Performance of BOADICEA and BRCAPRO genetic models and of empirical criteria based on cancer family history for predicting BRCA mutation carrier probabilities: A retrospective study in a sample of Italian cancer genetics clinics

PurposeTo evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing.Patients and methodsThe probability of BRCA mutation according to the three tools was retrospectively estimated in 918 index cases consecutively undergone BRCA testing at 15 Italian cancer genetics clinics between 2006 and 2008.Results179 of 918 cases (19.5%) carried BRCA mutations. With the strict use of the criteria based on cancer family history 173 BRCA (21.9%) mutations would have been detected in 789 individuals. At the commonly used 10% threshold of BRCA mutation carrier probability, the genetic models showed a similar performance [PPV (38% and 37%), sensitivity (76% and 77%) and specificity (70% and 69%)]. Their strict use would have avoided around 60% of the tests but would have missed approximately 1 every 4 carriers.ConclusionOur data highlight the complexity of BRCA testing referral in routine practice and question the strict use of genetic models for BRCA risk assessment.     

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.     

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.     

Establishing a Family Risk Assessment Clinic for Breast Cancer

Abstract:  Breast cancer is the most common cancer affecting European women and the leading cause of cancer-related death. A total of 15–20% of women who develop breast cancer have a family history and 5–10% a true genetic predisposition. The identification and screening of women at increased risk may allow early detection of breast cancer and improve prognosis. We established a family risk assessment clinic in May 2005 to assess and counsel women with a family history of breast cancer, to initiate surveillance, and to offer risk-reducing strategies for selected high-risk patients. Patients at medium or high risk of developing breast cancer according to NICE guidelines were accepted. Family history was determined by structured questionnaire and interview. Lifetime risk of developing breast cancer was calculated using Claus and Tyrer-Cuzick scoring. Risk of carrying a breast cancer-related gene mutation was calculated using the Manchester system. One thousand two hundred and forty-three patients have been referred. Ninety-two percent were at medium or high risk of developing breast cancer. Formal assessment of risk has been performed in 368 patients, 73% have a high lifetime risk of developing breast cancer, and 72% a Manchester score ≥16. BRCA1/2 mutations have been identified in 14 patients and breast cancer diagnosed in two. Our initial experience of family risk assessment has shown there to be a significant demand for this service. Identification of patients at increased risk of developing breast cancer allows us to provide individuals with accurate risk profiles, and enables patients to make informed choices regarding their follow-up and management.     

Awareness of heredity in colorectal cancer patients is insufficient among clinicians: a Norwegian population-based study

Objective  The assessment of family history and medical data is crucial in identifying families with Lynch syndrome (LS). Among consecutive colorectal cancer (CRC) patients, we aimed at identifying all patients with a hereditary predisposition, and to study a possible discrepancy with assessments made by the responsible clinicians.
Method  All consecutively diagnosed patients with CRC from two Norwegian hospitals were included, and information on family history was collected in a detailed interview. We assessed information in medical records, and tumours were examined for LS-associated histopathological features.
Results  Among 562 patients, there was no documentation of family history in 388 (69.0%) medical records, and in 174 (31.0%) patients, there was no clinical assessment of the information that was collected on family history. Based on detailed interviews and extended pathological examination, we found that 137 (24.4%) of the 562 patients could be classified as possible LS according to the Revised Bethesda Guidelines (RBG); and that 46 (33.6%) of these patients could be identified by family history alone.
Conclusion  Family history and relevant information in patient records can identify patients with possible LS. However, clinicians often fail to include information on hereditary factors and to assess relevant data in medical records. Familial CRC is therefore not acknowledged, and genetic counselling is not offered.     

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. ▪     

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.     

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.     

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.     

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.     

Colonoscopy for screening and follow up of patients with a family history of colorectal cancer

Objective To determine the minimum family history of colorectal cancer (CRC), which justifies colonoscopy and to establish whether further colonic assessment is necessary after a negative screening colonoscopy. Method A retrospective review of every colonoscopy undertaken for family screening at the Royal Berkshire and Battle Hospitals, Reading between October 1996 and July 2004. Results Four hundred and thirty‐two patients (261 women) with an average age of 48 years (range 14–84) were screened. Three cancers in patients over the age of 60 years and 49 adenomas were found in 37 patients. Twenty three of 281 (8%) patients with a ‘low‐risk’ family history (one in 12 or less lifetime risk of developing CRC) had either a cancer or an adenoma. Eighteen of 151 (12%) patients with a ‘high‐risk’ family history (one in 10 or greater) had a similar positive colonoscopy. Thirteen of 15 patients who had an adenoma aged under 45 years had a high‐risk family history. Seventy‐three patients subsequently underwent two or more follow‐up colonoscopies. There were 22 adenomatous polyps found in 12 patients (16%) at the first screening, nine adenomas in seven patients in the second colonoscopy and four adenomas found in four patients in all subsequent colonoscopies. Conclusion Patients with a low‐risk family history have a similar adenoma pick‐up to that of the general population. These patients need not be screened below the age of 50 unless symptomatic. Follow up of low‐risk family history (FH) patients with a negative screening colonoscopy is unlikely to be beneficial.     

