Hereditary Breast Cancer: Risk Assessment Is the Easy Part

Individuals who seek genetic testing to determine hereditary risk of breast cancer may not be aware that genetic testing is uninformative in many high-risk families or that they may be at increased risk of other cancers as well. Many mistakenly believe that current genetic testing provides definitive information about the magnitude of cancer risk to carriers. This article describes the assessment of hereditary risk by pedigree analysis, epidemiology, and genetic testing within the cancer risk assessment and counseling setting, and discusses other information that helps patients to make informed health care decisions. Because the risk of ovarian cancer is increased in many families at high risk of breast cancer, information about prophylactic oophorectomy and hormone replacement therapy is essential. A case history is presented to show the efficacy of cancer risk assessment and counseling when genetic testing is uninformative. ▪     

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.     

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.     

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.     

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.     

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.

     

Cancer Risk Information Services: Promise and Pitfalls

Abstract: As new information about cancer risk and etiology becomes available, physicians are requesting genetic testing for their patients and are expecting that they will receive appropriate information about risk, testing, and test results. Patients' reactions to risk suggest that the clinically effective presentation of risk information is a complex process, requiring multiple visits with skilled health professionals and includes helping patients to integrate sophisticated and often surprising information. Unless sufficient time and expertise are devoted to exploring patients' beliefs and concerns, as well as ascertaining and providing information about cancer risk that is relevant to them, patients may not learn enough to make informed health care decisions, even with state-of-the-art genetic testing and access to the latest risk information.?     

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.     

Preventive surgery for colon cancer in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer syndrome

BACKGROUND: A better understanding of the molecular basis of hereditary colorectal cancer syndromes such as hereditary nonpolyposis colorectal cancer syndrome (HNPCC) and familial adenomatous polyposis (FAP) has profound consequences for both the diagnosis and (prophylactic) treatment of (pre)malignant neoplastic lesions. DISCUSSION: Sequence analysis of the underlying genes for these conditions and the detection of disease-causing genetic alterations in an index patient enable predictive testing for individuals at risk within an affected family. However, the clinical implications of predictive molecular testing depend on the overall penetrance and variability in the expression of pathogenic mutations. The extent of these parameters differs considerably among the various known hereditary colorectal cancer syndromes. Hence the integration of genetic information into the daily surgical practice remains challenging. CONCLUSIONS: This review provides an update on the indications for family assessment, purpose and limitations of the genetic testing and resulting recommendations for prophylactic surgery in FAP and HNPCC.     

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.     

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.     

Prophylaktische Chirurgie des Mamma- und Ovarialkarzinoms

New insights into the genetic basis of carcinogenesis have been obtained by modern molecular biological techniques. Several susceptibility genes are known. The hereditary breast and ovarian cancer syndrome (germline mutations in BRCA1 and BRCA2) and endometrial cancer in the context of the hereditary non-polyposis colorectal cancer syndrome (HNPCC), germline mutations in mismatch-repair genes, are the most frequent hereditary cancer syndromes in gynaecology. Mutations in TP53 (Li-Fraumeni syndrome) and PTEN (Cowden's disease), associated with increased risk of breast cancer, are responsible for a smaller portion of familial breast cancer.The risk of inheritance and disease can be identified and defined by investigating family history, risk calculation programs, and genetic testing. Afterwards, options of primary, secondary, and tertiary prevention can be formulated. Presently, prophylactic surgery is the only option proven by clinical trials that can reduce the mortality of hereditary breast and ovarian cancer.     

Hereditary prostate cancer: clinical aspects

PURPOSE: We review the current epidemiological and genetic knowledge regarding hereditary prostate cancer, and outline its clinical implications. MATERIALS AND METHODS: Published articles on hereditary prostate cancer were identified using the MEDLINE data base. RESULTS: A risk of prostate cancer, particularly early onset disease, is strongly affected by family history (number of relatives with prostate cancer and their age at diagnosis). A family history of prostate cancer increases the positive predictive value of prostate specific antigen testing and, hence, heredity should always be assessed when deciding whether to perform biopsies in a man with a prostate specific antigen level of 3 to 10 ng./ml. Epidemiological studies indicate that dominantly inherited susceptibility genes with high penetrance cause 5% to 10% of all prostate cancer cases, and as much as 30% to 40% of early onset disease. More than a half dozen chromosome loci that may comprise such genes have been mapped, but as of May 2002 no prostate cancer susceptibility gene of major importance had been cloned. Most likely, environmental factors and comparatively common variants of several other genes affect prostate cancer risk in families with or without multiple cases of the disease. On average, hereditary prostate cancer is diagnosed 6 to 7 years earlier than sporadic prostate cancer, but does not otherwise differ clinically from the sporadic form. As a consequence of the earlier onset, a greater proportion of men with hereditary prostate cancer die of the disease than those with nonhereditary prostate cancer. At present, the only clinically applicable measure to reduce prostate cancer mortality in families with hereditary disease is screening, with the aim of diagnosing the disease when it is still in a curable stage. CONCLUSIONS: Hereditary susceptibility is now considered the strongest risk factor for prostate cancer and has profound clinical importance. The genetic mechanism behind such susceptibility has turned out to be more complex than initially thought, and will probably not be completely understood for many years to come.     

