- Email: [email protected]
2 mutation carriers
Preventive Medicine 48 (2009) 193–196
Contents lists available at ScienceDirect
Preventive Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y p m e d
Quality of life in asymptomatic BRCA1/2 mutation carriers Efrat Dagan a,b,⁎, Tamar Shochat a a b
Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel Rambam Health Care Campus, Institute of Human Genetics, Haifa, Israel
a r t i c l e
i n f o
Available online 24 November 2008 Keywords: BRCA1/2 Health-Related Quality of Life Hereditary breast–ovarian cancer Asymptomatic mutation carriers
a b s t r a c t Objective. To investigate the association between positive genetic diagnosis for BRCA1/2 mutations and Health-Related Quality of Life (HR-QOL) in Ashkenazi asymptomatic women. Methods. Socio-demographic, clinical, psychological and HR-QOL questionnaires were completed by 73 women, including 17 asymptomatic BRCA1/2 carriers and 20 non-carriers from the oncogenetic clinic at Rambam Health Care Campus in Israel; and 36 low-risk controls from the community, between January 2006 to November 2007. Results. Impaired HR-QOL was demonstrated in BRCA1/2 carriers compared to non-carriers and controls in the role limitation due to emotional problems subscale. When stratified by women free of menopausal symptoms and controlling for education level, this subscale remained significant, and likewise both physical functioning and overall HR-QOL scores were significantly lower in BRCA1/2 carriers. Conclusions. Our results suggest that BRCA1/2 carriers are prone to experience deficits in HR-QOL, especially in mental aspects affecting role functioning. © 2008 Elsevier Inc. All rights reserved.
Introduction In Ashkenazi Jews three predominant mutations in BRCA1/2 genes were found, with a frequency of 2–3% in the healthy population, and 20% to 40% in breast and ovarian cancer patients, respectively (Simchoni et al., 2006). Despite the headway towards risk reduction management, it is plausible to assume that BRCA1/2 carriage in asymptomatic women may result in a state of psychological distress, consequently leading to impairments in Health-Related Quality of Life (HR-QOL). Overall, major psychological vulnerability has not been found consequent to positive genetic testing (Braithwaite et al., 2006), although few studies have identified that probands (Smith et al., 1999) and women at risk who received inconclusive results (Claes et al., 2004) are most prone to distress due to genetic testing. Nevertheless, being at high-risk for developing breast–ovarian cancer may incur subtle disturbances in daily functioning related to aspects of HR-QOL. In patients with breast cancer, HR-QOL is commonly assessed, showing poor HR-QOL shortly after diagnosis and during treatment (Kuroi et al., 2007). To date, few studies have investigated HR-QOL in asymptomatic high-risk women, showing altered physical and emotional symptoms (e.g., Geirdal et al., 2006). While the clinical implications of being a BRCA1/2 carrier are acknowledged, the longterm effects on HR-QOL are far from clear in high-risk women. The aim
⁎ Corresponding author. Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel. Fax: +972 4 822017. E-mail address: [email protected] (E. Dagan). 0091-7435/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2008.11.007
of this study was to investigate the association between BRCA1/2 status and HR-QOL in Ashkenazi asymptomatic women. Methods Participants and study design This case-control design included asymptomatic BRCA1/2 mutation carriers and non-carriers who had undergone genetic testing at the Rambam Health Care Campus oncogenetic clinic during 1996–2006; and a community control group, all from the Greater Haifa area. Exclusion criteria were major chronic illnesses, pregnancy and young children under age one year; as these may alter usual lifestyle. Evaluation of the archived files revealed 39 asymptomatic BRCA1/2 carriers. Of these, five (13%) declined, nine (23%) were lost to follow-up, three (8%) had chronic illness and five (13%) were pregnant or had young children; leaving 17 (44%) carriers who completed the study. Non-carriers were consecutively recruited to obtain a quota of 20 women matched to carriers for age at genetic diagnosis and for time since testing. Seventy-seven women were contacted. Of these, nine (12%) declined, seven (9%) were lost to follow up, nine (12%) had chronic illnesses and 31 (40%) were unavailable at time of contact. To estimate the extent to which high-risk status, whether positive or negative, may impact QOL, age-matched low-risk controls (n = 36) with no family history of breast–ovarian cancer and not tested for BRCA1/2 mutations were recruited. Socio-demographic and clinical status, including self reported menopausal symptoms (e.g., hot flashes, vaginal dryness, etc.) was updated. Questionnaires aimed to assess HR-QOL, psychological
