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.     

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.     

Genetic testing for the BRCA1 gene and the need for protection from discrimination: an evolving legislative and social issue

Genetic testing for the BRCA1 gene is available commercially and clinically. The information gained from this test impacts not only on the individual tested, but on family members as well. The test can offer an individual and their family the opportunity to gain valuable information about their risks of developing certain forms of inherited breast cancer and other inherited cancers. In addition to its emotional and psychological impact, this information is associated with significant social and economic issues. This includes the potential for denial, loss, or increased rates for health insurance as well as denial and loss of employment based on genetic test information. The risk for such discrimination can lead to fear of seeking testing and can discourage participation in and potential benefit from prevention, screening, and treatment programs. Therefore, misuse of this information carries significant risk for the individual being tested and for their family members. It is imperative that the potential benefits of genetic testing and genetic information be afforded to all without this risk and fear. In addition to protecting all individuals from genetic discrimination, there is a need to protect the confidentiality of genetic information and an individual's right to privacy. This article discusses protection currently available through legislation at the federal and state level, focusing on the experience in North Carolina in developing and passing a genetic antidiscrimination bill. Although progress has been made, troublesome issues still remain.     

Recommendation and Acceptance of Counselling for Familial Cancer Risk in Newly Diagnosed Breast Cancer Cases

BackgroundIn clinical routine, not every patient who is offered genetic counselling and diagnostics in order to investigate a familial cancer risk predisposition opts for it. Little is known about acceptance of counselling and testing in newly diagnosed breast cancer cases in Germany.MethodsAll primary breast cancer cases and patients with DCIS (ductal carcinoma in situ) treated at the University Hospital of Dresden between 2016 and 2019 were included. The number of tumor board recommendations for genetic counselling on the basis of the GC-HBOC risk criteria was recorded. Acceptance was analyzed by number of cases with counselling in the GC-HBOC-Center Dresden.ResultsOf 996 primary breast cancer and DCIS cases, 262 (26.3%) were eligible for genetic counselling. Recommendation for genetic counselling was accepted by 64.1% (168/262). Of these 90.5% (152/168) opted for molecular genetic analysis. The acceptance rate for counselling increased between 2016 and 2019 from 58.3 to 72.6%. Altogether, 20.4% (31/152) patients were found to carry a pathogenic variant in the breast cancer genes BRCA1 or BRCA2.ConclusionAcceptance of recommendation is increasing as clinical consequences augment. Optimization in providing information about hereditary cancer risk and in accessibility of counselling and testing is required to further improve acceptance of recommendation.     

Emerging genomic biomarkers for improving kidney,prostate, and bladder cancer health disparities outcomes

BackgroundRecent advances in genomic and genetic technologies have facilitated better health outcomes for urologic cancer patients. Genomic and genetic heterogeneity may contribute to differences in tumor biology and urologic cancer burden across various populations.ObjectiveTo examine how emerging genomic and genetic biomarkers, self-reported race, and ancestry-informative markers are associated with kidney, prostate, and bladder cancer outcomes.ResultsGenomic and genetic alterations found in African American kidney cancer patients included distinct somatic mutations, somatic copy number alterations, chromosomal instability, germ-line risk alleles, and germ-line genetic variants. These changes correlated with improved risk prediction, prognosis, and survival; and a predicted decrease in response to targeted therapies. SNP risk alleles and ancestry-informative markers were associated with improved risk prediction in prostate cancer patients of both African and European descent. AKT activation suggest differential response to AKT-targeted therapies in African American, Asian American, and Tunisian bladder cancer patients. Both self-reported race and genetic ancestry predicted urologic cancer risk prediction.ConclusionPrecision medicine approaches that integrate population-specific genomic and genetic information with other known urologic cancer-specific characteristics can improve outcomes and be leveraged to reduce cancer health disparities. Further investigations are necessary to identify novel genomic biomarkers with clinical utility.     

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.

     

BRCA1/2 mutations and triple negative breast cancers

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

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.     

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.     

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.     

