Current approaches in familial colorectal cancer: a clinical perspective

Individuals with a family history of colorectal cancer or colorectal adenomas have an increased risk for colorectal cancer. When no hereditary syndrome is evident, screening is based on empiric risk estimates. The risk is greatest for individuals with specific inherited cancer-predisposing disorders. When conditions such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer are diagnosed, specific neoplasm risk estimates can usually be performed based on advances in molecular genetics. These estimates lead to more straightforward and cost-effective approaches to surveillance and management. The National Comprehensive Cancer Center Network (NCCN) and other groups have provided detailed guidelines for evaluating patients based on recognition of clinical syndrome characteristics, followed by appropriate genetic counseling, genetic testing, and optimal surveillance. The NCCN guidelines are used as a frame of reference for this discussion of selected recent advances in human cancer genetics as they apply to clinical practice.     

Familial prostate cancer

Prostate cancer is the most commonly diagnosed cancer among men in the United States as well as most Western countries. A significant proportion of men report having a positive family history of prostate cancer in a first-degree relative (father, brother, son), which is important in that family history is one of the only established risk factors for the disease and plays a role in decision-making for prostate cancer screening. Familial aggregation of prostate cancer is considered a surrogate marker of genetic susceptibility to developing the disease, but shared environment cannot be excluded as an explanation for clustering of cases among family members. Prostate cancer is both a clinically and genetically heterogeneous disease with inherited factors predicted to account for 40%–50% of cases, comprised of both rare highly to moderately penetrant gene variants, as well as common genetic variants of low penetrance. Most notably, HOXB13 and BRCA2 mutations have been consistently shown to increase prostate cancer risk, and are more commonly observed among patients diagnosed with early-onset disease. A recurrent mutation in HOXB13 has been shown to predispose to hereditary prostate cancer (HPC), and BRCA2 mutations to hereditary breast and ovarian cancer (HBOC). Genome-wide association studies (GWAS) have also identified approximately 100 loci that associate with modest (odds ratios <2.0) increases in prostate cancer risk, only some of which have been replicated in subsequent studies. Despite these efforts, genetic testing in prostate cancer lags behind other common tumors like breast and colorectal cancer. To date, National Comprehensive Cancer Network (NCCN) guidelines have highly selective criteria for BRCA1/2 testing for men with prostate cancer based on personal history and/or specific family cancer history. Tumor sequencing is also leading to the identification of germline mutations in prostate cancer patients, informing the scope of inheritance. Advances in genetic testing for inherited and familial prostate cancer (FPC) are needed to inform personalized cancer risk screening and treatment approaches.     

Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines

Hereditary cancer predisposition syndromes comprise approximately 10% of diagnosed cancers; however, familial forms are believed to account for up to 30% of some cancers. In Hispanics, the most commonly diagnosed hereditary cancers include colorectal cancer syndromes such as, Lynch Syndrome, Familial Adenomatous Polyposis, and hereditary breast and ovarian cancer syndromes. Although the incidence of hereditary cancers is low, patients diagnosed with hereditary cancer syndromes are at high-risk for developing secondary cancers. Furthermore, the productivity loss that occurs after cancer diagnosis in these high-risk patients has a negative socio-economic impact. This review summarizes the genetic basis, phenotype characteristics, and the National Comprehensive Cancer Network’s screening, testing, and surveillance guidelines for the leading hereditary cancer syndromes. The aim of this review is to promote a better understanding of cancer genetics and genetic testing in Hispanic patients.     

Inherited predisposition to pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the US by 2030. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of PDAC. Precision treatment, informed by germline genetic testing and molecular tumor analysis, can optimize therapeutic regimens and outcomes for those diagnosed with PDAC. As a result, the National Comprehensive Cancer Network currently recommends genetic testing for all newly diagnosed PDAC patients given the clinical implications for treatment but also for the identification of at-risk family members who can benefit from pancreatic cancer screening and other cancer prevention strategies. This article reviews inherited risk factors for the development of PDAC and current screening strategies for the early detection of PDAC in high-risk populations.     