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E. Dagan, T. Shochat / Preventive Medicine 48 (2009) 193–196
distress and cancer-related worry were completed during a home visit following written informed consent. This study was part of a larger project also investigating sleep disturbances and fatigue, which was approved by the Institutional Review Board at Rambam Health Care Campus. Measures Health-Related Quality of Life (HR-QOL) Short-Form (SF36) is a measure of health status, providing scores in areas of functioning and well-being related to mental and physical health (Ware and Sherbourne, 1992). Cancer Related Worry (CRW) measures how often a woman worries about breast and/or ovarian cancer and the effects of these worries on mood and daily performance (Lerman et al., 1991). The Brief Symptom Inventory (BSI) (Derogatis, 1975) assesses psychological distress, e.g., somatization, depression, anxiety, etc. Psychometric properties in the general population in Israel revealed scores under one in all subscales and global (GSI) score (Gilbar and Ben-Zur, 2002). Data management and statistical analyses The three groups were compared in respect to their sociodemographic, clinical and psychological characteristics using χ2 and one-way ANOVA when appropriate. Multiple analysis of variance (MANOVA) was performed both on the entire sample and stratified
based on presence of menopausal symptoms, to compare group differences in measures of HR-QOL. Post-hoc (Sidak) analysis was used to determine significant group differences. Mediator analysis was performed to assess the contribution of psychological factors in the relationship between carrier status and HR-QOL. Correlations were computed separately for the three groups, between CRW and BSI total scores and between HR-QOL scores that were found to be significantly different by group. Differences between correlations transformed to standardized Z-scores were assessed by Z-test analysis. Results The current study consisted of 73 high-risk women and controls. Of these, 37 (50.7%) were at high-risk, further subdivided to 17 (23.3%) BRCA1/2 carriers and 20 (27.4%) non-carriers; and 36 (49.3%) were low risk controls. Socio demographics and clinical characteristics are presented in Table 1. Psychological characteristics Cancer Related Worry Relatively higher levels of CRW were reported by BRCA1/2 carriers (0.75 ± 0.53) than non-carrier (0.67 ± 0.48) and controls (0.45 ± 0.44) (p = 0.067) (Table 2). When BRCA1/2 carriers and non-carriers were grouped together, significantly higher levels of CRW were reported compared to controls (0.71 ± 0.50 and 0.45 ± 0.44, respectively; p = 0.022).
Table 1 Socio-demographic and clinical characteristics in asymptomatic BRCA1/2 mutation carriers, non-carriers and controls, enrolled at the oncogenetic clinic, RAMBAM Health Care Campus and community, during January 10, 2006 to November 9, 2007
Age, mean (SD) Age at BRCA1/2 testing, mean (SD) Follow-up in years, mean (SD, range)
Total
High-risk
n = 73
BRCA1/2 carriers n = 17
BRCA1/2 non-carriers n = 20
n = 36
51.5 (8.9) 45.0 (9.0) 8.0 (1.9)
51.4 (9.1) 43.8 (8.8) 7.6 (2.5, 5–11)
54.5 (9.4) 46.0 (9.1) 8.4 (1.1, 7–11)
50.0 (8.3) – –
Family status (n, %) Married Single Divorce Widows
61 (83.6) 3 (4.1) 7 (9.6) 2 (2.7)
Have children (n, %) Yes No
71 (97.3) 2 (2.7)
16 (94.1) 1 (5.9)
Education (n, %) High-school College Graduate
14 (19.2) 7 (9.6) 52 (71.2)
8 (47.1) 3 (17.6) 6 (35.3)
Income (n, %) Lower than average Average Higher than average
3 (4.2) 37 (51.4) 32 (44.4)
1 (5.9) 9 (52.9) 7 (41.2)
Family history (n, %) 1st and/or 2nd degree of BCa or OCb Other cancer than BC or OC No family history of cancer
34 (46.6) 14 (19.2) 25 (34.2)
Prophylactic oophorectomy (n, %) Yes No Menopausal symptoms (n, %) Yes No a b
BC—breast cancer. OC—ovarian cancer.
