This randomized controlled trial evaluated the impact of an enhanced counseling intervention on knowledge about the heritability of breast and ovarian cancer and distress, as a function of BRCA test result, among high-risk women. Before deciding about whether or not to undergo genetic testing, participants were randomly assigned to the enhanced counseling intervention (N = 69), designed to promote cognitive and affective processing of cancer risk information (following the standard individualized counseling session), or to the control condition (N = 65), which involved standard individualized counseling followed by a general health information session to control for time and attention. Women in the enhanced counseling group exhibited greater knowledge than women in the control group one week after the intervention. Further, at the affective level, the intervention was found to be most beneficial for women testing positive: specifically one week after test result disclosure, women in the intervention group who tested positive experienced lower levels of distress than women in the control group who tested positive. The findings suggest that the design of counseling aids should include a component that explicitly activates the individual's cognitive-affective processing system.
Genetic testing; enhanced counseling; intrusive ideation; breast cancer; ovarian cancer
This study sought to examine changes in psychological distress following cancer genetic counselling. Women attending a family cancer clinic completed questionnaires before their appointment and at 2 weeks, 6 months and 12 months after their appointment. Twenty-six women were at low risk of developing breast or ovarian cancer, 76 were at moderate risk, 46 were at high risk and 46 women had previously had breast or ovarian cancer. All groups were compared with regard to measures of anxiety, depression, general psychological distress, worry about developing breast and ovarian cancer, and perceived risk of developing breast/ovarian cancer and perceived likelihood of carrying a genetic mutation. General psychological distress did not change over the course of the study and the groups did not differ on these measures. Worry about developing breast cancer and perceptions of the likelihood of carrying a genetic mutation significantly reduced following genetic counselling. On the whole women who had already had breast/ovarian cancer showed more concerns about ovarian cancer and raised perceptions of risk in comparison with the other groups, indicating the need for sensitive counselling of such women.
British Journal of Cancer (2002) 86, 43–50. DOI: 10.1038/sj/bjc/6600030 www.bjcancer.com
© 2002 The Cancer Research Campaign
breast and ovarian cancer genetics; affected and unaffected women; psychological distress; risk perceptions
Clinical evidence supports the value of BRCA1/2 genetic counseling and testing (GC/T) for managing hereditary breast and ovarian cancer risk; however, BRCA1/2 GC/T is underutilized among Black women and reasons for low use remain elusive. We examined the potential influence of socio-cultural factors (medical mistrust, concerns about genetic discrimination) on GC/T engagement in a sample of 100 Black women at increased risk for carrying a BRCA1/2 mutation. Eligible participants fell into one of three groups: 1) healthy women with ≥ 1 first-degree relative (FDR) affected by breast and/or ovarian cancer, 2) women diagnosed with breast cancer at age ≤ 50, and 3) women diagnosed with breast and/or ovarian cancer at age ≥ 50 with either one FDR or two second degree relatives with breast and/or ovarian cancer. Participants were recruited from clinical and community settings and completed a semi-structured interview. Study variable relationships were examined using bivariate tests and multivariate regression analysis. Forty-three percent of participants were aware of GC/T services. Yet referral and receipt of GC/T services in this sample was low (28%). After accounting for sociodemographic factors, women with higher self-efficacy had greater GC/T engagement (B = 0.37, p < .001), while those with higher medical mistrust had lower GC/T engagement (B = −0.26, p <. 01). Interventions targeted towards increasing provider referrals may facilitate higher levels of engagement in GC/T services. Individual interventions that enhance women’s personal confidence in obtaining GC/T may also be useful in promoting GC/T engagement.
Medical Mistrust; Self-efficacy; BRCA 1/2; African American
In women at increased risk for breast and ovarian cancer, the identification of a BRCA1/2 mutation has important implications for screening and prevention counseling. Uncertainty regarding the role of BRCA1/2 testing in high-risk women from diverse ancestral backgrounds exists due to variability in prevalence estimates of deleterious (disease-associated) mutations in non-White populations. We examined the prevalence of BRCA1/2 mutations in an ethnically diverse group of women referred for genetic testing.
We conducted a cross-sectional analysis to assess the prevalence of BRCA1/2 mutations in a group of non-Ashkenazi Jewish women undergoing genetic testing.
