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. Author manuscript; available in PMC: 2013 Mar 1.
Published in final edited form as: Cancer Epidemiol Biomarkers Prev. 2012 Feb 10;21(3):445–455. doi: 10.1158/1055-9965.EPI-11-0991

Long-term psychosocial outcomes of BRCA1/BRCA2 testing: Differences across affected status and risk-reducing surgery choice

Kristi D Graves 1, Patti Vegella 1, Elizabeth A Poggi 1, Beth N Peshkin 1, Angie Tong 1, Claudine Isaacs 2, Clinton Finch 1, Scott Kelly 1, Kathryn L Taylor 1, George Luta 3, Marc D Schwartz 1
PMCID: PMC3297701  NIHMSID: NIHMS355407  PMID: 22328347

Abstract

Background

Numerous studies have documented the short-term impact of BRCA1/BRCA2 (BRCA1/2) testing; however, little research has examined the long-term impact of testing. We conducted the first long-term prospective study of psychosocial outcomes in a U.S. sample of women who had BRCA1/2 testing.

Methods

Participants were 464 women who underwent genetic testing for BRCA1/2 mutations. Prior to testing, we measured sociodemographics, clinical variables, and cancer specific and general distress. At long-term follow-up (Median=5.0 years; Range=3.4 to 9.1 years), we assessed cancer specific and genetic testing distress, perceived stress and perceived cancer risk. We evaluated the impact of BRCA1/2 test result and risk reducing surgery on long-term psychosocial outcomes.

Results

Among participants who had been affected with breast or ovarian cancer, BRCA1/2 carriers reported higher genetic testing distress (β=0.41, P<0.0001), uncertainty (β=0.18, P<0.0001) and perceived stress (β=0.17, P=0.005) compared to women who received negative (i.e., uninformative) results. Among women unaffected with breast/ovarian cancer, BRCA1/2 carriers reported higher genetic testing distress (β=0.39, P<0.0001) and lower positive testing experiences (β=0.25, P=0.008) than women with negative results. Receipt of risk-reducing surgery was associated with lower perceived cancer risk (P<0.0001).

Conclusions

In this first prospective long-term study in a U.S. sample, we found modestly increased distress in BRCA1/2 carriers compared to women who received uninformative or negative test results. Despite this modest increase in distress, we found no evidence of clinically significant dysfunction.

Impact

While a positive BRCA1/2 result remains salient among carriers years after testing, testing does not appear to impact long-term psychological dysfunction.

Keywords: long-term, psychosocial outcomes, BRCA1/2 genetic testing, affected status, risk-reducing surgery

BRCA1/BRCA2 (BRCA1/2) gene testing is now part of routine care for women with significant family histories of breast or ovarian cancer (1, 2). The clinical utility of BRCA1/2 testing is evidenced by high rates of risk reducing surgeries by BRCA1/2 carriers over the long-term (3–8) and the resultant decrease in morbidity and mortality (9). In contrast, little is known about long-term psychosocial outcomes of BRCA1/2 genetic testing, particularly in the context of risk reducing surgery.

Numerous studies (10–16) have described the short-term psychosocial impact of BRCA1/2 genetic testing in the year after receipt of results. Mixed evidence suggests that BRCA1/2 mutation carriers may experience higher distress than noncarriers in the months following testing (16, 17), but such differences typically dissipate one-year post-result (10, 14). In fact, comparisons between carriers and age-matched general populations reveal no differences on psychosocial outcomes at one-year post-testing (10). The few studies that explored the psychosocial impact of receiving uninformative BRCA1/2 results reported decreased distress and worry over time (15, 18).

We are aware of three small studies that have evaluated the long-term impact of testing. Two studies focused on people unaffected with cancer and found no differences on psychosocial outcomes between carriers and noncarriers at three years (11) or five years post-testing (19). The third study, using a cross-sectional design with a sample of U.S. women, focused on genetic-testing specific concerns seven years post-test (20). Results indicated statistically significant, but not clinically significant, greater genetic-testing distress in BRCA1/2 carriers compared to non-carriers (20).

Likewise, few studies have evaluated the impact of risk-management choices on long-term psychosocial outcomes. In a large sample of high-risk women in the Netherlands (most of whom had not had BRCA1/2 testing), risk reducing oophorectomy was associated with reduced worry and perceived risk (21). Similarly, in a French cohort sample, risk reducing surgery was associated with lower perceived cancer risk (22).

The present study is the first to prospectively examine long-term psychosocial outcomes in a large U.S. sample. Given differences in risk-management decisions, health care systems, and participant demographics, data from European samples may not generalize to the U.S. This study further extends prior research in several ways. First, unlike some prior studies (11, 16), this study includes individuals with and without cancer. Second, while prior work has largely focused on a limited number of psychosocial outcomes, we included a broad range of outcomes spanning specific ratings of genetic testing distress to more global perceived daily stress. Third, in contrast to the only other long-term study with a U.S. sample (20), our prospective design allows us to control for pre-test psychosocial functioning levels. Finally, this study evaluated psychosocial outcomes within the context of risk reducing surgery choices.