15 (88.2) 1 (5.9)
Controls
17 (85.0) 2 (10.0) 1 (5.0)
1 (5.9)
–
20 (100)
p = 0.48
35 (97.2) 1 (2.8)
p = 0.55
3 (15.0) 3 (15.0) 14 (70.0)
3 (8.3) 1 (2.8) 32 (88.9)
p b 0.01
10 (50) 10 (50)
2 (5.6) 18 (50) 16 (44.4)
p = 0.88
11 (30.5) 25 (69.5)
p b 0.01
2 (5.5) 34 (94.5)
p = 0.05
–
–
17 (100) – –
p = 0.19 p = 0.46 p = 0.20
29 (80.6) 2 (5.6) 5 (13.9)
–
–
p value
17 (85.0) 3 (15.0) –
–
14 (82.3) 3 (17.7)
13 (17.8) 60 (82.2)
6 (35.3) 11 (64.7)
5 (25) 15 (75)
E. Dagan, T. Shochat / Preventive Medicine 48 (2009) 193–196
195
Table 2 Psychological characteristics and quality of life in asymptomatic BRCA1/2 mutation carriers, non-carriers and controls, enrolled at the oncogenetic clinic, RAMBAM Health Care Campus and community, during January 10, 2006 to November 9, 2007 Total
High-risk
n = 73
BRCA1/2 carriers n = 17
BRCA1/2 non-carriers n = 20
n = 36
0.58 (0.5)
0.75 (0.5)
0.67 (0.5)
0.45 (0.4)
p b 0.07
BSI , mean (SD) Somatization Obsessive–compulsive Sensitivity Depression Anxiety Hostility Phobic anxiety Paranoid thought Psychoticism Suicidal ideation Total
0.50 (0.5) 0.78 (0.7) 0.70 (0.6) 0.47 (0.5) 0.62 (0.5) 0.45 (0.4) 0.27 (0.4) 0.55 (0.6) 0.26 (0.5 0.42 (0.7) 0.52 (0.4)
0.66 (0.7) 0.93 (0.9) 0.59 (0.6) 0.48 (0.6) 0.61 (0.5) 0.54 (0.5) 0.16 (0.3) 0.48 (0.8) 0.19 (0.3) 0.24 (0.4) 0.53 (0.5)
0.35 (0.4) 0.63 (0.5) 0.49 (0.4) 0.37 (0.4) 0.43 (0.4) 0.29 (0.3) 0.24 (0.4) 0.52 (0.5) 0.29 (0.7) 0.45 (0.6) 0.41 (0.4)
0.50 (0.4) 0.80 (0.6) 0.87 (0.7 0.52 (0.6) 0.73 (0.6) 0.51 (0.5) 0.33 (0.5) 0.59 (0.6) 0.28 (0.4) 0.50 (0.9) 0.57 (0.4)
p = 0.21 p = 0.39 p N 0.05 p = 0.60 p = 0.12 p = 0.12 p = 0.35 p = 0.81 p = 0.78 p = 0.48 p = 0.37
QOLc, mean (SD) Physical functioning Role limitation due to physical problems Pain General health Vitality Social functioning Role limitation due to emotional problems Mental health Total
88.6 (15.3) 88.7 (23.6) 74.1 (21.9) 72.5 (18.0) 63.5 (19.6) 90.4 (17.0) 90.4 (23.2) 74.8 (14.7) 80.3 (13.9)
82.3 (19.0) 79.4 (30.9) 71.6 (28.5) 69.7 (22.1) 60.2 (25.9) 86.8 (19.5) 74.5 (36.4) 73.6 (17.3) 74.4 (19.2)
87.0 (18.81) 85.0 (28.6) 71.6 (22.5) 72.9 (20.6) 67.7 (16.2) 89.4 (14.8) 91.7 (21.3) 77.2 (14.0) 80.3 (13.7)
92.5 (9.3) 95.1 (13.1) 76.6 (18.0) 73.6 (14.5) 62.6 (17.8) 92.7 (17.0) 97.2 (9.3) 74.0 (13.9) 83.0 (10.2)
p b 0.07 p = 0.05 p = 0.64 p = 0.76 p = 0.47 p = 0.48 p b 0.01 p = 0.69 p = 0.11
Psychological characteristics CRWa, mean (SD)
Controls
p value
b
a b c
CRW—Cancer Related Worry. BSI—Brief Symptoms Inventory. QOL—quality of life.
