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© 2003 American Society for Clinical Oncology Bilateral Prophylactic Oophorectomy and Ovarian Cancer Screening Following BRCA1/BRCA2 Mutation Testing
From the Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC; and the Department of Psychiatry, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA. Address reprint requests to Marc D. Schwartz, PhD, Georgetown University School of Medicine, 2233 Wisconsin Ave NW, Suite 317, Washington, DC 20007; e-mail: schwartm{at}georgetown.edu.
Purpose: Despite the widespread availability of genetic testing for BRCA1/BRCA2 mutations, little is known about the impact of testing on ovarian cancer prevention and screening. For mutation testing to effect cancer mortality, positive test results must be followed by appropriate behavior change. In this study, we prospectively examined the impact of BRCA1/2 testing on the utilization of prophylactic oophorectomy and ovarian cancer screening. Participants and Methods: Participants were 289 high-risk women who underwent genetic counseling and testing for alterations in the BRCA1/2 genes. We measured self-reported receipt of bilateral prophylactic oophorectomy (BPO) and utilization of CA-125 and transvaginal ultrasound (TVU) in the year following testing, and examined the impact of test results on these outcomes. In addition, we examined the role of sociodemographic, medical, family history, and psychological variables on the receipt of BPO, CA-125, and TVU. Results: Twenty-seven percent of mutation carriers, 5% of uninformative patients, and 2% of noncarriers received a BPO in the year following testing. In addition to test results, perceived risk for ovarian cancer and family history of ovarian cancer independently predicted receipt of BPO. The receipt of a positive test result was associated with increased utilization of CA-125 and TVU. Additional predictors included perceived risk for ovarian cancer (both CA-125 and TVU) and state anxiety (CA-125). Conclusion: These results demonstrate the significant behavioral impact of receiving a positive BRCA1/2 test result. The increased rate of oophorectomy among mutation carriers suggests that testing for BRCA1/2 mutations may ultimately impact ovarian cancer mortality.
WOMEN WHO carry a BRCA1 mutation have a 15% to 60% risk of developing ovarian cancer.1–4 Although the risk for BRCA2 carriers is lower (15% to 25%), it remains significantly elevated compared to noncarriers.2,4 Given their elevated risk, BRCA1/2 mutation carriers are advised to strongly consider bilateral prophylactic oophorectomy (BPO).5,6 Recent studies among carriers have demonstrated an 85% to 96% ovarian cancer risk reduction and a 50% breast cancer risk reduction for BPO.7–9 Decision analytic studies suggest an increased life expectancy of 2.6 to 9.5 years for carriers who choose BPO.10–13 Although BPO is the most effective approach to reducing ovarian cancer risk, it is an unacceptable option for some carriers.14–16 Although of unproven efficacy,17–19 CA-125 and TVU screening every 6 to 12 months beginning at age 25 to 35 years are recommended for carriers who decide against BPO.17,20 Despite these clear management guidelines, there are limited data regarding the impact of receiving BRCA1/2 test results on the adoption of BPO and ovarian cancer screening. In clinic-based reports, 58% to 60% of mutation carriers obtained a BPO following testing.7,21 However, rates of BPO among women who received negative or uninformative test results were not reported. Similarly, ovarian cancer screening rates following BRCA1/2 testing are not clear. A single study of women recruited from a hereditary cancer registry found no effect of test results on screening rates.22 This is consistent with studies that have found no increase in mammography rates following a positive BRCA1/2 test result.22,23 For BRCA1/2 testing to reach its potential to reduce cancer mortality and morbidity, receipt of a positive test result must be followed by the adoption of appropriate prevention or surveillance behaviors. To date, there is little evidence to suggest that this occurs. This report is the first to compare the impact of positive, negative, and uninformative test results on BPO and ovarian cancer screening rates in a clinic-based research sample. We predicted that women who received positive test results would exhibit higher rates of BPO, CA-125, and TVU utilization compared with women who received negative or uninformative test results. We were also interested in identifying precounseling predictors of subsequent BPO, CA-125, and TVU utilization. Current theories of health behavior, such as self-regulation theory,24 posit central roles for both cognitive (eg, perceived risk) and affective (eg, distress) factors in the adoption of health-protective behaviors in the face of a health threat. Thus, as applied to the current study, and consistent with our previous research,25 we expected perceived risk and psychological distress to be associated with higher utilization of BPO, CA-125, and TVU.