Knowledge, beliefs and attitudes of kidney transplant recipients regarding their risk of cancer

Aim: Despite an increased risk of cancer post transplant, little is known about the knowledge, beliefs of and attitudes to cancer and its prevention among kidney transplant recipients. This study aims to explore these beliefs and attitudes, to better understand patient motives and potential barriers to early detection of cancer. Methods: Semi‐structured interviews were conducted with 14 kidney and eight kidney–pancreas transplant recipients based at a single transplant centre in Sydney, Australia, between October 2009 and February 2010. Results: Thematic data analysis identified four major themes: (1) skin cancer‐focused: participants were generally only aware about their increased risk of skin cancer and available prevention strategies for that cancer alone; (2) limited awareness: participants knew little about their excess risk for non‐skin cancers and possible preventative and screening strategies; (3) fear of cancer: cancer fears were heightened by prior experiences; some felt vulnerable to cancer and perceived that cancer outcomes were worse than kidney disease; and (4) prioritizing present health issues: participants believed cancer was not imminent and had limited capacity to absorb information about long‐term risks, particularly as current health concerns appeared pressing and important. Conclusion: Awareness of increased cancer risk and cancer screening among kidney transplant recipients is focused narrowly on skin cancer, with limited awareness for other cancers. Recipients prioritized current health issues rather than future risks to health such as cancer. Transplant care providers should provide evidence‐based information on cancer risk and screening, being sensitive to the timing and needs of the patient. Improved knowledge may empower patients to minimize their risk of cancer by participating in screening and cancer prevention programmes.     

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.     

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.     

Disparities in precision medicine—Examining germline genetic counseling and testing patterns among men with prostate cancer

IntroductionThis study sought to examine whether germline genetic counseling and testing were employed differentially among men with prostate cancer by race and/or ethnicity and other social factors.MethodsIn this retrospective analysis, all patients with prostate cancer listed as a visit diagnosis during the study period (April 2011 to August 2020) were identified from electronic health records. Patient characteristics were collected along with genetic counselor visits and germline genetic testing results in electronic health records. Multivariable analyses were performed with the primary outcome defined as the receipt of a genetic counseling visit and receipt of genetic testing.ResultsA total of 14,610 patients with a prostate cancer diagnosis code were identified. The majority of patients were White (72%), aged >=65 years (62.7%), English-speaking (95%), married (71.4%), and publicly insured (58.7%). A total of 667 patients completed an appointment with a genetic counselor. A total of 439 patients received germline genetic test result, of whom 403 (91.8%) had also completed an appointment with a genetic counselor. Patients that were 65 years or older (adjusted odds ratio 0.53, 95%CI 0.44–0.65) and non-English proficient (adjusted odds ratio 0.71, 95%CI 0.42–1.21) were less likely to receive genetic counseling. Receiving genetic counseling was the strongest independent predictor of receipt of genetic testing.ConclusionsThe results of the current study highlight that the role of social factors in contributing to disparities in genetic counseling and testing among men with prostate cancer. These results underscore the importance of developing novel strategies to tackle contributors of observed disparities including language, age, and insurance status.     

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.     

Preventive mastectomy in patients at breast cancer risk due to genetic alterations in the<Emphasis Type="Italic"> BRCA1</Emphasis> and<Emphasis Type="Italic"> BRCA2</Emphasis> gene

BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 and BRCA2 gene provides potentially valuable information to women at high risk of breast and ovarian cancer. METHODS AND FOCUS: We review the literature on the value of prophylactic surgical strategies in patients with hereditary predisposition to develop breast cancer and discuss the surgical options available in high-risk cancer patients, decision analyses, and possible complications. RESULTS: Preventive surgical interventions to reduce cancer risk in high-risk patients are often strongly recommended. A patient's life-time risk to develop breast cancer in the presence of BRCA1 and BRCA2 mutations is 50-90%. Despite the reduction in the risk of developing breast cancer, prophylactic mastectomy often leads to significant physical and psychological sequelae.     

The contemporary landscape of genetic testing and breast cancer: Emerging issues

The landscape of genetic testing for breast cancer susceptibility has transformed dramatically over the last decade and a half. Traditionally, the process of genetic testing resided fully within a medical infrastructure, from identification of appropriate testing candidates to gene selection to risk mitigation recommendations. More recently, decreasing costs, advancing technology, and a growing understanding of therapeutic implications of certain genetic test results have led to more widespread uptake of testing that increasingly involves broad multigene panels. Germline genetic testing for breast cancer susceptibility can now be obtained through one of three approaches: through clinical care; a direct‐to‐consumer (DTC) approach that is entirely consumer‐driven; or a hybrid, patient‐initiated, provider‐mediated model. Increased access to testing has led to extensive dialogue about the best way to conduct testing and act on results. Points of discussion include: selection of appropriate candidates for genetic testing; optimal composition of genes on panels; informed consent; safe return of results; privacy; and legal protections for those found to have relevant pathogenic or likely pathogenic variants. As more individuals undergo genetic testing, a growing population of individuals with inherited breast cancer predisposition informs optimal management of cancer risk and also highlights unanswered questions. This article aims to review the current state of genetic testing for inherited breast cancer susceptibility including testing approaches, the legal, ethical and social landscape, and selected contemporary management issues.