Strategies for clinical implementation of screening for hereditary cancer syndromes

Hereditary cancer syndromes generally account for 5%–10% of malignancies. While these syndromes are rare, affected patients carry significantly elevated risks of developing cancer, as do their at-risk relatives. Identification of these patients is critical to ensure timely and appropriate genetic testing relevant to cancer patients and their relatives. Several guidelines and tools are available to assist clinicians. Patients suspected to have hereditary cancer syndromes should be offered genetic testing in the setting of genetic counseling by a qualified genetics professional. Germline testing ranges from testing for a known specific familial mutation to testing of a broad differential diagnosis using a pan-cancer multi-gene panel. Taking a family history, referring specific types of tumors with higher likelihood of heredity, implementing universal screening protocols such as microsatellite instability/immunohistochemistry (MSI/IHC) for specific tumors, and referring patients with somatic tumor testing that have potentially germline consequences are all important components to the identification of hereditary cancer syndromes in the oncology clinic.     

Health Care Disparities and Demand for Expanding Hereditary Breast Cancer Screening Guidelines in African Americans

BackgroundGenomic medicine has led to significant advancements in the prevention and treatment of cancer. The National Comprehensive Cancer Network (NCCN) guidelines recommend BRCA1/2 screening in high-risk individuals; however, the guidelines have not incorporated differences within ethnic cohorts beyond Ashkenazi Jewish ethnicity. We analyzed the prevalence of BRCA1/2 mutations in various ethnicities and identified high-risk personal characteristics and family history incorporating differences within ethnic cohorts beyond Ashkenazi Jewish ethnicity.Patients and MethodsWe reviewed data collected by a Michigan medical genetic clinic in a community-based hospital from 2008 to 2018. A retrospective chart analysis was conducted of 1090 patients who received genetic counseling regarding hereditary cancer syndromes.ResultsWe found a statistically significant higher rate of pathogenic BRCA1/2 mutation prevalence in African American patients, at 8.1%, compared to non-Ashkenazi Jewish white patients, at 3.6% (P = .02). African Americans have a mutational prevalence nearing that of the Ashkenazi Jewish population.ConclusionRevision of the NCCN guidelines regarding hereditary cancer syndrome testing in various ethnic groups is imperative and overdue. Future studies are needed to identify health care disparities in and socioeconomic barriers to genetic testing.     

Genetic counseling and clinical cancer genetics services

Cancer genetic services, typically provided by clinicians with expertise in both oncology and genetics, include cancer risk assessment and education, facilitation of genetic testing, pre-and post-test counseling, provision of personally tailored cancer risk management options and recommendations, and psychosocial counseling and support services. All oncology providers should obtain basic information on the family cancer history of their patients to determine the likelihood of hereditary cancer risk as well as possible indications for providing brief or comprehensive cancer genetic counseling. Those who choose to provide these services themselves must be familiar with the complex issues of genetic counseling and testing, and be aware of the time and expertise required to adequately deliver these services. Genetic nurses and genetic counselors with master's degrees function as valuable members of a comprehensive cancer genetic service; they are trained to independently collect and confirm medical and family history information, perform risk assessments, offer patient education regarding cancer and genetics, and provide supportive counseling services for patients and families. It is hoped that specific risk interventions will significantly reduce morbidity and mortality from familial forms of cancer. This review outlines the process of cancer genetic counseling and defines the roles of the cancer genetic counselor and the function of the cancer genetics specialty clinic. The possible medical and legal implications for failing to obtain adequate family history information are reviewed, and the issues of genetic discrimination are discussed.     

Hereditary breast-ovarian cancer at the bedside: role of the medical oncologist.

PURPOSE: To provide practical considerations for diagnosing, counseling, and managing patients at high risk for hereditary breast cancer. DESIGN: We have studied 98 extended hereditary breast cancer (HBC)/hereditary breast-ovarian cancer (HBOC) families with BRCA1/2 germline mutations. From these families, 1,315 individuals were counseled and sampled for DNA testing. Herein, 716 of these individuals received their DNA test results in concert with genetic counseling. Several challenging pedigrees were selected from Creighton University's hereditary cancer family registry, as well as one family from Evanston/Northwestern Healthcare, to be discussed in this present report. RESULTS: Many obstacles were identified in diagnosis, counseling, and managing patients at high risk for HBC/HBOC. These obstacles were early noncancer death of key relatives, perception of insurance or employment discrimination, fear, anxiety, apprehension, reduced gene penetrance, and poor compliance. Other important issues such as physician culpability and malpractice implications for failure to collect or act on the cancer family history were identified. CONCLUSION: When clinical gene testing emerged for BRCA1 and BRCA2, little was known about the efficacy of medical interventions. Potential barriers to uptake of testing were largely unexplored. Identification and referral of high-risk patients and families to genetic counseling can greatly enhance the care of the population at the highest risk for cancer. However, because premonitory physical stigmata are absent in most of these syndromes, an HBOC diagnosis may be missed unless a careful family history of cancer of the breast, ovary, or several integrally associated cancers is obtained.     

Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management

Hereditary forms of colorectal cancer, as is the case with virtually all forms of hereditary cancer, show extensive phenotypic and genotypic heterogeneity, a phenomenon discussed throughout this special issue of Familial Cancer. Clearly, the family physician, oncology specialist, genetic counselor, and cancer geneticist must know fully the complexity of hereditary cancer syndromes, their differential diagnosis, in order to establish a diagnosis, direct highly-targeted surveillance and management, and then be able to communicate effectively with the molecular geneticist so that an at-risk patient’s DNA can be tested in accord with the syndrome of concern. Thus, a family with features of the Lynch syndrome will merit microsatellite instability testing, consideration for immunohistochemistry evaluation, and mismatch repair gene testing, while, in contrast, a patient with FAP will require APC testing. However, other germline mutations, yet to be identified, may be important should testing for these mutations prove to be absent and, therein, unrewarding to the patient. Nevertheless, our position is that if the patient’s family history is consistent with one of these syndromes, but a mutation is not found in the family, we still recommend the same surveillance and management strategies for patients from families with an established cancer-causing germline mutation. Our purpose in this paper is to provide a concise coverage of the major hereditary colorectal cancer syndromes, to discuss genetic counseling, molecular genetic evaluation, highly targeted surveillance and management, so that cancer control can be maximized for these high hereditary cancer risk patients.     

The importance of paternal family history in hereditary breast cancer is underappreciated by health care professionals

OBJECTIVES: Cancer genetics clinics have been established in many major oncology centers worldwide in recent years. For such specialized clinics to fulfill their function, primary care physicians need to identify high-risk patients for referral. METHODS: We conducted a survey to evaluate the level of awareness of breast cancer risk factors and hereditary breast cancer among health care providers and patients. RESULTS: 284 health care professionals, 221 medical students, 104 breast cancer patients and 177 cancer-free women participated in the study. Less than half of the patients with breast cancer were aware of their risk for another breast cancer or of the increased breast cancer risk of their sisters and daughters. Less than one quarter of the health care professionals and medical students knew the importance of paternal family history in the evaluation for hereditary breast cancer. Only about half of the health care professionals and medical students and less than one third of the breast cancer patients and cancer-free women knew about genetic testing and prophylactic mastectomy as options for women at risk for hereditary breast cancer. CONCLUSIONS: Health care providers and medical students lack basic genetic knowledge and are not aware of emerging diagnostic and preventive options for hereditary breast cancer. Inclusion of cancer genetics in the continuing medical education of health care providers is important to promote such awareness.     

Germline genetic testing in breast cancer: Rationale for the testing of all women diagnosed by the age of 60 years and for risk-based testing of those older than 60 years

Approximately 5% to 10% of women diagnosed with breast cancer will have a pathogenic variant (PV) in a hereditary cancer susceptibility gene, and this has significant implications for the management of these patients and their relatives. Despite the benefits of genetic testing, many eligible patients with breast cancer never undergo testing because of various barriers, including complicated testing criteria such as those from the National Comprehensive Cancer Network (NCCN). In 2019, the American Society of Breast Surgeons (ASBrS) proposed germline genetic testing for all patients with breast cancer to increase the identification of PV carriers. In 2020, a Mayo Clinic study highlighted the limitations of these 2 genetic testing guidelines (NCCN and ASBrS) and proposed a hybrid approach of testing all women diagnosed with breast cancer by the age of 65 years and using NCCN criteria for older patients. This commentary presents an updated analysis of the Mayo Clinic data and discusses the rationale for using the age of 60 years rather than 65 years as the cutoff for this hybrid approach. Using an age at diagnosis of ≤60 or ≤65 years for the universal testing of patients with breast cancer detected more PVs (11.9% [16 of 134] and 15.7% [21 of 134], respectively) in comparison with using the NCCN criteria. Lowering the age for universal testing from 65 to 60 years maintained the sensitivity of detecting a PV at >90% while sparing testing for an additional 10% of women. Compared with the testing of all patients, the hybrid approach would allow 31% of all women with breast cancer to forgo testing and result in fewer variants of uncertain significance identified and, therefore, would decrease the chance of harm from misinterpretation of these variants.     