From 1996-2006, 46,276 women meeting study criteria underwent DNA full-sequence analysis of the BRCA1 and BRCA2 genes. Deleterious mutations were identified in 12.5% of subjects, and recurrent deleterious mutations (prevalence > 2%) were identified in all ancestral groups. Women of non-European descent were younger (45.9 yrs, SD11.6) than European (50.0 yrs, SD11.9)(p<0.001). Women of African (15.6%)[OR 1.3(1.1-1.5)] and Latin American (14.8%)[OR 1.2(1.1-1.4)] ancestries had a significantly higher prevalence of deleterious BRCA1/2 mutations compared to women of Western European ancestry (12.1%), primarily due to an increased prevalence of BRCA1 mutations in these two groups. Non-European ethnicity was strongly associated with having a variant of uncertain significance; however, re-classification decreased variant reporting (12.8%→5.9%), with women of African ancestry experiencing the largest decline (58%).
Mutation prevalence is high among women referred for clinical BRCA1/2 testing, and risk is similar across diverse ethnicities. BRCA1/2 testing is integral to cancer risk assessment in all high-risk women.
BRCA1; BRCA2; genetic testing; race; ethnicity
The aim was to compare the psychological impact of a multidisciplinary specialist genetics service with surgical provision in women at high risk and those at lower risk of familial breast cancer. Women (n=735) were randomized to a surgical consultation with (trial group) or without (control group) specialist genetic risk assessment and the possible offer of presymptomatic genetic testing. Participants completed questionnaires before and immediately after the consultation to assess anxiety, cancer worry, perceived risk, interest in genetic testing and satisfaction. Responses of subgroups of women stratified by clinicians as low, moderate, or high risk were analyzed. There were no significant main effects of study intervention on any outcome variable. Regardless of risk information, there was a statistically significant reduction in state anxiety (P<0.001). Reductions in cancer worry and perceived risk were significant for women at low or moderate risk (P<0.001) but not those at high risk, and satisfaction was significantly lower in the high risk group (P<0.001). In high risk women who received specialist genetic input, there was a marginally significant trend towards increased perceived risk. The effect of risk information on interest in genetic testing was not significant. Breast care specialists other than geneticists might provide assessments of breast cancer risk, reassuring women at reduced risk and targeting those at high risk for specialist genetic counselling and testing services. These findings are discussed in relation to the existing UK Calman-Hine model of service delivery in cancer genetics.
British Journal of Cancer (2002) 86, 233–238. DOI: 10.1038/sj/bjc/6600051 www.bjcancer.com
© 2002 The Cancer Research Campaign
familial breast cancer; genetic risk assessment; psychological impact; service delivery
The aim of this multi-centre UK study is to examine the attributes of a cohort offered predictive genetic testing for breast/ovarian cancer predisposition. Participants are adults unaffected with cancer from families with a known BRCA1/2 mutation. This is the first large multi-centre study of this population in the UK. The study evaluates mental health, perceived risk of developing cancer, preferred risk management options, and motivation for genetic testing. Participants were assessed when coming forward for genetic counselling prior to proceeding to genetic testing. Three hundred and twelve individuals, 76% of whom are female, from nine UK centres participated in the study. There are no gender differences in rates of psychiatric morbidity. Younger women (<50 years) are more worried about developing cancer than older women. Few women provide accurate figures for the population risk of breast (37%) or ovarian (6%) cancer but most think that they are at higher risk of developing breast (88%) and ovarian (69%) cancer than the average woman. Cancer related worry is not associated with perceived risk or uptake of risk management options except breast self-examination. The findings indicate that younger women may be particularly vulnerable at the time of the offer of a predictive genetic test.
British Journal of Cancer (2002) 86, 1209–1216. DOI: 10.1038/sj/bjc/6600253 www.bjcancer.com
© 2002 Cancer Research UK
predictive genetic testing; worry; risk management
Women who participate in BRCA1/2 cancer genetic counseling do so for a variety of reasons, including learning quantitative risk information about their chances of developing hereditary breast-ovarian cancer at some point during their lifetimes. For these women, obtaining pre-test and disclosure genetic counseling with a professional affords them numerous potential benefits, including adequate preparation for, and accurate interpretation of, their test results. In consequence, women commonly report being highly satisfied with their cancer genetic counseling experience, even if the information learned through testing suggests they are at increased cancer risk. This occurrence raises an interesting question, namely what are the psychological aspects of satisfaction with genetic counseling for hereditary breast-ovarian cancer in women? To answer this question, we administered the Genetic Counseling Satisfaction Scale (GCSS) to a convenience sample of 61 women participating in BRCA1/2 pre-test genetic counseling, and re-administered the GCSS to approximately one-third of these women at disclosure. Available psychological data included personality, distress, and family functioning. In bivariate analyses, optimism and family functioning were positively associated with pre-test satisfaction. With respect to satisfaction at disclosure, general and cancer-specific distress were negatively associated with satisfaction. Our findings suggest that psychological aspects of satisfaction with cancer genetic counseling vary, with individual differences and family functioning playing a role at pre-test, and distress playing a role at disclosure. The implications for future research and clinical practice are discussed.
