Cancer Genetics Professionals Research Articles

EP430: Genetics professionals’ perspectives on the reporting of Variants of Uncertain Significance (VUS): Should they always be reported?

Variants of uncertain significance (VUS) are common. With increasing use of multi-gene panels (MGP), the numbers of VUS grow. Not all VUS have the same degree of uncertainty, presenting challenges to non-genetics healthcare providers (HCPs), patients and families. We report the results of a survey assessing attitudes of genetics professionals on the return of VUS results from MGP, emphasizing cancer genetics professionals in academic settings.

How Have Multigene Panels Changed the Clinical Practice of Genetic Counseling and Testing.

Historically, genetic testing (and billing) for hereditary cancer risk was essentially performed gene by gene, with clinicians ordering testing only for the genes most likely to explain a patient's or family's cancer presentation, with laboratories typically charging $1,000 to $1,500 for each gene that was sequenced. Given the expense, only patients at high risk of having a hereditary syndrome were offered testing. With the introduction of next-generation sequencing technologies, however, laboratories are able to test for multiple genes at the same time with greater efficiency, significantly decreased costs, and relatively little increased expense when adding additional genes. This has drastically altered clinical practice so that clinicians now typically order testing for a panel of multiple genes for most patients. Although this approach has streamlined the diagnostic odyssey, it has introduced several problems, as well, including difficulties in choosing the appropriate panel test for a given patient, assessing the significance of identified genetic variants (including variants of uncertain significance [VUS]), and understanding the disease risks and management associated with pathogenic variants in a given gene. Many laboratories offer testing for genes that have limited data supporting their associated cancer risks, which then leads to an inability to set management guidelines based on that gene. In addition, testing larger numbers of genes increases the likelihood of finding one or more VUS, which introduce their own management issues. Thus, although panel testing has certainly moved clinical practice forward in many ways, it has also raised its own set of problems that increase the complexity of genetic counseling and highlight the need for education of community practitioners on the complexities and nuances of this testing. Whenever possible, testing should be performed by, or in consultation with, cancer genetics professionals.

The management of BRCA1 and BRCA2 carriers in Singapore.

Singapore is a densely populated small island nation, with a multiethnic and multireligious population. Cancer is the leading cause of death in Singapore. The population is well educated and coupled with greater awareness, there is an increasing demand for genetic testing for hereditary cancer syndromes. In Singapore, the Singapore Cancer Action Network (SCAN) guidelines for referral for genetic testing serves as a guide for clinicians on appropriate referral. We examined the important factors in genetic counselling in such a diverse population, such as acknowledgement of psychosocial impact of BRCA1/2, cultural sensitivity and upskilling of healthcare professionals. Access to genetic services in Singapore is widely available, though the number of patients who undergo testing is lower due to need for out-of-pocket costs and lack of funding from government agencies and insurance companies. The delivery of clinical care and research accrual is performed concurrently in our centre. All patients undergo pre-test counselling before giving informed consent for germline genetic testing and post-test counselling for interpretation of test results. Patients who test positive for BRCA1/2 continue to be on follow up with the cancer genetics clinic for risk-management. Predictive testing is discussed and facilitated for all at-risk relatives. Challenges faced by cancer genetics professionals in Singapore include the high rate of variant of uncertain significance (VUS) and low predictive testing rates. We hold regular support group activities for patients to seek mutual support and to raise overall awareness of BRCA1/2. We believe our comprehensive cancer genetics service serves as a useful model for other Asian countries looking to set up their own unit. We continue to aspire to empower patients, family members and healthcare professionals with cancer genetics knowledge to improve personal and public health.

Practice Implications of Expanded Genetic Testing in Oncology

Genetic test use in oncology is growing, yet providers’ experiences with evolving testing norms and their implications for patient care remain under-explored. In interviews with oncologists and cancer genetics professionals, 22 key informants described the increasing importance of germline results for therapeutic decision-making, preference for ordering tests directly rather than referring, and rapid adoption of cancer gene panels for testing. Implications for informed consent, result interpretation, and patient management were identified. These results suggest concerns raised by the transition of genetic test delivery from cancer genetics professionals to oncologists that must be addressed in practice guidelines and provider training.

