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1.  Enhanced Counseling for Women Undergoing BRCA1/2 Testing: Impact on Knowledge and Psychological Distress – Results From a Randomized Clinical Trial 
Psychology & health  2010;25(4):401-415.
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.
PMCID: PMC2866521  PMID: 20204945
Genetic testing; enhanced counseling; intrusive ideation; breast cancer; ovarian cancer
2.  Psychosocial approaches to participation in BRCA1/2 genetic risk assessment among African American women: a systematic review 
Journal of Community Genetics  2013;5(2):89-98.
Breast cancer is a significant health concern for African American women. Nonetheless, uptake of genetic risk assessment (including both genetic counseling and testing) for breast cancer gene mutations among these populations remains low. This paper systematically reviews cognitive (i.e., beliefs) and affective (i.e., emotions) factors influencing BRCA1/2 genetic risk assessment among African American women as well as psychosocial interventions to facilitate informed decision making in this population. A systematic search of CINAHL, PubMed, and PsycINFO was undertaken, yielding 112 published studies. Of these, 18 met the eligibility criteria. African American woman are likely to participate in genetic risk assessment if they are knowledgeable about cancer genetics, perceive a high risk of developing breast cancer, have low expectancies of stigmatization from medical professionals, view themselves as independent from family, and have fatalistic beliefs and a future temporal orientation. Anticipated negative affective responses, such as an inability to “handle” the results of testing, are barriers to uptake. Specific perceptions, beliefs, and emotional factors are associated with genetic risk assessment among African American women. Understanding these factors is key in the development of interventions to facilitate informed decision making in this population.
PMCID: PMC3955455  PMID: 23934762
Genetic testing; African American; Breast cancer; Review; BRCA1/2
3.  Changes in psychological distress after cancer genetic counselling: a comparison of affected and unaffected women 
British Journal of Cancer  2002;86(1):43-50.
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
© 2002 The Cancer Research Campaign
PMCID: PMC2746544  PMID: 11857010
breast and ovarian cancer genetics; affected and unaffected women; psychological distress; risk perceptions
4.  Medical Mistrust and Self-efficacy Influence Black Women’s Level of Engagement in BRCA1/2 Genetic Counseling and Testing 
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.
PMCID: PMC3721431  PMID: 23862292
Medical Mistrust; Self-efficacy; BRCA 1/2; African American
5.  BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer 
Cancer  2009;115(10):2222-2233.
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.
PMCID: PMC2771545  PMID: 19241424
BRCA1; BRCA2; genetic testing; race; ethnicity
6.  A randomized trial of specialist genetic assessment: psychological impact on women at different levels of familial breast cancer risk 
British Journal of Cancer  2002;86(2):233-238.
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
© 2002 The Cancer Research Campaign
PMCID: PMC2375197  PMID: 11870512
familial breast cancer; genetic risk assessment; psychological impact; service delivery
7.  Predictive testing for BRCA1/2: attributes, risk perception and management in a multi-centre clinical cohort 
British Journal of Cancer  2002;86(8):1209-1216.
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
© 2002 Cancer Research UK
PMCID: PMC2375339  PMID: 11953874
predictive genetic testing; worry; risk management
8.  Women’s Satisfaction with Genetic Counseling for Hereditary Breast-Ovarian Cancer 
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.
PMCID: PMC3548224  PMID: 15389697
hereditary breast and ovarian cancer; genetic counseling; genetic testing; satisfaction; psychology
9.  Predictors and Outcomes of Contralateral Prophylactic Mastectomy Among Breast Cancer Survivors 
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.
PMCID: PMC3060055  PMID: 17066320
BRCA1/2; breast cancer survivors; contralateral prophylactic mastectomy; genetic testing; psychosocial predictors; distress outcomes
10.  Long Term Outcomes of BRCA1/BRCA2 Testing: Risk Reduction and Surveillance 
Cancer  2011;118(2):510-517.
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.
PMCID: PMC3286617  PMID: 21717445
11.  Social-Cognitive Processes Associated with Fear of Recurrence Among Women Newly Diagnosed with Gynecological Cancers 
Gynecologic oncology  2012;128(1):120-127.
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.