hereditary breast and ovarian cancer; genetic counseling; genetic testing; satisfaction; psychology
This cross sectional study aimed to characterize fears of recurrence among women newly diagnosed with gynecologic cancer. The study also evaluated models predicting the impact of recurrence fears on psychological distress through social and cognitive variables.
Women (N = 150) who participated in a randomized clinical trial comparing a coping and communication intervention to a supportive counseling intervention to usual care completed baseline surveys that were utilized for the study. The survey included the Concerns about Recurrence Scale (CARS), Beck Depression Inventory (BDI), Impact of Event Scale (IES), and measures of social (holding back from sharing concerns and negative responses from family and friends) and cognitive (positive reappraisal, efficacy appraisal, and self-esteem appraisal) variables. Medical data was obtained via medical chart review.
Moderate-to-high levels of recurrence fears were reported by 47% of the women. Younger age (p < .01) and functional impairment (p < .01) correlated with greater recurrence fears. A social-cognitive model of fear of recurrence and psychological distress was supported. Mediation analyses indicated that as a set, the social and cognitive variables mediated the association between fear of recurrence and both depression and cancer-specific distress. Holding back and self-esteem showed the strongest mediating effects.
Fears of recurrence are prevalent among women newly diagnosed with gynecologic cancer. Social and cognitive factors play a role in women’s adaptation to fears and impact overall psychological adjustment. These factors may be appropriate targets for intervention.
Recurrence fears; gynecological cancer; social-cognitive processing; psychological adaptation
For BRCA1/BRCA2 gene testing to benefit public health, mutation carriers must initiate appropriate risk management strategies. There has been little research examining the long-term use and prospective predictors of the full range of risk management behaviors among women who have undergone BRCA1/2 testing. We evaluated long-term uptake and predictors of risk reducing mastectomy (RRM), risk reducing oophorectomy (RRBSO), chemoprevention and cancer screening among women at a mean of 5.3 years post testing.
Patients and Methods
Participants were 465 women who underwent BRCA1/2 testing. Prior to genetic counseling, we measured family/personal cancer history, sociodemographics, perceived risk, cancer-specific and general distress. We contacted patients at a mean of 5.3-years post-testing to measure use of: RRM; RRBSO; chemoprevention; breast and ovarian cancer screening.
Among participants with intact breasts and/or ovaries at the time of testing, BRCA1/2 carriers were significantly more likely to obtain RRM (37%) and RRBSO (65%) compared to women who received uninformative (RRM=6.8%; RRBSO=13.3%) or negative (RRM=0%; RRBSO=1.9%) results. Among carriers, pre-counseling anxiety was associated with subsequent uptake of RRM. RRO was predicted by age. Carriers were also more likely have used breast cancer chemoprevention and have obtained a screening MRI.
This prospective evaluation of the uptake and predictors of long-term management outcomes provides a clearer picture of decision making in this population. By a mean of 5.3 years post-testing, more than 80% of carriers had obtained RRM, RRBSO or both, suggesting that BRCA1/2 testing is likely to favorably impact breast and ovarian cancer outcomes.
Women affected with breast cancer who carry a BRCA1 or BRCA2 (BRCA1/2) mutation are at risk of developing contralateral breast cancer. To reduce the risk of contralateral breast cancer, some patients opt for prophylactic surgery of the unaffected breast (contralateral prophylactic mastectomy; CPM) in addition to mastectomy of the affected breast.
We conducted the present study to determine the predictors and outcomes of CPM in the year following BRCA1/2 genetic counseling and testing. 435 women affected with unilateral breast cancer who received positive or uninformative BRCA1/2 genetic test results completed assessments prior to genetic counseling and testing and 1, 6, and 12 months after receipt of results.
Prior to testing, 16% had undergone CPM (in conjunction with mastectomy of the affected breast). In the year following testing, 18% with positive test results and 3% with uninformative test results opted for CPM. CPM following testing was associated with a positive genetic test result, younger age at cancer diagnosis (OR = .94), and higher cancer-specific distress at baseline (OR = 3.28). CPM was not associated with distress outcomes at 12-months.