Limitations of the Gail model in the specialized breast cancer risk assessment clinic

The Gail model is a risk assessment tool that is accurate for general breast cancer risk screening. Because of the limited way that this model incorporates family history information, however, there are concerns that it may underestimate risk for many women attending specialized breast cancer risk assessment clinics. We collected comprehensive breast cancer risk factor information for 213 women attending a specialized breast cancer risk assessment clinic using a modified version of the CancerGene software. Breast cancer risk was calculated using the models of Gail and Claus as well as BRCAPRO and the tables of Bodian (for women with lobular neoplasia). Eighty-six percent of the women had a family history of breast cancer. Although 74% of women had risk factor histories that are thought to confound the Gail model (family history of breast cancer in second-degree relatives, family history of breast cancer before the age of 50, family history of bilateral breast cancer, family history of ovarian cancer, or personal history of lobular neoplasia), the inclusion of other models increased the risk level assignment in only 13% of the cases. We conclude that the Gail model is an appropriate risk assessment tool for most women attending specialized clinics, although the inclusion of models better able to account for family history information and personal history of lobular neoplasia is required to accommodate all women.     

Prevalence of family history of breast and ovarian cancer in a single primary care practice using a self-administered questionnaire

Women at high risk of hereditary breast and/or ovarian cancer require specific management strategies for cancer prevention and early detection. The goal of this study was to determine the prevalence of familial breast and ovarian cancer among patients in a primary care practice. Questionnaires were mailed to the 608 women less than 81 years of age in a single primary care practice. Additional mailings and phone calls were used for nonresponders. Data were analyzed by bloodline, the degree of relative, age of diagnosis and cancer type. Women were grouped into three categories of breast/ovarian family history: "no family history,"insignificant family history," and "significant potentially high-risk family history" (women with two or more relatives in a single bloodline with breast and/or ovarian cancer, a single individual with bilateral breast cancer or breast and ovarian cancer, or breast and/or ovarian cancer at less than 40 years of age). A pedigree analysis of women categorized as "significant potentially high-risk family history" further classified these women as to the likelihood of being at risk for hereditary cancer. Data were obtained from 567 women (93%); 27 patients with a personal diagnosis of breast and/or ovarian cancer were excluded. Of the 540 remaining respondents, 351 (65%) had no family history of cancer, 138 (25.6%) had an insignificant family history, and 51 (9.4%) had a significant family history. Based on pedigree analysis of these 51 patients, 19 were unlikely to be at high risk for hereditary cancer, and 32 (6%) were likely to be at significant risk and warrant intensive evaluation. The large proportion of women identified with a significant family history of breast and/or ovarian cancer has major implications regarding the magnitude of a population-based process to identify and manage high-risk individuals.     

Electronic Health Records and the Management of Women at High Risk of Hereditary Breast and Ovarian Cancer

Abstract:  Currently, management strategies exist that can decrease the morbidity and mortality associated with having a BRCA1 or BRCA2 mutation. Unfortunately, the task of identifying these patients at high risk is a daunting challenge. This problem is intensified because Electronic Health Records (EHRs) today lack the functionality needed to identify these women and to manage those women once they have been identified. Numerous niche software programs have been developed to fill this gap. Unfortunately, these extremely valuable niche programs are prevented from being interoperable with the EHRs, on the premise that each EHR vendor will build their own programs. Effectively, in our efforts to adopt EHRs, we have lost sight of the fact that they can only have a major impact on quality of care if they contain structured data and if they interact with robust Clinical Decision Support (CDS) tools. We are at a cross roads in the development of the health care Information Technology infrastructure. We can choose a path where each EHR vendor develops each CDS module independently. Alternatively, we can choose a path where experts in each field develop external niche software modules that are interoperable with any EHR vendor. We believe that the modular approach to development of niche software programs that are interoperable with current EHRs will markedly increase the speed at which useful and functional EHRs that improve quality of care become a reality. Thus, in order to realize the benefits of CDS, we suggest vendors develop means to become interoperable with external modular niche programs.     