Brief Symptom Inventory Mean scores on subscales and total BSI were not different between groups, and were below threshold for psychopathology (Table 2). Health Related-Quality of Life Impaired HR-QOL was demonstrated in BRCA1/2 carriers compared to non-carriers and controls in role limitation due to emotional problems (carriers 74.51 ± 36.38, non carriers 91.67 ± 21.29, controls 97.22 ± 9.34; p = 0.003). Similar differences in HR-QOL measures reaching borderline significance were found in physical functioning, in role limitation due to physical problems and in mean total QOL scores (Table 2). These findings were maintained when education level was included as a covariate. While selecting women free of menopausal symptoms, differences in HR-QOL measures increased, with more impaired HR-QOL in BRCA1/2 carriers. Differences for carriers, non-carriers and controls respectively included physical functioning (79.55 ± 20.91, 89.58 ± 24.90, 92.73 ± 9.44; p = 0.025), role limitation due to emotional problems (75.76 ± 33.63, 94.44 ± 19.24, 96.97 ± 9.73; p = 0.007) and mean total QOL scores (73.12 ± 16.86, 85.65 ± 12.25, 83.29 ± 10.61; p = 0.036). When education level was entered as a covariate, only role limitation due to emotional problems remained significant (p b 0.01). Mediator analysis revealed a stronger correlation between total BSI and role limitation due to emotional problems in carriers (r = −.60) compared to controls (r = −.38), (p = 0.05). No other significant differences were found for the BSI or any of the CRW correlations. Discussion Asymptomatic BRCA1/2 carriers subsist in an uncertain situation in terms of health care expectations and risk reduction options. It
would be reasonable to assume that these women may develop disease related worry and distress which may result in poor QOL. While in cancer patients HR-QOL has commonly been studied in different stages of the disease (Kuroi et al., 2007), it has scarcely been explored in asymptomatic BRCA1/2 carriers. The significance of this study lies in the impact of positive BRCA1/2 diagnosis on health-related markers as reflected in HR-QOL of asymptomatic women. Here, indices of HR-QOL are impaired in BRCA1/2 carriers, particularly in role limitation due to emotional problems. This finding, likely mediated by psychological variables, stands firm when selecting women free of menopausal symptoms and when controlling for education level. It is supported by studies showing consistent mental awareness of cancer over time in high-risk women (e.g., Geirdal et al., 2006). The stratified analyses for women free of menopausal symptoms revealed further significant results, namely, impaired HR-QOL for physical functioning and overall HR-QOL in BRCA1/2 carriers compared to controls. Although the association between menopausal status and HR-QOL is not clearly defined, estrogen deprivation has been related to physical and mental symptoms. BRCA1/2 carriers often undergo prophylactic oophorectomy at a young age; yet in our sample, being a mutation carrier was associated with reduced indices of HR-QOL even after eliminating those with menopausal symptoms. Interestingly, physical functioning was compromised in carriers free of menopausal symptoms, a finding which warrants further investigation. In contrast to the impact of a positive genetic diagnosis on HR-QOL, negative results for predominant mutations in Ashkenazi Jews in Israel are not interpreted as inconclusive, which may explain the similar results in indices of HR-QOL for both non-carriers and controls in the present study. Nevertheless, BRCA1/2 non-carriers exhibited comparable levels of CRW to those in the carriers, indicating that their high-risk status remains a concern.
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Lower education level and age under 40 years are most associated with poor HR-QOL in high-risk women (Geirdal et al., 2006). In our sample, education level had a strong effect on all indices of HR-QOL, except for role limitation due to emotional problems, which remained significantly impaired in BRCA1/2 carriers compared to non-carriers and controls, despite lower education level in the former group. Study limitations and strengths Impaired QOL in asymptomatic BRCA1/2 carriers has been demonstrated, and validated following stratification of women free of menopausal symptoms and adjustment of education level. Nevertheless, a larger sample with comparable education levels and with a variety of populations at high-risk should be conducted. Assessment of HR-QOL several years following genetic testing indicates that our findings are enduring. However, a longitudinal study may investigate the development of impaired HR-QOL in women with BRCA1/2 mutations and in high-risk women. Conclusions BRCA1/2 carriers constitute a distinct group of women experiencing deficits in physical and mental components of HR-QOL. This study has clinical significance in terms of health promotion. Concurrently throughout the course of intensive surveillance applied for asympto-
matic BRCA1/2 carriers, emotional vulnerability in the context of HRQOL should be addressed and acted upon. Conflict of interest statement The authors declare that there are no conflicts of interest.