Familial colorectal cancer: a concept revisited

Objective  The family history of patients with colorectal cancer (CRC) shows an increased risk of disease although evident inherited syndromes are demonstrable in only a small percentage of patients. The purpose of this study was to identify factors that might suggest an inherited component in the transmission of CRC.
Method  The study monitored 880 consecutive patients between 1980 and 2005 treated for CRC.
Results  Familial adenomatous polyposis (FAP) was found in only one patient, and a classical mutation of hereditary nonpolyposis colon cancer was found in only two patients. The risk assessment was possible mainly because of factors such as early onset CRC, the presence of multiple primary tumours and a high risk family history. Considering these 36 more patients were suspected to be high risk and referred for further genetic testing. At least one first-degree relative with CRC was reported in 140 patients. In 49 patients, CRC was diagnosed before 50 years of age. Multiple primary tumours, colonic or extra colonic, synchronous or metachronous were found in 136 patients.
Conclusion  Our study suggests that if only patients with identified mutations are taken into consideration, then the percentage of evident hereditary colon cancer is very low, but this percentage quickly increases if we make marginal adjustments to the identifying criteria. It seems that it is the physician's clinical suspicion, more than the fulfilment of rigid criteria, which plays a fundamental role in the timely identification and a subsequent focused treatment of patients with hereditary CRC.     

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.     

Family history? The forgotten question in high‐risk colorectal cancer patients

Aim  The aim of the study was to investigate the frequency and detail of family history recorded for patients diagnosed with potentially high-risk colorectal cancer, and to determine the proportion of these patients referred to a high-risk assessment clinic.
Method  Medical records of patients diagnosed with colorectal cancer under the age of 50 admitted to a major Sydney teaching hospital were reviewed. The proportion of records containing information about family history was calculated. Associations between recording of family history and demographic and clinical characteristics of patients were investigated. Logistic regression modelling was performed to identify significant, independent predictors of study outcomes.
Results  Of 113 patients with colorectal cancer diagnosed under the age of 50 years, 61 (54%, 95% CI: 44–63%) had an entry in their hospital medical record about family history. Family history was significantly less likely to be recorded for females, for those admitted via the Emergency Department, and for those with shorter lengths of stay. A significant family history was found in 51% of the 61 patients who had a family history recorded. Records of patients attending specialist colorectal surgeons were significantly more likely to contain information about family history than those who attended other specialists ( P  = 0.04). Only 14 patients (12%, 95% CI: 7–20%) were formally referred for further genetic assessment.
Conclusion  These results suggest that family history is still being neglected in routine clinical practice, and high-risk assessment services are underutilized, implying the need for further dissemination of guidelines with regard to the recognition and management of hereditary colorectal cancer.     

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.     

Prophylactic Gynecologic Specimens from Hereditary Cancer Carriers

Hereditary breast ovarian cancer and Lynch/hereditary nonpolyposis colorectal cancer syndrome account for most hereditary gynecologic cancers. In the absence of effective cancer screening and other preventative strategies, risk-reducing surgery in women who are known to be at genetic risk of BRCA-associated or of Lynch syndrome carcinomas is effective in significantly decreasing the lifetime risk of developing malignancy. Reflex genomic testing of high-grade ovarian cancers and reflex immunohistochemistry in endometrial cancers will lead to greater recognition of germline-associated cancers. Approaches to processing surgical specimens, the recognition and classification of cancer precursor lesions, and differentiation from their mimics are discussed.     

Importance of family history and indications for genetic testing

Family history is an important cancer risk assessment tool, and it is easy to use. The family history is integral in identifying an individual's risk for primary cancer and assists in the assessment of risk for a second primary cancer. For oncology providers, the critical family history is defined as including first‐ and second‐degree family history, maternal and paternal history, type of primary cancer, and age at diagnosis and ethnicity. Family history should be taken at diagnosis and updated periodically. Despite the importance of family history to patient care, there are significant barriers to taking a family history. We review the impact of collecting complete family history data with respect to calculation of cancer risk, recommendations for screening, and prevention strategies and referral for genetic testing.