Subjective and objective risk of ovarian cancer in Ashkenazi Jewish women testing for BRCA1/2 mutations

OBJECTIVE: Ovarian cancer is the leading cause of gynecological death in the United States, and 14% of ovarian cancer cases are attributed to BRCA1/2 hereditary mutations. This study examined (1) change in subjective ovarian cancer risk in response to genetic counseling and testing, (2) accuracy of subjective ovarian cancer risk estimates, and (3) new methods for conceptualizing subjective ovarian cancer risk based on Leventhal's Common Sense Model, in women at increased risk to carry BRCA1/2 mutations. METHODS: Women (n=78) were asked their subjective risk of ovarian cancer (in terms of a percentage, estimated survival time, and projected age of onset) at pre-counseling, post-counseling, 1 week post-result, and 6 months post-result. RESULTS: Women with a personal history of breast cancer were most inaccurate at pre- but improved post-counseling. Subjective survival time increased post-counseling. Accuracy of subjective risk improved at post-result for those with uninformative negative results. Subjective percentage risk and subjective survival time decreased at 6 months. CONCLUSIONS: Subjective risk changed in response to genetic counseling and testing. Common Sense Model-derived assessments of risk may be useful for understanding the impact of genetic counseling and testing. PRACTICE IMPLICATIONS: Genetic counseling can assist women at risk of carrying BRCA1/2 mutations to understand their risk of ovarian cancer, and genetic testing further refines their risk.     

BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic

Germline mutations in BRCA1 and BRCA2 account for majority of hereditary breast and ovarian cancer. The complete coding sequence analysis of both genes was carried out in 197 breast/ovarian cancer patients from high-risk families and 53 patients with sporadic breast/ovarian cancer. In summary, 59 mutations (16 different) in BRCA1 and 29 mutations (17 different) in BRCA2 were identified in unrelated breast and/or ovarian index cases. Using the BIC Database numbering, the most frequently found mutations in BRCA1 were c.5385dupC (22 cases), c.3819_3823delGTAAA (8 cases) and c.300T>G (6 cases). The most frequently found mutations in BRCA2 were c.8138_8142delCCTTT (7 cases) and c.8765_8766delAG (7 cases). Altogether, these 5 mutations represented 56.8% of all detected mutations. A broad spectrum of other mutations was detected including four novel mutations (c.2881delA in BRCA1; and c. 6677_6678delAA, c.6982dupT and c.8397_8400dupTGGG in BRCA2). Deleterious mutations were found in 80 (40.6%) of 197 high risk-families, in 6 (37.5%) of 16 patients with sporadic bilateral breast, ovarian or both cancers and in 2 (6.2%) of 32 women with sporadic early-onset unilateral breast cancer. No mutation was detected in 5 cases of sporadic early-onset unilateral ovarian cancer.     

Psychosocial factors predicting BRCA1/BRCA2 testing decisions in members of hereditary breast and ovarian cancer families

Although BRCA1/2 testing has increasingly entered clinical practice, much is to be learned about the most effective ways to provide counseling to persons potentially interested in receiving test results. The purpose of this study was to identify factors affecting genetic testing decisions in a cohort of hereditary breast and ovarian cancer (HBOC) families presented with the choice to undergo testing. Relatives in these families are known to carry BRCA1 or BRCA2 mutations. Sociodemographics, personality traits, and family functioning were self-assessed using validated psychometric instruments at baseline. Among 172 individuals who participated in pretest education and counseling, 135 (78%) chose to undergo genetic testing and 37 (22%) chose not to be tested. Individuals who chose to undergo genetic testing were more likely to be older (> or =40 years), to have lower levels of optimism, and to report higher levels of cohesiveness in their families. A better understanding of factors that influence interest in predictive testing may help to inform the counseling that occurs prior to genetic testing.     

Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2

Ethnic differences in cancer incidence and mortality result from differences in genetic and epidemiologic risk factors. Mutations in BRCA1 and BRCA2 account for a small proportion of all breast cancer cases, but for a much higher proportion of cases with a strong family history of breast or ovarian cancer. Germline mutations in BRCA1 and BRCA2 have been identified in individuals of many races and ethnic groups and the frequency of mutations varies between these groups. Some of the differences in cancer risk between populations may be the result of founder mutations in these genes. The cost and time required for mutation analysis are reduced considerably when founder mutations are identified for a specific ethnic group. The BRCA2 999del5 mutation in Iceland and three BRCA mutations in Ashkenazi Jews are well characterized. However, considerably less is known about the contribution of mutations in the BRCA1 and BRCA2 genes outside of European groups. Studies conducted on the Asian populations described here have expanded our current knowledge of genetic susceptibility and its contribution to breast and ovarian cancer rates in Asian populations.     

BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study

Germline BRCA1/2 testing of breast and ovarian cancer patients is growing rapidly as the result affects both treatment and cancer prevention in patients and relatives. Through the DNA-BONus study we offered BRCA1/2 testing and familial risk assessment to all new patients with breast (N=893) or ovarian (N=122) cancer diagnosed between September 2012 and April 2015, irrespective of family history or age, and without prior face-to-face genetic counselling. BRCA1/2 testing was accepted by 405 (45.4%) and 83 (68.0%) of the patients with breast or ovarian cancer, respectively. A pathogenic BRCA1/2 variant was found in 7 (1.7%) of the breast cancer patients and 19 (22.3%) of the ovarian cancer patients. In retrospect, all BRCA1/2 mutation carriers appeared to fulfill current criteria for BRCA1/2 testing. Hospital Anxiety and Depression Scale (HADS) scores showed that the mean levels of anxiety and depression were comparable to those reported for breast and gynecological cancer patients in general, with a significant drop in anxiety symptoms during a 6-month follow-up period, during which the test result was forwarded to the patients. These results show that BRCA1/2 testing is well accepted in newly diagnosed breast and ovarian cancer patients. Current test criteria based on age and family history are sufficient to identify most BRCA1/2 mutation carriers among breast cancer patients. We recommend germline BRCA1/2 testing in all patients with epithelial ovarian cancer because of the high prevalence of pathogenic BRCA1/2 variants.     

Systematic review of the empirical investigation of resources to support decision-making regarding BRCA1 and BRCA2 genetic testing in women with breast cancer

Objective

Identify existing resources developed and/or evaluated empirically in the published literature designed to support women with breast cancer making decisions regarding genetic testing for BRCA1/2 mutations.

Impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with breast or ovarian cancer

To evaluate the impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with cancer. Longitudinal cohort study including women affected and unaffected with breast or ovarian cancer testing for a BRCA1/2 mutation. Data on well-being (anxiety, depression, cancer related distress, general health), treatment choice, and decision making about cancer prevention were collected at baseline (1 week after blood sampling; affected n = 192, unaffected n = 176) and at follow-up (2 weeks after disclosure of a positive test result; affected n = 23, unaffected n = 66). Women affected and unaffected with breast or ovarian cancer were compared using univariate statistics. Change over time was examined using repeated measures analysis of variance. With respect to well-being, affected women scored worse at baseline. At follow-up, both affected and unaffected women experienced a decline in well-being, which tended to be stronger in affected women. Women diagnosed with cancer less than 1 year previously tended to report a worse well-being than those diagnosed longer ago. With respect to treatment choice, more affected women intended to obtain prophylactic surgery and valued it higher at both time points. With respect to decision making, affected women had a lower preference for participation in decision making at baseline; no differences were found at follow-up. At follow-up, both affected and unaffected women showed an increase in strength of treatment preference and a decrease in decision uncertainty. Disclosure of a positive test result had a negative impact on well-being. Affected women, especially those who have been recently diagnosed with cancer, experienced the worst well-being and could benefit from psychosocial support.     

