2 Mutation in Individuals of Ashkenazi Jewish Descent.

P1: GXB Journal of Genetic Counseling [jgc]

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Style file version Nov 28th, 2002

C 2003) Journal of Genetic Counseling, Vol. 12, No. 4, August 2003 (°

Subjective and Objective Risks of Carrying a BRCA1/2 Mutation in Individuals of Ashkenazi Jewish Descent Kimberly Kelly,1,6 Howard Leventhal,2 Deborah Toppmeyer,3 Judy Much,3 James Dermody,4 Monica Marvin,5 Jill Baran,4 and Marvin Schwalb4

This repeated measures study examines (1) the change in subjective risk of mutations pre- to postcounseling, (2) the accuracy of BRCAPRO estimates of mutations, and (3) the discrepancy between subjective risk and BRCAPRO estimates of mutations before and after genetic counseling. Ninety-nine Ashkenazi Jewish individuals pursued testing for BRCA1/2 mutations. Most had a personal cancer history (N = 51; family only: N = 48) and received uninformative negative results (N = 66; positives: N = 23; informative negative: N = 10). The coping strategy of defensive pessimism predicts that individuals will believe the worst case scenario to better cope with a potential negative outcome. Consistent with this, most felt they would have a mutation, if not mutations in both genes. The BRCAPRO model appeared to overestimate risk of having a mutation in this sample ( p < .001). BRCAPRO overestimates notwithstanding, genetic counseling increased accuracy of subjective risk ( p < .01). Individuals with a family-only cancer history had the least accurate estimates of risk ( p < .05) and may need further intervention to either manage anxiety or improve knowledge. KEY WORDS: risk; breast cancer; hereditary cancer; genetic testing; BRCA; risk factors; decision making.

1 Department

of Behavioral Science, University of Kentucky, Lexington, Kentucky. for Health, Health Care Policy, and Aging Research, Rutgers University, New Brunswick, New Jersey. 3 Center for Human and Molecular Genetics, The New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey. 4 High Risk Clinic, Cancer Institute of New Jersey New Brunswick, New Jersey. 5 Spectrum Health, Grand Rapids, Michigan. 6 Correspondence should be directed to Kimberly Kelly, PhD, Department of Behavioral Science, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0086; e-mail: kmkell2@ uky.edu. 2 Institute

351 C 2003 National Society of Genetic Counselors, Inc. 1059-7700/03/0800-0351/1 °


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Kelly, Leventhal, Toppmeyer, Much, Dermody, Marvin, Baran, and Schwalb

INTRODUCTION Risk, the likelihood of occurrence of an event, can be estimated in two ways: (1) the individual’s perception of the probability that an event will occur (subjective risk) and (2) the actual probability that an event will occur (objective risk). Subjective risk has been proposed as a key predictor of health behavior (e.g., Becker, 1974). The provision of objective risk information is considered critical to genetic counseling (e.g., Baty et al., 1997). Discrepancies between subjective and objective risk estimates are common, and psychological studies have been designed to explain these discrepancies (Leventhal et al., 1999). The present study will focus on the discrepancy between subjective and objective risk (based primarily on Bayesian calculations) estimates of having a BRCA1/2 mutation. Specifically, the (1) subjective risk of having a BRCA1/2 mutation, (2) objective risk of having a BRCA1/2 mutation, and (3) discrepancy between subjective and objective risk estimates will be assessed before and after counseling. Objective Risk Bayes’ Theorem provides a rational model for belief updating (Bayes, 1958) and is a normative model for decision making (Baron, 1994). Given accurate probability information, an individual can choose a course of action that will maximize the expected utility of an outcome. Hence, according to normative theory, to maximize the utility of an outcome, subjective risk should match objective risk when such a choice is made. In the context of genetic screening for BRCA1/2 mutations, this means better decisions will presumably be made if subjective risk tracks objective risk of having a BRCA1/2 mutation. Current data suggests that the combined frequency of three different mutations (185delAG, 5382insC, and 6174delT) located on the BRCA1/2 genes may be as high as 2.6% in the Ashkenazi Jewish population (Roa et al., 1996). Further, the likelihood of detecting a mutation in an individual of Ashkenazi Jewish background is increased if a woman has a personal or family history of ovarian cancer at any age or breast cancer before age 50, or if a man has breast cancer at any age (Berry et al., 1997; Hall et al., 1990; Marcus et al., 1996). There is an estimated 30% chance of finding a BRCA1/2 mutation for these persons (Fitzgerald et al., 1996; Neuhausen et al., 1996; Offit et al., 1996). An individual’s objective risk of having a BRCA1/2 mutation can be computed from risk factors such as the personal history of breast cancer and the number of generations in his/her family that have been affected by breast/ovarian cancer. One of the most recent models for generating objective risk estimates for the likelihood of having a BRCA1/2 mutation is the BRCAPRO model (Berry et al., 1997; Parmigiani et al., 1998). The program uses Mendelian genetics and Bayes’ Theorem to generate these estimates on the basis of factors such as number of