MATERIALS AND METHODS

Study Population

We identified participants through the Lombardi Comprehensive Cancer Center (LCCC) Familial Cancer Registry (FCR). Participants were eligible if they were female, 25 to 75 years old, had received BRCA1/2 test results at LCCC, and were at least three years post-disclosure at the time of the current study. Methods for the current study and characteristics of FCR participants are described elsewhere (8, 23). Briefly, at the time participants in this report received genetic counseling/testing, all counseling and testing at LCCC was conducted through research protocols. Participants in the current report came from one of four genetic studies: two observational studies (24, 25) of short-term genetic counseling outcomes and two intervention trials (26, 27). One trial evaluated a psychosocial telephone counseling intervention for mutation carriers (26) and the other evaluated an interactive decision aid for mutation carriers (27). The present report includes 26 mutation carriers who had been randomized to the intervention arms of one of the trials; we thus controlled for randomization to intervention arm in subsequent analyses. All participants in this report had completed a baseline assessment prior to genetic counseling, received genetic counseling/testing, and had been followed for 12 months as part of their initial participation. The present report describes an additional long-term follow-up assessment.

We mailed letters of invitation to 655 potentially eligible FCR participants who had consented to recontact for future studies. Of the 655 eligible FCR participants, we lacked accurate contact information for 26 (4%), yielding 629 women. Of the 629, 118 (18.7%) declined participation and 47 (7.5%) could not be reached after repeated attempts. Our final sample (N=464) represents 73.8% of those eligible and for whom we had correct contact information. Compared to eligible non-participants, participants were more likely to be married and less likely to be Jewish (P<.05).

Procedures

Mailed invitation packets described the study and included IRB-approved consent documents, a printed version of the survey, a stamped postcard to decline participation, and a telephone number if the participant preferred to complete the survey by phone. Potential participants could decline participation by telephone or mail. Women interested in participating completed the 30-minute survey by print or telephone. Our institutional review board approved the research protocol, and all participants provided informed consent.

Measures

Control and Predictor Variables

Sociodemographics

We assessed age, race, education, marital status, employment status, income and religion.

Time Since Receipt of Test Result

We calculated the time between receipt of test results and current study completion; we dichotomized time at the median of 5 years.

Genetic Test Result

Results were classified as ‘positive’ if a woman was found to have a deleterious mutation, ‘negative’ if she was found not to carry a mutation previously identified in her family, and ‘uninformative’ when no mutation was detected in the first tested person in a family.

Personal/Family Cancer History

We assessed participants’ personal cancer history and the number of first and second degree relatives affected with breast or ovarian cancer.

Time Since Cancer Diagnosis

We stratified women affected with cancer into those diagnosed less than 10 years ago vs. those diagnosed more than 10 years ago. We selected 10 years since as this value was closest to the mean time since diagnosis (10.4 years).

Pre-Testing Distress

We measured cancer-specific distress prior to genetic testing using the 15-item, highly reliable (alpha=.88), Impact of Event Scale (IES) (28). For general distress, 87 participants completed the 20-item State Trait Anxiety Inventory (STAI) (29) and 366 participants completed the anxiety sub-scale of the Brief Symptom Inventory (30). Both measures are reliable (alphas=0.85–0.91). We z-scored the STAI and BSI and used these as a composite measure of general pre-test distress.

Risk Reducing Surgeries

We assessed receipt of risk reducing mastectomy (RRM) and risk reducing bilateral salpingo-oophorectomy (RRBSO) with face-valid interview items described in prior reports (8).

Outcome Variables

Perceived Risk for Breast and Ovarian Cancer

We assessed perceived risk for developing breast and ovarian cancer using a numeric perceived risk item (31, 32). Women responded with a number between 0 (“definitely won’t get breast cancer”) and 100 (“definitely will get breast cancer”). For individuals affected with cancer, we asked their perceived risk of developing cancer again, with separate items for breast and ovarian cancer.

Perceived Stress

We assessed perceived stress using the 4-item version of the psychometrically-sound Perceived Stress Scale (33). Responses were made on a 5-point scale ranging from “never” to “very often.” Internal consistency in the present study was good (alpha=0.82).

Distress

We assessed cancer-specific distress at the long-term follow-up using the IES (described above; alpha=0.89). We measured genetic testing distress with the 21-item Multi-Dimensional Assessment of Cancer Risk Assessment (MICRA) (34). The MICRA has subscales measuring distress, uncertainty and positive experiences related to the genetic test result. Subscale alphas ranged from 0.81–0.85.

Statistical Analysis

After generating descriptive statistics to characterize the sample, we conducted separate analyses for women affected with breast or ovarian cancer and for women unaffected with cancer. For affected women, we compared those who tested positive to those who received an uninformative genetic test result. For unaffected women, we compared those with a positive result to those with a definitive negative test result. We identified potential confounders for inclusion in multivariate models by first evaluating bivariate predictors of our psychosocial outcomes using t-tests (with Satterthwaite’s approximation for unequal variances when appropriate) and Pearson correlation coefficients. To be conservative, we included potential confounders with bivariate associations at the P <.10 level in our multivariate models.

Next we conducted a series of multiple regression models with hierarchical variable entry to evaluate the independent effect of test result on each outcome after adjusting for confounders identified in bivariate analyses. To minimize the number of multivariate models, we conducted multivariate modeling only for the outcomes that were statistically significantly associated (P<.05) with test result in bivariate analyses. Finally, in analyses limited to carriers, we evaluated the impact of risk reducing surgery on psychosocial outcomes by including RRM and RRBSO status in regression models, again adjusting for all variables with bivariate associations at the P < .10 level.

