Surgical Management of Hereditary Breast Cancer.

The identification that breast cancer is hereditary was first described in the nineteenth century. With the identification of the BRCA1 and BRCA 2 breast/ovarian cancer susceptibility genes in the mid-1990s and the introduction of genetic testing, significant advancements have been made in tailoring surveillance, guiding decisions on medical or surgical risk reduction and cancer treatments for genetic variant carriers. This review discusses various medical and surgical management options for hereditary breast cancers.

Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules.

Pathological mutations in homology-directed repair (HDR) genes impact both future cancer risk and therapeutic options for patients. HDR is a high-fidelity DNA repair pathway for resolving DNA double-strand breaks throughout the genome. BRCA2 is an essential protein that mediates the loading of RAD51 onto resected DNA breaks, a key step in HDR. Germline mutations in BRCA2 are associated with an increased risk for breast, ovarian, prostate, and pancreatic cancer. Clinical findings of germline or somatic BRCA2 mutations in tumors suggest treatment with platinum agents or PARP inhibitors. However, when genetic analysis reveals a variant of uncertain significance (VUS) in the BRCA2 gene, precision medicine-based decisions become complex. VUS are genetic changes with unknown pathological impact. Current statistics indicate that between 10-20% of BRCA sequencing results are VUS, and of these, more than 50% are missense mutations. Functional assays to determine the pathological outcome of VUS are urgently needed to provide clinical guidance regarding cancer risk and treatment options. In this review, we provide a brief overview of BRCA2 functions in HDR, describe how BRCA2 VUS are currently assessed in the clinic, and how genetic and biochemical functional assays could be integrated into the clinical decision process. We suggest a multi-step workflow composed of robust and accurate functional assays to correctly evaluate the potential pathogenic or benign nature of BRCA2 VUS. Success in this precision medicine endeavor will offer actionable information to patients and their physicians.

Determinants of serum adiponectin levels: a cross-sectional study.

OBJECTIVES: To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. CONTENT: Women with a gBRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. SUMMARY AND OUTLOOK: Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1-deficient models in vitro. The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.

Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis.

Breast cancer is a common cancer affecting a large number of patients. Notably, 5-10% of all breast cancer patients are genetically predisposed to cancers. Although the most common breast cancer susceptibility genes are BRCA1 and BRCA2, which are also associated with the risk of developing ovarian and pancreatic cancer, advances in next-generation sequencing (NGS) analysis technology enabled the discovery of several non-BRCA genes responsible for breast and ovarian cancers. Studies on hereditary breast and ovarian cancer (HBOC) involve not only determining the predisposition to developing cancer, but also considering the current treatment for breast cancer, prevention of next cancer, risk diagnosis, and adoption of protective measures for relatives. We present a comprehensive review of HBOC, which will be a useful resource in the clinical setting. Many hereditary tumors, including HBOC, are syndromes characterized by the development of different types of cancer in succession. Taking advantage of knowing predisposition of susceptibility to cancer, it is important to continue and update cancer management protocols, which includes the adoption of preventive measures, countermeasures, and treatments, to accurately assess and prevent the impact of cancer on the quality of life of the next generation of patients.

Culturally Targeted Video Improves Psychosocial Outcomes in Latina Women at Risk of Hereditary Breast and Ovarian Cancer.

Latina women at risk of hereditary breast and ovarian cancer (HBOC) have lower awareness, knowledge, and use of genetic counseling and testing services (GCT) than non-Latina Whites. Few interventions have been developed to reduce these disparities among at-risk Latinas. This pilot study assessed the impact of a culturally targeted narrative video developed by our team. The study included 40 Latina immigrants living in the United States who were at risk of HBOC, including affected and unaffected women. We assessed pre-post differences in psychosocial outcomes. Participants were 47.35 years old on average (SD = 9.48). Most (70%) were unaffected with cancer, had an annual income of $40,000 or less (65%), an education of High School or less (62.5%), and were uninsured (77.5%). The video significantly enhanced knowledge (p < 0.001), positive attitudes (p < 0.05), anticipatory positive emotions (p < 0.05), and intentions to participate in counseling (p < 0.001). Importantly, the video also significantly reduced negative attitudes (p < 0.05), and attitudinal ambivalence (p < 0.001). The culturally targeted video shows preliminary evidence in improving psychosocial outcomes related to GCT uptake in Latinas at risk for HBOC. This intervention is a promising easily-disseminable strategy to address disparities in GCT utilization.

Identification and management of familial breast cancer in Austria.

