IInherited genetic mutations are found in 5 to 10 percent of all cancers. When mutations in the BRCA1 gene were implicated in hereditary forms of breast cancer nearly 20 years ago, it sparked an interest in cancer genetic screening. Since then, several other genes have been identified as potential contributors to heritable forms of cancer.
Genetic testing can parse the effects of inherited mutations from shared environmental or lifestyle factors between family members. Whereas early detection is critical for successful outcomes in various cancers, prevention is key to lowering the financial burden associated with medical care and loss of productivity. Robust screening criteria are the cornerstone of cancer prevention, diagnosis, and effective treatment. However, there is ongoing debate in the clinical oncology and genetics community on the best approach for genetic screening of cancer.
Guideline-based approach to cancer genetic screening omits patients
Technological advances in genome sequencing have increased throughput while reducing the costs associated with genetic testing. Given the growing adoption and potential benefits of genetic testing, organizations like the American Cancer Society (ACS) and the National Comprehensive Cancer Network (NCCN) have formulated guidelines for cancer genetic screening.
Current guidelines recommend genetic testing for individuals diagnosed with cancer at a young age or those deemed at high risk on the basis of a family and/ or personal history of cancer. Genetic testing is used to confirm either the presence or absence of pathogenic variants of cancer-causing genes in these high-risk individuals.
This targeted, guideline-based approach has several advantages. Identifying a high-risk genetic variant affords individuals the opportunity to manage their cancer risks through lifestyle or surgical interventions. For instance, women at high risk for heritable forms of breast cancer may undergo prophylactic mastectomy to lower their risk of developing the disease. For individuals who have already been diagnosed with cancer, genetic testing helps inform clinical decisions about the feasibility of therapeutic approaches.
Yet, some studies have shown that a guideline-based approach to cancer genetic screening may overlook a large percentage of individuals with heritable or germline pathogenic variants. A survey of over 40,000 women found that only around 20 percent of women with breast or ovarian cancer had undergone genetic testing.1 When extrapolated to the US population, an estimated 1.3 million women with breast or ovarian cancer are excluded from genetic testing, partly because they do not fulfill the family history criteria of current testing guidelines. Another study reported similar rates of pathogenic variants in 959 patients with breast cancer who did and did not meet NCCN guidelines.2 This indicates that nearly half the patients carrying a clinically actionable pathogenic variant for breast cancer are missed by current testing guidelines.
Population-based genetic testing has limited clinical relevance
To ensure that all individuals with heritable forms of cancer receive genetic testing, some experts propose more widespread screening of the general population. Indeed, germline pathogenic variants for some genes are likely to be up to 10 times higher in the general population than in individuals with a personal or family history of cancer.3 Compared with current guidelines, population-based testing for BRCA mutations is likely to prevent up to 2,666 additional breast cancer cases and 449 additional ovarian cancer cases per million women.4 Instead of treating cancer, preventative interventions that reduce the risk of developing cancer by identifying pathogenic variants early on are deemed highly costeffective for health care systems around the world.
This approach has led to the rise of direct-to-consumer (DTC) genetic testing kits that measure an individual’s risk of developing certain cancers. In 2018, the U.S. FDA approved the first DTC kit for assessing breast cancer susceptibility by testing three pathogenic variants of BRCA1 and BRCA2.5 The test benefits individuals of Ashkenazi Jewish heritage in whom these mutations are most common. However, with over a thousand known BRCA mutations implicated in breast and ovarian cancer, this test has limited applicability to most women at average risk of breast cancer. For most, the results of DTC tests for cancer may be uninformative or misleading; without proper genetic counseling, people are likely to misinterpret their cancer predisposition based on DTC test results alone.
Some studies suggest that population-wide genomic testing for hereditary breast and ovarian cancer in all adult women may be cost-effective.6,7 While genomic testing is capable of identifying all variants of a gene of interest, understanding which variant leads to a high degree of pathogenicity is important. Genome-wide screening is likely to detect several variants of unknown significance and further complicate clinical management of the disease.
Universal testing for patients with cancer: A clinically viable and cost-effective alternative
An approach that offers a middle ground between guideline-based and population-based genetic testing is now emerging. Universally testing all patients diagnosed with cancer may help overcome the rigidity of guideline-based testing, while providing more clinically relevant insights than population-wide genetic testing. Clinically viable and cost-effective methods for universal testing, such as multi-gene panel testing, tumor-normal sequencing, and cascade testing, could help usher universal testing into clinical practice.
Multi-gene panel testing
As the list of genes found to be causally linked to hereditary forms of cancer continues to grow, multi-gene panels are replacing individual gene testing. Multigene panels that detect high and moderate penetrance pathogenic gene variants have the potential to aid clinical decision-making. For instance, in a recent study of nearly 3,000 patients with solid tumors, germline sequencing using a panel of 83 genes prompted a change in clinical management for 28 percent of the patients with high-risk variants.8 Nearly half of these variants would not have been detected using standard guidelines.
Although universal testing of all patients diagnosed with cancer may help identify many more patients with pathogenic variants compared with single-gene testing based on current clinical guidelines alone, multi-gene panels have a few limitations. The number of genes and variants identified by commercially available panels varies greatly. Large panels often assess genes that are newly identified, and their role in cancer susceptibility may not be adequately characterized. Multi-gene panels also differ in turnaround times, variant classification protocols, and insurance coverage. As pathogenic variants remain poorly characterized in diverse racial and ethnic groups, the implications of multi-gene panel testing in underrepresented populations are unclear. Despite rapidly falling costs of genome sequencing, multi-gene panel testing has additional costs associated with genetic counseling. The limited availability of genetic counselors is a barrier to the widespread implementation of this approach.
