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© 2002 American Society for Clinical Oncology Impact of BRCA1/BRCA2 Mutation Testing on Psychologic Distress in a Clinic-Based SampleByFrom the Department of Oncology, Georgetown University, and Lombardi Cancer Center, Washington, DC; and Department of Psychiatry, University of Pennsylvania, Philadelphia, PA. Address reprint requests to Marc D. Schwartz, PhD, Lombardi Cancer Center, Cancer Control, 2233 Wisconsin Ave, Ste 317, Washington, DC 20007; email: schwartm{at}georgetown.edu
PURPOSE: Despite the increasingly widespread availability of BRCA1 and BRCA2 genetic testing, little is known about the psychologic impact of such testing in the clinical setting. The objective of this study was to examine the long-term psychologic impact of receiving BRCA1/2 test results within a clinic-based testing program. PATIENTS AND METHODS: The participants were 279 high-risk women who underwent genetic counseling and testing for alterations in the BRCA1/2 genes. At baseline (before genetic testing) and at 6 months after the disclosure of mutation status, we measured perceived risk for breast and ovarian cancer, cancer-specific distress, and general distress. We examined the impact of the test result on each of these outcomes at the 6-month follow-up. Analyses were conducted separately for probands and their relatives who were unaffected with cancer. RESULTS: We found no effect of test result among affected probands. Among unaffected relatives, we found that participants who received definitive negative test results exhibited significant reductions in perceived risk and distress compared with participants who received positive test results. Importantly, relatives who received positive test results did not exhibit increased distress or perceived risk. CONCLUSION: These results suggest that clinic-based BRCA1/2 testing can lead to psychologic benefits for individuals who receive negative test results. At 6 months after disclosure, those who receive positive or uninformative test results do not exhibit increased psychologic distress or perceived risk.
THE BRCA1 AND BRCA2 genes are believed to account for most hereditary breast cancer (HBC) cases.1 Women with a mutation in BRCA1/2 are at 55% to 85% lifetime risk for developing breast cancer and 15% to 60% risk for developing ovarian cancer.1-4 Among women affected with breast cancer, inherited mutations in BRCA1/2 are associated with a significantly increased risk for the development of new primary cancers.4-6 As genetic counseling and testing is increasingly available to individuals with strong family histories of breast and/or ovarian cancer, it becomes important to understand the psychologic impact of receiving BRCA1/2 mutation test results. The potential adverse psychologic impact of BRCA1/2 testing has been widely considered a risk of undergoing testing.7 However, there are scarce data that address this issue. Two studies have examined the short-term psychologic impact of BRCA1/2 testing among research families. Lerman et al8 reported that 1 month after disclosure, individuals who received negative test results exhibited decreased depression and role impairment. Participants who received positive test results exhibited neither increased nor decreased distress. Similarly, Croyle et al9 found that individuals who received negative test results exhibited decreased anxiety 1 week after testing, although those who received positive test results exhibited no change in their anxiety levels. These studies suggest that, although the receipt of negative BRCA1/2 test results may be psychologically beneficial, receiving positive test results does not seem to cause increased distress. However, participants in these studies were members of a few large HBC families who were identified from hereditary cancer registries. Many of these individuals had participated in prior genetics research and were already aware that a BRCA1/2 mutation was segregating in their family. This highly selected sample may not be representative of newly ascertained patients and their family members who self-refer to clinic-based genetic counseling programs.8 To date, a single study has evaluated the psychologic outcomes of a clinic-based genetic testing program.10 This study, which focused on 41 BRCA1 and 24 p53 testing participants, found that individuals who initially underestimated the short-term negative emotional impact of receiving test results reported higher levels of psychologic distress 6 months after disclosure. In the present study, we sought to extend previous research by investigating the psychologic effects of BRCA1/BRCA2 mutation testing within the largest clinic-based sample reported to date. In the present report, we conducted separate analyses for affected probands (ie, the first family member to be tested) and their unaffected relatives. In clinic-based testing programs, it is important to distinguish between probands and their unaffected relatives because of differences in test result interpretation and clinical management issues. Because a negative test result in a proband is generally considered uninformative, we did not expect to see significant reductions in distress or perceived risk among probands. Among unaffected relatives for whom a negative test result is a true negative, we predicted that those who received a negative test result would exhibit significant reductions in perceived risk and distress relative to those who received a positive result.
Study Population This study was approved by the institutional review board at Georgetown University. Participants were 279 women  18 years of age who provided written informed consent before undergoing genetic counseling and testing. These services were offered to participants at no cost. Individuals were self-referred to the program and participated between 1995 and 1999. To be eligible and included in this analysis, probands (ie, the first individual in the family to be tested; n = 186) had to have a personal history of breast and/or ovarian cancer and a family history of these cancers that resulted in roughly a 10% or higher prior probability of harboring a mutation in BRCA1 or BRCA2.5,11,12 If a deleterious mutation in BRCA1/2 was identified, testing was extended to at-risk relatives (usually first-degree or second-degree relatives of the proband). In this analysis, 93 female relatives without a history of breast or ovarian cancer were considered.
