Breast cancer risk assessment in patients who test negative for a hereditary cancer syndrome

BackgroundThe majority of women who undergo genetic testing due to a significant family history of breast cancer will receive a negative result. The purpose of this study was to calculate the lifetime risk of breast cancer in women undergoing genetic counseling who received an uninformative genetic test result.MethodsA retrospective chart review of mutation-negative women presenting to a cancer risk assessment clinic was performed. Lifetime risks of breast cancer were calculated using the Claus, Gail, and Tyrer-Cuzick risk assessment models.ResultsApproximately half (51%) of the women were classified as high-risk by at least one risk assessment model. The Tyrer-Cuzick model identified the highest proportion (43.2%) of patients as high-risk. Four percent (n = 4) of the sample was considered high-risk by all three models.ConclusionsMore than half (51%) of women who underwent genetic counseling and received an uninformative negative genetic test result had a significantly elevated risk for the development of breast cancer. It is, therefore, imperative that women do not conclude that a negative genetic test result represents a lack of risk.     

Breast Cancer Risk Assessment and Counseling: A Clinician's Guide

Abstract: Most individuals concerned about hereditary breast cancer risk will neither order nor benefit from genetic testing at the present time. Many will, however, seek information about their risk and testing. Risk assessment services, in addition to providing information about hereditary risk and genetic testing, need also to include assessment of non-hereditary risks, information about how to evaluate risks, early detection modalities, the etiology of cancer, and assistance in devising follow-up health care plans. Psychosocial factors, particularly those pertaining to the individual's past history with illness and beliefs about causes and prognosis, must be taken into account to provide relevant information that is understood. A case history with examples of some of the types of information that lead to informed consent in a cancer risk assessment setting is provided.     

Update on multi‐gene panel testing and communication of genetic test results

With technological advances, multi‐gene panel testing has become increasingly used to identify patients at risk for hereditary breast cancer (HBC). There are currently evidence‐based interventions and breast cancer screening strategies that exist for cancer prevention and early detection among patients with HBC. Moreover, in addition to the personal impact of identifying HBC, this information may be shared with at‐risk family members to amplify the benefits of testing and subsequent care among those at high risk. Opportunities and challenges with the utilization of updated multi‐gene panel testing for HBC, including: (a) tumor sequencing with germline consequences; (b) genetic counseling implications; and (c) strategies to improve the communication of genetic test results to family members will be reviewed. With the advances and expansion of genetic testing, all health care providers need to be updated on both the importance and complexities of HBC counseling and testing, in order to optimize patient care.     

Influence of Race/Ethnicity on Genetic Counseling and Testing for Hereditary Breast and Ovarian Cancer

Abstract:  Risk assessment coupled with genetic counseling and testing for the cancer predisposition genes BRCA1 and BRCA2 ( BRCA1/2 ) has become an integral element of comprehensive patient evaluation and cancer risk management in the United States for individuals meeting high-risk criteria for hereditary breast and ovarian cancer (HBOC). For mutation carriers, several options for risk modification have achieved substantial reductions in future cancer risk. However, several recent studies have shown lower rates of BRCA1/2 counseling and testing among minority populations. Here, we explore the role of race/ethnicity in cancer risk assessment, genetic counseling and genetic testing for HBOC and the BRCA1/2 cancer predisposition genes. Barriers to genetic services related to race/ethnicity and underserved populations, including socioeconomic barriers (e.g., time, access, geographic, language/cultural, awareness, cost) and psychosocial barriers (e.g., medical mistrust, perceived disadvantages to genetic services), as well as additional barriers to care once mutation carriers are identified, will be reviewed.     

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.     

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.     

Recall of and Reactions to a Surgeon Referral Letter for BRCA Genetic Counseling Among High-Risk Breast Cancer Patients

Background  The oncology care setting represents an important opportunity to identify and refer women at increased risk for hereditary breast and ovarian cancer. However, little is known about the effectiveness of provider approaches to inform patients of hereditary cancer risk or patient uptake of genetic counseling (GC). This qualitative study examined the impact of a surgeon referral letter on recently diagnosed breast cancer patients’ uptake of BRCA GC. Methods  Qualitative open-ended, in-depth interviews were conducted with 26 high-risk breast cancer patients sent a referral letter for BRCA GC by their surgeon. Data were analyzed by a grounded theory approach. Results  Most women (~80%) recalled receiving the letter, and 62% of all (n = 16) women pursued GC. Recall of the letter did not seem to be associated with uptake of GC (P = .49, Fisher’s exact test). The results highlight key areas for improvement that may help increase the impact of the letter. Half of the women in this sample believed that the letter was sent to all breast cancer patients, rather than those with specific risk factors. Few women mentioned any implications for the information obtained during GC or testing regarding their current breast cancer diagnosis or treatment. Of the women who did not attend, many perceived that dealing with the GC and testing process in the midst of a cancer diagnosis and treatment was overwhelming. Among the women who had chosen not to attend GC, most stated they would reconsider after completing their treatment. Conclusions  Patient recall of a surgeon referral letter does not seem to increase the number of high-risk women who attend GC after a breast cancer diagnosis. The letter approach in its current format does not seem to be a wholly effective means of communicating with some patients who may be overwhelmed by their cancer diagnosis or unaware that GC and testing may have implications for their current treatment decisions, possibly resulting in a missed opportunity to engage in informed decision making.     

Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons

Background

The purpose of this consensus guideline is to outline recommendations for genetic testing that medical professionals can use to assess hereditary risk for breast cancer.

Methods

Literature review included large datasets, basic and clinical science publications, and recent updated national guidelines. Genetic testing to assess hereditary risk of cancer is a complex, broad, and dynamic area of medical research. The dominant focus of this guideline is limited in scope to breast cancer.

Results

There is a lack of consensus among experts regarding which genes among many should be tested in different clinical scenarios. There is also variation in the degree of consensus regarding the understanding of risk and appropriate clinical management of mutations in many genes.

Conclusions

Genetic testing should be made available to all patients with a personal history of breast cancer. Recent data are reviewed that support genetic testing being offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment recommendations. Patients who had genetic testing previously may benefit from updated testing. Genetic testing should be made available to patients without a history of breast cancer who meet National Comprehensive Cancer Network guidelines. Finally, variants of uncertain significance are not clinically actionable and these patients should be managed based on their individual risk factors.

     

Hereditary Breast Cancer: Practical Pursuit for Clinical Translation

The benefits of a skillful medical history and histologic confirmation of relevant pathology are potentially lifesaving. Appropriately directed DNA testing based on these initial steps provides an opportunity for clinical translation into a cancer prevention program targeted to family members. Unfortunately, cancer prevention strategies that are based on genetics are frequently overlooked or underestimated in the overall practical management of patients at high risk for breast cancer as well as integral cancers that constitute a hereditary breast cancer syndrome. DNA testing, particularly for BRCA1 and BRCA2 in hereditary breast-ovarian cancer syndrome and p53 in the Li-Fraumeni syndrome, and many other syndromes is commercially available for inclusion in a cancer control program and merits attention in this major public health problem. It is clear that the time and effort expended for a hereditary cancer syndrome diagnosis may significantly reduce both morbidity and mortality in breast cancer. We have found that genetic counselors can partner with the clinical physicians and make significant contributions to this labor-intensive effort.     

Complexities of genetic screening and testing in hereditary colorectal cancer

It is becoming increasingly important to identify patients at risk for hereditary colorectal cancer (CRC) given the opportunity to impact medical management and reduce morbidity and mortality among patients and their family members once inherited CRC predisposition is confirmed. Methods by which patients are identified are evolving as genetic testing costs have plummeted, resulting in many more genetic screening and testing options. Opportunities and challenges with newer approaches to genetic testing and screening for hereditary CRC are reviewed along with benefits and limitations of each approach. Regardless of how methods evolve for identifying patients with hereditary cancer risk, the need for patient education, family history taking, appropriate risk counseling, and enhancing sharing across family members will remain critical for optimal patient care.     

The management of familial breast cancer

Epidemiological studies over the past several decades have consistently supported the concept that a proportion of breast cancers develop as the result of an inherited familial predisposition. However, until recently our understanding and knowledge of the underlying genetic processes involved have been limited. Current advances in molecular biology have shown that hereditary breast cancer may arise as the result of mutations of 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. It is estimated that approximately 5-10% of all breast cancers involve one of these inherited predisposition genes, with BRCA1 and BRCA2 accounting for up to 90% of this group. Mutation analysis is complex in nature and is presently in a developmental and evolving phase, for which reason genetic testing should be offered on a selective basis and through genetic counselling clinics. This report reviews the current knowledge and roles of the various predisposition genes and discusses the management implications for both affected and nonaffected members of breast cancer families. Comprehensive and informative counselling is critical for women with an inherited predisposition to breast cancer and this has led to the evolution of familial cancer clinics involving a multi-disciplinary specialist team approach. Familial cancer clinics can provide individuals with information about their risk of developing breast cancer and offer advice regarding the various management options presently available.     

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.     

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.     