Study Population This study was approved by the institutional review board at Georgetown University. Participants were 289 women  25 years of age who had received free genetic counseling and testing through Lombardi Cancer Center’s Cancer Assessment and Risk Evaluation (CARE) program from 1995 to 2000. Eligibility criteria for the CARE program have been described elsewhere.26,27 Women with a history of ovarian cancer (n = 71), therapeutic oophorectomy (n = 186), or prophylactic oophorectomy (n = 55) were excluded. Women with a previous diagnosis of breast cancer remained eligible. Of 362 eligible women, 73 were dropped for missing data (n = 18) or failure to complete the 12-months follow-up (n = 55). Our final sample size of 289 represents 79% of eligible women.
Procedures Probands received either positive (ie, deleterious mutation detected) or uninformative test results. If testing in a proband did not reveal a deleterious mutation, this result was considered uninformative, given that current methods of BRCA1/2 testing do not detect all BRCA1/2 mutations, and other unidentified genes may be responsible for the cancers seen in their families. Among relatives of probands found to carry a deleterious mutation, a positive result indicated the presence of the known mutation. A negative result indicated the absence of the mutation known to be segregating in their family. Consistent with current guidelines, carriers were strongly advised to consider BPO and to obtain CA-125 and TVU every 6 to 12 months beginning at age 25 to 35 years. Probands who received uninformative results were advised that they may still be at increased risk for ovarian cancer (particularly if they have a family history of ovarian cancer) and should therefore consider options for surveillance and possible risk reduction.28 Relatives who received a definitive negative result were reassured that their cancer risks returned to the level of the general population, and were informed that ovarian cancer screening is not recommended for the general population. Structured telephone interviews were conducted at 1, 6, and 12 months postdisclosure to assess ovarian cancer screening and BPO as well as behavioral and psychosocial outcomes that are reported elsewhere.23,26
Measures Perceived risk. At each assessment, we measured perceived risk for breast and ovarian cancer with two Likert-style items that we have employed in previous studies29: "In your opinion, compared to other women your age, what are your chances of getting breast/ovarian cancer?" (1 = much lower to 5 = much higher). For analysis, both measures were dichotomized to compare patients who rated their risk as much higher/higher versus the same/lower/much lower.
Distress.
We measured cancer-specific distress with the 15-item Impact of Events Scale (IES).30 The IES has two subscales that measure intrusive and avoidant ideation. We used the total IES score ( Test results. Results were classified as "positive" if a deleterious mutation was identified; "uninformative" if a deleterious mutation was not detected in a proband (the uninformative group in this sample included 26 Ashkenazi Jewish women with breast cancer, but who had no additional family history. Failure to detect a mutation in these individuals, though not definitive, may be considered somewhat informative. However, analyses conducted with and without these individuals did not substantively differ. Thus, we chose to include these individuals in this report); and "true-negative" if an individual was found not to carry the mutation known to be segregating in the family. Ovarian cancer screening and prophylactic oophorectomy. Participants who reported BPO at any follow-up were classified as having a BPO (n = 31). Among participants who did not obtain a BPO (n = 258), those who reported a screening CA-125 were classified as utilizing CA-125, and those who reported a screening TVU were classified as receiving a TVU.
Data Analysis
Sample Characteristics The mean age of the sample was 47 years (standard deviation [SD], 11 years). The majority of participants were white (94%), married (78%), employed (55%), and college-educated (77%). Twenty-two percent had two or more first-degree relatives with breast or ovarian cancer, and 70% were themselves affected with breast cancer. Seventy-nine participants (27%) received positive test results, 44 participants (15%) received negative test results, and 166 participants (57%) received uninformative test results.
