Practical aspects of genetic counseling in breast cancer: Lights and shadows

In unselected populations, less than 10% of breast cancers are associated with germline mutations in predisposing genes. Breast cancer type 1 and 2 (BRCA1 and BRCA2) susceptibility genes are the most common involved genes and confer a 10–30 times higher risk of developing the disease compared to the general population. A personal or family history suggestive of inherited breast cancer syndrome may be further evaluated to assess the risk of genetic predisposition and the presence of a genetic mutation. Breast cancer genetic counseling should include a careful risk assessment with associated psychosocial evaluation and support, possible molecular testing, personalized discussion of results. Knowledge of BRCA status can influence individualized cancer risk-reduction strategies. i.e. active surveillance, prophylactic surgery and/or pharmacoprevention.     

The Impact of Mental Illness on Uptake of Genetic Counseling for Hereditary Breast Cancer and Ovarian Cancer in a Multiethnic Cohort of Breast Cancer Patients

We evaluated whether mental illness is a barrier to genetic counseling for hereditary breast and ovarian cancer (HBOC) in multiethnic breast cancer patients. We conducted a retrospective analysis of 308 women with newly diagnosed breast cancer and eligible for HBOC genetic testing seen in the breast clinic of an academic, urban medical center from 2007 to 2015. Uptake of genetic services and history of mental health disorder (MHD), defined as a psychiatric diagnosis or treatment with an antidepressant, mood stabilizer, anxiolytic, or antipsychotic medication, were ascertained by medical chart review. The mean age at breast cancer diagnosis was 56 years, with 44% non‐Hispanic whites, 37% Hispanics, and 15% non‐Hispanic blacks. Ninety‐nine (32%) women met study criteria for MHD, 73% had a genetics referral, 57% had genetic counseling, and 54% completed BRCA testing. Uptake of genetic counseling services did not differ by race/ethnicity or presence of MHD. In multivariable analysis, younger age at diagnosis, Ashkenazi Jewish heritage, and family history of breast cancer were associated with HBOC genetic counseling. A relatively high proportion of breast cancer patients eligible for HBOC genetic testing were referred to a genetic counselor and referral status did not vary by MHD or race/ethnicity.     

Testing for hereditary breast and ovarian cancer in the southeastern United States

OBJECTIVES: To detail characterization of mutations and uncharacterized variants in the breast cancer susceptibility genes BRCA1 and BRCA2, as observed in a population of breast cancer patients from the southeastern United States, and to examine baseline characteristics of women referred for counseling and testing and provide a preliminary look at how counseling and testing affected intentions toward prophylactic surgery. BACKGROUND: Mutations in the BRCA1 and BRCA2 genes give rise to a dramatically increased risk of developing breast or ovarian cancer or both. There are many reports about special populations in which deleterious mutations are present at a high frequency. It is useful to study these genes in more heterogeneous populations, reflecting different geographic regions. Interest in preventive surgery for gene carriers is high in women and their surgeons. METHODS: Women were recruited through a prospective clinical trial of counseling and free genetic testing. BRCA1 and BRCA2 were screened for mutations using standard techniques, and results were given to participants. Baseline questionnaires determined interest in preventive surgery at the beginning of the study. Follow-up questionnaires for those who completed testing surveyed interest in prophylactic surgery after counseling and receiving test results. RESULTS: Of 213 women who completed counseling and testing, 44 (20.6%) had 29 separate mutations; there were 11 Jewish women carrying three founder mutations. Twenty-eight women (13.1%) had uncharacterized variants in BRCA1 or BRCA2; nine were not previously reported. Women overestimated their chances of possessing a deleterious gene mutation compared to a statistical estimate of carrier risk. A number of women changed their intentions toward preventive surgery after genetic counseling and testing. CONCLUSIONS: Hereditary breast cancer due to mutations in BRCA1 and BRCA2 was a heterogeneous syndrome in the southeastern United States. Most mutations were seen just once, and uncharacterized variants were common and of uncertain clinical significance. In general, positive test results tended to reinforce intentions toward prophylactic surgery. In contrast, women not interested in surgery at the time of entry tended to remain reluctant after testing and counseling.     