Following a positive test result, 18% of women previously affected with unilateral breast cancer had a CPM. Women affected with breast cancer at a younger age, particularly those with positive genetic test results and higher cancer-specific distress, are more likely to choose CPM than women who receive uninformative test results and who are less distressed and older at diagnosis. CPM does not appear to impact distress outcomes.
BRCA1/2; breast cancer survivors; contralateral prophylactic mastectomy; genetic testing; psychosocial predictors; distress outcomes
Epithelial ovarian cancer is the seventh most frequent cancer in European women. Many theories have been postulated regarding the pathogenesis of ovarian cancer. Risk factors are not well defined, with the exception of low parity and oral contraceptive use. Approximately 10% of ovarian cancer are hereditary, with BRCA1 and BRCA2 explaining the majority (approximately 90%) of hereditary ovarian cancer cases. The lifetime risk varies between 15 and 66%, suggesting the existence of modifying genetic or environmental factors.Family history can be used to define women who are at increased risk of ovarian cancer. Individuals at high risk are those with a first degree relative (mother, father, sister, brother, daughter or son) affected by cancer. It must be noted that currently available tests do not attain the aforementioned high level of sensitivity. Evidence suggest that presymptomatic screening by grey scale ultrasound (with or without Doppler), CA125, pelvic examination, or combinations of these, are not effective in detecting tumors at an early stage. Women identified as being at high risk of ovarian cancer can be offered prophylactic oophorectomy. The decision whether or not to proceed to prophylactic oophorectomy is influenced by the fact that most women at increased risk of ovarian cancer are also at increased risk of breast cancer and there is evidence that oophorectomy reduces breast cancer in these cases.
prophylactic oophorectomy; CA125; hereditary cancer
Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Female carriers of BRCA1 or BRCA2 gene mutations have very high lifetime risks for breast and ovarian cancers. Genetic abnormalities occur in all cancers so BRCA-related pathways are critical because they serve to safeguard genetic content. Although protecting genetic information is a general function, BRCA-related pathways appear largely specific to preventing breast and ovarian cancer. The objective of this study was to resolve this difference between the theoretical functions of BRCA genes and their specific clinical effects.
Data sources, data extraction, data synthesis
I collected data published in >30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation carriers and in large populations eligible for mutation testing. Data was extracted and used directly as published whenever possible with a minimum of statistical manipulation.
Although mutations target breast and ovary, a broader spectrum of cancers also occurs with statistically significant elevated frequencies. Risks for “all cancers except breast or ovary” are elevated, with some population subgroups differing in how often elevated risks were found at individual sites. Additional sites at risk included stomach, pancreas, prostate and colon. The increased risk ranged from about 20-60% with the greatest increases in risk in stomach and pancreas.
The collected data shows BRCA-pathway functions are probably required at multiple sites, not just in breast or ovary. Known interactions and relationships among BRCA-related pathways strongly support the idea that their inactivation provides growth or survival advantages for a variety of cancers. The data suggest applying an increased level of clinical alertness to those with defects in BRCA-related pathways. Identifying molecules that confer growth or survival advantages to BRCA-related cancers may provide broadly useful targets for chemotherapy or chemoprevention.
Presymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87%) or ovarian cancer (10-60%) and may opt for intensive breast and ovary surveillance or prophylactic surgery (mastectomy/oophorectomy).
We studied general and cancer related distress in 85 healthy women with a 25% or 50% risk of being carrier of a BRCA1/BRCA2 gene mutation and 66 partners in the six to eight week period between genetic counselling/blood sampling and disclosure of the test result. Questionnaire and interview data are analysed. Associations are explored between levels of distress and (1) expected consequences of being identified as a mutation carrier, (2) personality traits, (3) sociodemographic variables, and (4) experiences related to HBOC.
Mean pre-test anxiety and depression levels in women at risk of being a carrier and partners were similar to those of a normal Dutch population. In about 25% of those at risk of being a carrier and 10% of the partners, increased to high levels of general and cancer related distress were found. Increased levels of distress were reported by women who (1) anticipated an increase in problems after an unfavourable test outcome, (2) considered prophylactic mastectomy if found to be mutation carrier, (3) had an unoptimistic personality, (4) tended to suppress their emotions, (5) were younger than 40 years, and (6) were more familiar with the serious consequences of HBOC. Recently obtained awareness of the genetic nature of cancer in the family was not predictive of distress.