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relatives with breast-ovarian cancer, age of onset, and number of relatives without breast-ovarian cancer. BRCAPRO estimates for mutation are expected to be more accurate than those generated by the Shattuck-Eidens (1997), Couch (1996), and/or Frank (1998) models because (1) it has been tested on a large, diverse sample including Ashkenazi individuals (e.g., Berry et al., 2002); (2) it uses more factors in deriving estimates (e.g., male breast cancer, age of onset of relatives with cancer, and number of generations affected); and (3) a recent paper has demonstrated its validity and sensitivity at six counseling centers (Berry et al., 2002). Further, BRCAPRO estimates are easily accessible to clinicians using the Cancer Gene Program (Euhus, 1998). However, the BRCAPRO model does not provide risk figures for computing the risk of BRCA1, BRCA2, or BRCA1/2 mutations in the Ashkenazi Jewish panel (185delAG, 5382insC, and 6174delT), and this could be a source of error for estimates in this study. In this study, four BRCA1/BRCA2 mutations (Ashkenazi Jewish panel plus 188del11) were tested. Among Ashkenazi Jewish individuals with a BRCA1/2 mutation, the likelihood of having a mutation other than these four mutations is approximately 10% (Frank et al., 1998). Thus, in the Ashkenazi Jewish population, there is a 10% chance that other, untested for mutations are responsible for cancer risk in that individual and family. The Cancer Gene Software generates a number for the risk of having a mutation if full sequencing of the BRCA1/2 genes had been conducted. Formula A estimates the posterior probability of having a mutation that has not been tested and is calculated as P (C ) × P (O/C ) [P (C) × P (O/C)] + [P (NC) × P (O/NC)] where P(C) = prior probability of being a BRCA1/2 carrier based on BRCAPRO, P(NC) = prior probability of not being a BRCA1/2 carrier (1-BRCAPRO), P(O/C) = conditional probability of being negative for Ashkenazi Jewish mutations (0.10), P(O/NC) = conditional probability of being negative for Ashkenazi Jewish mutations if not a BRCA1/2 carrier (1.0). This is the residual risk of having a BRCA1 or BRCA2 mutation, a mutation other than the four mutations tested in the study. Clearly a great deal of risk information is available to the individual who is at risk for an inherited genetic mutation, and a model such as the BRCAPRO is one of the best available predictors of the likelihood of having a mutation. However, even with knowledge of objective risk information, individuals may not believe their personal, subjective risk to be the same as their objective risk. Subjective Risk Understanding subjective risk has long been considered an important component in health behavior models for predicting and understanding health action


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(Ajzen & Fishbein, 1980; Becker, 1974). Specifically, it is presumed that perceptions of subjective risk play a key role in motivating health behaviors intended to prevent or delay disease onset and has been shown to be a factor in the decision to test (Chaliki et al., 1995) and levels of distress (Lerman et al., 1996). This is true in the context of genetic screening as choosing to screen is most often self-motivated rather than doctor-dictated (Geller et al., 1997). Protocols for genetic counseling are consistent with the emphasis on risk in behavioral models. The presentation of objective risk information in quantitative terms is widely considered critical to the genetic counseling process and has been recommended in numerous model protocols in the BRCA1/2 area (Baty et al., 1997; Lerman et al., 1997). Subjective risk estimates are expected to change as individuals receive information regarding their objective risk as they move through the sequence from pre- to postcounseling. If risk information is processed accurately, subjective risk estimates should become more consistent with objective risk estimates. An increase in the match of subjective and objective risks may not occur, however, as other psychological processes may come into play that affect attention to and interpretation of objective risk information. Research has been conducted to understand the subjective risk estimates made by individuals undergoing genetic counseling for BRCA1/2 mutations and how these estimates change over time. One study reported that the gap between subjective and objective estimates of lifetime risk of breast cancer narrowed from pre- to postcounseling (Lerman et al., 1995). However, even after extensive counseling, subjective risk of breast cancer continues to differ from estimates of actual risk (Evans et al., 1993, 1994). Studies have shown that college students tend to underestimate their likelihood of having adverse health events, a phenomenon known as “unrealistic optimism,” (Weinstein, 1983; Weinstein and Klein, 1995). However, studies conducted on women who are being tested for BRCA1/2 mutations have shown that individuals overestimate their risk of having a mutation (Bluman et al., 1999; Iglehart et al., 1998). In these studies, precounseling estimates of subjective risk were compared to objective estimates of risk generated by the BRCAPRO model and a panel of experts. Participants were found to overestimate their likelihood of having a mutation, with some giving estimates of 100%. Indeed, these overestimates of risk should not be surprising. The selfregulation theory posits that the combination of (1) believing that personal and family history of cancer are caused by a hereditary mutation plus (2) having the self-system factor of a personal or family history of cancer are likely to result in higher subjective risk of having a mutation. The self-regulation theory is a process model of how an individual responds to a health threat. The self is at the center of the self-regulation theory, and the self-system includes all of those background characteristics that are essential to perception of the health threat (Leventhal et al., 1997) such as age, family or personal history of disease, and being Ashkenazi Jewish.