BRCA1/2 mutations and triple negative breast cancers

Identifying breast cancer patients at increased risk for carrying a mutation in the BRCA1 and BRCA2 genes is an important objective in clinical practice. Although age at diagnosis, family history of breast and/or ovarian cancer, and ethnicity are all essential parameters to consider when assessing risk, there are limitations as to how well such factors accurately predict BRCA1/2 status, even when quantitative risk models are applied. Integrating information about triple negative (TN) disease may help refine these estimates. Among newly diagnosed breast cancer patients, fewer than 10% have a mutation in the BRCA1 or BRCA2 genes, and up to 20% present However, among BRCA1 mutation carriers at least one-third have TN breast cancers. In this paper, we review key studies that have assessed breast cancer cases with a known BRCA1/2 status and triple marker data. We also discuss how integrating such information into qualitative and quantitative risk assessments of BRCA1/2 carrier probability may improve the ability to identify women who are appropriate candidates for genetic testing. Identifying women at increased risk is critical as knowledge of mutation status may impact surgical and systemic treatment in newly diagnosed patients, as well as recommendations for ovarian cancer risk management.     

BRCA mutation genetic testing implications in the United States

BRCA mutation carriers have a very high risk of breast and ovarian cancer by age 70, in the ranges 47%–66% and 40%–57%, respectively. Additionally, women with BRCA mutation-associated breast cancer also have an elevated risk of other or secondary malignancies. Fortunately, the breast and ovarian cancer outcome for BRCA1/2 mutation carriers is at least as good as for non-carriers with chemoprevention, prophylactic surgeries and appropriate use of therapies. Therefore, identification of those who might have a mutation is important so that genetic counseling, testing, screening and prevention strategies can be applied in a timely manner. This article reviews the impact of genetic testing in general, timing of genetic testing after diagnosis and prior knowledge of mutation status in BRCA carriers with newly diagnosed breast cancer. Additionally, risk-reducing surgeries including the prophylactic contralateral mastectomy, and bilateral salpingo-oophorectomy and the sensitivity of BRCA-defective breast cancer cell lines to differential chemotherapeutic agents will be discussed.     

Genotype–Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers

The genotype–phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi‐ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi‐Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0–12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation‐specific counseling and be more aggressively managed for risk reduction.     

Prevalence of BRCA Mutations Among Women with Triple-Negative Breast Cancer (TNBC) in a Genetic Counseling Cohort

Background

Revised NCCN guidelines recommend that women ≤60 years with triple-negative breast cancer (TNBC) be referred for consideration of genetic counseling. Small, homogeneous samples have limited evaluation of BRCA mutation prevalence among different ethnicities affected by TNBC subtype. We sought to determine whether the prevalence of BRCA mutations within a TNBC cohort differs by demographic factors.

Methods

We performed a retrospective review of patients with TNBC referred for genetic counseling at two academic Hereditary Cancer Clinics between 2000 and 2012. Demographic data were collected, including age at diagnosis and race/ethnicity. Race was categorized as African American (AA), Ashkenazi Jewish (AJ), Asian, Caucasian, Hispanic, or other. Primary outcome was BRCA mutation status, analyzed by race/ethnicity and age at diagnosis.

Results

A total of 469 patients with TNBC who underwent testing for BRCA genetic mutations were identified, of which 450 patients had evaluable BRCA testing results; 139 (30.8 %) had confirmed BRCA1 (n = 106) or BRCA2 (n = 32) mutations. BRCA mutation prevalence differed by ethnicity and race: AA (20.4 %), AJ (50 %), Asian (28.5 %), Caucasian (33.3 %), and Hispanic (20 %). The prevalence of genetic mutations also differed by age at diagnosis: <40 years (43.8 %), 40–49 years (27.4 %), 50–59 years (25.3 %), 60–69 years (12.5 %), and >70 years (16.6 %).