Aim The aim of this study is to review the legal implications, the technology, the indications and the management of women with a familial background of breast and/or ovarian cancer. Methods We have reviewed the literature and national Austrian guidelines to describe the uptake of genetic counseling and the management options offered in Austria. Results Genetic testing for the BRCA1 and 2 mutations is free and readily available through a nation-wide program. Increased awareness and the availability of screening programs and prophylactic surgery have resulted in a profound increase in genetic counseling and testing in women with a familial background of breast and ovarian cancer in Austria. Conclusion While readily available country-wide counseling has led to an increase in counseling and testing, Austrian legislation mandates "non-directional counseling" resulting in a comparatively low uptake of prophylactic surgery.

Final report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology, on a fact-finding questionnaire on the status of treatment of hereditary breast and ovarian cancer syndrome in Japan.

Hereditary breast and ovarian cancer syndrome (HBOC) is a hereditary tumor that can be definitively diagnosed by detection of germline mutation of the BRCA1 or BRCA2 gene. The HBOC Public Awareness and Management Sub-committee of the Tumor Committee, Japan Society of Obstetrics and Gynecology carried out a fact-finding survey on the status of treatment of HBOC in Japan. The directors of medical specialty teaching facilities were notified of the questionnaire by post, with the request for one respondent per facility. The response period was from 8 July 2014 to 31 March 2015. Of the 678 facilities that were asked to compete the questionnaire, 341 (50.3%) responded. The responses are shown in the respective tables. For questions with free responses, similar answers have been grouped together, and the written answers have been freely translated. Based on these results, the Japan Society of Obstetrics and Gynecology considers that the 14 conditions, including consultations by specialist staff, must be met before risk-reducing salpingo-oophorectomy is carried out.

The Changing Landscape of Genetic Testing for Inherited Breast Cancer Predisposition.

OPINION STATEMENT: The advent of multiple-gene germline panel testing has led to significant advances in hereditary breast and ovarian cancer risk assessment. These include guideline-specific cancer risk management recommendations for patients and their families, such as screening with breast magnetic resonance imaging and risk-reducing surgeries, which have the potential to reduce substantially the morbidity and mortality associated with a hereditary cancer predisposition. However, controversy remains about the clinical validity and actionability of genetic testing in a broader patient population. We discuss events leading to the wider availability of commercialized multiple-gene germline panel testing, the recent data that support using this powerful tool to improve cancer risk assessment and reduction strategies, and remaining challenges to clinical optimization of this new genetic technology.

Racial disparities in BRCA testing and cancer risk management across a population-based sample of young breast cancer survivors.

BACKGROUND: Breast cancer (BC) disparities may widen with genomic advances. The authors compared non-Hispanic white (NHW), black, and Hispanic BC survivors for 1) cancer risk-management practices among BRCA carriers and 2) provider discussion and receipt of genetic testing. METHODS: A population-based sample of NHW, black, and Hispanic women who had been diagnosed with invasive BC at age 50 years or younger from 2009 to 2012 were recruited through the state cancer registry. Multiple logistic regression was used to compare cancer risk-management practices in BRCA carriers and associations of demographic and clinical variables with provider discussion and receipt of testing. RESULTS: Of 1622 participants, 159 of 440 (36.1%) black women, 579 of 897 (64.5%) NHW women, 58 of 117 (49.6%) Spanish-speaking Hispanic women, and 116 of 168 (69%) English-speaking Hispanic women underwent BRCA testing, of whom 90 had a pathogenic BRCA mutation identified. Among BRCA carriers, the rates of risk-reducing mastectomy and risk-reducing salpingo-oophorectomy were significantly lower among black women compared with Hispanic and NHW women after controlling for clinical and demographic variables (P = .025 and P = .008, respectively). Compared with NHW women, discussion of genetic testing with a provider was 16 times less likely among black women (P < .0001) and nearly 2 times less likely among Spanish-speaking Hispanic women (P = .04) after controlling for clinical and sociodemographic factors. CONCLUSIONS: The current results suggest that the rates of risk-reducing salpingo-oophorectomy are lower among black BRCA carriers compared with their Hispanic and NHW counterparts, which is concerning because benefits from genetic testing arise from cancer risk-management practice options. Furthermore, lower BRCA testing rates among blacks may partially be because of a lower likelihood of provider discussion. Future studies are needed to improve cancer risk identification and management practices across all populations to prevent the widening of disparities. Cancer 2017;123:2497-05. © 2017 American Cancer Society.

Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care.