The majority of the women and their partners experienced a relatively calm period before the disclosure of the test result and seemed to postpone distressing thoughts until the week of disclosure of the result. The low distress levels may partly be explained by the use of strategies to minimise the emotional impact of a possibly unfavourable test outcome. However, a minority reported feeling very distressed. Several factors were found to be predictive for increased distress levels.
Keywords: genetic testing; cancer; BRCA1/BRCA2; psychological distress
We assessed ovarian cancer screening outcomes in women with a positive family history of ovarian cancer divided into a low-, moderate- or high-risk group for development of ovarian cancer.
545 women with a positive family history of ovarian cancer referred to the Ovarian Screening Service at the Royal Marsden Hospital, London from January 2000- December 2008 were included. They were stratified into three risk-groups according to family history (high-, moderate- and low-risk) of developing ovarian cancer and offered annual serum CA 125 and transvaginal ultrasound screening. The high-risk group was offered genetic testing.
The median age at entry was 44 years. The number of women in the high, moderate and low-risk groups was 397, 112, and 36, respectively. During 2266 women years of follow-up two ovarian cancer cases were found: one advanced stage at her fourth annual screening, and one early stage at prophylactic bilateral salpingo-oophorectomy (BSO). Prophylactic BSO was performed in 138 women (25.3%). Forty-three women had an abnormal CA125, resulting in 59 repeat tests. The re-call rate in the high, moderate and low-risk group was 14%, 3% and 6%. Equivocal transvaginal ultrasound results required 108 recalls in 71 women. The re-call rate in the high, moderate, and low-risk group was 25%, 6% and 17%.
No early stage ovarian cancer was picked up at annual screening and a significant number of re-calls for repeat screening tests was identified.
ovarian cancer; screening; transvaginal ultrasound; serum CA125; BRCA gene mutation; bilateral salpingo-oophorectomy
In Western countries, the mutation status of the BRCA1 and BRCA2 genes is commonly determined for genetic counseling among members of families with a history of breast or ovarian cancer, especially for women of the Ashkenazi Jewish ethnicity. Recent studies in the Cancer Genome Atlas project have demonstrated that BRCA2 mutation carriers are more responsive to platinum-based chemotherapy among high-grade serous ovarian cancer patients. Thus, in Western countries, the mutation status of BRCA1 and BRCA2 is recognized to have an important value with which to assess cancer risk and therapeutic response. However, very limited studies of BRCA1 and BRCA2 mutations and their implications for counseling and therapeutic prediction have been conducted in China. Therefore, a potentially important genetic test that is technically simple has not benefited Chinese women with an increased risk of breast or ovarian cancer. This article summarizes the current progress in the study of BRCA1/2 mutation in China and recommends an increased effort in applying advances in genetic testing to the clinical management of Chinese patients with ovarian cancer.
Ovarian cancer; BRCA mutation; drug response; survival
To determine the prevalence of fathers’ attendance at pretest cancer genetic counseling sessions with mothers undergoing BRCA1/2 genetic testing for hereditary breast/ovarian cancer (HBOC) risk, and to identify psychosocial and other correlates of fathers’ attendance.
One hundred twenty-one fathers of minor-age children who were spouses/partners of women (mothers) undergoing such counseling and testing were recruited, completed a behavioral self-report survey, and provided data about their sociodemographic backgrounds, father-child cancer communication histories, parenting relationship quality, and information-seeking and perceived knowledge.
A total of 27.3% of fathers attended pretest cancer genetic counseling with mothers. Compared to fathers who did not attend pretest cancer genetic counseling, those who did had stronger parenting alliances with mothers, were more likely to have sought out information about BRCA1/2 testing, and felt more informed about testing. In an adjusted logistic regression model of session attendance, the strength of the parenting alliance was associated with a 6% increase in the likelihood of attending genetic counseling (Odds Ratio [OR] = 1.06, 95% Confidence Interval [CI] = 1.01, 1.12, p < .05) and greater perceived knowledge about BRCA1/2 testing was associated a four-fold increase in the likelihood of session attendance (OR = 4.03, CI = 1.77, 9.37, p < .001).
One in three fathers attend pretest cancer genetic counseling with mothers undergoing BRCA1/2 testing; those who do have closer parenting relationships and are more informed about BRCA1/2 testing.
When possible, providers should discuss mothers including fathers in cancer genetic counseling sessions as this may affect outcomes of HBOC genetic counseling and testing.