References Braithwaite, D., Emery, J., Walter, F., Sutton, S., et al., 2006. Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis. Fam. Cancer. 5, 61–75. Claes, E., Evers-Kiebooms, G., Boogaerts, A., et al., 2004. Diagnostic genetic testing for hereditary breast and ovarian cancer in cancer patients: women's looking back on the pre-test period and a psychological evaluation. Genet. Test. 8, 13–21. Derogatis, L.R., 1975. Brief Symptom Inventory. Clinical Research, Baltimore, MD. Geirdal, A.Ø., Maehle, L., Heimdal, K., et al., 2006. Quality of life and its relation to cancer-related stress in women of families with hereditary cancer without demonstrated mutation. Qual. Life Res. 15, 461–470. Gilbar, O., Ben-Zur, H., 2002. Cancer and the family caregiver, distress and coping. Springfield, Illinois, USA, p. 71. Kuroi, K., Shimozuma, K., Ohsumi, S., et al., 2007. Current status of health outcome assessment of medical treatment in breast cancer. Breast Cancer 14, 74–80. Lerman, C., Trock, B., Rimer, B.K., et al., 1991. Psychological side effects of breast cancer screening. Health Psychol. 10, 259–267. Simchoni, S., Friedman, E., Kaufman, B., et al., 2006. Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc. Natl. Acad. Sci. U. S. A. 103, 3770–3774. Smith, K.R., West, J.A., Croyle, R.T., et al., 1999. Familial context of genetic testing for cancer susceptibility: moderating effect of siblings' test results on psychological distress one to two weeks after BRCA1 mutation testing. Cancer Epidemiol. Biomarkers Prev. 8, 385–392. Ware Jr, J.E., Sherbourne, C.D., 1992. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 30, 473–483.
Contents lists available at ScienceDirect
Preventive Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y p m e d
Quality of life in asymptomatic BRCA1/2 mutation carriers Efrat Dagan a,b,⁎, Tamar Shochat a a b
Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel Rambam Health Care Campus, Institute of Human Genetics, Haifa, Israel
a r t i c l e
i n f o
Available online 24 November 2008 Keywords: BRCA1/2 Health-Related Quality of Life Hereditary breast–ovarian cancer Asymptomatic mutation carriers
a b s t r a c t Objective. To investigate the association between positive genetic diagnosis for BRCA1/2 mutations and Health-Related Quality of Life (HR-QOL) in Ashkenazi asymptomatic women. Methods. Socio-demographic, clinical, psychological and HR-QOL questionnaires were completed by 73 women, including 17 asymptomatic BRCA1/2 carriers and 20 non-carriers from the oncogenetic clinic at Rambam Health Care Campus in Israel; and 36 low-risk controls from the community, between January 2006 to November 2007. Results. Impaired HR-QOL was demonstrated in BRCA1/2 carriers compared to non-carriers and controls in the role limitation due to emotional problems subscale. When stratified by women free of menopausal symptoms and controlling for education level, this subscale remained significant, and likewise both physical functioning and overall HR-QOL scores were significantly lower in BRCA1/2 carriers. Conclusions. Our results suggest that BRCA1/2 carriers are prone to experience deficits in HR-QOL, especially in mental aspects affecting role functioning. © 2008 Elsevier Inc. All rights reserved.
Introduction In Ashkenazi Jews three predominant mutations in BRCA1/2 genes were found, with a frequency of 2–3% in the healthy population, and 20% to 40% in breast and ovarian cancer patients, respectively (Simchoni et al., 2006). Despite the headway towards risk reduction management, it is plausible to assume that BRCA1/2 carriage in asymptomatic women may result in a state of psychological distress, consequently leading to impairments in Health-Related Quality of Life (HR-QOL). Overall, major psychological vulnerability has not been found consequent to positive genetic testing (Braithwaite et al., 2006), although few studies have identified that probands (Smith et al., 1999) and women at risk who received inconclusive results (Claes et al., 2004) are most prone to distress due to genetic testing. Nevertheless, being at high-risk for developing breast–ovarian cancer may incur subtle disturbances in daily functioning related to aspects of HR-QOL. In patients with breast cancer, HR-QOL is commonly assessed, showing poor HR-QOL shortly after diagnosis and during treatment (Kuroi et al., 2007). To date, few studies have investigated HR-QOL in asymptomatic high-risk women, showing altered physical and emotional symptoms (e.g., Geirdal et al., 2006). While the clinical implications of being a BRCA1/2 carrier are acknowledged, the longterm effects on HR-QOL are far from clear in high-risk women. The aim
⁎ Corresponding author. Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel. Fax: +972 4 822017. E-mail address: [email protected] (E. Dagan). 0091-7435/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2008.11.007