Compared with individuals who completed all follow-up assessments, those who dropped out of the study (n = 73) were: older (mean age, 50 years [SD, 10.6 years] v 47 years [SD, 11.5], respectively; t = 2.3, P = .02), less likely to have a BRCA1/2 mutation (14% v 27%;
Prophylactic Surgery
In multivariate modeling, all variables with significant bivariate association with BPO were included in a logistic regression with backward variable deletion. We treated test results as a four-level variable (BRCA1+, BRCA2+, uninformative, negative), with the BRCA1+ group serving as the referent. In the final model (Table 3  ), negative participants (OR, 0.03; 95% CI, 0.01 to 0.30), uninformatives (OR, 0.13; 95% CI, 0.05 to 0.32), and BRCA2 carriers (OR, 0.23; 95% CI, 0.04 to 1.2) were less likely than BRCA1 carriers to obtain a BPO. Perceived risk for ovarian cancer (OR, 11.7; 95% CI, 1.9 to 92.4) and family history of ovarian cancer (OR, 4.2; 95% CI, 1.4 to 8.1) also had independent associations with BPO. GEE modeling to adjust for familial recruitment (Table 3) yielded results virtually identical to those of the standard logistic model.
We also examined the bivariate predictors of BPO among BRCA1/2 mutation carriers. Test result (BRCA1 v BRCA2;  21 = 5.32 [n = 79]; P = .02), older age (21 = 4.9 [n = 79]; P = .03), perceived ovarian cancer risk (21 = 8.2 [n = 79]; P = .004), family history of ovarian cancer (21 = 12.6 [n = 79]; P < .001), and ovarian cancer worries (t77 = 2.7; P = .01) predicted BPO. In a follow-up analysis, we tested the possibility that psychosocial variables measured at 1-month posttesting would predict subsequent use of BPO over and above the baseline variables already entered into the model. After eliminating participants who had obtained a BPO by the 1-month follow-up (n = 4), we evaluated the bivariate associations between the 1-month psychosocial variables and subsequent receipt of BPO. Patients who subsequently obtained a BPO had higher general distress score (mean, 38.7 v 34.5; t283 = 2.45; P = .02), cancer-specific distress score (mean, 25.8 v 13.9; t283 = 3.49; P < .001), and ovarian cancer worry (mean, 5.3 v 3.6; t283 = 7.2; P < .001). However, when these variables were added to the baseline model, they did not significantly (P < .05) predict the receipt of BPO.
Ovarian Cancer Screening
Bivariate predictors of CA-125 use were baseline perceived ovarian cancer risk (X21 = 5.9 [n = 258]; P = .02), previous CA-125 (S1 = 7.8 [n = 258]; P = .005), and personal history of breast cancer ( 21 = 7.1 [n = 258]; P = .008). We entered these variables into a backward logistic regression along with test results. Since BRCA1 and BRCA2 carriers did not differ in their use of CA-125 (21 = 0.34 [n = 58]; P = .58), we combined these groups. However, since test results were confounded with personal history of breast cancer (ie, all uninformative participants were affected with breast cancer), we created a composite variable to represent both test result and affected status. This composite was included in our logistic model, with affected/BRCA+ as the referent to generate the following comparisons: affected/BRCA+ versus affected/uninformative, unaffected/positive, and unaffected/BRCA-. There were no terms for affected/BRCA- or unaffected/uninformative because there were no individuals in these categories.
The final logistic model (Table 4
After eliminating participants who had obtained a CA-125 within 1 month of receipt of test results (n = 12), we evaluated the bivariate associations between the 1-month psychosocial variables and subsequent receipt of CA-125. Use of CA-125 was associated with having high perceived risk for ovarian cancer (34% v 12%; 21 = 14.9 [n = 246]; P < .001) and elevated ovarian cancer worry (mean, 4.3 v 3.6; t244 = 3.8; P < .001). When these variables were added to the baseline model displayed in Table 4 , they did not significantly predict receipt of CA-125.
Ultrasound.
TVU was reported by 40% of carriers, 29% of uninformative participants, and 21% of negative participants (
In bivariate analyses (Tables 1 and 2), baseline perceived risk for ovarian cancer (21 = 5.67 [n = 258]; P = .02), baseline perceived risk for breast cancer (21 = 3.96 [n = 258]; P = .05), baseline anxiety (t256 = 2.11; P = .04), baseline cancer-specific distress (t256 = 2.01; P = .05), and previous ultrasound (S1 = 4.95 [n = 258]; P = .03) predicted TVU utilization. These variables were included in our logistic model, along with test results. As presented in Table 5, receipt of ultrasound in the year before testing (OR, 3.83; 95% CI, 2.02 to 7.29), baseline anxiety (OR, 1.16; 95% CI, 1.01 to 1.34), perceived ovarian cancer risk (OR, 1.96; 95% CI, 1.03 to 3.74), and genetic test results remained in the final model. Compared with mutation carriers, uninformative participants (OR, 0.46; 95% CI, 0.23 to 0.92) and true-negative participants (OR, 0.30; 95% CI, 0.11 to 0.78) were less likely to receive a TVU. GEE modeling yielded identical results.