Cancer screening and genetic counseling

Familial predisposition to cancer has been recognized for many years. The discovery fifteen years ago of some of the genes that are involved in the heritance of very common malignant diseases, like breast and colorectal cancer, has represented a major advance, and a challenge, for cancer prevention. Colorectal cancer is the first incident malignancy in our population, and breast cancer can affect 1 in 12 women in some European countries. There are several models that calculate the risk of cancer based on personal conditions or familial history. Testing for genes related to hereditary cancer allows the selection of individuals who will really benefit of prevention measures in such high prevalent diseases. The majority of these genes belong to the category of tumor suppressor genes, a second genetic hit is always needed for tumor developing. Epigenetics, defined as the factors that modulate the penetrance of a genetic disease, play an important role in hereditary cancer predisposition. Due to the complexity of genetics and clinical management of the hereditary cancers, all individuals with risk should be seen at Cancer Genetic Counseling units or Cancer Family Clinics. The clinicians that work in these Units should have special training in genetic counseling, cancer genetics and hereditary cancer management. Cancer Genetic Counseling is a communication process in which genetics, medical and psychological issues related to hereditary cancer risk development and prevention options are discussed with the individuals and families. Counseling must not be biased, and individual autonomy must be protected. A collaborative model between counselor and patient is preferred, and all the following points should be included in the informed consent process: options for risk estimation if genetic testing is not done,information on the specific test (accuracy, limitations), interpretation of all possible test results, implications of results for the individual and family, confidentiality issues, risk of psychological distress, options for care after testing and limitations. Some ethical and legal issues arise in the global processes of cancer genetic counseling that must be recognized and taken in account. Many questions have still not answers in this field. Nonetheless, it would be inappropiate to dismiss the potential benefits of genetic counseling as a reaction to sporadic uncritical application of genetic testing. This paper will review the genetic basis and the opportunity for screening and prevention of the hereditary predisposition to cancer, mainly focused to breast, ovarian and colorectal cancer.     

Inherited DNA repair gene mutations detected by tumor next generation sequencing in urinary tract cancers

Interpretation of next-generation sequencing (NGS) of tumor tissue in patients with advanced Urinary Tract Cancer (UTC) is performed to guide treatment selection but may reveal pathogenic variants with germline implications. We identified three patients with UTC with unexpected germline DNA repair gene mutations. Specific testing for these was prompted by the detection of these mutations by tumor NGS. All three patients were nonsmokers with a strong family history of cancer. Two patients had upper tract UTC with age at diagnosis in the 40 s. One had a family history suggestive of hereditary breast/ovarian predisposition and a FANCA mutation detected on NGS was confirmed to be germline. The second patient had a family history suggestive of Lynch syndrome but was found to have a germline BRCA2 mutation that was suggested by NGS. The third patient had bladder cancer at an advanced age, a family history of late-onset gastrointestinal malignancies that did not meet criteria for clinical testing for a hereditary cancer predisposition syndrome. NGS identified an MUTYH mutation, and targeted testing confirmed a monoallelic germline MUTYH mutation. Detection of variants with germline implications by tumor NGS may be clinically relevant for patients and their families and warrant genetic counseling and germline genetic testing. The prevalence of germline DNA repair defects in the context of inherited predisposition to UTC merits further study.     

Adverse events in cancer genetic testing: medical, ethical, legal, and financial implications

ABSTRACT: Cancer genetic counseling and testing are now integral services in progressive cancer care. There has been much debate over whether these services should be delivered by providers with specialized training in genetics or by all clinicians. Adverse outcomes resulting from cancer genetic counseling and testing performed by clinicians without specialization in genetics have been reported, but formal documentation is sparse. In this review, we present a series of national cases illustrating major patterns of errors in cancer genetic counseling and testing and the resulting impact on medical liability, health care costs, and the patients and their families.     

Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions

Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like poly-ADP ribose polymerase inhibitors (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and post-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.     