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These self-system factors are interpreted by two parallel and interacting representations, the cognitive and affective representation of the health threat (e.g., Leventhal et al., 1983, 1984). The cognitive representation (or lay conceptualization) of a health threat (e.g., having a mutation) within the self-regulation theory includes five attributes of the health threat delineated by Leventhal et al. (1992): (1) the identity/label, (2) the time-line (e.g., acute, chronic, or cyclic), (3) the consequences (e.g., psychological, economic, social, or physical), (4) the causes (e.g., inheritance or age), and (5) the cure/control (e.g., surgery or medicine). Although all of these factors are believed to be important to the estimation of subjective risk, the cause of personal or family history of cancer is believed to be particularly salient for Ashkenazi Jewish individuals with a family or personal history of cancer who are at risk to carry hereditary mutations in BRCA1/2 genes, and thus this feeling of “Self as At-Risk” (cause + self-system factor) will drive overestimates of subjective risk of having a mutation. The impact of family history versus personal history should be explored in relation to estimates of subjective risk. These overestimates of risk are further expected by the coping strategy known as “defensive pessimism,” (Cantor and Norem, 1989; Norem and Cantor, 1986; Showers, 1992), first illustrated in studies of college students before examinations. Some students believed that they would perform poorly, and this was found to manage their feelings of anxiety. In fact, when these students were taught to be optimistic/realistic about the outcome or their pessimistic strategy was interrupted (e.g. to believe that they would perform well on the test or perform well in a social situation), their performance suffered (Norem and Cantor, 1986; Showers, 1992). Hence, individuals pursuing testing may assume that they will test positive so that (1) test results can only be better than expected, (2) a positive result will not be as shocking and distressing, and (3) coping with everyday life will not be obstructed by anxiety about the outcome of the test. This study will assess the discrepancy of subjective and objective risk estimates at two key time points (before counseling and after counseling) and includes actual test results. Hence, our design parallels that of the Iglehart et al. (1998) study, but our study includes two competing models for risk (theoretical explanatory frameworks) and a close inspection of discrepancies between subjective and objective estimates of risk. In addition, we report both pre- and postcounseling estimates of subjective risk to better understand the impact of genetic counseling. We hypothesize that (1) prior to receipt of test results, the mean of these objective risk estimates should closely reflect the percentage of individuals testing positive; (2) rather than exhibit unrealistic optimism, we believe individuals will assume that they have an inherited BRCA1 or BRCA2 mutation or that they have mutations in both genes (the worst case scenario), consistent with defensive pessimism; (3) personal and family history will play a differential role in elevated risk of cancer, and (4) subjective risk of mutation and the gap between subjective


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and objective risk of mutation is expected to decline from before to after genetic counseling. METHOD Participants A total of 99 women and 13 men participated from approximately 70 families participated in a larger study, investigating the response to counseling and testing for BRCA1 and BRCA2 mutations. We report here the data on subjective and objective risk of having a mutation collected as part of this study. All participants self-identified as of Ashkenazi Jewish descent. For individuals with a family history of cancer (whether or not they had a personal history of cancer), the line of transmission was traced to an Ashkenazi Jewish grandparent. For individuals with a personal history with no family history (N = 12) at least one grandparent was of Ashkenazi Jewish descent. Additionally, participants met one of the criteria noted below. Participation was limited to the Ashkenazi Jewish population because the high prevalence of these mutations in this population made testing more feasible than in other populations. The criteria were designed to include only those individuals whose family histories were suggestive of an inherited predisposition to breast and/or ovarian cancer. This increased the probability of finding a BRCA1 or BRCA2 mutation. Personal History Women with a previous diagnosis of cancer were eligible if (1) their breast cancer was diagnosed before the age of 50; (2) they had breast cancer at any age and had at least one first- or second-degree relative with either breast cancer diagnosed before the age of 50 or ovarian cancer at any age; or (3) they had been diagnosed with ovarian cancer at any age. Men with breast cancer were eligible regardless of their age at diagnosis. Family History But No Personal History Men and women were eligible if they (1) had one first-degree relative with breast cancer before the age of 50, ovarian cancer at any age, and another first- or second-degree relative with breast cancer before the age of 60 or ovarian cancer at any age; (2) had both a paternal second-degree relative with breast cancer before the age of 50 or ovarian cancer at any age and a paternal second-degree relative with breast cancer before the age of 60 or ovarian cancer at any age; (3) were first-degree relatives of a male with breast cancer at any age; (4) were first- or second-degree relatives of an individual with a documented BRCA1 or BRCA2 mutation.