Conclusions

The prevalence of genetic mutations among women with TNBC referred for genetic counseling is high and differs significantly by ethnicity/race and age. This data helps to refine mutation risk estimates among women with TNBC, allowing for more personalized genetic counseling potentially aiding in improved patient decision-making.     

Family Information Service Participation Increases the Rates of Mutation Testing Among Members of Families with BRCA1/2 Mutations

Abstract:  Some members of hereditary breast-ovarian cancer (HBOC) families may not participate in BRCA testing to determine their mutation status in part because they are unaware of their cancer risk and the availability of BRCA testing. Participation in a family information service (FIS), of which we have provided more than 100 sessions during the past 30 years, has been seen to effectively allow family members to be educated regarding their cancer genetic risk and potential benefits from cancer control measures such as mutation testing. However, the effect of the FIS on the rate of mutation testing has not been studied. One thousand five hundred seventy-four eligible (>18-year old, at a 25% or higher pedigree risk) members from 60 extended HBOC families with BRCA1/2 mutations were invited to attend a FIS to learn about their risk and undergo genetic testing. The rates of mutation testing were compared between those who had attended an FIS, and those who had not with chi-squared test and logistic regression analysis. Seventy five percent (334/444) of FIS attendees had undergone mutation testing following or during an FIS which was significantly higher than the 33.8% (382/1130) rate among nonattendees (p   <   0.0001). Logistic regression analysis showed that FIS attendance, breast-ovarian cancer history, gender, and age were significant variables for undertaking a mutation test. FIS attendance significantly increased the rate of mutation testing among high-risk family members.     

Assessing the Knowledge and Attitudes Regarding Genetic Testing for Breast Cancer Risk in our Region of Southeastern Georgia

Abstract: Genetic testing for the breast cancer susceptibility genes, BRCA1 and BRCA2, has been available for over a decade. Positive test results carry significant medical, psychological, and social implications. Knowledge of the public’s awareness concerning BRCA testing, and perceived benefits and barriers to testing can help refine educational programs and identify subgroups needing additional support. Patients and their acquaintances with a breast complaint attending a surgical clinic or private office were asked to complete a questionnaire about their knowledge of breast cancer genes and their desire to be tested. Demographic information collected included ethnicity, education background, age, income, and personal and family history of breast cancer, knowledge of BRCA genes and testing, and their willingness to participate in genetic counseling. A total of 222 people completed the questionnaire that showed the majority of subjects in southeast Georgia believe breast cancer is inherited 26–50% of the time. Caucasians and those with advanced degrees are the most informed regarding awareness of BRCA genes (p < 0.05); the least informed groups include African Americans and those with no more than a college education. Participants with a family history of breast cancer were significantly more likely to know that genes had been identified that indicate an increased risk of breast cancer (p < 0.05). A history of breast cancer did not impact the degree of awareness (p > 0.05). Subjects aware of genetic testing are more willing to utilize counseling (p < 0.05). Perceptions of breast cancer inheritance, awareness of susceptibility genes, and availability of testing and counseling are not uniform among all population subgroups. In southeast Georgia, educational efforts should focus on the less educated and minority groups.     

Breast cancer in women at high risk: The role of rapid genetic testing for BRCA1 and -2 mutations and the consequences for treatment strategies

Specific clinical questions rise when patients, who are diagnosed with breast cancer, are at risk of carrying a mutation in BRCA1 and -2 gene due to a strong family history or young age at diagnosis. These questions concern topics such as 1. Timing of genetic counseling and testing, 2. Choices to be made for BRCA1 or -2 mutation carriers in local treatment, contralateral treatment, (neo)adjuvant systemic therapy, and 3. The psychological effects of rapid testing. The knowledge of the genetic status might have several advantages for the patient in treatment planning, such as the choice whether or not to undergo mastectomy and/or prophylactic contralateral mastectomy. The increased risk of developing a second breast cancer in the ipsilateral breast in mutation carriers, is only slightly higher after primary cancer treatment, than in the general population. Prophylactic contralateral mastectomy provides a substantial reduction of contralateral breast cancer, although only a small breast cancer specific survival benefit. Patients should be enrolled in clinical trials to investigate (neo)-adjuvant drug regimens, that based on preclinical and early clinical evidence might be targeting the homologous recombination defect, such as platinum compounds and PARP inhibitors. If rapid testing is performed, the patient can make a well-balanced decision. Although rapid genetic counseling and testing might cause some distress, most women reported this approach to be worthwhile. In this review the literature regarding these topics is evaluated. Answers and suggestions, useful in clinical practice are discussed.     

