider, 1994), the experience gained from developing protocols for this study and counseling individuals contemplating genetic testing for a specific BRCAl mutation, we have developed a suggested list of counseling topics for developing cancer risk counseling protocols (Table VI). Because education, counseling issues, and medical management are complex and challenging, multidisciplinary teams can provide the necessary expertise to offer comprehensive services to individuals considering cancer susceptibility testing.

DISCUSSION OF COUNSELING ISSUES During the course of counseling the first 175 subjects, many counseling issues have arisen, not all of which were anticipated. As we suspected, before genetic counseling, many subjects had inaccurate information even though many close relatives had already received accurate information in genetic counseling sessions and follow-up letters. For example, people were surprised to learn of a prostate and colon cancer risk for males with a BRCAl mutation. Many people did not realize that the BRCAl mutation does not "skip generations." Family members sometimes draw incorrect conclusions about who has a BRCAl mutation, since some individuals with cancer do not have the mutation. Many individuals are surprised, and sometimes quite dismayed, that prophylactic mastectomy and prophylactic oophorectomy are options for managing increased cancer risk. Many individuals have not thought about the psychological risks of testing and appreciate being made aware of possible psychological responses to both positive and negative BRCAl mutation status. The size of this kindred offers interesting insights which may be important when developing protocols for smaller families. K2082 is a large kindred with enough affected individuals to generate accurate family-spe-

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Table VI. Suggested Topics for BRCA1 Genetic Counseling Intake • • • •

Discussion of testing protocol and its costs Eliciting family history Documentation and review of cancers in family, including pathology reports Focused medical history, including previous cancer, risk factors for cancer, and previous cancer screening

Psychosocial assessment and intervention • Psychosocial assessment and intervention, when apprpriate (e.g., grief counseling, strengthening coping mechanisms, facilitating decision-making) • Supportive counseling • Discussion of strategies for discussing BRCA1 issues with other family members, especially offspring • Discussion of intrafamilial dynamics relating to cancer, the risk of cancer and genetic testing • Assessment of readiness for genetic testing, including protocol for deferral, when appropriate Education • Education about cancer in general, specific cancers, cancer susceptibility genes, cancer screening, and DNA testing • Discussion of specific age-related risks for cancers among male and female gene mutation carriers compared to risks in the general population • Discussion of a priori risks of being a gene mutation carrier and possible changes in risk after testing • Discussion of confidentiality, both medical, and intrafamilial • Discussion of nongenetic risk factors • Discussion of dominant inheritance and the risks to other family members, including children • Discussion of early detection and prevention options for both positive and negative results • Risks, benefits, and limitations of genetic testing, including medical, social (e.g., insurance and employment discrimination), and psychological, when results are positive and negative Testing • • • • • • •

and risk analysis Pedigree analysis to determine risks and appropriate genetic tests Obtaining informed consent Obtaining specimen and laboratory analysis Provision of genetic testing results Determination of residual risk if testing is negative Develop an individual plan of action Written counseling information

Follow-up • Active interventions to foster relevant health promotion (e.g., training in breast self-exam) • Referral to consultants (e.g., surgery, oncology, genetics, psychology, psychiatry, social work, depending on the specialty of the primary practitioner), when appropriate • Referral to other support services (e.g., support groups, prevention trials) • Long-term follow-up (medical and psychological)

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cific risks. However, these statistics differ from the BCLC combined data. Further analysis may demonstrate whether this difference is due to the small numbers of affected individuals in this family compared to BCLC data. Is the result of the 1313 C-»T mutation conferring risks different from other BRCA1 mutations? As researchers develop a better understanding of the genotype-phenotype correlations of BRCA1 mutations, genetic counselors will have more mutation-specific breast and ovarian cancer risks and have less need to extrapolate data to the smaller families. Another interesting aspect of working within such a large kindred is the variability of cancers in different branches of the family and individual experiences with cancer. The frequency of breast cancer, ovarian cancer, or both, varies in different branches of this pedigree. As individual family histories are obtained, some subjects do not report some of the cancer diagnoses or report the wrong cancer site, indicating that cancer diagnoses are not necessarily shared. Other subjects are shocked at the high risks for breast or ovarian cancers, especially if the subject is in a branch which does not contain that particular type of cancer. Additional studies to evaluate the presence of modifier genes or environmental factors which may account for these differences may yield important results for the provision of accurate genetic risk information for at-risk families. We strongly recommend that each subject bring a support person who is not at increased risk for cancer. This support person can provide emotional support, and can hear the counseling information first-hand and thus be available to discuss it with the subject. We have observed that a support person who is also at risk may be compromised in their ability to provide support for the counselee. Married subjects who come to the initial counseling session alone are sometimes disappointed that they did not bring their spouse because spouses frequently have as many concerns as the subjects. When spouses come only to results sessions, it is often evident that they need more information to understand the implications of the results for their families. Many subjects initially comment that they don't feel the need for genetic counseling, and some subjects ask to circumvent it. Often after the initial genetic counseling session, those same subjects have a better understanding of the purpose of our protocol, and many state that they now support the counseling. On the other hand, some individuals still feel strongly that the counseling is unnecessary, excessive, and/or paternalistic. Subjects are asked in the follow-up questionnaires how they feel about the role of genetic and family counseling. Females and males with BRCA1 gene mutations are not at equal risks for cancer. At the beginning of the study, we thought that women would be much more likely than men to participate since this has been observed