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Fig. 1. Study design

Design and Procedure The study design was repeated measures with observations at two key time points: before counseling and 1–2 days after counseling (Fig. 1). IRB approval was obtained by all participating institutions. Participants were recruited for counseling initially through newspaper articles, a television program on public television, presentations at Jewish community organizations, and breast cancer interest groups, and later through letters to local oncologists and gynecologists. Recruitment materials included eligibility criteria without providing an estimation of risk. Interested individuals contacted a board certified or board eligible genetic counselor participating in the study. An effort was then made to confirm eligibility by medical records. Before counseling, a questionnaire packet including a consent form, the baseline questionnaire, and a guide with different ways of expressing probabilities was mailed to all individuals eligible for the study. The consent form asked for their


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participation in (1) genetic counseling, (2) tape-recording of the counseling session, and (3) study assessments. Free genetic counseling and testing was offered to participants as part of the study. Participation did not require tape-recording of counseling sessions. The baseline questionnaire contained questions designed to assess dispositional characteristics, subjective risk of breast-ovarian cancer, plans to test, expectations of test results, cancer control procedures, sources of information, and beliefs about cancer and genetics. Each participant also received a one-page illustration of the different ways one could think about probabilities (e.g., pie charts, ratios, etc.). Participants could use this page to assist them in answering questions about risk information. After completing the baseline questionnaire, participants were instructed to phone the University of Medicine of New Jersey, the New Jersey Medical School to schedule a counseling session. The consent form and baseline questionnaire were returned at the counseling session. The counselor reviewed the consent form with the participant and answered questions prior to beginning the counseling session. Sessions lasted 1– 2 hr. One to two days following the counseling session, a member of the research team other than the genetic counselor conducted a telephone interview. It covered the decision to test, changes in attitudes and knowledge about genetic testing for breast cancer, and likelihood of having a mutation in BRCA1/2. The participants’ decision to proceed with testing was obtained by the genetic counselor in a subsequent phone call. If individuals opted for testing, an additional consent form was signed. Blood was drawn from all individuals electing to be tested. Testing was done by a CLIA-approved laboratory by standard methods (Tonin et al., 1996). All four mutations were tested for each individual in the study. Individuals who tested positive for a BRCA1 or BRCA2 mutation were encouraged to notify relatives so they too could consider testing. A negative result for an individual where a mutation has not been located in the family was essentially uninformative because other mutations in BRCA1, BRCA2, or other breast cancer genes may still be present. Individuals who had not been diagnosed with cancer were encouraged to be tested only after a relative with breast-ovarian cancer had been found positive for a BRCA1/2 mutation. Test results were communicated to participants by the genetic counselor in a face-to-face meeting. Implications of results for both the participant and relatives were reviewed. Subjects were encouraged to notify other at-risk family members of test results. Cancer control options were discussed and provided to the participant’s primary care physician if the participant requested. Genetic Counseling All counseling was conducted by a board certified (N = 1) or board eligible genetic counselor (N = 1), and sessions were tape-recorded to ensure consistent


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presentation of information. Counseling began with an assessment of familial and personal medical history to determine objective risk. A visual flipbook that outlined the orally presented information was used throughout the educational session. The information presented in the educational session was as follows.

Mechanisms of Cancer Inheritance: Genetics Review Terms such as DNA, chromosomes, genes, chromosome and gene pairings, dominant genes, and mutations were reviewed with illustrations. A discussion of cancer specific genetics followed. Its main points were as follows (1) all cancer is due to changes in the genetic material that allow a cell to grow and divide more than it should; (2) these changes, called genetic mutations, can be inherited or somatic (e.g., caused by environmental factors); (3) BRCA1 and BRCA2 mutations are examples of hereditary mutations that can be inherited from the father or mother; (4) other gene mutations may be involved in hereditary breast cancer; and (5) features of inherited cancer include early-onset and bilateral disease. Further, it was noted that, at the time of the study, only one person had both a BRCA1 and a BRCA2 mutation, and this individual had similar cancer risks as those with only one mutation.

Meaning of a Negative Result The difference between informative and uninformative negative gene status was explained. For those who receive a negative result and are the first in the family to be tested, other unknown and untested for mutations could be responsible for cancer in that family. For individuals who receive a negative result and whose close relative has tested positive for the BRCA1 or BRCA2 mutation (the reason for cancer has been identified in the family), their cancer risk is the same as that for the general population as they do not possess the gene responsible for elevated risk in their family, and their children are also not at risk (assuming there is no genetic risk in the spouse).

Meaning of a Positive Test Result Women who tested positive were told of their increased likelihood of breast and/or ovarian cancer. For men, the risk of breast cancer was only increased with a BRCA2 mutation. It was also clearly stated that no health care provider can tell if and when a cancer will occur given an inherited mutation. Even if a cancer does not occur in an individual with a mutation, other family members may be at risk for having the gene.