PURPOSE: Genetic evaluation is increasingly becoming an integral part of the management of women with newly diagnosed breast and ovarian cancer (OC), and of individuals at high risk for these diseases. Genetic counseling and testing have been incorporated into oncological care to help and complete management and treatment strategies. Risk assessment and early detection strategies in individuals with BRCA1/2 mutations and with Lynch syndrome have been quite extensively studied, whereas much less is known about the management of mutation carriers with less common high-penetrance cancer susceptibility genes (PTEN, TP53, STK11, CDH1), and particularly those who carry mutations in moderate-penetrance genes (e.g., PALB2, CHEK2, ATM, NF1, RAD51C, RAD51D, BRIP1). METHODS: The latter patient groups represent important ongoing research opportunities to enable informed counseling about appropriate clinical management. CONCLUSION: We summarize the current guidelines for the management of high and moderate-penetrance mutations for breast and OC susceptibility. Continuous updating of guidelines for proper clinical management of these individuals is ongoing because of rapid advances in technology and knowledge in this field. Thus, we exhort the use of multigene panels for the assessment of cancer risk beyond the classic predisposition syndromes as a new standard of care in cancer genetics. We further support an increase of genetic counselors in Europe and use of their expertise to support genetic testing in specialist multidisciplinary teams.

Current Status of the Management of Hereditary Breast and Ovarian Cancer in Asia: First Report by the Asian BRCA Consortium.

BACKGROUND: BRCA1/BRCA2 mutations are associated with an increased lifetime risk for hereditary breast and ovarian cancer (HBOC). Compared with the Western developed countries, genetic testing and risk assessment for HBOC in Asia are less available, thus prohibiting the appropriate surveillance, clinical strategies and cancer management. METHODS: The current status of HBOC management in 14 Asian countries, including genetic counselling/testing uptakes and clinical management options, was reviewed. We analysed how economic factors, healthcare and legal frameworks, and cultural issues affect the genetic service availability in Asia. RESULTS: In 2012, only an estimated 4,000 breast cancer cases from 14 Asian countries have benefited from genetic services. Genetic testing costs and the absence of their adoption into national healthcare systems are the main economic barriers for approaching genetic services. Training programmes, regional accredited laboratories and healthcare professionals are not readily available in most of the studied countries. A lack of legal frameworks against genetic discrimination and a lack of public awareness of cancer risk assessment also provide challenges to HBOC management in Asia. CONCLUSIONS: The Asian BRCA Consortium reports the current disparities in genetic services for HBOC in Asia and urges the policy makers, healthcare sectors and researchers to address the limitations in HBOC management.

A Rare Case of BRCA2-Associated Breast Cancer in Pregnancy.

A 30-year old woman was referred to our department with symptomatic breast cancer at 35 weeks gestation. Genetic testing revealed a pathogenic BRCA2 mutation. Labour was induced at 38 weeks. Mastectomy and axillary clearance were performed with a view to adjuvant chemotherapy, radiation and hormonal therapy. Multidisciplinary involvement is crucial for management of BRCA-associated breast cancer, especially in the context of pregnancy. Bilateral mastectomy may be indicated given the increased risk of ipsilateral and contralateral breast cancers. Tamoxifen may lower contralateral breast cancer risk in those in whom risk-reducing surgery is not performed.

American BRCA Outcomes and Utilization of Testing (ABOUT) study: a pragmatic research model that incorporates personalized medicine/patient-centered outcomes in a real world setting.

Research to date regarding identification and management of hereditary breast and ovarian cancer syndrome (HBOC) in the U.S. has been confined primarily to academic center-based studies with limited patient engagement. To begin to understand and address the current gaps and disparities in delivery of services for the appropriate identification and optimal risk management of individuals with HBOC, we designed and have initiated the American BRCA Outcomes and Utilization of Testing (ABOUT) Study. ABOUT relies on a collaborative patient advocacy, academic and industry partnership to recruit and engage U.S. individuals who are at increased risk for HBOC and investigate their experiences, decisions and outcomes. It utilizes an extensive research infrastructure, including an interactive web-based data system and electronic interfaces for secure online participation and automated data exchange. We describe the novel recruitment approach that was designed for collaboration with a national commercial health plan partner to identify all individuals for whom a healthcare provider orders a BRCA test and mail to each individual an invitation to participate and study packet. The study packet contains detailed information about the study, a baseline questionnaire and informed consent for participation in the study, for release of relevant medical and health plan records and for ongoing research engagement. This approach employs patient-reported, laboratory-reported and health plan-reported outcomes and facilitates longitudinal engagement. We believe that the type of innovative methodology and collaborative framework we have developed for ABOUT is an ideal foundation for a patient-powered research network. This approach can make substantial contributions to identifying current and best practices in HBOC, leading to improved strategies for clinical care and optimal health outcomes among individuals with high inherited risk for cancer.