Procedures After this initial session, participants were offered the opportunity to provide a blood sample for BRCA1/2 mutation testing. In most cases, Jewish probands were offered testing only for the three founder mutations common in that population.2 Non-Jewish probands were offered full BRCA1/2 testing. Although the methods of full testing varied, the methods used (eg, sequencing and conformation sensitive gel electrophoresis) are thought to detect most deleterious mutations in the gene; however, none of the methods is 100% sensitive.16 As is standard practice, relatives were tested only for the presence or absence of the deleterious mutation identified in their family. However, owing to the high background frequency of the founder mutations, relatives of Jewish probands were tested for all three mutations regardless of the one found in their family. When test results were available, individuals were invited to an in-person disclosure/genetic counseling session. In general, these sessions lasted approximately 1 hour and included disclosure and interpretation of test results, discussion of screening/prevention guidelines in relation to test result, implications of test result for family members, discussion of psychologic impact of test result, and re-examination of other pertinent issues from the pretest session. The vast majority of probands received one of two possible test results: positive for a deleterious mutation or uninformative (a deleterious mutation was not detected). A small number of Jewish probands without a family history of cancer participated in the study. Because a negative result in these women can be considered clinically informative, we excluded these women from the analyses reported here. Inclusion of these women did not alter the final results. Probands who received an uninformative result were told that, because this result did not rule out the possibility of HBC, they may still be at increased risk for developing breast and/or ovarian cancer and should therefore consider options for surveillance and possible risk reduction. However, in the absence of a family history of ovarian cancer, it was emphasized that the risk for developing this cancer is unclear when no deleterious mutation was found. Among unaffected relatives, a positive result indicated the presence of the mutation known to be segregating in their family. A negative result definitively indicated the absence of the mutation known to be segregating in their family. Relatives who received a definitive negative result were reassured that their cancer risks returned to the level of the general population and were instructed to follow the standard screening/prevention guidelines for the general population. All participants received an individualized written summary of test results and management guidelines as well as supplementary educational materials. For those who tested positive, the process and logistics of providing cascade testing (ie, extending testing to at-risk relatives) was explained in detail. Regardless of the test result obtained, all participants were called by the genetic counselor or nurse educator at 2 weeks after disclosure to review issues of concern to the participant, such as clarification of test result interpretation or screening options, and to provide referrals for medical or psychologic follow-up if needed or requested. Structured telephone interviews were conducted at 1 and 6 months after disclosure to assess perceived risk and psychologic distress.
In a previous report that focused solely on uptake of BRCA1/2 testing, we found that that 82% of those who self-refer to the program ultimately choose to receive BRCA1/2 test results.12 The current report focuses on psychologic outcomes of participants who received either positive (n = 78), definitive negative (n = 58), or uninformative (n = 143) test results and who completed a telephone interview 6 months after the receipt of test results. Overall, 80% of eligible participants completed the 6-month follow-up assessment. Probands who received positive test results were more likely to complete the follow-up than those who received uninformative test results (90% v 76%;
Measures Personal and family history of cancer. At baseline, we assessed personal history of cancer and whether the participant had bilateral mastectomy and/or oophorectomy. The number of first-degree and second-degree relatives (ie, mother, sisters, daughters, children, aunts, grandmothers) affected with breast and/or ovarian cancer was also ascertained. Perceived risk. We measured perceived risk for breast and ovarian cancer with two Likert-style items: "In your opinion, compared with other women your age, what are your chances of getting breast cancer?" (1, much lower; 5, much higher) and "In your opinion, compared with other women your age, what are your chances of getting ovarian cancer?" (1, much lower; 5, much higher). The measure was adapted from an item used and validated in previous studies.17 For analysis, the baseline measure of perceived breast cancer risk was dichotomized as close to the median as possible (much higher [n = 144] v higher/the same/lower/much lower [n = 103]). The measure of perceived ovarian cancer risk was also dichotomized as close to the median as possible (much higher/higher (n = 145) v the same/lower/much lower [n = 102]). Participants who had undergone either bilateral mastectomy or oophorectomy did not complete the perceived risk items. Thus, the sample size for analyses involving perceived risk (total, 247 patients) is lower than for other outcomes. Cancer-specific distress. We measured cancer-specific distress with the Impact of Events Scale (IES).18 The IES is a 15-item Likert-style scale used to assess the experience of stress for a specific life event. The IES has two subscales that measure (1) intrusive thoughts and feelings and (2) avoidance of thoughts and feelings related to the stressor (in this case having a family history of cancer). In the present study, we used the total score on the IES. Internal consistency in the present study was 0.89. General distress. We measured general distress with the short form of the Hopkins Symptom Checklist (HSCL-25).19,20 The HSCL-25 is a 25-item Likert-style scale used to assess the presence and severity of anxiety and depression symptoms present during the previous month. In the present study, we used the total score on the HSCL-25. Internal consistency in the present study was 0.88. Test result. Results were classified as positive if a deleterious, risk-conferring mutation was identified in BRCA1 or BRCA2. Results were classified as uninformative if probands tested negative for a deleterious mutation in the genes or if an ambiguous result was obtained (ie, a genetic variant of uncertain significance). In both of these cases, the possibility of HBC could not be definitively ruled out. Definitive negative results applied only to relatives who tested negative for the mutation in their family.