BRCA1/2 testing in hereditary breast and ovarian cancer families II: impact on relationships

Members of hereditary breast and ovarian cancer (HBOC) families often express concern during genetic counseling about the impact of BRCA1/2 testing on close relatives. Yet whether there are likely to be adverse effects of either the decision to undergo genetic testing or the results of testing on family relationships is unknown. One purpose of this study was to assess the impact on close family relationships. Within a randomized trial of breast cancer genetic counseling methods, members of 13 HBOC families were offered BRCA1/2 testing for a known family mutation. The Family Relationship Index (FRI) of the Family Environment Scale (FES) was used to measure perceived family cohesion, conflict, and expressiveness at baseline and again 6-9 months following the receipt of test results, or at the equivalent time for those who declined testing. Participants (n = 212) completed baseline and follow-up questionnaires. Comparisons were made between testers and non-testers as well as between those who tested positive and negative for the family mutation. One hundred eighty-one participants elected to undergo genetic testing (85%) and 47 (26%) were identified to have a mutation. After adjusting for baseline family relationship scores, counseling intervention, gender and marital status, non-testers reported a greater increase in expressiveness (P = 0.006) and cohesion (P = 0.04) than testers. Individuals who tested positive reported a decrease in expressiveness (P = 0.07), although as a trend. Regardless of test decision or test result, those who were randomized to a client-centered counseling intervention reported a decrease in conflict (P = 0.006). Overall, study results suggest that undergoing genetic testing and learning ones BRCA1/2 status may affect family relationships. Those individuals who declined testing reported feeling closer to family members and more encouraged to express emotions to other family members demonstrating potential benefit from the offer of testing. Since those who tested positive reported feeling less encouraged to express their emotions within the family, we recommend helping clients to identify others with whom they feel comfortable sharing their thoughts and feelings about their positive gene status and increased cancer risk.     

Characteristics associated with genetic counseling referral and BRCA1/2 testing among women in a large integrated health system

BackgroundEvidence shows underutilization of cancer genetics services. To explore the reasons behind this underutilization, this study evaluated characteristics of women who were referred for genetic counseling and/or had undergone BRCA1/2 testing.MethodsAn ovarian cancer risk perception study stratified 16,720 eligible women from the Henry Ford Health System into average-, elevated-, and high-risk groups based on family history. We randomly selected 3,307 subjects and interviewed 2,524 of them (76.3% response rate).ResultsAmong the average-, elevated-, and high-risk groups, 2.3, 10.1, and 20.2%, respectively, reported genetic counseling referrals, and 0.8, 3.3, and 9.5%, respectively, reported having undergone BRCA testing. Personal breast cancer history, high risk, and perceived ovarian cancer risk were associated with both referral and testing. Discussion of family history with a doctor predicted counseling referral, whereas belief that family history influenced risk was the strongest BRCA testing predictor. Women perceiving their cancer risk as much higher than other women their age were twice as likely (95% confidence interval: 2.0–9.6) to report genetic counseling referral.ConclusionIn a health system with ready access to cancer genetic counseling and BRCA testing, women who were at high risk underutilized these services. There were strong associations between perceived ovarian cancer risk and genetic counseling referral, and between a belief that family history influenced risk and BRCA testing.Genet Med advance online publication 19 June 2014     

Estimating survival rates after ovarian cancer among women tested for BRCA1 and BRCA2 mutations

Several studies have reported that women with ovarian cancer and a BRCA1 or BRCA2 mutations have better survival than women with ovarian cancer and no mutation. Potential reasons for this include possible differences in histologic subtype, stage, grade and response to chemotherapy, but some of the difference in survival may be due to systematic bias, i.e. a difference in survival rates for women who do and who do not undergo genetic testing. We estimated the survival rate in 1423 ovarian cancer patients from Ontario who had genetic testing and compared this with the survival rate for all 3367 ovarian cancer patients from the province from whom the tested sample was derived. Tested women had a 10‐year survival of 54.5%, compared to 35.8% for all patients in the province. We evaluated the extent to which three different methods of adjustment eliminated the observed difference. The adjusted rates for the tested cohort were closer to the provincial average, but each adjustment method resulted in a modest over‐estimate of 10‐year survival, ranging from 6.1% to 10.0%. The mortality advantage for tested women was due, in part, to a lower than expected mortality rate of tested women in the period following genetic testing.     