of this study was to investigate the association between BRCA1/2 status and HR-QOL in Ashkenazi asymptomatic women. Methods Participants and study design This case-control design included asymptomatic BRCA1/2 mutation carriers and non-carriers who had undergone genetic testing at the Rambam Health Care Campus oncogenetic clinic during 1996–2006; and a community control group, all from the Greater Haifa area. Exclusion criteria were major chronic illnesses, pregnancy and young children under age one year; as these may alter usual lifestyle. Evaluation of the archived files revealed 39 asymptomatic BRCA1/2 carriers. Of these, five (13%) declined, nine (23%) were lost to follow-up, three (8%) had chronic illness and five (13%) were pregnant or had young children; leaving 17 (44%) carriers who completed the study. Non-carriers were consecutively recruited to obtain a quota of 20 women matched to carriers for age at genetic diagnosis and for time since testing. Seventy-seven women were contacted. Of these, nine (12%) declined, seven (9%) were lost to follow up, nine (12%) had chronic illnesses and 31 (40%) were unavailable at time of contact. To estimate the extent to which high-risk status, whether positive or negative, may impact QOL, age-matched low-risk controls (n = 36) with no family history of breast–ovarian cancer and not tested for BRCA1/2 mutations were recruited. Socio-demographic and clinical status, including self reported menopausal symptoms (e.g., hot flashes, vaginal dryness, etc.) was updated. Questionnaires aimed to assess HR-QOL, psychological
194
E. Dagan, T. Shochat / Preventive Medicine 48 (2009) 193–196
distress and cancer-related worry were completed during a home visit following written informed consent. This study was part of a larger project also investigating sleep disturbances and fatigue, which was approved by the Institutional Review Board at Rambam Health Care Campus. Measures Health-Related Quality of Life (HR-QOL) Short-Form (SF36) is a measure of health status, providing scores in areas of functioning and well-being related to mental and physical health (Ware and Sherbourne, 1992). Cancer Related Worry (CRW) measures how often a woman worries about breast and/or ovarian cancer and the effects of these worries on mood and daily performance (Lerman et al., 1991). The Brief Symptom Inventory (BSI) (Derogatis, 1975) assesses psychological distress, e.g., somatization, depression, anxiety, etc. Psychometric properties in the general population in Israel revealed scores under one in all subscales and global (GSI) score (Gilbar and Ben-Zur, 2002). Data management and statistical analyses The three groups were compared in respect to their sociodemographic, clinical and psychological characteristics using χ2 and one-way ANOVA when appropriate. Multiple analysis of variance (MANOVA) was performed both on the entire sample and stratified
based on presence of menopausal symptoms, to compare group differences in measures of HR-QOL. Post-hoc (Sidak) analysis was used to determine significant group differences. Mediator analysis was performed to assess the contribution of psychological factors in the relationship between carrier status and HR-QOL. Correlations were computed separately for the three groups, between CRW and BSI total scores and between HR-QOL scores that were found to be significantly different by group. Differences between correlations transformed to standardized Z-scores were assessed by Z-test analysis. Results The current study consisted of 73 high-risk women and controls. Of these, 37 (50.7%) were at high-risk, further subdivided to 17 (23.3%) BRCA1/2 carriers and 20 (27.4%) non-carriers; and 36 (49.3%) were low risk controls. Socio demographics and clinical characteristics are presented in Table 1. Psychological characteristics Cancer Related Worry Relatively higher levels of CRW were reported by BRCA1/2 carriers (0.75 ± 0.53) than non-carrier (0.67 ± 0.48) and controls (0.45 ± 0.44) (p = 0.067) (Table 2). When BRCA1/2 carriers and non-carriers were grouped together, significantly higher levels of CRW were reported compared to controls (0.71 ± 0.50 and 0.45 ± 0.44, respectively; p = 0.022).
Table 1 Socio-demographic and clinical characteristics in asymptomatic BRCA1/2 mutation carriers, non-carriers and controls, enrolled at the oncogenetic clinic, RAMBAM Health Care Campus and community, during January 10, 2006 to November 9, 2007
Age, mean (SD) Age at BRCA1/2 testing, mean (SD) Follow-up in years, mean (SD, range)
Total
High-risk
n = 73
BRCA1/2 carriers n = 17
BRCA1/2 non-carriers n = 20
n = 36
51.5 (8.9) 45.0 (9.0) 8.0 (1.9)
51.4 (9.1) 43.8 (8.8) 7.6 (2.5, 5–11)
54.5 (9.4) 46.0 (9.1) 8.4 (1.1, 7–11)
50.0 (8.3) – –
Family status (n, %) Married Single Divorce Widows
61 (83.6) 3 (4.1) 7 (9.6) 2 (2.7)
Have children (n, %) Yes No
71 (97.3) 2 (2.7)
16 (94.1) 1 (5.9)
Education (n, %) High-school College Graduate
14 (19.2) 7 (9.6) 52 (71.2)
8 (47.1) 3 (17.6) 6 (35.3)
Income (n, %) Lower than average Average Higher than average
3 (4.2) 37 (51.4) 32 (44.4)
1 (5.9) 9 (52.9) 7 (41.2)
Family history (n, %) 1st and/or 2nd degree of BCa or OCb Other cancer than BC or OC No family history of cancer
34 (46.6) 14 (19.2) 25 (34.2)
Prophylactic oophorectomy (n, %) Yes No Menopausal symptoms (n, %) Yes No a b
BC—breast cancer. OC—ovarian cancer.