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Risks and Benefits Associated With Mutation Testing Other risks mentioned during counseling included psychological difficulties and insurance and employment discrimination. Benefits include the opportunity for individuals with positive results to develop a management program (e.g., breast cancer screening) and to inform at-risk relatives who may wish to consider gene testing and engaging in cancer control behaviors. Efficacy of Health Interventions to Reduce Risk Although a plan for cancer screening may be developed for those testing positive, the efficacy of health interventions is unknown, and no scientific data has shown that increased surveillance and regimented diet and exercise will increase survival time for those with a BRCA1 or BRCA2 mutation. An informative negative result does not mean freedom from cancer risk. The risk of cancer is at least that of the general population. For the general population, personal behavior and environmental conditions should be of concern for those at risk for somatic (e.g., environmental) cancers. Risks Associated With BRCA1 and BRCA2 Mutations A pie chart was used to illustrate 10% of breast and ovarian cancer due to inherited genes in the general population. The percentage risk of several cancers (including prostate and colon cancer but focusing on breast and ovarian cancer) with BRCA1 and BRCA2 mutations was illustrated by a graph. For example, the breast cancer risk with a BRCA1 or BRCA2 mutation may be as high as 85% but has more recently been adjusted to 60%. The ovarian cancer risk with a BRCA1 mutation may be as high as 63%. The ovarian cancer risk with a BRCA2 mutation may be as high as 25%. Measures Data was collected from medical records (e.g., cancer history), genetic counseling sessions (e.g., family history), the pre-counseling questionnaire and the postcounseling phone interview. The following measures were included in the study. Background Characteristics Before counseling, questions on a biographical data sheet asked if the participant had a personal history of cancer (Yes/No) and if so what type (Categorical). Age and gender of participant were also recorded.


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Objective Risk of Having a Mutation Pedigrees (e.g., family members, relationships of family members, cancer history, age of onset of cancer) were entered into the Cancer Gene software (Euhus, 1998). A combined risk of having a BRCA1 or BRCA2 mutation was computed. Although the BRCAPRO model can compute the risk of having a BRCA1 mutation and a risk of having a BRCA2 mutation, no models were located which corrects these numbers for testing only the Ashkenazi Jewish panel. Subjective Risk of Having a Mutation One item assessed the individual’s perceived likelihood of having one of the BRCA1 mutations [“If you proceed with testing, you will be checked for specific mutations in the BRCA 1 gene. If you had to guess about the outcome of this test, what do you think are the chances that YOU have one of these BRCA1 mutations? %”]. A second item assessed the individual’s perceived likelihood (0–100%) of having one of the BRCA2 mutations [“If you proceed with testing, you will be checked for a specific mutation in the BRCA 2 gene. If you had to guess about the outcome of this test, what do you think are the chances that YOU have %”]. These questions were asked before and after this mutation? (0–100%) genetic counseling. At the time of the study, the risk of having a BRCA1 or BRCA2 mutation was considered mutually exclusive as only one individual had been found to carry both BRCA1/2 mutations, and participants were counseled as such. Thus, these two items were added to determine the subjective risk of having a BRCA1 or BRCA2 mutation with the probability statement computed for this study as p(BRCA1) + p(BRCA2). BRCA1 and BRCA2 are now thought to be independent. If the study were conducted today with incorporating the independence of BRCA1 and 2, the probability statement would be computed as p(BRCA1) + p(BRCA2) − [ p(BRCA1) p(BRCA2)]. Test Result Two days after the postcounseling interview, the genetic counselor phoned participants to get their actual decision to test for mutations in the BRCA1 and BRCA2 genes. When test results were available, the genetic counselor phoned participants for interview. Participants who received test results were coded as (1) receiving a positive result, (2) receiving an informative negative result, or (3) receiving an uninformative negative result. Statistical Analysis Distributions, frequencies, ranges, means, and standard deviations were generated along with other indices of normality as needed to describe the sample and


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to insure the suitability of the data for parametric, statistical analysis. A priori power for a small effect size was computed for each proposed analysis (N = 99 and α = .05). A one-sample t test was computed to compare the mean of the BRCAPRO model estimates of risk of mutation to the actual number of individuals testing positive (a priori power = 85%). Paired samples t tests were conducted to test if BRCA1 and BRCA2 were seen as different at pre- and postcounseling (a priori power = 94%). Repeated measures analyses of variance were computed to determine change in risk over time. In these models, cancer history and age were considered as between-participants factors (a prior power = 97%). Further, a hierarchial regression was computed for the dependent variable of subjective risk at postcounseling with pre-counseling subjective risk, cancer history, age, and time of joining the study as predictors (a priori power = 83%). RESULTS Of the 112 individuals who presented for genetic counseling, 13 did not proceed with genetic testing, and they are not included in the following analyses. Table I includes relevant demographic data for the sample. Table I. Demographics of Individuals Testing for BRCA1/2 Mutations Percent Cancer History Prior personal cancer history Breast Ovarian Other Family history only Test result Positive (mutation present) Informative Negative Uninformative Negative Marital status Married Single, never married Divorced/separated Widowed Highest level of education Some graduate school Some college High school (12th grade) Annual family income $100,000 or greater $50,000–99,000 $20,000–49,999 $19,999 or less Agea

a Percentage

51.1 48.5 6.1 5.1 47.9 23.2 10.1 66.7 80.6 4.1 5.1 10.1 48.0 45.9 6.1 41.0 40.0 15.8 3.2 Range = 27–83 Mean = 51.2 Standard Deviation = 12.7

frequencies were not reported for age.