Men in the women’s world of hereditary breast and ovarian cancer—a systematic review

Little is known about men seeking genetic counseling for hereditary breast and ovarian cancer (HBOC). We review the sparse literature on men attending such genetic consultations. Two main themes are identified: the women’s influence on the genetic counseling process, and the psychological impact on men. The women in the HBOC families have an influence on the men’s decision to request genetic testing, and they take the leading role in communicating genetic information. With respect to psychological impact, the men suffer from grief and fear of developing cancer, and they seem to use avoidance as a coping strategy. Carrier males experience feelings of guilt because they might have passed on a mutation to their children. Non-carriers experience test-related stress if their siblings tested positive. Mutation status may have an impact on reproductive issues. These findings are discussed in light of gender issues and literature concerning men’s health behavior. Further studies are needed to provide optimal care for men seeking genetic counseling for hereditary breast and ovarian cancer.     

Reported referral for genetic counseling or BRCA 1/2 testing among United States physicians: a vignette-based study

BACKGROUND:

Genetic counseling and testing is recommended for women at high but not average risk of ovarian cancer. National estimates of physician adherence to genetic counseling and testing recommendations are lacking.

METHODS:

Using a vignette‐based study, we surveyed 3200 United States family physicians, general internists, and obstetrician/gynecologists and received 1878 (62%) responses. The questionnaire included an annual examination vignette asking about genetic counseling and testing. The vignette varied patient age, race, insurance status, and ovarian cancer risk. Estimates of physician adherence to genetic counseling and testing recommendations were weighted to the United States primary care physician population. Multivariable logistic regression identified independent patient and physician predictors of adherence.

RESULTS:

For average‐risk women, 71% of physicians self‐reported adhering to recommendations against genetic counseling or testing. In multivariable modeling, predictors of adherence against referral/testing included black versus white race (relative risk [RR], 1.16; 95% confidence interval [CI], 1.03‐1.31), Medicaid versus private insurance (RR, 1.15; 95% CI, 1.02‐1.29), and rural versus urban location. Among high‐risk women, 41% of physicians self‐reported adhering to recommendations to refer for genetic counseling or testing. Predictors of adherence for referral/testing were younger patient age [35 vs 51 years [RR, 1.78; 95% CI, 1.41‐2.24]), physician sex (female vs male [RR, 1.30; 95% CI, 1.07‐1.64]), and obstetrician/gynecologist versus family medicine specialty (RR, 1.64; 95% CI, 1.31‐2.05). For both average‐risk and high‐risk women, physician‐estimated ovarian cancer risk was the most powerful predictor of recommendation adherence.

CONCLUSION:

Physicians reported that they would refer many average‐risk women and would not refer many high‐risk women for genetic counseling/testing. Intervention efforts, including promotion of accurate risk assessment, are needed. Cancer 2011;. © 2011 American Cancer Society.     

Genetic testing for colorectal carcinoma susceptibility: focus group responses of individuals with colorectal carcinoma and first-degree relatives

BACKGROUND: Colorectal carcinoma (CRC) may be the most frequent form of hereditary cancer. Genetic counseling and testing for heritable CRC is a promising approach for reducing the high incidence and mortality rates associated with the disease. Patients with CRC or those with at least one family member with the disease are the most likely persons to request or be offered genetic testing in the clinical or research setting. Currently, however, little is known about the behavioral, psychosocial, ethical, legal, and economic outcomes of CRC genetic counseling and testing. METHODS: Eight focus group interviews, four for CRC patients (n = 28) and four for first-degree relatives (n = 33), were conducted to obtain insights into attitudes, beliefs, and informational needs about genetic testing for hereditary CRC. RESULTS: Focus group interviews revealed a general lack of knowledge about cancer genetics and genetic testing; worry about confidentiality issues; strong concern for family members, particularly children; and a need for primary care providers to be informed about these issues. Major perceived advantages of genetic testing included improving health-related decisions, guiding physicians in making recommendations for surveillance, and informing relatives about risk potential. Disadvantages included potential discrimination, adverse psychologic effects, and financial costs associated with testing. CONCLUSIONS: As knowledge and media coverage of genetics continue to expand, it becomes increasingly important to continue efforts on behalf of, and in partnership with, those individuals most affected by genetic testing for hereditary cancer syndromes. These findings provide data needed to develop and implement informational, educational, counseling, and research-oriented programs that are sensitive to individuals' concerns and preferences.