家族性胰腺癌

家族性胰腺癌（familial pancreatic cancer,FPC）是已经确定的遗传肿瘤综合征,占全部胰腺癌的3％左右。因此,对FPC的研究将有利于发现胰腺癌的高危人群,包括家族中出现胰腺癌的其他成员和其他遗传肿瘤综合征：如皮肤黏膜黑色素斑一胃肠道多发性息肉综合征（Peutz—Jeghers综合征）,家族性非典型恶性黑色素瘤,家族性乳腺卵巢癌综合征,遗传性非腺瘤性结直肠癌等。胰腺癌易患基因和环境因素的确定将能够更加准确预测发病的危险,加强对高危人群的随访和及时的根治性手术是改善预后的重要方法。     

The influence of family history on prostate cancer risk: implications for clinical management

? The most recent evidence for the link between a family history of prostate cancer and individual risk for future disease was examined, with the aim of understanding what the existence and nature of a family history of prostate cancer does to a man's risk of developing the disease. ? Our findings highlighted the clear association between a family history of prostate cancer and increased risk of developing the disease; with a greater proximity of relatedness, greater number of family members affected and/or earlier age at diagnosis of the family member elevating risk further. ? These findings have important clinical implications for the identification and subsequent management of men deemed to be at increased risk of developing prostate cancer. The evidence for prostate cancer risk reduction with the mono 5α-reductase inhibitor (5ARI) finasteride in a low-risk population and, more recently, with the dual 5ARI dutasteride in a population at increased risk of developing the disease, has potential to expand management options for men at risk of developing prostate cancer beyond more frequent and/or earlier surveillance. ? Given that family history can be easily assessed in routine clinical practice, it should be regarded as an important parameter to consider alongside PSA level for prostate cancer risk assessment.     

Genetics and clinical practice in rheumatology

The dramatic advances made recently in human genome research are fueling considerable interest in genetic testing. A specific feature of genetic testing is that the results are final and impact not only the patient, but also the entire family. Those elements should be factored into the risk/benefit ratio evaluation. In France, legislation the differentiates diagnostic tests in symptomatic patients from predictive tests in asymptomatic patients with affected family members. Only multidisciplinary groups with both clinical and genetic expertise can order predictive tests. In all cases the physician must sign a statement that informed consent was obtained from the patient prior to testing. The test must be done in an accredited laboratory and the result communicated by the physician to the patient. Patient confidentiality must be respected, particularly regarding family members. In monogenic diseases, the diagnostic weight of genetic testing is often considerable, although the limitations should be borne in mind. In multifactorial diseases, genetic testing seeks to identify risk factors that are usually associated with a low level of risk. The result should be interpreted in the light of the clinical presentation, family history, and genetic background. The predictive value is closely dependent on the clinical presentation but is generally limited, most notably when family members are affected. Great care should be taken to avoid causing undue anxiety among individuals with positive test results. Diseases that illustrate these aspects include Paget's disease of bone, of which inherited variants caused by a mutation in a single gene on chromosome 5 have been identified recently, and rheumatoid arthritis, which is a multifactorial disease.     

Clinicopathological characteristics of gene-positive breast cancer in the United Arab Emirates

IntroductionBreast cancer is the most prevalent cancer in the United Arab Emirates (UAE). This is the first study to provide data on predisposition of breast cancer susceptibility genes with associated clinical and pathological aspects in the UAE.Material & methodsA retrospective chart review for breast cancer patients undergoing genetic testing from 2016 to 2018. According to National Comprehensive Cancer Network (NCCN) guidelines genetic testing was offered. The analyzed data included; age, ethnicity, family cancer history, pathogenic variant, histopathology, stage, molecular subtype and proliferation.Results309 patients underwent genetic testing with a positive result in 130 patients (11.9%) over a period of 36 months. In 34.6% pathogenic and likely pathogenic variants were identified. BRCA2 was the most common gene identified. The mean age was 42.9 years (±9.01). Positive family history was identified in 66 patients (50.7%). Majority had stage 1 or 2 disease (66.2%), invasive ductal carcinoma (81.5%) and hormone receptor positive cancer (45.3%).ConclusionsThis is the first study in the UAE to describe the clinical and pathological characteristics of hereditary breast cancer in a mixed ethnic group with dominant Arabic population. Further genetic studies will be required in the UAE population, as the prevalence of breast cancer continues to rise.     

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.