Singapore Cancer Network (SCAN) Guidelines for Referral for Genetic Evaluation of Common Hereditary Cancer Syndromes.

INTRODUCTION: The SCAN cancer genetics workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for referral for genetic evaluation of common hereditary cancer syndromes. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: To formulate referral guidelines for the 3 most commonly encountered hereditary cancer syndromes to guide healthcare providers in Singapore who care for cancer patients and/or their family members, 7, 5, and 3 sets of international guidelines respectively for hereditary breast and ovarian cancer (HBOC) syndrome, Lynch syndrome (LS), and familial adenomatous polyposis (FAP) were evaluated. For each syndrome, the most applicable one was selected, with modifications made such that they would be appropriate to the local context. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for referral for genetic evaluation of common hereditary cancer syndromes.

Clinical implications of genetic testing for BRCA1 and BRCA2 mutations in Austria.

The objective of this study was to describe the experience of genetic testing in Austrian women with a BRCA1 or BRCA2 mutation in terms of preventive measures taken and incident cancers diagnosed. We collected clinical information on 246 Austrian women with a BRCA1 or BRCA2 mutation tested between 1995 and 2012 and followed 182 of them for an average of 6.5 years. Of the 90 women who were cancer-free at baseline, 21.4% underwent preventive bilateral mastectomy, 46.1% had preventive bilateral salpingo-oophorectomy, and 1 took tamoxifen; 58.8% of the at-risk women underwent at least one screening breast magnetic resonance imaging (MRI). Of the 85 women with breast cancer, 69.4% had a unilateral mastectomy or lumpectomy and 30.6% had a contralateral mastectomy. In the follow-up period, 14 new invasive breast cancers (6 first primary and 8 contralateral), 1 ductal carcinoma in situ case, 2 incident ovarian cancer cases, and 1 peritoneal cancer were diagnosed. In Austria, the majority of healthy women with a BRCA1 or BRCA2 mutation opt for preventive oophorectomy and MRI screening to manage their breast cancer risk; few have preventive mastectomy or take tamoxifen.

Opportunities and hurdles in the treatment of BRCA1-related breast cancer.

BRCA1 functions as a classical tumor suppressor in breast and ovarian cancer. While the role of BRCA1 in homology-directed repair of DNA double-strand breaks contributes to its tumor suppressive activity, it also renders BRCA1-deficient cells highly sensitive to DNA-damaging agents. Although BRCA1 deficiency is therefore considered to be an attractive therapeutic target, re-activation of BRCA1 by secondary mutations has been shown to cause therapy resistance. In this review, we will assess the role of BRCA1 in both hereditary and sporadic breast cancer and discuss how different functionalities of the BRCA1 protein can contribute to its tumor suppressor function. In addition, we will discuss how this knowledge on BRCA1 function can help to overcome the hurdles encountered in the clinic and improve current treatment strategies for patients with BRCA1-related breast cancer.

Clinicians' attitudes toward general screening of the Ashkenazi-Jewish population for prevalent founder BRCA1/2 and LRRK2 mutations.

AIMS: Advances in genomics may eventually lead to genetic susceptibility screening of the general population, regardless of a personal or familial history of the disease in question. Yet, little is known about clinicians' attitudes toward such programs. We explored attitudes of family practitioners, medical geneticists and genetic counselors toward genetic screening of the general Ashkenazi-Jewish population for the common founder mutations in BRCA1/2 and LRRK2 genes (which increase the risk of hereditary breast/ovarian cancers and Parkinson's disease, respectively). METHODS: Participants (n = 204) completed a specially designed questionnaire, distributed by e-mail, regular mail or in-person. RESULTS: Slightly more than half (52%) were in favor of BRCA screening, while the vast majority (86%) opposed to LRRK2 screening. About two-thirds (68%) of the respondents supported pre-test genetic counseling. Attitudes were largely independent of professional background and sociodemographic characteristics, though a correlation was found with personal interest in genetic self-testing for the above genes. Adverse psychological impact and discrimination in insurance and employment were the major concerns cited by respondents with regard to screening programs. CONCLUSION: Our findings suggest that the availability of measures for prevention and/or treatment is a major factor in the attitudes of healthcare providers toward population screening for late-onset conditions.