Cancer; Breast cancer; Genetic counseling; BRCA1/2 testing; Parents
Limited empirical data are available on the effects of genetic counseling and testing among African American women.
To evaluate the effects of genetic counseling and testing in African American women based on different levels of exposure: (a) women who were randomized to culturally tailored (CTGC) and standard genetic counseling (SGC) to women who declined randomization (non-randomized group), (b) participants and non-participants in genetic counseling, and (c) BRCA1 and BRCA2 (BRCA1/2) test result acceptors and decliners.
Randomized trial of genetic counseling conducted from February 2003 to November 2006.
We evaluated changes in perceived risk of developing breast cancer and cancer worry.
Women randomized to CTGC and SGC did not differ in terms of changes in risk perception and cancer worry compared to decliners. However, counseling participants had a significantly greater likelihood of reporting reductions in perceived risk compared to non-participants (p = 0.03). Test result acceptors also had a significantly greater likelihood of reporting decreases in cancer worry (p = 0.03). However, having a cancer history (p = 0.03) and a BRCA1/2 prior probability (p = 0.04) were associated with increases in cancer worry.
Although CTGC did not lead to significant improvements in perceived risk or psychological functioning, African American women may benefit from genetic counseling and testing. Continued efforts should be made to increase access to genetic counseling and testing among African American women at increased risk for hereditary disease. But, follow-up support may be needed for women who have a personal history of cancer and those with a greater prior probability of having a BRCA1/2 mutation.
African American; BRCA1; BRCA2; Cultural factors; Genetic counseling
The availability of family-centred services for women genetically at-risk for breast and ovarian cancer (BRCA) due to deleterious genetic mutations is still scarce, despite the distress that these women and their families may experience. This study describes a multi-family group intervention for women who tested positive for BRCA mutations and their families. Methods include a time-limited psycho-educational programme involving educational and support components and consisting of four semi-structured multi-family sessions. Three families (a total of nine people) attended the programme in genetic counselling for hereditary cancers at a Portuguese public hospital. A focus group interview was performed 1 month after the last session to assess both the practical and the psychosocial impacts and to collect suggestions from participants. The present paper focuses on the practical aspects of the intervention, its development and its evaluation. Participants reported that the programme is well-structured and that responds to the needs of patients and their families by improving coping skills and medical awareness in the adaptation to genetic illness. Results reinforce the need to integrate psychosocial and family-oriented interventions in genetic counselling, addressing the holistic experience of hereditary disease. Recommendations for enhancing the services available are provided. The multi-family discussion group, combining educative and supportive services with a family focus, can be successfully adapted in genetic counselling protocols.
Genetic counselling; Hereditary cancer; Psychosocial genetics; Psycho-education; Multi-family groups
It has been estimated that between 5% and 10% of women diagnosed with breast cancer have a hereditary form of the disease, primarily caused by a BRCA1 or BRCA2 gene mutation. Such women have an increased risk of developing a new primary breast and/or ovarian tumor, and may therefore opt for preventive surgery (e.g., bilateral mastectomy, oophorectomy). It is common practice to offer high-risk patients genetic counseling and DNA testing after their primary treatment, with genetic test results being available within 4-6 months. However, some non-commercial laboratories can currently generate test results within 3 to 6 weeks, and thus make it possible to provide rapid genetic counseling and testing (RGCT) prior to primary treatment. The aim of this study is to determine the effect of RGCT on treatment decisions and on psychosocial health.
In this randomized controlled trial, 255 newly diagnosed breast cancer patients with at least a 10% risk of carrying a BRCA gene mutation are being recruited from 12 hospitals in the Netherlands. Participants are randomized in a 2:1 ratio to either a RGCT intervention group (the offer of RGCT directly following diagnosis with tests results available before surgical treatment) or to a usual care control group. The primary behavioral outcome is the uptake of direct bilateral mastectomy or delayed prophylactic contralateral mastectomy. Psychosocial outcomes include cancer risk perception, cancer-related worry and distress, health-related quality of life, decisional satisfaction and the perceived need for and use of additional decisional counseling and psychosocial support. Data are collected via medical chart audits and self-report questionnaires administered prior to randomization, and at 6 month and at 12 month follow-up.
This trial will provide essential information on the impact of RGCT on the choice of primary surgical treatment among women with breast cancer with an increased risk of hereditary cancer. This study will also provide data on the psychosocial consequences of RGCT and of risk-reducing behavior.