Attitudes and distress levels in women at risk to carry a BRCA1/BRCA2 gene mutation who decline genetic testing

Genetic testing enables women at risk for hereditary breast and/or ovarian cancer to find out whether they have inherited the gene mutation, and if so, to opt for undergoing frequent surveillance and/or prophylactic surgery. However, the option to know about one's genetic status is not always seen as a benefit by women at risk. Motives for declining genetic testing were explored in 13 women at 25% or 50% risk to be a BRCA1/BRCA2 mutation carrier, who participated in a surveillance program for breast/ovarian cancer (the non-tested group). We hypothesized that high anxiety might be an important motive to decline testing. In addition, we investigated whether the non-tested group differed from a reference group of women who did undergo the test (tested group; n = 85) with regard to biographical factors, experience with cancer in relatives, and personality traits. Most non-tested women (10/13) were satisfied with participating in the surveillance program. Four reported to feel emotionally unprepared to cope with the consequences of testing. Compared with the tested group, the non-tested women had similar mean distress levels (which were not high), but a higher education level, they were more often childless, showed more reluctance towards prophylactic surgery, were younger when first confronted with a relative affected with breast/ovarian cancer, and were longer aware of the genetic nature of the disease. This study showed that women were more likely to have thoroughly reflected on their decision not to undergo genetic testing, than to deny the whole issue due to high anxiety. Being confronted at a relatively young age with breast/ovarian cancer in a relative, and being aware of the genetic risk for a many years, may have resulted in the risk for cancer becoming an integrated part of their lives. However, generalization of these results to women who neither underwent the test nor participated in a surveillance program should be considered with caution.     

Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer

In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) account for the majority of germline mutations in high-risk breast and/or ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG, Tyr978Ter, and a handful of "private" mutations have been reported anecdotally within both genes. In this study we attempted to determine the spectrum of BRCA1 and BRCA2 mutations in high-risk Jewish individuals, non-carriers of any of the predominant Jewish mutations. We employed multiplex PCR and denaturing gradient gel electrophoresis (DGGE) analysis for BRCA2, and combined denaturing high performance liquid chromatography (DHPLC) and protein truncation test (PTT) for BRCA1, complemented by DNA sequencing. We screened 47 high-risk Jewish individuals, 26 Ashkenazis, and 21 non-Ashkenazis. Overall, 13 sequence alterations in BRCA1 and eight in BRCA2 were detected: nine neutral polymorphisms and 12 missense mutations, including five novel ones. The novel missense mutations did not co-segregate with disease in BRCA1 and were detected at rates of 6.25% to 52.5% in the general population for BRCA2. Our findings suggest that except for the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, there are only a handful of pathogenic mutations within these genes. It may imply novel genes may underlie inherited susceptibility to breast/ovarian cancer in Jewish individuals.     

BRCA1 and BRCA2 mutations in breast/ovarian cancer patients from central Italy

We report on the screening of the entire BRCA1/BRCA2 coding sequence by SSCP, PTT, and direct sequencing in 68 Italian families with recurrent breast or ovarian cancer. For each investigated proband, the probability of being carrier of a BRCA1/BRCA2 mutation was evaluated using the BRCAPRO software. We detected BRCA1/BRCA2 mutations in 8 patients (11.7%). However, if considering only patients with a carrier probability >10%, the detection rate was 36.8%, confirming the usefulness of the BRCAPRO software. One change (BRCA1 4172insT) was a novel mutation not reported in BIC database.     