Management of breast cancer risk in BRCA1/2 mutation carriers who are unaffected with cancer

Pathogenic mutations in BRCA1 and BRCA2 genes markedly increase the risk of breast cancer and other cancers such as ovarian/fallopian tube, pancreatic, prostate, and melanoma. Patients with BRCA1 mutations have a slightly higher lifetime risk of breast cancer than BRCA2 mutation carriers, and both BRCA1 and BRCA2 carriers tend to develop breast cancer at an earlier age than the general population. In this review, we will discuss management recommendations to reduce breast cancer risk for BRCA1/2 mutation carriers including special populations of carriers such as pregnant or lactating patients and men. Breast cancer screening, including clinical breast examination, mammogram, and breast MRI, is important for detecting breast cancer at an early and likely curable stage. In addition to screening, counseling on risk‐reducing surgeries is strongly recommended for BRCA1/2 carriers. Risk‐reducing mastectomy decreases the risk of breast cancer development, and risk‐reducing salpingo‐oophorectomy decreases ovarian cancer‐specific as well as overall mortality, but controversy exists regarding its impact on breast cancer‐specific mortality. Given the effectiveness of screening for breast cancer, further management should be carried out on an individual basis taking into account quality of life and psychosocial factors, and recommendations should be readdressed periodically as science progresses and patients’ goals may change.     

Educational Review: Role of the Surgeon in Hereditary Breast Cancer

Up to 10% of the breast cancers detected in the United States are related to an inherited germline mutation, usually in the BRCA1 or BRCA2 genes, and the majority of these patients will at some point require surgical evaluation and/or treatment. Women who harbor a genetic predisposition for breast cancer face an increased risk for early onset disease, bilateral tumors, and other non-breast malignancies, such as ovarian cancer. These issues raise questions regarding the appropriate surveillance regimen, and the potential efficacy of risk reduction strategies that should be considered. Once a breast cancer diagnosis has been established, the prognosis appears to be similar to stage-controlled sporadic breast cancer, despite an increased prevalence of adverse primary tumor features. However, the role of breast conservation therapy for these patients and the optimal means of addressing the substantially increased risk for contralateral tumors is not yet defined. The reported literature in this area, including a discussion of the value of genetic counseling and genetic testing, is reviewed.     

The genetic basis of breast cancer and its clinical implications

While it has long been recognized that a proportion of breast cancer cases are the result of an inherited familial predisposition, precise knowledge of the underlying genetic processes has been lacking. Recent advances in molecular biology, however, have shown that hereditary breast cancer may eventuate as a result of mutations on several specific gene loci including BRCA1, BRCA2, ATM gene, PTEN and p53. Several other less frequently occurring predisposition genes such as the androgen receptor gene (AR), the HNPCC genes and the oestrogen receptor gene may also be involved, but to a lesser extent. Overall, approximately 5-10% of all breast cancers are thought to involve one of these inherited predisposition genes, with BRCA1 and BRCA2 being responsible for as much as 90% of this group. Because of the complex nature of genetic testing, mutation analysis is not presently routinely available outside genetic counselling clinics. In this review the current knowledge and role of each predisposition gene is outlined and the management implications of genetic testing for members of breast cancer families for both affected and non-affected members are discussed. The need to provide comprehensive counselling for women with an inherited predisposition to breast cancer has seen the evolution of the familial cancer clinic, involving a multidisciplinary specialist team approach. Familial cancer clinics will provide individuals with information about their risk of developing breast cancer and offer advice regarding further management strategies. It is important that surgeons, who have traditionally played a key role in breast cancer treatment, remain cognizant of these advances in genetic molecular biology, and in so doing continue to remain key participants in the conduct of breast cancer management.     