We have organized the results as follows: sample characteristics, results for women affected with cancer, results for women unaffected with cancer, and then results related to risk reducing surgery among BRCA1/2 carriers and psychosocial outcomes.

RESULTS

Sample Characteristics

Sample characteristics by affected/unaffected status are displayed in Tables 1.1 and 1.2. Overall, 144 (31%) participants received positive results, 261 (56.1%) received uninformative results and 60 (12.9%) received definitive negative results. Participants’ mean age was 52.5 (SD=10.1); women received BRCA1/2 results a median of 5.0 years (Range = 3.4 to 9.1 years; SD=1.2 years). Most participants were white (92%), college educated (95%), employed (57%), and married (77%). The majority were affected with breast cancer (72%); only 4% (n=18) had ovarian cancer, and 4 women had both breast and ovarian cancer. Affected women were on average 10.4 years post-diagnosis (SD=6.9). Participants had a mean of 2.3 (SD=1.6) relatives affected with breast or ovarian cancer.

Table 1.1.

Bivariate predictors of psychosocial outcomes among affected women

Variable Perceived Stress Perceived BC Risk Perceived OC Risk Cancer Distress MICRA Distress MICRA Uncertainty MICRA Positive
Genetic Test Result
 Positive (n=97) 5.1 (3.2)* 28.4 (27.3) 20.7 (27.8) 12.8 (14.8) 3.5 (5.5)** 6.5 (8.1)** 7.4 (5.8)
 Uninformative (n=260) 4.0 (3.0) 34.5 (26.3)† 17.1 (19.4) 12.7 (12.4) 0.4 (1.4) 4.0 (5.5) 7.9 (7.7)
RRM
 No (n=259) 4.2 (3.0) 36.8 (26.2) 17.9 (20.4) 12.7 (13.0) 1.1 (2.9) 4.7 (6.4) 7.8 (7.4)
 Yes (n=98) 4.4 (3.2) 22.6(25.2)** 18.6 (25.5) 12.7 (13.2) 1.8 (4.3) 4.5 (6.2) 7.6 (6.6)
RRBSO
 No (n=254) 4.2 (3.1) 34.7 (26.7) 21.3 (22.5) 13.0 (12.8) 1.0 (3.0) 4.5 (6.0) 7.9 (7.4)
 Yes (n=103) 4.5 (3.1) 27.8 (26.2)* 10.5(18.5)** 12.0 (13.7) 1.9 (4.2)† 5.2 (7.2) 7.4 (6.8)
Education
 <College (n=12) 2.7 (3.1) 25.1 (28.9) 20.2 (31.4) 6.4 (10.0) 0.4 (0.9) 4.2 (4.0) 8.3 (6.9)
 College + (n=345) 4.3 (3.1) † 33.0 (26.6) 18.0 (21.7) 12.9 (13.1)† 1.3 (3.4)* 4.7 (6.4) 7.7 (7.2)
Religion/Ethnicity
 Non-Jewish (n=222) 4.1 (3.0) 33.0 (27.5) 18.9 (22.6) 12.1 (12.8) 1.2 (3.1) 4.7 (6.3) 7.8 (7.1)
 Jewish (n=135) 4.5 (3.1) 32.4 (25.3) 16.7 (20.9) 13.8 (13.5) 1.4 (3.8) 4.6 (6.4) 7.7 (7.4)
Race
 Non-Caucasian (n=23) 4.1 (3.9) 24.8 (23.3) 14.7 (19.5) 20.2(17.0)* 1.5 (3.5) 9.0 (9.6)* 10.8 (7.7)*
 Caucasian (n=326) 4.3 (3.0) 33.1 (26.8) 18.3 (22.3) 12.3 (12.7) 1.2 (3.4) 4.3 (5.8) 7.6 (7.1)
Marital Status
 Unmarried (n=83) 4.7 (3.1) 35.7 (27.5) 19.2 (21.9) 13.0 (13.7) 1.1 (3.0) 4.5 (6.7) 7.1 (7.3)
 Married/Partner (n=274) 4.1 (3.0) 31.9 (26.4) 17.8 (22.0) 12.6 (12.9) 1.3 (3.5) 4.7 (6.3) 8.0 (7.2)
Employment
 Not Full Time (n=159) 4.1 (3.1) 33.9 (28.0) 20.5 (23.2)† 11.7 (12.8) 1.4 (3.4) 4.4 (6.6) 8.0 (7.0)
 Full Time (n=198) 4.4 (3.0) 31.9 (25.6) 16.2 (20.8) 13.5 (13.2) 1.2 (3.4) 4.9 (6.2) 7.5 (7.4)
Annual Income
 < 85,000 USD (n=86) 4.6 (3.0) 34.6 (28.3) 21.9 (25.5) 13.7 (14.3) 1.3 (3.1) 5.6 (7.4) 9.1 (7.5)
 ≥ 85,000 USD (n=238) 4.1 (3.0) 32.1 (26.6) 17.3 (21.0) 12.9 (12.8) 1.3 (3.6) 4.6 (6.2) 7.7 (7.1)
Years Since Testing
 < 5.0 Years (n=186) 4.3 (3.1) 32.4 (26.1) 18.2 (21.8) 13.4 (13.4) 1.3 (3.3) 4.5 (6.0) 8.5 (7.5)*
 ≥ 5.0 Years (n=171) 4.3 (3.1) 33.2 (27.4) 18.0 (22.3) 11.9 (12.6) 1.2 (3.5) 4.9 (6.8) 6.9 (6.8)
Time Since Ca Diagnosis
 < 10 Years (n=221) 4.4 (3.0) 34.8 (25.9)* 19.1 (22.9) 13.9(12.9)* 1.3 (3.4) 4.9 (6.3) 7.6 (7.3)
 10+ Years (n=135) 4.0 (3.1) 27.8 (26.6) 16.6 (20.6) 10.8 (13.3) 1.2 (3.4) 4.2 (6.5) 8.0 (7.1)
Intervention Arm
 No Intervention (n=343) 4.3 (3.1) 32.9 (26.6) 18.2 (21.9) 13.0(13.2)* 1.1 (3.2) 4.7 (6.4) 7.8 (7.3)
 Intervention (n=14) 3.4 (2.2) 30.9 (29.6) 16.1 (25.3) 5.3 (6.2) 4.6 (5.3)* 4.6 (4.7) 6.7 (5.5)
Continuous Predictors
Age (M= 54.1, SD=9.6) r=−0.10* r=−0.00 r=−0.06 r=−0.16* r=−0.10* r= −0.12* r= 0.07
FDRs w/Br/Ov Cancer (M=1.0, SD=1.0) r=−0.03 r= 0.05 r= 0.05 r=−0.10* r= 0.05 r= 0.06 r=−0.02
Relatives w/Br/Ov Cancer (M=2.1, SD=1.4) r=−0.02 r= 0.04 r= 0.04 r=−0.08 r= 0.03 r= 0.02 r=−0.05
Pre-Test Cancer Distress (M=20.5, SD=14.4) r= 0.30** r= 0.15* r= 0.16* r= 0.41** r=0.18* r= 0.17* r=−0.03
Pre-Test Anxiety (M=0.08, SD=1.0) r= 0.37** r= 0.09 r= 0.02 r= 0.39** r=0.12* r= 0.22** r=−0.08
Open in a new tab
†