The study is registered at the Netherlands Trial Register (NTR1493) and ClinicalTrials.gov (NCT00783822).
Few studies have quantitatively evaluated the uptake and outcomes of BRCA1/2 genetic counseling and testing in men. We conducted a prospective longitudinal study to describe and compare uptake of and psychosocial outcomes following BRCA1/2 testing in a sample of men and women at high-risk for carrying a BRCA1/2 mutation. Men (n = 98) and women (n = 243) unaffected with cancer completed baseline assessments prior to genetic counseling and testing and then 6- and 12-months post-testing. Most men (n = 94; 95.9%) opted to have genetic testing, of whom 44 received positive BRCA1/2 genetic test results and 50 received true negative results. Among women, 93.4% had genetic testing, of whom 79 received positive results and 148 received negative results. In multivariate models, male BRCA1/2 carriers reported significantly higher genetic testing distress (6-months: Z = 4.48, P < 0.0001; 12-months: Z = 2.78, P < 0.01) than male non-carriers. After controlling for baseline levels of distress, no statistically significant differences emerged between male and female BRCA1/2 carriers in psychological distress at 12-months post-testing, although absolute differences were evident over time. Predictors of distress related to genetic testing among male carriers at 12-months included higher baseline cancer-specific distress (Z = 4.73, P < 0.0001) and being unmarried (Z = 2.18, P < 0.05). Similarly, baseline cancer-specific distress was independently associated with cancer-specific distress at 6- (Z = 3.66, P < 0.001) and 12-months (Z = 4.44, P < 0.0001) post-testing among male carriers. Clinically, our results suggest that pre-test assessment of distress and creation of educational materials specifically tailored to the needs and concerns of male carriers may be appropriate in this important but understudied high-risk group.
BRCA1/2; Cancer risk; Genetic testing; Male female comparisons; Men; Psychosocial outcomes; Test uptake
The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases). 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS). BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82–94%), poor for BRCAX with an LCS (40–50%), and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71–100%). This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.
Inherited mutations in the genes BRCA1 and BRCA2 increase risk of breast cancer and contribute to a proportion of breast cancer families. However, more than half of the reported sequence alterations in BRCA1 and BRCA2 are currently of unknown clinical significance. We analysed gene expression in lymphoblastoid cell lines derived from blood of patients with sequence alterations in BRCA1 and BRCA2 and compared these to lymphoblastoid cells from familial breast cancer patients without such alterations. We then classified these lymphoblastoid cells based on their gene profiles. We found that BRCA1 and BRCA2 samples were more similar to each other than to familial breast cancer patients without BRCA1/2 mutations, and that the type of sequence change in BRCA1 and BRCA2 (missense or truncating) influenced gene expression. We included in the study ten familial breast cancer samples, which carried sequence changes in BRCA1 or BRCA2, that are believed to be of little clinical significance. Interestingly these samples were distinct from other familial breast cancer cases without any sequence alteration in BRCA1 or BRCA2, indicating that further work needs to be performed to determine the possible association of these “low clinical significance” sequence changes with a low to moderate risk of cancer.
Approximately 13% of ovarian cancers in Canada are attributable to a mutation in BRCA1 or BRCA2. In 2001, genetic testing for BRCA1 and BRCA2 became freely available to all women in Ontario with a diagnosis of invasive ovarian cancer. It is unknown what proportion of women with ovarian cancer receive genetic testing as a result of this recommendation.
Patients in Ontario who had been diagnosed with epithelial ovarian cancer from 2002 to 2004 were identified using the Ontario Cancer Registry. Information was collected on demographic and risk factors, including information on previous testing for BRCA1 and BRCA2. Women were asked to provide a blood sample for genetic testing or to provide a genetic test result if clinical testing had been done. Genetic testing for BRCA1 and BRCA2 mutations was conducted on all blood samples.
Of the 416 women, 80 women (19%) had undergone previous clinical genetic testing for BRCA1 and BRCA2. Of these 80 women, 30% had a positive genetic test result, compared to 5% of 336 women who had not had clinical genetic testing (p <0.0001). Sixty percent of all mutations were identified within this group of 80 women.
Genetic testing is available in Ontario to all women with invasive ovarian cancer. However, only a small proportion of women are being referred for testing. This study suggests that increased public awareness directed at physicians and at women with cancer may expand the use of genetic testing.