Genetic predisposition to breast cancer: a surgical perspective

BACKGROUND: Molecular alterations in proto-oncogenes, tumour suppressor genes, and genes that function in DNA damage recognition and repair are considered to be hallmarks of a carcinogenic process, including breast carcinogenesis. METHODS: A computer-assisted search of the English literature (Medline database, 1990-1999) was performed, followed by a manual search of the reference list of pertinent articles retrieved. RESULTS: Hereditary breast cancer accounts for 5-10 per cent of all breast cancer cases. About 90 per cent of hereditary breast cancers involve mutation of the BRCA1 and/or BRCA2 genes. Other cancer-related genes (including myc, c-erbB2, Tsg101 and Mdgi) are involved in breast carcinogenesis, but they do not give rise to familial breast cancer syndromes. Risk estimation is the most important clinical implication. Management options for the high-risk mutation carriers include cancer surveillance and preventive strategies (prophylactic surgery or chemoprevention). CONCLUSION: Despite inadequate knowledge about the genetic predisposition to breast cancer and its clinical implications, the demand for genetic testing is likely to expand rapidly. In addition to risk estimation, cancer surveillance and preventive strategies, gene therapy offers a new and theoretically attractive approach to breast cancer management.     

The breast surgeon's role in BRCA1 and BRCA2 testing

Five percent to 10% of all women who develop breast cancer carry a hereditary mutation in the genes BRCA1 or BRCA2. Genetic testing is now clinically available, and the results of such testing can dramatically alter a patient's risks for an ipsilateral or contralateral primary breast cancer and ovarian cancer. Therefore, genetic testing will become integral in tailoring surveillance, chemoprevention, and surgical management plans for patients at risk for hereditary cancer syndromes. Such results will also impact the cancer risks for the patient's nuclear and extended family members. Surgeons will play a pivotal role in eliciting personal and family histories from patients, determining which of those histories is suggestive of a germline mutation, facilitating referrals for genetic counseling and testing, and incorporating the results of genetic testing into the patient's short- and long-term management plans.     

Survey on Physicians' Knowledge and Training Needs in Genetic Counseling in Germany

BackgroundIn recent years, germline testing of women with a risk of developing breast and ovarian cancer has increased rapidly. This is due to lower costs for new high-throughput sequencing technologies and the manifold preventive and therapeutic options for germline mutation carriers. The growing demand for genetic counseling meets a shortfall of counselors and illustrates the need to involve the treating clinicians in the genetic testing process. This survey was undertaken to assess their state of knowledge and training needs in the field of genetic counseling and testing.MethodsA cross-sectional survey within the European Bridges Study (Breast Cancer Risk after Diagnostic Gene Sequencing) was conducted among physician members (n = 111) of the German Cancer Society who were primarily gynecologists. It was designed to examine their experience in genetic counseling and testing.ResultsOverall, the study revealed a need for training in risk communication and clinical recommendations for persons at risk. One-third of respondents communicated only relative disease risks (31.5%) instead of absolute disease risks in manageable time spans. Moreover, almost one-third of the respondents (31.2%) communicated bilateral and contralateral risk-reducing mastectomy as an option for healthy women and unilateral-diseased breast cancer patients without mutations in high-risk genes (e.g. BRCA1 or BRCA2). Most respondents expressed training needs in the field of risk assessment models, the clinical interpretation of genetic test results, and the decision-making process.ConclusionThe survey demonstrates a gap of genetic and risk literacy in a relevant proportion of physicians and the need for appropriate training concepts.     