Identification and Management of Women at High Risk for Hereditary Breast/Ovarian Cancer Syndrome

Abstract:  Despite advances in identifying genetic markers of high risk patients and the availability of genetic testing, it remains challenging to efficiently identify women who are at hereditary risk and to manage their care appropriately. HughesRiskApps, an open-source family history collection, risk assessment, and Clinical Decision Support (CDS) software package, was developed to address the shortcomings in our ability to identify and treat the high risk population. This system is designed for use in primary care clinics, breast centers, and cancer risk clinics to collect family history and risk information and provide the necessary CDS to increase quality of care and efficiency. This paper reports on the first implementation of HughesRiskApps in the community hospital setting. HughesRiskApps was implemented at the Newton-Wellesley Hospital. Between April 1, 2007 and March 31, 2008, 32,966 analyses were performed on 25,763 individuals. Within this population, 915 (3.6%) individuals were found to be eligible for risk assessment and possible genetic testing based on the 10% risk of mutation threshold. During the first year of implementation, physicians and patients have fully accepted the system, and 3.6% of patients assessed have been referred to risk assessment and consideration of genetic testing. These early results indicate that the number of patients identified for risk assessment has increased dramatically and that the care of these patients is more efficient and likely more effective.     

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.     

BRCA2 mutation screening is clinically relevant in breast and early prostate cancer families

It is known that in some families an association exists between breast and prostate cancer. Several reports have suggested that BRCA2 mutations may be associated with an increased risk of these cancers. Herein, we report three cases of early onset of prostate cancer in families with female and male breast cancers. In each case, the familial phenotype is associated with a mutation of the BRCA2 gene. More generally, genetic counseling, including screening for BRCA2 mutations, should become standard practice in kindred with prostate and breast cancers.     

Initial experience with surgical treatment planning in the newly diagnosed breast cancer patient at high risk for BRCA-1 or BRCA-2 mutation

Despite an abundance of information available for dealing with patients with BRCA-1 and BRCA-2 mutations, little guidance is available to assist the surgeon in dealing with the genetically high-risk patient recently diagnosed with breast cancer. A retrospective review was undertaken of 170 patients who underwent genetic counseling and testing over a 3-year period from March 2000 to March 2003. Forty-three of the 170 patients tested were diagnosed with breast cancer prior to genetic testing. Nine patients (20.9%) tested positive for a deleterious mutation. Fifty-eight percent underwent genetic counseling prior to definitive cancer surgery. Five of the 25 patients who underwent lumpectomy tested positive for a deleterious mutation. Testing results became available during systemic therapy or radiation was delayed until results were known. After counseling, all five patients testing positive went on to bilateral prophylactic mastectomy and reconstruction. None had radiation therapy. Because of a strong family history, eight patients elected to undergo prophylactic mastectomy and reconstruction prior to obtaining genetic test results; and despite compelling histories, all eight tested negative for a mutation. Treatment algorithms are developed to manage patients that are first discovered to be at high risk for a BRCA-1 or BRCA-2 mutation at the time they are diagnosed with breast cancer. Patients diagnosed with breast cancer who are discovered to be at high risk for a genetic mutation should undergo counseling prior to definitive surgery. This maximizes the time that patients have to consider options for prophylaxis and monitoring should their test be positive. It also prevents women who would otherwise be candidates for breast preservation from undergoing unnecessary radiation therapy should they chose prophylactic mastectomy in the face of a positive test.     

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.     

Importance of genetic counseling and molecular diagnosis testing in families at high risk for cancer

Individuals with a family history of certain cancer types are at higher risk to develop a malignancy during their lifetime. The availability of the family history is a basic component for genetic counseling of these patients to determine illnesses that may affect other family members. The family history can help us to identify some inheritance patterns of cancer transmission among families. Nowadays it is possible to identify by clinical and molecular testing many of these familial cancer syndromes. The objective of this review is to provide a basis to the physician who the patient contacts first, in order to recognize the possibility of illnesses with a genetic transmission. This will allow the treating physician to refer the patient to a genetic specialist for possible molecular diagnosis of the illness.     

Towards population-based genetic screenings for breast and ovarian cancer: A comprehensive review from economic evaluations to patient perspectives

Genetic testing for hereditary breast and ovarian cancer following genetic counseling is based on guidelines that take into account particular features of the personal and family history, and clinical criteria conferring a probability of having a BRCA mutation greater than 10% as a threshold for accessing the test. However, besides reducing mortality and social impact, the extension of screening programs also for healthy family members would allow a huge saving of the rising costs associated with these pathologies, supporting the choice of the “Test” strategy versus a “No Test” one. Analyses of different health care systems show that by applying the “Test” strategy on patients and their families, a decrease in breast and ovarian cancer cases is achieved, as well as a substantial decrease in costs of economic resources, including the costs of the clinical management of early detected tumors.In this review, we analyzed the most recent papers published on this topic and we summarized the findings on the economic evaluations related to breast and ovarian cancer population screenings. These results proved and validated that the population-wide testing approach is a more accurate screening and preventive intervention than traditional guidelines based on personal/family history and clinical criteria to reduce breast and ovarian cancer risk.