Challenges in managing genetic cancer risk: a long-term qualitative study of unaffected women carrying BRCA1/BRCA2 mutations

PurposeWomen carrying BRCA1/BRCA2 germ-line mutations have an increased risk of developing breast/ovarian cancer. To minimize this risk, international guidelines recommend lifelong surveillance and preventive measures. This study explores the challenges that unaffected women genetically predisposed to breast/ovarian cancer face in managing their risk over time and the psychosocial processes behind these challenges.MethodsBetween 2011 and 2013, biographical qualitative interviews were conducted in Switzerland with 32 unaffected French- and Italian-speaking women carrying BRCA1/BRCA2 mutations. Their mutation status had been known for at least 3 years (mean, 6 years). Data were analyzed through constant comparative analysis using software for qualitative analysis.ResultsFrom the time these women received their positive genetic test results, they were encouraged to follow medical guidelines. Meanwhile, their adherence to these guidelines was constantly questioned by their social and medical environments. As a result of these contradictory pressures, BRCA1/BRCA2 mutation carriers experienced a sense of disorientation about the most appropriate way of dealing with genetic risk.ConclusionGiven the contradictory attitudes of health-care professionals in caring for unaffected BRCA1/BRCA2 mutation carriers, there is an urgent need to educate physicians in dealing with genetically at-risk women and to promote a shared representation of this condition among them.Genet Med17 9, 726–732.     

Perceptions of Ashkenazi Jewish breast cancer patients on genetic testing for mutations in BRCA1 and BRCA2

The perceived benefits and risks of genetic testing may vary between groups of individuals with different cultural, demographic, and family history features. This multicentre study examined the factors that influenced the decision to undergo genetic testing for BRCA1 and BRCA2 in Canadian Jewish women with breast cancer. A self-administered questionnaire was developed and distributed to 134 individuals enrolled in a research-based testing program for Ashkenazi women. The questionnaire assessed demographic, social, and family history parameters, and the influence of medical, family, social, psychological, and cultural/religious factors on decision making about genetic testing. Seventy-six percent of women completed the questionnaire. Forty-one percent of study participants had no family history of breast or ovarian cancer. The most important factors influencing the decision to undergo testing were a desire to contribute to research, potential benefit to other family members, curiosity, and the potential for relief if not found to be a carrier (endorsed by 87, 78, 70, and 60% of participants, respectively). The main perceived risks of undergoing genetic testing related to insurance discrimination, confidentiality, accuracy and interpretability of results, potential impact on marriage prospects for family members, and focus on the Jewish community (endorsed by 28, 24, 30, 17, and 14% of participants, respectively). This study provides novel information on the motivating factors for BRCA1 and BRCA2 mutation testing in Canadian women of Ashkenazi Jewish descent. The focus on altruistic factors and those related to perceived psychological benefits of testing is notable.     

BRCA1/2 testing in hereditary breast and ovarian cancer families III: risk perception and screening

This study aimed to ascertain whether cancer risk perception changed following the offer and subsequent receipt of BRCA1/2 results and to evaluate breast and ovarian screening practices in testers and non-testers. Members of thirteen HBOC families were offered BRCA1/2 testing for a known family mutation. Perceived risk for developing breast cancer, ovarian cancer or for carrying the familial BRCA1/2 mutation, was assessed at baseline and again at 6-9 months following the receipt of test results. Breast and ovarian cancer screening data were obtained at both time-points. A total of 138 women participated and 120 (87%) chose to be tested for a known familial mutation. Twenty-eight women (24%) were identified as carriers and their perceived ovarian cancer risk and their perception of being a mutation carrier increased (P = 0.01 for both). Those testing negatives had a significant decrease in all dimensions of risk perception (P < 0.01). Regression analysis showed test results to be strong predictors of follow-up risk perception (P = 0.001), however, they were not predictors of screening practices at follow-up. Testers were more likely to have completed a clinical breast exam following testing than decliners. Mammography was positively associated with baseline adherence, age, and intrusive thoughts. Ovarian cancer worries only predicted pelvic ultrasound screening post-testing. Baseline practices and psychological factors appear to be stronger predictors of health behavior than test results.