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in studies that reported utilization rates for Huntington disease testing (Wiggins et al., 1992; Craufurd et al., 1989). In a recently published study of BRCA1 counseling and testing, Lerman et al. (1996) found that 66% of females and 48% of males requested testing, which is very similar to our uptake. A common reason that men participate in the study is "for their children." Sometimes men participate when they do not yet have children, or have completed families with all male children, citing risks to their granddaughters as a justification. Although some males attempt to minimize the impact of cancer and cancer risk on the family, many males appear to be very concerned about illness in their female relatives, their children, and grandchildren. A few males express strong feelings of guilt about passing on the gene mutation, and some worry that their children will limit their family size because of the risk. This family is of LDS background (Church of Jesus Christ of Latter-Day Saints) with expectations for large family size. A few men express strong feelings of trauma related to deaths of female relatives. Although males also have some increased cancer risk associated with BRCA1 mutations, this is less likely to be a major concern of male subjects during either the pretest or posttest counseling sessions. Following are reasons that we think the impact of being a gene mutation carrier may differ in various age groups. Older individuals typically face fewer changes in their current medical recommendations, are more likely to have completed their families, may feel more satisfied with their quality of life, are less likely to feel cheated by the possibility of an early death, and have older children. Younger women may face greater changes in medical recommendations (e.g., earlier mammograms, more frequent examinations and tests than others their age). However, younger women may have more time to complete their family before arriving at an age that may necessitate a decision about prophylactic surgery. They may also be more hopeful that better means of cancer prevention or a cure for cancer will become available in their lifetime. Occasionally, subjects had experienced major family and/or personal dysfunction due to a relative's, typically the mother's, cancer. This usually happened when a diagnosis of cancer and death of a parent occurred during adolescence. Problems were often exacerbated by a lack of relationship building with a stepparent, especially if the surviving parent remarried soon after the spouse's death, and if the individual was not encouraged to grieve for the lost parent. There is an overwhelming concern among subjects about their children. Our protocol originally did not include a discussion of communication between parents and their minor and adult offspring regarding risks in the family, but this has turned out to be an important theme. It is helpful to ask about the subject's plans for discussing cancer risks with their offspring,

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to discuss age-appropriate communication to educate minors regarding the issues involved in the testing of family members, and to prepare children for future availability of testing. It is helpful to consider the parents' communication styles and level of openness when discussing these issues. We do not have standard recommendations in this area except to exclude testing in minor children, but we think that many parents find discussion of these issues to be helpful. Another concern involving offspring is promoting communication of parental test results. Subjects with adult children are asked if they will sign a consent for the genetic counselors to discuss parent's results with their adult children. Since the parent's results directly determine whether their offspring are at risk to inherit the gene mutation, we actively ask for parents' permission to discuss their results with their children rather than assume confidentiality. We also suggest that the parent be certain to relay their results to each of their adult children and to consider copying their result letter for each adult offspring. If the parent does not relay results to a minor child because the child is too young, we suggest that the parent consider putting a copy of their result letter into their child's home medical file. The genetic counselors on our team have often found that this type of information and medical documentation is lost when children reach adulthood. Because parents may not accurately communicate genetic information to their children, genetic counseling is available to adult offspring of parents who test negative for the family specific mutation, and we have had multiple genetic counseling sessions with individuals who requested genetic counseling although they knew their parent's test result was negative. The issue of physician-patient communication concerning genetic test results has arisen in many genetic counseling sessions. An established relationship with a health care provider can help subjects with positive test results to obtain appropriate medical surveillance. If no established relationship exists, we encourage consultation with one of the study team physicians and/or a local health care provider. Clients report varying degrees of trust in their health care providers. It has also been apparent that the expertise of primary care physicians in cancer genetics varies. Some subjects have expressed reservations about discussing their test results with their primary care provider because of concerns about potential medical management or insurance discrimination. The study outcomes will assess whom subjects inform about their genetic status. Confidentiality and privacy issues are a concern to many participants. For this study, records are kept in separate research charts and subjects are not registered in the hospital records system. Information is released only with a signed request from the subject. Since subjects receive two letters, an extensive one which reviews the pretest counseling and a second