Data Analysis
Sample Characteristics Sample characteristics for probands and relatives are shown in Table 1. The majority of participants were white, aged 45 years and older, married, employed, and college-educated, and had annual family incomes greater than $75,000.
BRCA1/2 Test Results Of the 186 eligible probands, 23% (n = 43) received positive BRCA1/BRCA2 test results, and 77% (n = 143) received uninformative test results. Among the 93 relatives, 38% (n = 35) received positive BRCA1/BRCA2 test results, and 62% (n = 58) received definitive negative test results.
Baseline Group Differences
Psychologic Outcomes Among Probands
Mean scores on the distress outcomes for probands by study group (positive v uninformative) are displayed in Figs 3 and 4. The groups did not differ at baseline on either cancer-specific distress (t185 = 1.1; P = .29) or general distress (t185 = 0.8; P = .43). We conducted a series of ANOVAs to evaluate differences between the positive and uninformative groups on changes from baseline to 6 months after disclosure. The groups did not differ on change in cancer-specific distress (F1,184 = 0.1, P = .78) (Fig 3) or general distress (F1,184 = 0.4, P = .52) (Fig 4).
To evaluate the impact of test result on perceived risk after adjusting for potential confounders, we used logistic regression with hierarchical variable entry. On step 1, we controlled for baseline perceived risk, age, race, and number of affected first-degree relatives. On step 2, we entered the test result variable (positive v uninformative). Test result was not associated with either perceived breast cancer risk (  2 [1, n = 156] = 1.4; P > .20; odds ratio [OR], 1.8; 95% confidence interval [CI], 0.7 to 4.2) or perceived ovarian cancer risk (2 [1, n = 156] = 0.1; P > .20; OR, 1.2; 95% CI, 0.5 to 2.9). To evaluate the impact of test result on general and cancer-specific distress after adjusting for confounders, we used multiple linear regression with hierarchical variable entry. On step 1, we controlled for the baseline scores on the outcome of interest, age, race, and number of affected first-degree relatives. On step 2, we entered the test result variable (positive v uninformative). Consistent with the bivariate analyses, test result was not associated with change in cancer-specific distress (R21,180 = 0.00, ß = -.01; P = .88) or general distress (R21,180 = 0.01; ß = .08; P = .20).
Psychologic Outcomes Among Relatives The mean scores on the distress outcomes for relatives by study group (positive v negative) are displayed in Figs 3 and 4. The groups did not differ at baseline on either cancer-specific (t92 = 0.1; P = .95) or general (t92 = 0.8; P = .43) distress. We conducted ANOVAs to evaluate differences between the positive and negative groups on changes from baseline to six-months. Compared with women who received a positive test result, those who received a negative result exhibited significantly decreased cancer-specific distress (F1,91 = 5.6, P = .02) (Fig 3). Test result was unrelated to change from baseline to follow-up on general distress (F1,91 = 1.5; P = .23) (Fig 4).
To evaluate the impact of test result on perceived risk after adjusting for potential confounders, we used logistic regression with hierarchical variable entry. On step 1, we controlled for baseline perceived risk and employment status. On step 2, we entered the test result variable (positive v definitive negative). Test result was strongly associated with both perceived breast cancer risk ( We used multiple linear regression with hierarchical variable entry to evaluate the impact of test result on general and cancer-specific distress, after adjusting for potential confounders. On step 1, we controlled for the baseline scores on the outcome of interest and employment status. On step 2, we entered the test result variable (positive v negative). Compared with those who received positive results, relatives who received definitive negative results exhibited a significant decrease in cancer-specific distress (R21,89 = 0.06; ß = .26; P = .006) but not general distress (R21,89 = 0.02; ß = .14; P = .08). Unlike analyses limited to probands, analyses of unaffected relatives included multiple family members (the 93 women included in the unaffected relatives group were from 50 families, for a mean of 1.9 relatives/family). To account for the dependence of these data, we confirmed our results using generalized estimating equations. The generalized estimating equations models confirmed that receiving a negative test result led to decreased perceived breast cancer risk (OR, 35.9; 95% CI, 7.1 to 181.9), perceived ovarian cancer risk (OR, 91.0; 95% CI, 16.7 to 495.1), and cancer-specific distress (parameter estimate, 8.1, z = 3.2; P = .002). However, after accounting for familial clustering, our analysis revealed that receipt of a negative test result was also associated with significantly reduced general distress (parameter estimate, 2.2; z = 2.1; P = .04).