Abstract ES1-1: Management of non-BRCA breast cancer predisposition

Abstract In the years since the discovery of BRCA1 and BRCA2, researchers have extended our understanding of the genetic architecture of breast cancer risk. Breast cancer has been described as a component tumor or a number of high penetrance autosomal dominant predisposition syndromes, such as Li-Fraumeni, Cowden Syndrome, Hereditary Diffuse Gastric Cancer, Peutz-Jeghers Syndrome, and possibly Lynch Syndrome. These are rare, but have clear clinical relevance once identified. At the other end of the spectrum, a series of genome-wide association studies (GWAS) identified over 80 common variants (SNPs) associated with breast cancer risk in the general population. The risk of an individual SNP is very low. An individual inheriting a significant number of risk alleles, however, may be a a clinically relevant degree of risk, even without a family history. An individual polygenic risk score can be calculated and correlates with risk, although how to apply this clinically is uncertain. Lastly, mutations in a number of moderate penetrance genes have been found that confer average relative risks of 2-3, with even higher risks in the setting of a family history. These genes include CHEK2, ATM, PALB2, and possibly others such as NBN. Other genes such as BARD1 and MRE11A have also been suggested to be moderate penetrance predisposition genes, but evidence of clinical validity is lacking. None of these are clearly linked to ovarian cancer risk. Genes such as BRIP1 and RAD51B/C/D appear to be moderate penetrance ovarian cancer predisposition genes, but their association with breast cancer is uncertain. Cancer genetics professionals had not been routinely testing patients for moderate penetrance predispositions before next generation sequencing facilitated the development of multi-gene panel testing. Since the commercial deployment of panel testing, hundreds (even thousands) of individuals, mainly women, have been identified as carriers of mutations in these genes. The appropriate management of these predispositions remains unclear, as guidelines developed for those with high penetrance mutations are not appropriate for most of those with more moderate risks. The effectiveness (and cost-effectiveness) of incremental MRI screening for women at moderate risk is unclear, although the lifetime risks associated with several moderate penetrance mutations cross the 20% threshold proposed by the American Cancer Society and American College of Radiology. There is no consensus, however, as to the age at which to begin this screening. Preventive mastectomy is probably not appropriate for most women with moderate penetrance mutations without a substantial family history. Risk-reducing sapling-oophorectomy may be appropriate for women with BRIP1 and RAD51B/C/D mutations, but the procedure can probably be delayed until around the time of natural menopause in most women, unless they have a significant family history of ovarian cancer. Moderate penetrance mutations can best be thought of as risk factors, which interact with other genetic (e.g. Family history) and non-genetic factors to influence an individual's breast or ovarian cancer risk. This is different from the situation with high penetrance mutations, where the mutation is causative in isolation. Management should be directed by this concept, tailored to the family history. Citation Format: Robson M. Management of non-BRCA breast cancer predisposition. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES1-1.

The evolution of cancer risk assessment in the era of next generation sequencing.

Cancer genetics professionals face a new opportunity and challenge in adapting to the availability of cancer genetic testing panels, now available as a result of Next Generation Sequencing (NGS) technology. While cancer panels have been available for over a year, we believe that there is not yet enough data to create practice guidelines. Despite this, a year of experience allows us to provide our opinion on points to consider as cancer genetic counselors incorporate this testing technology into genetic counseling practice models. NGS technology offers the ability to potentially diagnose hereditary cancer syndromes more efficiently by testing many genes at once for a fraction of what it would cost to test each gene individually. However, there are limitations and additional risks to consider with these tests. Obtaining informed consent for concurrent testing of multiple genes requires that genetics professionals modify their discussions with patients regarding the potential cancer risks and the associated implications to medical management. We propose dividing the genes on each panel into categories that vary by degree of cancer risk (e.g. penetrance of the syndrome) and availability of management guidelines, with the aim to improve patient understanding of the range of information that can come from this testing. The increased risk for identifying variants of uncertain significance (VUS) when testing many genes at once must be discussed with patients. Pretest genetic counseling must also include the possibility to receive unexpected results as well as the potential to receive a result in the absence of related medical management guidelines. It is also important to consider whether a single gene test remains the best testing option for some patients. As panels expand, it is important that documentation reflects exactly which genes have been analyzed for each patient. While this technology holds the promise of more efficient diagnosis for many of our patients, it also comes with new challenges that we must recognize and address.