After eliminating participants who had obtained a TVU within 1-month of receipt of test results (n = 13), high perceived risk for ovarian cancer (34% v 16%; X21 = 9.6 [n = 245]; P = .002), breast cancer worry (mean, 5.1 v 4.3; t243 = 3.5; P < .001), and cancer specific distress (mean, 17.3 v 12.4; t243 = 2.1; P = .03) were associated with the receipt of TVU. Once again however, these variables did not exhibit statistically significant independent associations when added to the baseline logistic model.
This prospective study clearly demonstrates the increased use of preventive and surveillance strategies among BRCA1/2 carriers compared with women who receive negative or uninformative test results. Although long-term data on the efficacy of these strategies in reducing ovarian cancer mortality are not yet available, the adoption of these strategies by carriers may be a necessary precursor to potential morbidity and mortality reductions associated with BRCA1/2 testing. The 27% rate of BPO among carriers was significantly higher than the rates among uninformative participants and true-negative participants. However, this rate is substantially lower than the 58% to 60% reported in previous clinical samples.7,21 Although we observed participants for only 12 months, previous research suggests that the majority of BPOs are obtained soon after testing.7 Still, it is likely that additional participants will obtain BPOs in the future. Our sample was somewhat younger than previous studies, which have been limited to women older than 30 years21 or 35 years.7 Had we limited our sample to women 35 years and older, our BPO rate for carriers would have increased minimally (to 30%). Another explanation for our lower BPO rate may be that the data for this report were based on individuals who sought BRCA1/2 testing between 1995 and 2001. It is likely that more recent samples would have higher rates of BPO based on more recent findings regarding its efficacy in breast and ovarian cancer risk reduction.8,35 Finally, unlike most clinical programs, the CARE program provides free genetic counseling and testing. This may yield a sample that is less inclined to opt for BPO. Consistent with our BPO results, screening increased following a positive test result. This contrasts with previous studies that have found no increase in ovarian or breast cancer screening22 among carriers. This may be the result of the larger sample size and the use of a clinical sample in the present report. Consistent with previous reports in the general population36 and among women at increased risk for ovarian cancer,16,37 overall rates of screening remained relatively low even among carriers. Although the low rates of screening likely reflect the unproven efficacy of current approaches, it is important to note that previous reports have identified early ovarian cancers via screening among BRCA1/2 carriers.7 In addition to test result, baseline (ie, precounseling) psychosocial factors emerged as important predictors of both BPO and ovarian cancer surveillance. Surprisingly, the same psychosocial variables measured 1 month following the receipt of test results did not independently predict behavior. Given the high association between baseline scores and 1-month follow-up scores on these variables, and the association between test result and subsequent distress, it is likely that much of the variance in the 1-month psychosocial predictors was already accounted for by these antecedent variables. The association between baseline distress or perceived risk, and subsequent prevention or surveillance behavior is in line with theory that has identified cognitive and affective factors as key motivators of health-protective behavior.24 Further, these findings are consistent with research that has reported heightened distress and perceived risk among mutation carriers who opt for bilateral mastectomy,25,38 and among at-risk women who are considering BPO16 or who utilize ovarian cancer screening.39 These data support the possibility that psychosocial factors may be key motivators of BPO and ovarian cancer surveillance.40–42 Further, these results raise the possibility that patients’ pre-existing risk perceptions may influence how they interpret the risks discussed during genetic counseling. Thus, intervening to address inaccurate baseline risk perceptions could enhance the outcomes of genetic counseling and testing. Several limitations to this study should be noted. First, since our sample received free genetic counseling and testing, they may not be representative of a true clinical sample. Second, participants were observed for only 12 months following the receipt of test results. It is likely that additional women will opt for BPO in subsequent years. Third, our data on BPO and surveillance behaviors are based on self-report. Although self-reports of these behaviors are generally accurate,43 future research should confirm these reports via medical records. A fourth limitation is that we had differential drop out between baseline and the 12-month follow-up. Specifically, drop outs were more likely to be noncarriers and were less likely to have elevated perceived risk for ovarian cancer. Although it is reasonable to assume that drop outs may have been less likely to obtain a BPO or to utilize ovarian cancer screening, we cannot be sure of the rates of utilization among those who did not complete follow-up. Finally, our analyses included a relatively small number of participants who obtained a BPO, leading to wide confidence intervals in this analysis. This was particularly true of the significant effect of perceived risk on BPO utilization. Importantly however, excluding perceived risk from this analysis did not alter the final odds ratios of the remaining variables. Thus, given the potential clinical importance of perceived risk, we chose to keep it in the final model. Despite these limitations, our data clearly indicate that the receipt of a positive BRCA1/2 test result is associated with increased use of BPO, CA-125, and TVU in the year following testing. For BRCA1/2 testing to fulfill its promise in reducing ovarian cancer mortality, receipt of positive test results must translate into behavioral change. The present report suggests that this may be the case for both BPO and ovarian cancer surveillance.