This prospective study extends previous research by investigating the impact of BRCA1/2 testing on perceived risk, cancer-related distress, and global distress in a cohort of HBC family members followed for 6 months after counseling. We found no evidence for adverse effects on these psychologic outcomes among affected probands or unaffected relatives. Psychologic benefits, reflected in decreases in cancer-related distress, were observed among unaffected relatives. Previous studies in members of hereditary cancer registries have generated similar results8,9; however, it was not known whether these participants were representative of women seeking counseling in a clinical setting. To date, the present study is the largest clinic-based prospective study to confirm the absence of psychologic sequelae of BRCA1/2 testing in most participants. Although increased distress does not seem to be a consequence for most individuals who receive BRCA1/BRCA2 test results, certain subgroups may be at greater risk for increased distress. A recent study of p53 and BRCA1/2 testing suggested that mutation carriers who did not expect to receive positive results reported heightened distress after result disclosure.10 Thus, preparation for the possibility of positive test results may buffer the impact of bad news for the more vulnerable subset. Another potentially vulnerable group may be members of HBC families who decline testing despite knowledge of a mutation carried by a close relative. Recent evidence suggests that those who experience precounseling distress but decline to be tested may be more vulnerable to depressive symptoms during the following 6 months.8 Although participants who received positive or uninformative test results did not experience increases in distress, they did not exhibit the substantial decreases in distress reported among relatives who received negative test results. Thus, 6 months after testing, participants who received positive or uninformative results did report higher levels of distress than participants who received negative test results. Although the clinical significance of such modestly elevated distress is not clear,21 it is likely that those who receive positive or uninformative test results could benefit from continued support. A possible area for support in this population might be medical decision making. Previous research has reported that, despite knowledge of a positive mutation status, up to one third of women do not obtain the recommended annual mammograms, and only 10% obtain recommended ovarian cancer screening tests.22 Other reports suggest that, although prophylactic mastectomy may have psychologic benefits for some,23 between 10 and 25% of women who choose prophylactic mastectomy report dissatisfaction or an adverse psychologic impact.24,25 These data suggest that interventions designed to aid in medical decision-making have the potential to serve as a valuable adjunct to BRCA1/2 testing. In sum, the present study does not provide evidence for adverse psychologic effects among women participating in clinic-based BRCA1/2 testing programs. However, caution should be exercised in interpreting these results. First, differential drop-out may have biased the results of this study. Compared with participants who received positive test results, those who received uninformative or definitive negative test results were more likely to be lost to follow-up. Thus, if participants who were lost to follow-up were less distressed than those who completed follow-up, it is possible that the present study underestimated the distress reductions associated with the receipt of negative and/or uninformative test results. Another concern centers on the homogeneity of the study sample. Our findings should be validated in more ethnically diverse populations and other primary care settings in which testing may be offered. Finally, settings that fail to provide extensive pretest and posttest genetic counseling may not yield such favorable results. Future research should focus on why knowledge of risk status may not motivate adoption of prevention and screening options.22 Until such time as preventive therapies are proven effective in mutation carriers, changes in health-related behavior will be critical to reduce morbidity and mortality from HBC.
Supported by grant no. DAMB 17-96-C-6069 from the Department of Defense, Washington, DC, grant no. RO1 CA/HG74861 from the National Cancer Institute and Institute for Human Genome Research, Rockville, MD, and grant no. KO7 CA65597 from the National Cancer Institute, Bethesda, MD.
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Horowitz M, Wilner N, Alvarez W: Impact of event scale: A measure of subjective stress. Psychosom Med 41: 209–218, 1979 19. Hesbacher PT, Rickels K, Morris RJ, et al: Psychiatric illness in family practice. J Clin Psychol 41: 6–10, 1980 20. Derogatis LR: SCL-90 Administration Scoring and Procedures Manual: I. Baltimore MD, Clinical Psychometrics Research, 1977 21. Coyne JC, Benazon NR, Gaba CG, et al: Distress and psychiatric morbidity among women from high-risk breast and ovarian cancer families. J Consult Clin Psychol 68: 864–874, 2000[CrossRef][Medline] 22. Lerman C, Hughes C, Croyle RT, et al: Prophylactic surgery decision and surveillance practices one year following BRCA1/2 testing. Prev Med 31: 75–80, 2000[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