PMCID: PMC3534914  PMID: 23088925
Recurrence fears; gynecological cancer; social-cognitive processing; psychological adaptation
12.  Epithelial ovarian cancer. Risk factors, screening and the role of prophylactic oophorectomy 
Hippokratia  2007;11(2):63-66.
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.
PMCID: PMC2464274  PMID: 19582179
prophylactic oophorectomy; CA125; hereditary cancer
13.  Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks? 
Journal of Medical Genetics  1999;36(12):906-913.
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
PMCID: PMC1734277  PMID: 10593998
14.  BRCA1 and BRCA2 Pathways and the Risk of Cancers Other Than Breast or Ovarian 
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.
PMCID: PMC1681605  PMID: 16369438
15.  Patient-reported hereditary breast and ovarian cancer in a primary care practice 
Journal of Community Genetics  2013;5(2):179-183.
Identifying women appropriate for cancer genetic counseling referral depends on patient-reported family history. Understanding predictors of reporting a high-risk family is critical in ensuring compliance with current referral guidelines. Our objectives were to (1) assess prevalence of candidates for BRCA1 and BRCA2 counseling referral in a primary care setting, (2) explore associations with high-risk status and various patient (e.g., race) and family structure (e.g., number of relatives) characteristics, and (3) determine whether high-risk patients had genetic counseling and/or testing. Survey and pedigree data were collected between 2010 and 2012 for 486 Women’s Health Clinic patients. Analyses in 2013 investigated perceived cancer risk and worry, family structure, and receipt of genetic counseling. We explored whether these were associated with meeting USPSTF guidelines for genetic counseling referral. Twenty-two (4.5 %) women met the criteria for BRCA referral. Only one of these women had previous genetic counseling, and one reported prior genetic testing. Older women were more likely to meet BRCA referral criteria (P < 0.001). Although perceived risk was higher among high-risk women, 27 % of high-risk women felt their breast cancer risk was “low”, and 32 % felt their risk was lower than average. About one in 22 women in primary care may require genetics services for hereditary breast and ovarian cancer, but alarmingly, few actually receive these services. Also, a significant proportion do not perceive that they are at increased risk. Educational interventions may be needed for both providers and patients to increase awareness of familial risk and appropriate genetic counseling services.
PMCID: PMC3955454  PMID: 23872790
Hereditary breast and ovarian cancer syndrome; Primary health care; Women’s health; Genetic counseling
16.  Screening for ovarian cancer in women with varying levels of risk, using annual tests, results in high recall for repeat screening tests 
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.
PMCID: PMC3231989  PMID: 22112691
ovarian cancer; screening; transvaginal ultrasound; serum CA125; BRCA gene mutation; bilateral salpingo-oophorectomy
17.  Will Chinese ovarian cancer patients benefit from knowing the BRCA2 mutation status? 
Chinese Journal of Cancer  2012;31(1):1-4.
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.
PMCID: PMC3777467  PMID: 22176776
Ovarian cancer; BRCA mutation; drug response; survival
18.  Prevalence and correlates of mothers and fathers attending pretest cancer genetic counseling together 
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.
Practice implications
When possible, providers should discuss mothers including fathers in cancer genetic counseling sessions as this may affect outcomes of HBOC genetic counseling and testing.
PMCID: PMC2787643  PMID: 19545972
Cancer; Breast cancer; Genetic counseling; BRCA1/2 testing; Parents
19.  Effect of Genetic Counseling and Testing for BRCA1 and BRCA2 Mutations in African American Women: A Randomized Trial 
Public Health Genomics  2010;13(7-8):440-448.
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.
PMCID: PMC3025895  PMID: 20234119
African American; BRCA1; BRCA2; Cultural factors; Genetic counseling
20.  BRCA1/2 genetic testing uptake and psychosocial outcomes in men 
Familial cancer  2011;10(2):213-223.
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.
PMCID: PMC3144746  PMID: 21365268
BRCA1/2; Cancer risk; Genetic testing; Male female comparisons; Men; Psychosocial outcomes; Test uptake
21.  Family matters: examining a multi-family group intervention for women with BRCA mutations in the scope of genetic counselling 
Journal of community genetics  2010;1(4):161-168.
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.
PMCID: PMC3186004  PMID: 22460298
Genetic counselling; Hereditary cancer; Psychosocial genetics; Psycho-education; Multi-family groups
22.  Behavioral and psychosocial effects of rapid genetic counseling and testing in newly diagnosed breast cancer patients: Design of a multicenter randomized clinical trial 
BMC Cancer  2011;11:6.