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one which documents results and provides medical recommendations, subjects who wish to provide information to their health care provider often copy these letters themselves. The counselors do not reveal information to other family members, about test results, which relatives are participating, or when relatives' appointments are scheduled. Family members occasionally are surprised by meeting relatives in the hallway. At one point we stopped using a return address on our envelopes when a family member felt it violated his confidentiality. Confidentiality of deceased family members has been a concern in some instances. It is probably optimal to protect confidentiality whenever possible. It is difficult to ascertain when information about a deceased family member may become problematic for a living relative. However, sometimes accurate knowledge of a cancer diagnosis or a genetic test result of a relative may help a family member to better comprehend their own risk and this can be weighed against possible harm that may occur by revealing a deceased family member's status. There is also a potential for researchers or participants to coerce relatives to undergo testing or enroll in the study. Relatives may try to influence a potential subject's participation in the study or may be opinionated about medical management, such as whether a particular doctor is knowledgeable about cancer screening and prevention, or whether a relative should have prophylactic surgery. The study team has strict guidelines forbidding coercion by team members, but it is evident that coercion occasionally occurs among family members with differing viewpoints. The counselors try to reinforce the idea that different people have different needs for privacy and support, and that family communication may be improved if everyone's needs are respected. It can be challenging to discuss risks with other family members in a way that is supportive but allows feelings to be expressed. Discussion of confidentiality, privacy, the potential for coercion, and communication issues within the family are often important counseling topics. Sometimes relatives' needs conflict, which has led to ethical dilemmas as the study has progressed. Before genetic counseling was initiated, possible ethical dilemmas were discussed by the study team to try and establish protocols for anticipated problems. The study team decided that such situations would best be handled on a case by case basis. A core of 12 individuals are integrally involved with the study and meet on a biweekly basis to discuss study issues. The core group consists of a medical ethicist (also principal investigator), physicians, genetic counselors, a psychologist, a sociologist, a family counselor, coordinators, and office staff. This regular meeting provides a forum for discussing ethical dilemmas. In addition, a community advisory group was formed which can be called on for help in resolving difficult issues. The most common problem has been a conflict

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between the rights of parents and their adult offspring when a parent indicates he or she does not want to know their BRCA1 status and one or more of their adult offspring requests testing. Several of these situations have been resolved with the help of genetic counseling. In such situations, the genetic counselors inform family members who consent to counseling about BRCA1 testing why the situation poses an ethical dilemma and explore possible solutions that are acceptable to everyone. Some of the ethical dilemmas we have encountered and their resolutions will be reported in detail in a future paper. Another important issue is the distinction between education and counseling. Education is mainly a process of providing information in a manner which is accessible to the counselee. Counseling is an interactive process which incorporates past and immediate psychosocial issues into the process of information transfer. We have chosen a genetic counseling model to provide both education and counseling. Although some of the material presented can be handled using an education model, counseling is intertwined with the process of education. We feel that it is important to distinguish the need for genetic education from the need for counseling and to provide for both needs. There are inherent differences in goals and objectives in genetic counseling in a clinical and a research setting. In general, the primary goal in a research setting is to prove or disprove a specific set of hypotheses. The primary goal in a clinical setting is to provide appropriate genetic counseling to counselees. In practice, genetic counseling for an emerging test often combines both; it is clinical counseling in a research setting. This may necessitate compromises between the goals of clinical service and the goals of research. For example, in K2082, the study team is evaluating what follow-up services individuals undergoing genetic testing will seek through their own initiative. Because of this research goal, counselees are offered follow-up services, but they can choose whether to participate. Some protocols which have been considered models for testing in adult onset disease (e.g., Huntington disease predictive testing) have included follow-up services which consultands agree to participate in as a condition of testing. Because K2082 is offered optional follow-up we will be able to assess what follow-up services family members seek, but we will not be able to assess the value of follow-up services which are an expected part of a protocol. Randomized controlled trials can help to assess various counseling strategies for cancer susceptibility testing, such as the role of follow-up services. Our observations presented in this article are based on the clinical experience of the counselors who are providing genetic counseling and psychological assessment to this family. Family members also participate in a series of extensive interviews and complete questionnaires before counsel-

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ing and four times after genetic test results are received (1-2 weeks, 4 months, 1 year, and 2 years). These questionnaires explore many of the areas discussed in this article as well as many other areas. Preliminary findings based on the 1 to 2 week interviews of the first 60 women tested are reported in Croyle et al, (1996). Audiotapes of the genetic counseling sessions will be analyzed and will also provide a rich source of information. As further data become available from the questionnaires and tapes, we will be able to correlate these data with the observations of study counselors and extend our investigation to many other areas of interest.

ACKNOWLEDGMENTS

We would like to thank Debra Dutson, Linda Steele, and Lisa Coy for help with data collection, storage and analysis, and David Goldgar (Genetic Epidemiology, Department of Medical Informatics, University of Utah; now at the Unit of Genetic Epidemiology, IARC, Lyon, France) for providing the BCLC data for risk for breast and ovarian cancer in BRCA1 gene mutation carriers. We would also like to thank the many Kindred 2082 members who participated in our study and shared their experiences with study investigators. This investigation was supported by Public Health Service grants CA63681 (National Cancer Institute), HG00199 (National Center for Human Genome Research), and RR00064 (National Center for Research Resources) from the National Institutes of Health, Department of Health and Human Services.

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