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Objective Risk of Having a BRCA1/2 Mutation We hypothesized that BRCAPRO models estimates should closely reflect actual test results. However, BRCAPRO model estimates of a positive test result for the BRCA1 or BRCA2 mutation were higher than the percentage of participants who tested were positive, t(98) = 74.2, p < .001. The latter percentage is more consistent with the 30% estimate from prior studies (Fitzgerald et al., 1996; Neuhausen et al., 1996; Offit et al., 1996). Subjective Risk of Having a BRCA1/2 Mutation Individuals did not perceive a difference in their subjective risk of BRCA1 and BRCA2 mutations at pre- and postcounseling (Table II). We hypothesized that subjective risk of mutation would decline from before to after genetic counseling. To determine whether counseling affected subjective risk of having a BRCA1/2 mutation, and if the effect held across cancer history, a repeated measures analysis of variance was performed for the dependent variable of subjective risk of having a mutation with the between-participants factor of cancer history (personal vs. family only). Consistent with our hypothesis, subjective risk of having a BRCA1 or BRCA2 mutation decreased over time (Table II). Subjective risk of having a mutation was not different from pre- to postcounseling as a function of personal history. Table II. Means and Standard Deviations of Risk Estimates Precounseling

BRCAPRO estimate of BRCA1 or BRCA2 BRCAPRO estimate of BRCA1 BRCAPRO estimate of BRCA2 Actual Percentage of Individuals Testing Positive Subjective Risk of BRCA1 Mutation Subjective Risk of BRCA2 Mutation Subjective Risk of BRCA1/2 Mutation Subjective Risk of BRCA1/2 Mutation with Product Term Removed Discrepancy (Subjective Risk BRCA1/2 – Objective Risk BRCA1/2) a Mean

M

SD

48.7

30.2

22.5

21.1

26.7

25.3

Postcounseling M

SD

Significance F(1, 93)

p

23a 54.2

30.0

48.6

32.0

55.1

29.1

49.3

30.4

109.3

57.9

98.6

59.7

6.68

.01

72.6

29.2

66.2

30.7

4.81

.03

60.36

64.3

49.0

63.2

6.68

.01

and standard deviation were not reported for individuals testing positive.


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Results of repeated measures analyses of BRCA1 individually at pre- and postcounseling by cancer history and BRCA2 individually at pre- and postcounseling by cancer history revealed consistent results. Further, a hierarchical regression was performed for the dependent variable of subjective risk of having a mutation at postcounseling. Predictors entered into the model were pre-counseling subjective risk of having a mutation, cancer history, age, and time of joining the study. Although the overall model was significant, R 2 = .6, F(4, 90) = 33.7, p < .001, only precounseling subjective risk of having a mutation was a predictor (r 2 = .59, β = .77). Subjective versus Objective Risk of Having a BRCA1/2 Mutation We hypothesized that individuals would assume that they have an inherited BRCA1 or BRCA2 mutation or that they have mutations in both genes. At precounseling, only approximately 10% of participants believed their risk of having a BRCA1 or BRCA2 mutation to be between 20 and 50%, a range defined by the percentage of individuals testing positive in the study (lower bound) and by the percentage likelihood of having a BRCA1 or BRCA2 mutation determined by BRCAPRO (upper bound). A majority (71.9%) of participants believed their risk of having a mutation to be greater than or equal to 100%, and of these, 8.3% of participants believed they would have mutations in both genes, as evidenced by a subjective risk estimate of 100% for BRCA1 and of 100% for BRCA2. At postcounseling, results were similar. Only 16% believed their risk of having a mutation to be between 20 and 50%, most (62.2%) participants continued to believe their risk of having a mutation to be greater than or equal to 100%, and some believed they would have mutations in both genes (6.1%). These results support our hypothesis. A repeated measures analysis of variance for the dependent variable of discrepancy between objective and subjective risks of having a mutation with the between-participant factor of cancer was performed. A main effect emerged for change in discrepancy over time (See Fig. 2). Given the decline in subjective risk of having a mutation from before to after counseling, it is not surprising that the discrepancy between objective and subjective risk of having a mutation decreased over time. There was also a main effect for cancer history such that those with a family only history of cancer had higher discrepancy than those with a personal history, family only, M = 67.4 (SD = 8.8); personal, M = 42.8 (SD = 8.7), F = 3.97, 1.93, p = .05. No interaction effect of discrepancy over time by cancer history was noted. DISCUSSION This study examined subjective and objective risks at two key time points in the genetic screening process: before counseling and 1–2 days after counseling.


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Fig. 2. Discrepancy between subjective and objective risk of having a mutation over time with cancer history: Individuals without a personal history had the highest discrepancy between objective and subjective risk of having a BRCA1/2 mutation.