P<0.10,

*

P<0.05,

**

P<0.01.

RRM = Risk Reducing Mastectomy; RRBSO = Risk Reducing Bilateral Salpingo-Oophorectomy; USD = United States Dollars; FDRs= First Degree Relatives. Values are means (SD) for categorical predictors and Pearson correlations for continuous predictors.

Table 1.2.

Bivariate predictors of psychosocial outcomes among unaffected women

Variable Perceived Stress Perceived BC Risk Perceived OC Risk Cancer Distress MICRA Distress MICRA Uncertainty MICRA Positive
Genetic Test Result
 True Negative (n=60) 4.3 (3.0) 38.8 (23.1) 21.9 (20.1) 10.7 (13.9) 0.9 (2.2) 4.0 (5.7) 9.8 (8.2)**
 Positive (n=47) 4.3 (3.1) 42.5 (31.8) 23.0 (23.4) 10.5 (11.7) 2.6 (4.6)* 5.1 (6.7) 6.1 (5.8)
RRM
 No (n=90) 4.2 (2.9) 44.6 (25.2) 22.5 (20.3) 9.7 (12.6) 1.8 (3.8)* 4.4 (6.3) 8.4 (7.7)
 Yes (n=17) 4.8 (3.4) 18.5(27.6)** 22.0 (27.8) 15.3 (13.4)† 0.7 (1.3) 4.9 (5.2) 6.8 (6.7)
RRBSO
 No (n=76) 4.4 (3.1) 41.4 (26.2) 27.3 (22.2) 10.8 (13.3) 1.7 (3.4) 4.8 (6.3) 8.7 (7.7)
 Yes (n=31) 4.1 (2.8) 37.8 (29.9) 10.4 (14.0)** 10.2 (12.1) 1.5 (3.9) 3.6 (5.7) 6.9 (6.7)
Education
 <College (n=9) 4.6 (2.5) 32.8 (27.3) 27.0 (21.6) 4.7 (6.1) 1.2 (1.9) 2.3 (2.3) 11.4 (7.8)
 College+ (n=98) 4.3 (3.1) 41.1 (27.2) 22.0 (21.6) 11.1 (13.2) 1.7 (3.7) 4.7 (6.4)* 7.8 (7.4)
Religion/Ethnicity
 Non-Jewish (n=73) 4.3 (3.1) 43.4 (27.5)† 24.0 (21.5) 10.0 (13.3) 1.9 (3.8) 4.6 (6.8) 8.9 (7.8)
 Jewish (n=34) 4.4 (2.8) 33.8 (25.6) 18.9 (21.4) 12.0 (12.0) 1.2 (2.9) 4.1 (4.5) 6.6 (6.5)
Race
 Non-Caucasian (n=5) 5.6 (4.3) 34.0 (24.3) 25.0 (20.9) 12.6 (12.6) 2.2 (2.6) 5.6 (6.3) 10.2 (7.2)
 Caucasian (n=101) 4.2 (3.0) 40.4 (37.4) 22.0 (21.5) 10.3 (12.9) 1.6 (3.6) 4.3 (6.2) 8.0 (7.5)
Marital Status
 Unmarried (n=25) 5.1 (3.0) 49.5 (28.9)† 24.8 (23.5) 12.2 (13.3) 0.6 (1.6) 2.5 (3.1) 9.0 (9.2)
 Married/Partner(n=82) 4.1 (3.0) 37.6 (26.2) 21.6 (20.9) 10.1 (12.8) 2.0 (3.9)* 5.1 (6.7)* 7.9 (6.9)
Employment
 Not Full Time (n=42) 4.1 (2.9) 33.4 (25.5) 17.2 (18.6) 10.0 (12.8) 1.4 (3.3) 4.2 (6.6) 8.5 (7.0)
 Full Time (n=65) 4.5 (3.1) 45.0 (27.5)* 25.7 (22.7)* 10.9 (13.0) 1.8 (3.8) 4.6 (5.9) 7.9 (7.8)
Annual Income
 < 85,000 USD (n=33) 5.0 (3.3) 44.5 (27.7) 29.6 (24.5)* 15.0(15.0)* 2.1 (3.7) 5.3 (7.5) 10.5 (7.6)*
 ≥ 85,000 USD (n=70) 4.0 (2.9) 37.5 (27.1) 18.8 (19.3) 8.8 (11.6) 1.3 (3.1) 4.0 (5.4) 7.0 (7.1)
Years Since Testing
 < 5.0 Years(n=55) 4.3 (3.0) 41.5 (27.4) 20.4 (17.7) 11.5 (13.4) 1.5 (3.4) 4.7 (7.1) 9.2 (7.4)
 ≥ 5.0 Years (n=52) 4.3 (3.1) 39.2 (27.2) 24.5 (24.9) 9.7 (12.3) 1.8 (3.7) 4.2 (5.1) 7.0 (7.4)
Intervention Arm
 No Intervention (n=95) 4.32 (3.0) 40.69 (27.2) 22.2 (22.1) 10.6 (12.9) 1.40 (3.1) 4.33 (6.2) 8.39 (7.7)