Systematic review of educational tools used during the BRCA1/2 genetic testing process.

This review describes the characteristics of available educational tools used for BRCA1/2 genetic testing. To identify the tools, we conducted a systematic search in electronic databases, and contacted over 1000 cancer genetics professionals. This review is based on 68 tools from the USA, Canada, Australia, the UK, France and Ireland. The tools vary in format and scope depending on the genetic testing phase for which they are intended. We found that a wide diversity of educational materials are available and used for BRCA1/2 genetic testing around the world. However, a substantial number of tools fail to address important aspects of genetic testing.

Adherence patterns to National Comprehensive Cancer Network (NCCN) guidelines for referral to cancer genetics professionals

Objective: Genetic predisposition is responsible for 5-10% of breast cancer, 10% of ovarian cancer and 2-5% of uterine cancer. The National Comprehensive Cancer Network (NCCN) established guidelines delineating appropriate candidates for genetic counseling and testing. This study aims to determine referral patterns for genetic counseling and testing among women who met NCCN referral guidelines at an academic center.

Challenges in recruiting Mexican women for cancer genetics research.

Hispanic women often have low participation rates in cancer genetics research. Additionally, Hispanic sub-ethnicities may have varying accrual rates based on unique cultural factors. Hispanic women were recruited through flyers placed in the Tampa Bay Community to participate in an interview about knowledge of hereditary breast and ovarian cancer. The study goal was to recruit 20 women from each Hispanic sub-ethnicity: Puerto Rican, Mexican, and Cuban. This article reports on the difficulty in recruiting Mexican women. One hundred forty-three women called the study hotline to inquire about participation. Seventy-six callers were ineligible for the study. Thirty-four percent (n = 26) of ineligibles were Mexican women; within this group, 62% (n = 16) were unable to participate because they did not know the cancer site of their first degree relative. Inclusion criteria requiring knowledge of family history of cancer for behavioral research may be too stringent. The socio-cultural norms of Mexican families may not include discussions of cancer specifics. This study demonstrates Mexican women may have limited knowledge about their family history of cancer. Considerations of these knowledge limitations should be built into cancer genetics-related research. Referral criteria to assess the risk of hereditary breast and ovarian cancer by cancer genetics professionals are predicated on the patient providing details about cancer within multiple generations of family members, thus, posing a barrier for Mexican women who may have limited knowledge of their family history of cancer.

Abstract CN04-04: Cancer predisposition: I say genetics, you say genomics, but are we there yet?