Tumor-normal sequencing is a two-pronged approach that involves paired analysis of DNA isolated from tumors and from normal non-malignant cells of the same individual.9 It can be used to determine the best therapeutic route for the patient by identifying variants susceptible to targeted therapies. Additionally, by analyzing non-malignant cells it can be used to distinguish between non-heritable somatic mutations and heritable germline mutations. This provides an unbiased assessment of the hereditary contribution to cancer.
In one study, tumor-normal sequencing in approximately 1,000 patients with advanced cancers identified clinically actionable germline pathogenic variants in 17.5 percent of the patients.10 Corroborating previous results, this study also found that 55 percent of these patients would have been overlooked in guideline-based testing. Recently, tumor-normal sequencing was also performed in pediatric cancer patients. Of the 751 children tested, 13 percent were found to have moderate-to-high penetrance pathogenic germline mutations, with 34 percent of the variants identified being unexpected based on the patient’s diagnosis and previous history.11
Filtering out germline variants from tumor-only sequencing data boosts the accuracy of genetic testing by reducing the rate of false positives and false negatives. However, to make tumor-normal sequencing a standard clinical practice, institutions need infrastructure that allows testing of both blood and tumor specimens. Protocols for filtration and sequence analysis also need to be standardized to ensure reliability of results across testing centers.
The discovery of pathogenic germline variants is relevant to patients with cancer and their relatives. Also called predictive testing, cascade testing involves genetic testing family members of patients with cancers that are attributed to clinically relevant pathogenic variants. For example, two cases wherein germline BRCA2 mutations were detected in pediatric patients found similar mutations in the patients' mothers.12 The presence of pathogenic variants in these women would have gone unnoticed without cascade testing. In a larger study of 751 pediatric cancer patients, cascade testing identified 27 mutation carriers who were previously unaware of their genetic status.11 When firstdegree relatives of adult patients with germline variants underwent cascade testing, 45 percent of these relatives were also found to carry pathogenic variants.8
Cascade testing can rapidly detect individuals predisposed to heritable forms of cancer. A model-based analysis of cascade testing in the United States provides encouraging results. The analysis predicts that 3.9 million individuals carrying pathogenic variants on 18 cancer susceptibility genes would be detected within 10 years if cascade testing was performed in 70 percent of first, second, and third-degree relatives, as opposed to 60 years without cascade testing.13
Historically, cascade testing has been performed in fewer than 30 percent of at-risk relatives. Despite direct outreach by clinicians and use of at-home genetic testing kits, the rate of cascade testing only rose to 58 percent.14 Limited understanding of the potential risk, concerns about insurance coverage and discrimination, and the emotional burden of a potential cancer diagnosis may contribute to low uptake rates. Appropriate genetic and mental health counseling is needed to allay these concerns and promote widespread implementation of this cost-effective and time-efficient approach.
Finding a middle ground
Germline testing provides individuals and their family members the opportunity to learn about their risk of developing hereditary forms of cancer. On one hand, current guidelines for cancer genetic testing exclude a large percentage of individuals who would benefit from this information. On the other hand, population-wide testing may cause undue stress to individuals with low cancer risk and fail to produce clinically relevant insights. Prescribing genetic testing for all individuals diagnosed with cancer is an ideal middle ground. Doing so would help clinicians determine the best course of action for treating these patients, while also providing valuable information on germline pathogenic variants. Currently, challenges associated with insurance coverage, access to genetic counseling, and detection of variants of unknown significance limits widespread implementation of the approach in clinical practice. Once these challenges are overcome, universal genetic testing could prove to be a gamechanger for patients with cancer, their families, and health care systems across the world.
1. Childers, Christopher P., et al. "National estimates of genetic testing in women with a history of breast or ovarian cancer." Journal of Clinical Oncology 35.34 (2017): 3800.
2. Beitsch, Peter D., et al. "Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle?" Journal of Clinical Oncology 37.6 (2019): 453.
3. de Andrade, Kelvin César, et al. "Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history." Human Mutation 38.12 (2017): 1723-1730.
4. Manchanda, Ranjit, et al. "Economic evaluation of population- based BRCA1/BRCA2 mutation testing across multiple countries and health systems." Cancers 12.7 (2020): 1929.
5. FDA authorizes, with special controls, direct-to-consumer test that reports three mutations in the BRCA breast cancer genes | FDA. https://www.fda.gov/news-events/press-announcements/ fda-authorizes-special-controls-direct-consumer-testreports- three-mutations-brca-breast-cancer.
6. Zhang, Lei, et al. "Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis." Genetics in Medicine 21.9 (2019): 1958-1968.
7. Manchanda, Ranjit, et al. "Cost-effectiveness of populationbased BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women." Journal of the National Cancer Institute 110.7 (2018): 714-725.
8. Samadder, N. Jewel, et al. "Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome." JAMA Oncology 7.2 (2021): 230-237.
9. Mandelker, Diana, and Ozge Ceyhan-Birsoy. "Evolving significance of tumor-normal sequencing in cancer care." Trends in Cancer 6.1 (2020): 31-39.
10. Mandelker, Diana, et al. "Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing." JAMA 318.9 (2017): 825-835.
11. Fiala, Elise M., et al. "Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors." Nature Cancer (2021): 1-9.
12. Walsh, Michael F., et al. "Germline BRCA2 mutations detected in pediatric sequencing studies impact parents’ evaluation and care." Molecular Case Studies 3.6 (2017): a001925.
13. Offit, Kenneth, et al. "Cascading after peridiagnostic cancer genetic testing: an alternative to population-based screening." Journal of Clinical Oncology 38.13 (2020): 1398.
14. Frey, Melissa K., et al. "Prospective feasibility trial of a novel strategy of facilitated cascade genetic testing using telephone counseling." Journal of Clinical Oncology 38.13 (2020): 1389-1397.