 Intervention (n=12) 4.17 (3.4) 38.0 (28.0) 23.8 (16.7) 10.3 (13.0) 3.58 (6.0) 5.42 (6.1) 6.17 (5.2)
Continuous Predictors
Age at Interview (M=47.4,SD=9.7) r=0.09 r=−0.15 r=−0.24 r=−0.05 r=−0.16 r=−0.21* r=−0.10
FDRsw/Br/Ov Cancer (M=1.8, SD=1.3) r=0.03 r=−0.02 r=−0.02 r=0.13 r=−0.03 r=−0.04 r=0.03
Relatives w/Br/Ov Cancer (M=3.3, SD=1.7) r=0.15 r=−0.02 r=−0.07 r=0.17* r=−0.08 r=−0.09 r=0.06
Pre-Test Cancer Distress (M=15.0, SD=14.6) r=0.26* r= 0.07 r= 0.20* r=0.53** r=0.29* r=0.49** r=0.21*
Pre-Test Anxiety (M=−0.25, SD=0.84) r=0.23* r= 0.05 r= 0.01 r=0.49** r= 0.02 r=0.19* r=0.03
Open in a new tab
†

P<0.10,

*

P<0.05,

**

P<0.01.

RRM = Risk Reducing Mastectomy; RRBSO = Risk Reducing Bilateral Salpingo-Oophorectomy; USD = United States Dollars; FDRs= First Degree Relatives. Values are means (SD) for categorical predictors and Pearson correlations for continuous predictors.

Psychosocial Outcomes Among Affected Women

As displayed in Table 1.1, since test result was not statistically significantly associated with long-term cancer distress, genetic testing positive experiences, or perceived breast or ovarian cancer risk (see Table 1.1), we did not conduct further multivariate analyses among affected women for these variables. Test result (positive vs. uninformative) was statistically significantly associated with genetic testing distress (Satterthwaite t(99.5)=5.44, p<.001), uncertainty (Satterthwaite t(129)=2.79, P=0.006) and perceived stress (t(352)=3.08, P=0.002). Thus, we proceeded with multivariate modeling for these outcomes.

Genetic Testing Distress

Distress Subscale

As displayed in Table 2, we used multiple regression to examine the independent impact of test result among women affected with cancer, adjusting for potential confounders identified in bivariate analyses (Table 1.1). Specifically, we adjusted for potential confounders by entering variables with a bivariate association of P<0.10 (age, pre-test cancer specific distress and anxiety, intervention arm and RRBSO status) on step 1. These confounders accounted for 10% of the variance in genetic testing distress (R2=0.10, P<0.0001). When entered on the next step, test result (positive vs. uninformative) accounted for an additional 10% of the variation in long-term genetic testing distress (ΔR2=0.10, F=45.6, P<0.0001). Among women affected with cancer, BRCA1/2 carriers reported higher levels of long-term genetic testing distress compared to women who received uninformative test results (β=0.45, P<0.0001).

Table 2.