15 (88.2) 1 (5.9)
Controls
17 (85.0) 2 (10.0) 1 (5.0)
1 (5.9)
–
20 (100)
p = 0.48
35 (97.2) 1 (2.8)
p = 0.55
3 (15.0) 3 (15.0) 14 (70.0)
3 (8.3) 1 (2.8) 32 (88.9)
p b 0.01
10 (50) 10 (50)
2 (5.6) 18 (50) 16 (44.4)
p = 0.88
11 (30.5) 25 (69.5)
p b 0.01
2 (5.5) 34 (94.5)
p = 0.05
–
–
17 (100) – –
p = 0.19 p = 0.46 p = 0.20
29 (80.6) 2 (5.6) 5 (13.9)
–
–
p value
17 (85.0) 3 (15.0) –
–
14 (82.3) 3 (17.7)
13 (17.8) 60 (82.2)
6 (35.3) 11 (64.7)
5 (25) 15 (75)
E. Dagan, T. Shochat / Preventive Medicine 48 (2009) 193–196
195
Table 2 Psychological characteristics and quality of life in asymptomatic BRCA1/2 mutation carriers, non-carriers and controls, enrolled at the oncogenetic clinic, RAMBAM Health Care Campus and community, during January 10, 2006 to November 9, 2007 Total
High-risk
n = 73
BRCA1/2 carriers n = 17
BRCA1/2 non-carriers n = 20
n = 36
0.58 (0.5)
0.75 (0.5)
0.67 (0.5)
0.45 (0.4)
p b 0.07
BSI , mean (SD) Somatization Obsessive–compulsive Sensitivity Depression Anxiety Hostility Phobic anxiety Paranoid thought Psychoticism Suicidal ideation Total
0.50 (0.5) 0.78 (0.7) 0.70 (0.6) 0.47 (0.5) 0.62 (0.5) 0.45 (0.4) 0.27 (0.4) 0.55 (0.6) 0.26 (0.5 0.42 (0.7) 0.52 (0.4)
0.66 (0.7) 0.93 (0.9) 0.59 (0.6) 0.48 (0.6) 0.61 (0.5) 0.54 (0.5) 0.16 (0.3) 0.48 (0.8) 0.19 (0.3) 0.24 (0.4) 0.53 (0.5)
0.35 (0.4) 0.63 (0.5) 0.49 (0.4) 0.37 (0.4) 0.43 (0.4) 0.29 (0.3) 0.24 (0.4) 0.52 (0.5) 0.29 (0.7) 0.45 (0.6) 0.41 (0.4)
0.50 (0.4) 0.80 (0.6) 0.87 (0.7 0.52 (0.6) 0.73 (0.6) 0.51 (0.5) 0.33 (0.5) 0.59 (0.6) 0.28 (0.4) 0.50 (0.9) 0.57 (0.4)
p = 0.21 p = 0.39 p N 0.05 p = 0.60 p = 0.12 p = 0.12 p = 0.35 p = 0.81 p = 0.78 p = 0.48 p = 0.37
QOLc, mean (SD) Physical functioning Role limitation due to physical problems Pain General health Vitality Social functioning Role limitation due to emotional problems Mental health Total
88.6 (15.3) 88.7 (23.6) 74.1 (21.9) 72.5 (18.0) 63.5 (19.6) 90.4 (17.0) 90.4 (23.2) 74.8 (14.7) 80.3 (13.9)
82.3 (19.0) 79.4 (30.9) 71.6 (28.5) 69.7 (22.1) 60.2 (25.9) 86.8 (19.5) 74.5 (36.4) 73.6 (17.3) 74.4 (19.2)
87.0 (18.81) 85.0 (28.6) 71.6 (22.5) 72.9 (20.6) 67.7 (16.2) 89.4 (14.8) 91.7 (21.3) 77.2 (14.0) 80.3 (13.7)
92.5 (9.3) 95.1 (13.1) 76.6 (18.0) 73.6 (14.5) 62.6 (17.8) 92.7 (17.0) 97.2 (9.3) 74.0 (13.9) 83.0 (10.2)
p b 0.07 p = 0.05 p = 0.64 p = 0.76 p = 0.47 p = 0.48 p b 0.01 p = 0.69 p = 0.11
Psychological characteristics CRWa, mean (SD)
Controls
p value
b
a b c
CRW—Cancer Related Worry. BSI—Brief Symptoms Inventory. QOL—quality of life.