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.
Trial registration
The study is registered at the Netherlands Trial Register (NTR1493) and (NCT00783822).
PMCID: PMC3022885  PMID: 21219598
23.  Prospective study of high-risk, BRCA1/2-mutation negative women: the ‘negative study’ 
BMC Cancer  2014;14:221.
We previously reported that women from high-risk families who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation were four times more likely to develop breast cancer compared to women in the general population. Preventive measures and risk factors for breast cancer development in these high-risk women have not been evaluated to the same extent as BRCA1/2 positive women. Further, there is virtually no scientific evidence about best practices in their management and care. The proposed study will examine a role of genetic and non-genetic factors and develop the systems and parameters for the monitoring and surveillance necessary to help establish guidelines for the care of this high-risk population.
To achieve our goals, we will assemble and follow a Canadian cohort of 1,000 cancer-free women with a strong family history breast cancer (defined as two or more relatives affected by breast cancer under the age of 50, or three or more relatives diagnosed with breast cancer at any age from one side of the family and with no BRCA1/2 mutation in the family). All eligible participants will be mailed a study package including invitation to participate, consent form, a research questionnaire to collect data regarding family history, reproductive and lifestyle factors, as well as screening and surgery. Usual dietary intake will be assessed by a diet history questionnaire. Biological samples including toenail clippings, urine and blood samples will be collected. These women will be followed every two years by questionnaire to update exposure information, screening practices, surgical and chemoprevention, and disease development.
Findings from this study will serve to help establish clinical guidelines for the implementation of prevention, counseling, and treatment practices for women who face an elevated risk of breast cancer due to family history, but who do not carry a BRCA1/2 mutation.
PMCID: PMC3973748  PMID: 24667084
Family history; Breast cancer; Risk factors; Prevention; BRCA1/2 mutation; Diet; Lifestyle; Hormones; Prospective cohort; Screening
24.  Differences in DNA methylation by extent of breast cancer family history in unaffected women 
Epigenetics  2013;9(2):243-248.
Breast cancer clusters within families but genetic factors identified to date explain only a portion of this clustering. Lower global DNA methylation in white blood cells (WBC) has been associated with increased breast cancer risk. We examined whether WBC DNA methylation varies by extent of breast cancer family history in unaffected women from high-risk breast cancer families. We evaluated DNA methylation levels in LINE-1, Alu and Sat2 in 333 cancer-free female family members of the New York site of the Breast Cancer Family Registry, the minority of which were known BRCA1 or BRCA2 mutation carriers. We used generalized estimated equation models to test for differences in DNA methylation levels by extent of their breast cancer family history after adjusting for age. All unaffected women had at least one sister affected with breast cancer. LINE-1 and Sat2 DNA methylation levels were lower in individuals with 3 or more (3+) first-degree relatives with breast cancer relative to women with only one first-degree relative. For LINE-1, Alu, and Sat2, having 3+ affected first-degree relatives was associated with a decrease of 23.4% (95%CI = −46.8%, 0.1%), 17.9% (95%CI = −39.5%, 3.7%) and 11.4% (95% CI = −20.3%, −2.5%), respectively, relative to individuals with only one affected first-degree relative, but the results were only statistically significant for Sat2. Individuals having an affected mother had 17.9% lower LINE-1 DNA methylation levels (95% CI = −28.8%, −7.1%) when compared with those not having an affected mother. No associations were observed for Alu or Sat2 by maternal breast cancer status. If replicated, these results indicate that lower global WBC DNA methylation levels in families with extensive cancer histories may be one explanation for the clustering of cancers in these families. Family clustering of disease may reflect epigenetic as well as genetic and shared environmental factors.
PMCID: PMC3962534  PMID: 24172832
breast cancer; family history; LINE-1; Sat2; DNA methylation; white blood cells
25.  BRCA1 and BRCA2 Missense Variants of High and Low Clinical Significance Influence Lymphoblastoid Cell Line Post-Irradiation Gene Expression 
PLoS Genetics  2008;4(5):e1000080.
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.
Author Summary
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.
PMCID: PMC2375115  PMID: 18497862

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