Impact of BRCA1/2 test result on psychosocial outcomes among women affected by cancer

Variable Total R2 ΔR2 df Final β
Genetic Testing Distress
Model 1: 0.10*** 0.10*** 6, 347
 Age 0.02
 Education 0.03
 Randomized to Intervention 0.08
 Pre-Test Cancer Distress 0.12**
 Pre-Test Cancer Anxiety 0.06
 Risk Reducing Oophorectomy −0.09
Model 2: 0.20*** 0.10*** 7, 346
 Genetic Test Result 0.41***
Genetic Testing Uncertainty
Model 1: 0.10*** 0.10*** 4, 343
 Age at Interview −0.04
 Race −0.19**
 Pre-Test Cancer Distress 0.04
 Pre-Test Anxiety 0.21**
Model 2: 0.13*** 0.03** 5, 342
 Genetic Test Result 0.18**
Perceived Stress
Model 1: 0.16*** 0.16*** 4, 349
 Age at Interview 0.01
 Education 0.10*
 Pre-test Anxiety 0.30***
 Pre-test Cancer Distress 0.14**
Model 2: 0.18*** 0.02** 5, 348
 Genetic Test Result 0.14**
Open in a new tab
†

P<0.10,

*

P<0.05,

**

P<0.01,

***

P<0.0001

Note: Bivariate predictors (P<0.10) were entered in Model 1. Test Result was entered in Model 2 and the change in R square was tested for significance. Reference for test result is uninformative. Standardized betas (β) represent betas in the final model.

Uncertainty Subscale

As displayed in Table 2, we used multiple regression to examine the independent impact of test result on uncertainty among women affected with cancer, adjusting for potential confounders identified in bivariate analyses (Table 1.1). We entered potential confounders with a bivariate association of P<0.10 (race, age, pre-test cancer distress, and pre-test anxiety) on step 1. These potential confounders accounted for 10% of the variance in genetic testing uncertainty (R2=0.10, P<0.0001). Test result (positive vs. uninformative) accounted for an additional 3% of the variation in genetic testing uncertainty (ΔR2=0.03, P=0.0005). Affected carriers reported greater long-term uncertainty relative to affected uninformatives (β=0.18, P=0.0005).

Perceived Stress

As displayed in Table 2, we used multiple regression to examine the independent impact of test result on perceived stress among women affected with cancer, adjusting for potential confounders identified in bivariate analyses (Table 1.1) by entering those variables with a bivariate association of P<0.10 (education, age, pre-test cancer distress, and anxiety). As shown in Table 2, confounders accounted for 16% of the variation in perceived stress (R2=0.16, P<0.0001). Genetic test result (positive vs. uninformative), entered on step 2, accounted for an additional 2% of the variation in perceived stress [ΔR2 =0.02, P=0.005]. Affected women who received a positive test result reported statistically significantly higher levels of long-term perceived stress compared to affected uninformatives (β=0.14, P=0.005).

Psychosocial Outcomes Among Unaffected Women

As displayed in Table 1.2, test result (positive vs. true negative) was not associated with cancer distress, perceived stress, genetic testing uncertainty, perceived breast cancer risk or perceived ovarian cancer risk among women unaffected with cancer. Thus, we did not conduct further multivariate analyses for these outcomes. In bivariate analyses, test result was statistically significantly associated with genetic testing distress (Satterthwaite t(63)=−2.29, P=0.03) and positive experiences (Satterthwaite t(104)=2.70, P=0.008) among unaffected women. We proceeded with multivariate modeling for these two outcomes.

Genetic Testing Distress

Distress Subscale

As displayed in Table 3, we used multiple regression to examine the independent impact of test result on genetic testing distress among unaffected women, adjusting for potential confounders identified in bivariate analyses (Table 1.1). We adjusted for potential confounders by entering variables with a bivariate association of P<0.10 (marital status, pre-test cancer distress, and receipt of RRM). These confounders, entered on step 1, accounted for 13% of the variance in genetic testing distress (R2=0.13, P=0.003). Test result (positive vs. negative), entered on step 2, accounted for an additional 12% of the variance in genetic testing distress (ΔR2=0.12, P=0.0001). Among unaffected women, BRCA1/2 carriers reported higher genetic testing distress compared to BRCA1/2 negatives (β=0.39, P<0.0001).

Table 3.

Long-term impact of BRCA1/2 test results on psychosocial outcomes among women unaffected by cancer

Variable Total R2 ΔR2 df Final β
Genetic Testing Distress
Model 1: 0.13** 0.13** 3, 103
 Marital Status 0.13
 Pre-Test Cancer Distress 0.31**
 Risk Reducing Mastectomy −0.36**
Model 2: 0.25*** 0.12*** 4, 102
 Genetic Test Result 0.39***
Genetic Testing Positive Experiences
Model 1: 0.08** 0.08** 3, 99
 Income −0.18†
 First Degree Relatives w/breast/ovarian cancer 0.06
 Pre-Test Cancer Distress 0.20**
Model 2: 0.14** 0.06** 4, 98
 Genetic Test Result −0.25**
Open in a new tab
†

P<0.10,

*

P<0.05,

**

P<0.01,

***

P<0.0001

Note: Bivariate predictors (P<0.10) were entered in Model 1. Test Result was entered in Model 2 and the change in R square was tested for significance. Reference for test result is True Negative. Standardized betas (β) represent betas in the final model.

Genetic Testing Positive Experiences

As displayed in Table 3, we used multiple regression to examine the independent impact of test result on genetic testing distress among unaffected women, again adjusting for potential confounders identified in bivariate analyses (Table 1.1). As before, we adjusted for potential confounders by entering variables with a bivariate association of P<0.10 (income and pre-test cancer distress). When entered on step 1, these confounders accounted for 8% of the variance in positive experiences (R2=0.08, P=0.04). Test result (positive vs. true negative) accounted for an additional 6% of the variance (ΔR2=0.06, P=0.008). Specifically, unaffected BRCA1/2 carriers reported lower positive experiences compared to unaffected women who received negative test results (β= 0.25, P=0.008).