Brief Symptom Inventory Mean scores on subscales and total BSI were not different between groups, and were below threshold for psychopathology (Table 2). Health Related-Quality of Life Impaired HR-QOL was demonstrated in BRCA1/2 carriers compared to non-carriers and controls in role limitation due to emotional problems (carriers 74.51 ± 36.38, non carriers 91.67 ± 21.29, controls 97.22 ± 9.34; p = 0.003). Similar differences in HR-QOL measures reaching borderline significance were found in physical functioning, in role limitation due to physical problems and in mean total QOL scores (Table 2). These findings were maintained when education level was included as a covariate. While selecting women free of menopausal symptoms, differences in HR-QOL measures increased, with more impaired HR-QOL in BRCA1/2 carriers. Differences for carriers, non-carriers and controls respectively included physical functioning (79.55 ± 20.91, 89.58 ± 24.90, 92.73 ± 9.44; p = 0.025), role limitation due to emotional problems (75.76 ± 33.63, 94.44 ± 19.24, 96.97 ± 9.73; p = 0.007) and mean total QOL scores (73.12 ± 16.86, 85.65 ± 12.25, 83.29 ± 10.61; p = 0.036). When education level was entered as a covariate, only role limitation due to emotional problems remained significant (p b 0.01). Mediator analysis revealed a stronger correlation between total BSI and role limitation due to emotional problems in carriers (r = −.60) compared to controls (r = −.38), (p = 0.05). No other significant differences were found for the BSI or any of the CRW correlations. Discussion Asymptomatic BRCA1/2 carriers subsist in an uncertain situation in terms of health care expectations and risk reduction options. It
would be reasonable to assume that these women may develop disease related worry and distress which may result in poor QOL. While in cancer patients HR-QOL has commonly been studied in different stages of the disease (Kuroi et al., 2007), it has scarcely been explored in asymptomatic BRCA1/2 carriers. The significance of this study lies in the impact of positive BRCA1/2 diagnosis on health-related markers as reflected in HR-QOL of asymptomatic women. Here, indices of HR-QOL are impaired in BRCA1/2 carriers, particularly in role limitation due to emotional problems. This finding, likely mediated by psychological variables, stands firm when selecting women free of menopausal symptoms and when controlling for education level. It is supported by studies showing consistent mental awareness of cancer over time in high-risk women (e.g., Geirdal et al., 2006). The stratified analyses for women free of menopausal symptoms revealed further significant results, namely, impaired HR-QOL for physical functioning and overall HR-QOL in BRCA1/2 carriers compared to controls. Although the association between menopausal status and HR-QOL is not clearly defined, estrogen deprivation has been related to physical and mental symptoms. BRCA1/2 carriers often undergo prophylactic oophorectomy at a young age; yet in our sample, being a mutation carrier was associated with reduced indices of HR-QOL even after eliminating those with menopausal symptoms. Interestingly, physical functioning was compromised in carriers free of menopausal symptoms, a finding which warrants further investigation. In contrast to the impact of a positive genetic diagnosis on HR-QOL, negative results for predominant mutations in Ashkenazi Jews in Israel are not interpreted as inconclusive, which may explain the similar results in indices of HR-QOL for both non-carriers and controls in the present study. Nevertheless, BRCA1/2 non-carriers exhibited comparable levels of CRW to those in the carriers, indicating that their high-risk status remains a concern.
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Lower education level and age under 40 years are most associated with poor HR-QOL in high-risk women (Geirdal et al., 2006). In our sample, education level had a strong effect on all indices of HR-QOL, except for role limitation due to emotional problems, which remained significantly impaired in BRCA1/2 carriers compared to non-carriers and controls, despite lower education level in the former group. Study limitations and strengths Impaired QOL in asymptomatic BRCA1/2 carriers has been demonstrated, and validated following stratification of women free of menopausal symptoms and adjustment of education level. Nevertheless, a larger sample with comparable education levels and with a variety of populations at high-risk should be conducted. Assessment of HR-QOL several years following genetic testing indicates that our findings are enduring. However, a longitudinal study may investigate the development of impaired HR-QOL in women with BRCA1/2 mutations and in high-risk women. Conclusions BRCA1/2 carriers constitute a distinct group of women experiencing deficits in physical and mental components of HR-QOL. This study has clinical significance in terms of health promotion. Concurrently throughout the course of intensive surveillance applied for asympto-
matic BRCA1/2 carriers, emotional vulnerability in the context of HRQOL should be addressed and acted upon. Conflict of interest statement The authors declare that there are no conflicts of interest.
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