The BRCAPRO model was found to overestimate risk of having a mutation in the BRCA1/2 genes for our sample. Further, individuals were found to have high subjective risk of having these mutations. Subjective risk was found to decrease after genetic counseling, with those with a personal cancer history having the most accurate subjective estimates of risk. Age and time of joining the study did not appear to influence subjective estimates of risk. Objective Risk The mean of all BRCAPRO estimates of having a mutation was 50%, but approximately 20% of participants in the study were found positive for a mutation. The discrepancy in these numbers could be accounted for by (1) an underestimate of the number of mutated genes by the testing procedure (meaning the traditional Ashkenazi panel may not account for as many of mutations in that population as previously thought, e.g., Frank et al., 1998, which is even less likely in light of Frank et al., 2002, which found a 2.2% residual risk for a mutation after testing for the Ashkenazi Jewish panel), (2) participants were of mixed Ashkenazi Jewish ancestry, or (3) an overestimate of the BRCAPRO model. These three possibilities are supported by findings from this study. First, this study only tested for four mutations in the Ashkenazi Jewish sample. It remains possible that individuals testing negative in our study may have some other mutation in the BRCA1 or BRCA2 genes. Only about one third of participants in


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the study received informative results (positive: N = 23, informative negative: N = 10). Yet, testing for these particular mutations rules out a large amount of risk of having an inherited mutation for individuals even of mixed Ashkenazi Jewish descent (Frank et al., 2002). In fact, after an individual tested negative for the four common mutations (see Formula A), individuals only had approximately a 5% risk of having a mutation. However, it is possible that other unknown mutations may account for a larger portion of mutations in the Ashkenazi Jewish population than previously expected. The BRCAPRO model may be a less effective decisionmaking tool for individuals of Ashkenazi Jewish descent at high risk. Although such individuals may receive a high numeric probability of having a mutation from BRCAPRO and may have a hereditary form of cancer, current capabilities of testing may not match estimates provided by BRCAPRO. Subjective Risk In many cases, the subjective risk of having a BRCA1 or BRCA2 mutation was above 100%. As noted previously, because only one individual was known to have mutations in both genes at the time of our study, a message that was reinforced in genetic counseling, the majority of participants should not have believed that they would have mutations in both BRCA1 and BRCA2. Most participants felt they would definitely have one or the other mutation, and some believed that, in spite of the information given in counseling to the contrary, that they would have mutations in both genes. Even when the product term was removed from the equation { p(BRCA1) + p(BRCA2) − [ p(BRCA1) p(BRCA2)]}, subjective risk estimates continued to be elevated (Table II). These elevated levels of subjective risk may be of concern as individuals may engage in inappropriate health behaviors based on excessive levels of subjective risk of having a mutation. These findings support and extend the concept of “Self as At-Risk” from the self-regulation theory and the coping strategy of defensive pessimism to the field of subjective risk of having a BRCA1/2 mutation. Individuals may tell themselves that they will have the worst case scenario (two mutations) to prepare themselves for test results revealing that they have a mutation. Further, the perception of “Self as At-Risk” may be difficult to assuage in spite of education to the contrary. These findings do not support unrealistic optimism in this population. Hence, individuals seem to be looking to factors other than objective risk when making their estimates of subjective risk of having a mutation. Perceived accuracy of the test, fatalism, and other factors within the self-regulation theory could play a role in subjective risk estimates, such as negative affect. An important caveat should be noted about the dependent measure: the subjective risk of having a mutation. When individuals were asked for their risk of having a mutation in BRCA1 and BRCA2 individually, did participants really think in terms of the additivity of their responses? Or when asked about the probability


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of having a BRCA2 mutation, did they think in terms of their probability of having both a BRCA1 and a BRCA2 mutation? During interviews, participants were made aware that they should consider these probabilities separately. However, even when considered separately, individuals overestimated their risk. Future study could elucidate if individuals respond differentially to the question about mutation status dependent on whether all mutations are asked together or whether BRCA1 and BRCA2 mutations are asked separately. Objective Risk vs. Subjective Risk The discrepancy between objective and subjective risk decreased over time. However, individuals in the study drastically overestimated their risk of having a mutation, even after genetic counseling. Individuals with a prior history of cancer, the more accurate group, continued to overestimate their risk by a mean difference of approximately 40%. Although cancer history did not appear to play a role in subjective risk of having a mutation, it was related to discrepancy between subjective and objective risk. This result appeared because BRCAPRO estimates of genetic risk were higher for individuals with a personal cancer history (M = 62% at risk for BRCA1/2) than for individuals with no prior history of cancer (M = 35% at risk for BRCA1/2, p < .001). Hence, the difference between objective estimates of risk of mutation and the upper limit of the scale is greater for an individual with no prior history of cancer than for an individual with a personal history of cancer. This difference could make it more likely that an individual with no prior cancer would overestimate risk of having a mutation. Anecdotally from reviews of tape-recorded counseling sessions and notations from phone interviews, individuals often believed that they had at least one mutation, if not two, in spite of much genetic counseling to the contrary. And this belief was more problematic for individuals without a personal history of cancer. In most cases, individuals without a personal history of cancer were at risk of developing breast cancer due to familial cancer on the maternal or paternal side, and seldom both. This being the case, the individual without cancer has a 50% risk, at most, of inheriting a mutation from a parent. For an individual with a prior history of cancer, the risk of having a mutation can be much higher. These findings indicate that individuals’ subjective risk estimates were discrepant with actual test results of having a BRCA1 or BRCA2 mutation. Further, BRCAPRO estimates of objective risk were also discrepant with actual test results. Yet, if individuals’ subjective risk estimates were closer to BRCAPRO objective risk estimates, subjective risk estimates would be more accurate. A key question emerges in response to these findings. Given the inaccuracies of subjective risk estimates for individuals testing for these mutations: Is presenting objective risk information in genetic counseling worthwhile? This is a challenging question. A few things are clear from this study. First, available risk models may