Abstract In the United States, major contributors to premature mortality are behavior (40%) and genetics (35%). Amongst all diseases, scientific knowledge regarding genetic predisposition to cancer is one of the most advanced. Based on multidisciplinary research spanning the last 2 deacdes, the practice of clinical cancer genetics has empowered patients, their family members and healthcare providers with genetics-informed cancer risk assessment and management. On average, 10% of all cancers are caused by a strong (high penetrance) genetic predisposition, with a range between 5% and 30%. Yet, are those at genetic risk for cancer reaching proper care for prevention? An interactive-electronic family cancer history survey performed in a cancer hospital serving the population of central Ohio revealed that only 7% of all those assessed by cancer genetics professionals to be at high risk for cancer predisposition were recognized either by the patients' healthcare providers or the patients themselves, and referred to cancer genetics professionals. A recent national survey of >35,000 women without personal breast or ovarian cancer histories revealed that ∼1% (∼350) were at high risk for breast and/or ovarian cancer based on family history alone (i.e., at risk for carrying BRCA1/2 mutation). Yet, of these ∼350, only 10% (∼35) discussed this genetic risk with any healthcare provider, and only ∼1.5% (∼4) had BRCA1/2 gene testing. BRCA1/2 are “the most popular”” breast cancer predisposition genes and yet this population is under-serviced. There are at least 6 other high penetrance breast cancer-predisposition genes, including PTEN. Because of the lack of a systematic manner of identifying and managing all individuals at genetic risk for cancer, the great majority of individuals at high risk for cancer predisposition are never identified (in this BRCA1/2 national survey, 90%) nor reach appropriate medical care (99%). Therefore, we believe that individuals and their families at genetic risk for cancer are an under-served population. Paradoxically or perhaps due to the lack of knowledge of the availability and the power of validated genetics services, direct-to-consumer (DTC) personal genome scanning or screening has begun to gain popularity or at least peak public interest. In contrast to validated genetic testing, that is always focused on one or very few genes guided by medical and family histories, personal genomic scanning is currently based on multiple statistical comparisons called genome-wide association. Validated genetic testing is offered by healthcare providers to individuals at high risk of Mendelian genetic disease. This model of validated Mendelian genetic testing focuses only on one or a few genes that are known to be strongly associated with disease. If a gene mutation is identified, the individual is at high risk (sometime ∼100% likelihood) of developing the associated disease, and this type of genetic knowledge is clinically utile and actionable for prevention or very early detection. A few examples include Lynch syndrome, hereditary breast-ovarian cancer syndrome and Cowden syndrome. Personal genomic screening, or personal genome testing or profiling, uses data derived from genome-wide association studies to predict an individual's probability of developing many different disorders and traits in a lifetime. The majority of such genome-wide association studies are case-control studies which study hundreds to thousands of individuals to search for genetic markers shown to be statistically more common in individuals with disease compared with controls. These genetic markers are most commonly Single Nucleotide Polymorphisms (SNPs). They are common in the general population and may or may not have a known functional consequence. These types of data usually provide an odds ratio or relative risk of the likelihood that an individual with a particular genotype will have disease. As a result, most such DTC scanning currently has no to little analytic validity (because SNP choice and algorithms may differ), no clinical validity, no clinical utility and no actionability. Thus, interdisciplinary research directed at clinical outcomes or subsets of individuals or clinical situations where they can be used in a valid and actionable way should be performed. Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN04-04.

Statewide Cancer Genomics Integration in Michigan

The Michigan Cancer Genetics Alliance (MCGA) was created in 2003, and facilitated by the MDCH Genomics Program. In parallel, the State Genetics Plan and the Michigan Cancer Strategic Plan identified the need to create MCGA to serve as an organization of cancer genetics professionals with the purposes to promote communication, serve as a source of expert information, and participate in the Michigan Cancer Consortium (MCC). MCGA and cancer genetics received further support by a Centers for Disease Control and Prevention Cooperative Agreement to develop state capacity for integration of genomics into chronic disease prevention programs (♯U58/CCU522826). Highlights of MCGA’s accomplishments include a six-session course entitled, ‘Cancer Genomics for Public Health’, which was created and piloted for the MDCH Cancer Section. Additionally, MCGA has been working to enhance the state’s cancer surveillance system by addition of cancer genetics elements to the state cancer registry. MCGA members have representation on MCC subcommittees that are working to create risk assessment guidelines for breast, colorectal, and prostate cancer. MCGA is also addressing access to care, health disparities and health literacy issues. Michigan’s experience is one model of integrating cancer genomics knowledge into practice through partnerships and the development of projects and collaborations.

Genetic testing for cancer predisposition.

Clinical cancer genetics is becoming an integral part of the care of cancer patients. This review describes the clinical aspects, genetics, and clinical genetic management of most of the major hereditary cancer susceptibility syndromes. Multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and familial adenomatous polyposis are examples of syndromes for which genetic testing to identify at-risk family members is considered the standard of care. Genetic testing for these syndromes is sensitive and affordable, and it will change medical management. Cancer genetic counseling and testing is probably beneficial in other syndromes, such as the hereditary breast cancer syndromes, hereditary nonpolyposis colorectal cancer syndrome, Peutz-Jeghers syndrome, and juvenile polyposis. There are also hereditary cancer syndromes for which testing is not yet available and/or is unlikely to change medical management, including Li-Fraumeni syndrome and hereditary malignant melanoma. Thorough medical care requires the identification of families likely to have a hereditary cancer susceptibility syndrome for referral to cancer genetics professionals.