Impact of Risk Reducing Surgery on Distress Outcomes among BRCA1/2 Mutation Carriers

To examine the impact of risk reducing surgery on psychosocial outcomes, we conducted a series of regressions limited to BRCA1/2 mutation carriers (n=144).

RRM

After excluding 13 carriers with bilateral breast cancer or ovarian cancer, 48% (n=63) of carriers had RRM. The only outcome associated with RRM was perceived risk for breast cancer (t(119)=5.22, P<0.0001). In a multiple regression in which we controlled potential confounders [affected status, pre-test anxiety and distress (due to association with RRM uptake in previous reports) (8)], RRM was independently associated with reduced perceived breast cancer risk among BRCA1/2 carriers (ΔR2=0.18, P<0.0001, β= −0.44, P<0.0001; see Table 4).

Table 4.

Impact of risk reducing surgery on psychosocial outcomes among BRCA1/2 mutation carriers

Variable Total R2 ΔR2 df Final β
Impact of Risk Reducing Mastectomy
Perceived Breast Cancer Risk
Model 1: 0.05† 0.05† 3, 117
 Affected status −0.15†
 Pre-Test Cancer Distress 0.01
 Pre-Test Anxiety 0.18†
Model 2: 0.23*** 0.18*** 4, 116
 Risk Reducing Mastectomy −0.44***
Impact of Risk Reducing Oophorectomy
Perceived Breast Cancer Risk
 Model 1: 0.08** 0.08** 5, 105
 Affected Status −0.26**
 Pre-Test Cancer Distress −0.01
 Pre-Test Anxiety 0.11
Model 2: 0.11† 0.02† 4, 104
 Risk Reducing Oophorectomy −0.16†
Perceived Ovarian Cancer Risk
Model 1: 0.06** 0.06** 1,113
 Age at Interview 0.07
Model 2: 0.30*** 0.24*** 2, 112
 Risk Reducing Oophorectomy −0.58***
Genetic Testing Distress
Model 1: 0.14** 0.14** 4, 112
 Education 0.08
 Total Relatives with breast/ovarian cancer −0.16**
 Pre-Test Cancer Distress 0.33**
 Pre-Test Anxiety −0.06
Model 2: 0.16** 0.02* 5, 111
 Risk Reducing Oophorectomy −0.16†
Open in a new tab
†

P<0.10,

*

P<0.05,

**

P<0.01,

***

P<0.0001

Note: Bivariate predictors (P<0.10) were entered in Model 1. For Risk Reducing Mastectomy (RRM) outcomes, RRM was entered in Model 2 and the change in R square was tested for significance. Reference for risk reducing mastectomy (RRM) is no RRM. For Risk Reducing Oophorectomy (BSRRO) outcomes, BSRRO was entered in Model 2 and the change in R square was tested for significance. Reference for risk reducing oophorectomy (BSRRO) is no BSRRO.

RRBSO

After we excluded 13 carriers with bilateral breast cancer and/or ovarian cancer and 13 carriers who reported BSO for reasons other than breast or ovarian cancer prevention, 73% (n=86) of carriers had RRBSO. In bivariate analyses, RRBSO was statistically significantly associated only with genetic testing distress (t(115)=2.18, P=0.03), perceived ovarian cancer risk (t(113)=6.90, P<0.0001) and perceived breast cancer risk (t(107)=2.25, P=0.03). Thus, we proceeded with multivariate analyses for these outcomes.

For genetic testing distress, after adjusting for potential confounders (education, number of relatives with breast/ovarian cancer, and pre-test distress), receipt of RRBSO was marginally associated with decreased genetic testing distress among BRCA1/2 carriers (ΔR2=0.02, β= −0.16, P=0.06; see Table 4). For perceived ovarian cancer risk, after adjusting for the potential confounder of age, RRBSO was independently associated with reduced perceived ovarian cancer risk among BRCA1/2 carriers (ΔR2=0.24, β= −0.58, P<0.0001; see Table 4). For perceived breast cancer risk, after controlling for confounders (affected status, pre-test anxiety and pre-test cancer specific distress), RRBSO was not related to perceived breast cancer risk among BRCA1/2 carriers (ΔR2=0.02, P=0.10; see Table 4).

DISCUSSION

To our knowledge, this is the first U.S. report to prospectively examine long-term psychosocial outcomes following BRCA1/2 testing in a large sample of women affected and unaffected with cancer. Prior studies have focused on psychosocial outcomes during the year following testing (10, 14), have focused only on unaffected individuals (11, 19, 22), or were not prospective (20). For women both affected and unaffected with cancer, genetic test results appear to impact certain long-term psychosocial outcomes.