Benchmarking of a checklist for the identification of familial risk for breast and ovarian cancers in a prospective cohort

The detection of deleterious germline mutations in BRCA1 and BRCA2 considerably influences the clinical management of healthy and diseased carriers. Therefore, the identification of persons at risk who could uptake genetic counseling and testing is pivotal. We developed a checklist with validated criteria to improve the identification, and prospectively evaluate the incidence, of familial cancer history in 5091 breast cancer patients. The rate of 30.4% of patients at high genetic risk underpins the demand for care in risk identification and counseling. The easy‐to‐use instrument promotes the implementation and dissemination of risk counseling by physicians.     

Identification of twenty-nine novel germline unclassified variants of BRCA1 and BRCA2 genes in 1400 Italian individuals

ObjectivesBreast and/or ovarian cancers are complex multifactorial diseases caused by interaction of both genetic and non-genetic factors and characterized by predisposition to inheritance. BRCA1 and BRCA2 genes are the most clinically involved with these kinds of cancer and the spectrum of variants affecting these genes is very wide. In fact, point variants, large or small insertions/deletions, genomic rearrangements can be found in these patients, although a large number of variants with uncertain biological and clinical significance continues to be identified. Next-generation sequencing (NGS) technology is actually the most powerful tool for the discovering of causative mutations and novel disease genes, moreover it allows to make a rapid diagnosis of genetic variants giving fast, inexpensive and detailed genetic information.Material and methodsIn this study, we report the screening of BRCA1 and BRCA2 genes on 1400 consecutive Caucasian patients with breast and/or ovarian cancer history or family risk, attending the oncogenetic ambulatory at the Foundation Policlinico Agostino Gemelli in Rome.ResultsWe describe twenty-nine novel BRCA1 and BRCA2 variants detected in Italian individuals suffering from hereditary breast and ovarian cancer syndrome (HBOC).ConclusionData regarding novel variants can provide useful information not only at epidemiological but also at clinical level, allowing for the better managing of breast and ovarian cancer patients and their family members.     

What factors may influence psychological well being at three months and one year post BRCA genetic result disclosure?

Genetic testing for breast cancer predisposition has been available in the clinical practice for more than a decade. How the result of genetic testing affects the psychological well-being of the individuals is an under-researched area in many populations. Follow-up analysis of psychological well-being via HADS scale was performed in 364 individuals at 3 months and 1 year after the disclosure of BRCA1/2 genetic result. We analyzed potential predictors for pathological anxiety and variables associated to the variation of HADS scores over time. At pre-test only 16% and 4% of individuals presented symptoms of anxiety and depression, respectively. Having a prior diagnosis of cancer and presenting a pathological HADS-A score at the baseline were associated with clinically significant anxiety scores at one year, but the genetic test result was not. Thus, BRCA genetic testing does not influence short and long term anxiety and depression levels among those identified as mutation carriers. It is our task to demystify the allegedly negative impact of BRCA testing on psychological well being to increase the uptake of genetic testing and benefit those who are at high risk of developing breast, ovarian and prostate cancer.     

The prevalence of germline BRCA1 and BRCA2 mutations in young women with breast cancer undergoing breast-conservation therapy

BACKGROUND: Germline mutations of BRCA1 and BRCA2 increase the risk for breast cancer. Mutation carriers selecting breast-conservation therapy (BCT) for treatment of operable breast cancer experience a higher rate of new primary breast cancers. We sought to determine the frequency of BRCA1/BRCA2 mutations in women who underwent BCT. Genetic testing results were compared with the prior probability of mutations in either gene. METHODS: Eighty-nine patients age 39 or younger entered the study. Genetic testing was performed for BRCA1 and BRCA2 and the BRCAPRO model determined the probability of carrying a mutation. RESULTS: Eight mutations were discovered (prevalence, 9.0%). Twenty (22%) uncharacterized sequence variants were found. The prior probability of carrying a mutation was 14%. Mutation carriers had a higher prior probability (.49) compared with women with uncharacterized variants (.09) or with normal genes (.11). CONCLUSIONS: BRCA1 and BRCA2 mutations are common (9%) among unselected young breast cancer patients undergoing BCT.