The authors indicated no potential conflicts of interest.
Supported by grant No. DAMB 17-96-C-6069 from the Department of Defense, grant No. RO1 HG01846 from the National Institute for Human Genome Research, and grant No. KO7 CA65597 from the National Cancer Institute.
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23. Peshkin BN, Schwartz MD, Isaacs C, Main D, et al: Utilization of mammography in a clinically-based sample of women following BRCA1/2 testing. Cancer Epidemiol Biomarkers Prev 11:1115–1118, 2002 24. Leventhal H: Educational and behavioral processes, in Johnson M, Wallace L (eds): Stress and Medical Procedures. New York, NY, Oxford Science and Medical Publications, 1989, pp 3–35 25. Schwartz M, Lerman C, Daly M, et al: Utilization of ovarian cancer screening by women at increased risk. Cancer Epidemiol Biomarkers Prev 4:269–273, 1995[Abstract]
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30. Horowitz M, Wilner N, Alvarez W: Impact of events scale: A measure of subjective stress. Psychosom Med 41:209–218, 1979 31. Spileberger CD, Gorsuch RL, Lushene R, et al: State-Trait Anxiety Inventory for Adults: Sampler Set — Manual, Test, Scoring Key: Palo Alto, CA, Mind Garden, 1983 32. Hesbacher PT, Rickels K, Morris RJ, et al: Psychiatric illness in family practice. J Clin Psychol 41:6–10, 1980 33. Derogatis LR : SCL-90 Administration Scoring and Procedures Manual (vol 1). Baltimore, MD, Clinical Psychometrics Research, 1977 34. Schwartz MD, Taylor KL, Willard K. Prospective association of distress and mammography among women with a family history of breast cancer. J Behav Med (in press) 35. Rebbeck TR. Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 18:100–103, 2000
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39. Hallowell N, Jacobs I, Richards M, et al: Surveillance or surgery? A description of the factors that influence high risk premenopausal women’s decisions about prophylactic oophorectomy. J Med Genet 38:683–691, 2001 40. Fry A, Rush R, Busby-Earle C, et al: Deciding about prophylactic oophorectomy: What is important to women at increased risk of ovarian cancer? Prev Med 33:578–585, 2001[CrossRef][Medline] 41. Hurley KE, Miller SM, Costalas JW, et al: Anxiety/uncertainty reduction as a motivation for interest in prophylactic oophorectomy in women with a family history of ovarian cancer. J Women Health Gend Based Med 10:189–199, 2001[CrossRef][Medline] 42. Miller SM, Fang CY, Manne SL, et al: Decision making about prophylactic oophorectomy among at-risk women: Psychological influences and implications. Gynecol Oncol 75:406–412, 1999[CrossRef][Medline] 43. King ES, Rimer BK, Trock B, et al: How valid are mammography self-reports? Am J Pub Health 80:386–388, 1990 Submitted January 14, 2003; accepted August 13, 2003. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
= .88). We measured anxiety with the well-validated and highly reliable (