Approximately 5 years after testing, women who received positive BRCA1/2 results reported greater genetic testing distress than women who received uninformative or negative results. This contrasts with prior studies with shorter follow-ups (10, 14), but is consistent with a recent cross-sectional study that assessed genetic testing concerns a median of 7 years post-testing (20). The impact of BRCA1/2 results on genetic testing distress remains statistically significant even after controlling for the receipt of risk reducing surgery. Our measure of genetic testing distress, the MICRA, may be more sensitive than more global distress measures used in prior studies. Indeed, the MICRA was specifically designed to measure distress associated with receipt of a positive BRCA1/2 result (34). The present findings suggest that a positive BRCA1/2 result remains salient years after testing, perhaps due to ongoing decisions about risk management or worry over family members’ cancer risk (35). Whether these results have clinical or behavioral implications is not yet clear. Despite elevations in genetic testing distress among carriers, our results suggest that genetic testing distress is unrelated to more global psychological dysfunction. This mirrors an earlier report in which distress due to high-risk cancer status was unrelated to general psychological functioning (36) and the recent long-term follow-up by Hughes Halbert and colleagues (20). More research is needed to determine whether elevated genetic testing distress has clinical implications.

Unique to the present study was our measurement of perceived stress. Among affected women, BRCA1/2 carriers exhibited greater perceived stress five years post-testing compared to uninformatives. The Perceived Stress Scale is designed to measure global stress and not psychological symptoms (33). Thus, it is possible that the Perceived Stress Scale better captures subtle influences of a positive BRCA1/2 result on everyday functioning compared to traditional assessments of psychological symptoms in previous studies. These results—together with our findings of elevated genetic testing distress —suggest that BRCA1/2 carriers continue to experience slightly higher levels of perceived stress compared to women who receive uninformative or true negative BRCA1/2 results. Whether such modest elevations in perceived stress are clinically relevant or actionable is not clear. The seminal work of Cohen and colleagues suggests that perceived stress can have important physiological effects (37). Future research can explore whether elevated perceived stress impacts psychosocial or physical functioning in BRCA1/2 carriers.

Somewhat surprisingly, affected women with positive results reported statistically significantly more uncertainty related to genetic testing than women who received uninformative results. Given clear risk management guidelines for BRCA1/2 carriers, and the lack of such guidance for women with uninformative results, the increased uncertainty among positives warrants further examination. Perhaps the experience of uncertainty among carriers relates to lingering risk management questions. For example, several theoretical approaches suggest that health-related decision making is impacted by emotions [e.g., Peters and colleagues’ work (38); Lazarus’s cognitive-motivational-relational theory (39)] and are relevant to outcomes such as decisional conflict (40). Although we evaluated the impact of test result on genetic testing distress and uncertainty separately, these outcomes are correlated (r = 0.53, P <0.0001) and the factors that underlie their association may also be responsible for the present results related to greater uncertainty in BRCA1/2 carriers compared to women with uninformative results. Future research that carefully explores the psychological and emotional pathways relevant to genetic testing distress may help explain these specific findings.

BRCA1/2 results were unrelated to perceived risk for breast or ovarian cancer, likely reflecting the high uptake of risk reducing surgery in our sample and the impact of risk reducing surgery on perceived risk. For example, among BRCA1/2 carriers, uptake of RRM and RRBSO were associated with lower perceived breast and ovarian cancer risk, respectively. This is consistent with the substantially decreased objective risk following these procedures (9, 41, 42). Of note, the decrease in perceived risk following risk reducing surgery did not translate to reduced distress over the long-term. Given that distress and worry reduction are frequently cited reasons for obtaining risk reducing surgery (43), our findings may be relevant to women considering such surgery. However, these results should be interpreted cautiously due to the relatively small number of BRCA1/2 carriers without RRBSO at follow-up.

The present findings should be considered in context of study limitations. Data were drawn from a single institution and all participants were previously enrolled in clinical research studies, thus limiting the generalizability of results. Despite the single site, women were referred to our center by diverse community providers across a large metropolitan area. Although our sample has characteristics similar to patients seen at other large cancer genetics referral centers, the homogeneity in participants’ education level and the lack of racial diversity warrant caution in interpretation of results. Our finding that women of Jewish descent were less likely to participate in the study is interesting and deserves attention in future prospective studies. In other work, we found a similar but marginal trend in which men and women of Jewish descent were less likely to enroll in a familial cancer registry (44). However, the reasons for lower participation remain unclear. Finally, results should also be interpreted cautiously given the large number of comparisons we conducted. Rather than adjusting for multiple comparisons, we opted to minimize the chance of a Type II error by maintaining a traditional alpha level. Importantly, with two exceptions (e.g., genetic test result and perceived stress among affected women, P = 0.005; genetic test result and positive genetic testing experiences among unaffected women, P = 0.008), the statistically significant multivariate comparisons we found were significant at a level of P ≤ 0.0005.

Despite these limitations, this is the first U.S. study to prospectively evaluate a broad range of long-term psychosocial outcomes in a cohort of BRCA1/2 tested women. We found evidence of modestly increased perceived stress in affected carriers and increased genetic testing distress in both affected and unaffected carriers; however, we did not find evidence for clinically significant dysfunction. Further, although risk reducing surgeries appropriately lower perceptions of cancer risk among BRCA1/2 carriers, we did not find evidence to support broader psychosocial benefits. Future research can confirm our results with representative cohorts and examine whether elevated genetic testing distress or perceived stress is clinically meaningful.

Acknowledgments

This research was supported by Department of Defense Grant DAMD BC021733, by the Jess and Mildred Fisher Center for Familial Cancer Research, and by the Lombardi Comprehensive Cancer Center’s Familial Cancer Registry and Clinical and Molecular Epidemiology Shared Resources. We thank Susan Marx for her assistance with manuscript preparation. The authors do not have any financial conflicts to disclose.

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