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not be very accurate in providing objective risk information. Second, individuals improved in accuracy of subjective risk of having a mutation; although, they continued to greatly overestimate their risk. Third, the utility of risk information may be in making decisions about testing and treatment options (e.g., prophylactic surgery). It is possible that subjective and/or objective risk estimates do not need to be accurate to make a good decision about testing or engaging in other relevant health behaviors (Leventhal et al., 1999). Fourth, and consistent with the Parallel Process Model (Leventhal, 1970), gathering cognitive information, such as objective risk information, may be helpful in regulating affect: If an individual is eligible for this study but has a comparatively low risk and can alleviate distress by learning test results, receiving genetic test results could decrease distress levels. Study Limitations Certain limitations of the study should be noted. To begin, it is uncertain how accurate theoretical models of objective risk can be. Parmigiani (personal communication, 2000) cautions using such model generated estimates as objective risk. In light of Berry et al. (2002), it may be that Mendelian/Bayesian models may not be as effective as empirical models of estimating objective risk for those of Ashkenazi Jewish descent with strong family histories, although it may be helpful in predicting a hereditary form of cancer. Further even though the BRCAPRO model may have overestimated the risk of having a mutation, it was still considerably more accurate than the participants’ subjective risk of having a mutation. A second limitation to consider is the independence of data gleaned in this study. As noted in the Participants section, once one individual was found to be positive other family members were encouraged to have genetic counseling. It was often the case that two or more family members presented for the initial genetic counseling together. Hence, some individuals in the study were from families where three or more relatives tested. Relatives may have influenced other family member’s baseline (or later) estimates of subjective risk. However, retrospective correlations within and between families were similar, indicating that the data appears to be independent. A similar concern is that probands who initiated genetic counseling may have had higher levels of subjective risk than relatives participating in the study. Our data collection methodology did not allow us to address this potential limitation. However, we examined time of joining the study as a proxy measure for comparing probands and relatives, and time of joining the study did not appear to play a role in subjective risk. Also, concerns about the generalizability of the findings should be considered. The study focused on the Ashkenazi Jewish population that may have different characteristics than individuals in the general population who may be interested in


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testing. This limitation is corroborated by the high socioeconomic status (income level, education level, etc.) of participants in the study. It is unknown if other, less educated populations will experience greater knowledge gains or if the information will be too difficult to understand. Second, individuals who are interested in and volunteer for this genetic counseling research study may differ from those individuals for whom genetic screening may also be useful but who do not voluntarily pursue genetic counseling and testing (i.e., participants in the study may have higher estimates of subjective risk than those in the larger population of at-risk individuals). By studying those who volunteer, a full picture of the experience of those who are eligible for genetic screening for BRCA1/2 mutations cannot be obtained (Codori et al., 1994; Lachenmeyer, 1995). Conclusions The current genetic screening literature for BRCA1/2 mutations is in its fledgling state, and more studies are needed to investigate subjective risk in this context. A key reason for understanding subjective risk in the context of genetic screening is to improve the experience of genetic counseling and testing, providing individuals with the best tools to make necessary decisions about testing and cancer control procedures. The need for rational, normative decision making is juxtaposed with the need to manage feelings of negative affect, as in the coping strategy of defensive pessimism. We believe an understanding of the cognitive and affective processes that occur during the genetic counseling process is key to effective genetic counseling and patient decision making. Indeed, cognitive representations/lay conceptualizations of health threats are very resistant to change, especially if not directly addressed during the counseling session. Rather than take an educational approach where the consultand is seen as a passive receiver, we advocate an approach to genetic counseling, whereby the genetic counselor directly assesses the consultand’s cognitive representation of the health threat (e.g., hereditary mutation, breast cancer, and ovarian cancer), helping the individual (1) to incorporate more scientific views into their cognitive representation and (2) to regulate affect in such a way as to pursue appropriate health behaviors such as pursuing genetic testing and engaging in cancer screening.

ACKNOWLEDGMENTS The authors thank Gretchen Chapman, PhD, Michael Andrykowski, PhD, and Richard Rende, PhD, for their comments on drafts of this paper. This study was supported by grants from the New Jersey Commission on Cancer Research and the Mid-Atlantic Regional Human Genetics Network.


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