BRCA1; BRCA2; Ovarian cancer; Genetic testing
BACKGROUND—The discovery of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has improved our ability to counsel women at increased risk of developing breast and ovarian cancer. The objective of our study was to identify the needs of women who have undergone genetic counselling and testing for BRCA1/2 and to determine the impact of receiving a positive BRCA1/2 result. This is the first study to report on a large group of women who have received positive BRCA1/2 mutation results.
METHODS—Questionnaires were distributed to 105 women who had received pre- and post-test genetic counselling for a positive BRCA1/2 result at the University of Toronto or at McGill University in Montreal, Canada between the years of 1994 and 1998. The questionnaire items included patient motivation for seeking genetic services, information needs, screening and prophylactic surgery practices, satisfaction with access to services and support, the desire for a support group, and overall client satisfaction.
RESULTS—Seventy nine female carriers were surveyed. The majority of the respondents (77%) were satisfied with the information they received during the genetic counselling process. Women with a previous diagnosis of cancer indicated that they needed more information relating to cancer treatment compared to women without cancer (p=0.05). Nineteen percent of the women felt they needed more support than was received. Fifty eight percent of the women reported that their screening practices had changed since they received their result. Young women (below the age of 50) and women with no previous diagnosis of cancer were most likely to have changed their screening practices. Nearly two thirds of the respondents said they had considered prophylactic surgery of the breasts or ovaries. Twenty eight percent of the women had prophylactic mastectomy and 54% had undergone prophylactic oophorectomy. Women with an educational level of high school or more were more likely to have undergone prophylactic bilateral mastectomy than those with less education (p=0.07) but were less likely to undergo prophylactic oophorectomy (p=0.0007).
CONCLUSION—These findings have a direct impact on the counselling and risk management of female BRCA mutation carriers. Age, education, and a previous diagnosis of cancer are important determinants in a woman's decision making after receiving positive genetic test results.
Keywords: genetic counselling; BRCA1; BRCA2; cancer genetics
Women with a germline BRCA1 or BRCA2 mutation or a hereditary predisposition for breast and ovarian cancer have substantial risk of breast or ovarian cancer relative to the general US population. Health care professionals can be instrumental in identifying women at increased risk through obtaining a comprehensive family history and becoming familiar with family history characteristics associated with hereditary predisposition for breast and ovarian cancer. BRCA carriers and women at very high risk benefit from multidisciplinary, individualized medical evaluation and risk management. We conducted a search of MEDLINE from 1989 through 2010 for the terms BRCA1, BRCA2, breast cancer, ovarian cancer, risk assessment, and genetic testing. We reviewed abstracts and relevant randomized and prospective studies that included very high-risk patient groups and BRCA mutation carriers. Herein, we review the role of genetic consultation and BRCA testing and the comprehensive, multisystem recommendations for risk management. A multidisciplinary approach offers the ability to educate those at very high risk about cancer prevention, reduce cancer risk, maximize early detection of breast and ovarian cancer, and improve survival.
BRCA1/2 mutation carriers and women from a hereditary breast(/ovarian) cancer family have a highly increased risk of developing breast cancer (BC). Prophylactic mastectomy (PM) results in the greatest BC risk reduction. Long-term data on the efficacy and sequels of PM are scarce.
From 358 high-risk women (including 236 BRCA1/2 carriers) undergoing PM between 1994 and 2004, relevant data on the occurrence of BC in relation to PM, complications in relation to breast reconstruction (BR), mutation status, age at PM and preoperative imaging examination results were extracted from the medical records, and analyzed separately for women without (unaffected, n = 177) and with a BC history (affected, n = 181).
No primary BCs occurred after PM (median follow-up 4.5 years). In one previously unaffected woman, metastatic BC was detected almost 4 years after PM (primary BC not found). Median age at PM was younger in unaffected women (P < .001), affected women more frequently were 50% risk carriers (P < .001). Unexpected (pre)malignant changes at PM were found in 3% of the patients (in 5 affected, and 5 unaffected women, respectively). In 49.6% of the women opting for BR one or more complications were registered, totaling 215 complications, leading to 153 surgical interventions (71%). Complications were mainly related to cosmetic outcome (36%) and capsular formation (24%).
The risk of developing a primary BC after PM remains low after longer follow-up. Preoperative imaging and careful histological examination is warranted because of potential unexpected (pre)malignant findings. The high complication rate after breast reconstruction mainly concerns cosmetic issues.
BRCA1/2; Breast cancer; Mastectomy; Prevention; Complications; Unexpected carcinomas