Genetic Testing for Cancer Susceptibility | Genetics and Genomics | JAMA

Approximately 10% of patients diagnosed with cancer have a germline variant in a gene that increases susceptibility to cancer.1 The most common examples include germline pathogenic variants (mutations) in BRCA1 and BRCA2, which are associated with an increased risk of breast, ovarian, pancreatic, and prostate cancer, and germline pathogenic variants in MLH1, MSH2, MSH6, and PMS2 (Lynch syndrome), which are associated with increased risk of colorectal cancer, endometrial cancer, and other cancer types.

More than 100 genes that increase susceptibility to cancer (with varied levels of penetrance and association with cancer susceptibility) have been described.2 The prevalence of these germline genetic variants varies by cancer type, ranging from 4% to 6% in patients with lung cancer, esophageal cancer, and head and neck cancer to 30% for male patients with breast cancer.³

For patients diagnosed with cancer for whom practice guidelines recommend genetic susceptibility testing, multiple-panel genetic testing is covered by most health insurance entities. Practice guidelines now recommend testing for inherited cancer susceptibility genes for all patients with ovarian, male breast, and pancreatic cancer.4 For other cancer types, including female breast, prostate, and colorectal, the criteria for testing have expanded, with more practice guidelines now advocating for genetic susceptibility testing for all patients or increasing subsets of patients.^4–6

Genetic testing for inherited cancer syndromes has become an integral component of cancer care because it directly affects management and therapy.1^,7 In 2014, the first poly(adenosine diphosphate–ribose) polymerase inhibitor was approved by the US Food and Drug Administration for BRCA-associated ovarian cancer, and more recently approval has been expanded to include treatment for BRCA-associated breast cancer, pancreatic cancer, and prostate cancer.⁸ At the time of breast cancer diagnosis, identifying a high-risk variant in a susceptibility gene such as BRCA1 or BRCA2 may encourage some women to select risk-reducing bilateral mastectomy or risk-reducing salpingo-oophorectomy.^9,10 Patients with variants in cancer-predisposing genes are also candidates for more frequent or intensive cancer screening. Examples include colonoscopy every 1 to 2 years in Lynch syndrome, breast magnetic resonance imaging in females with BRCA1 and BRCA2 genetic variants, and whole-body magnetic resonance imaging in patients with Li-Fraumeni syndrome.^4,5

In this issue of JAMA, Kurian et al11 report the rate of genetic testing in inherited cancer susceptibility in more than 1.36 million patients diagnosed with cancer between 2013 and 2019. Kurian et al¹¹ linked genetic test results from the 4 major commercial laboratories to incident cancer diagnoses reported to the California and Georgia Surveillance, Epidemiology, and End Results tumor registries. Kurian et al¹¹ report that only 6.8% of patients with cancer underwent genetic susceptibility testing within 2 years of the cancer diagnosis. The testing rates were higher for male breast cancer and ovarian cancer, for which practice guidelines recommend universal testing for all diagnosed patients.

However, even for ovarian cancer, for which universal genetic testing has been recommended since 2010, the rate of genetic testing was only 38.6%. The highest rate of testing was 50% for men with breast cancer. For pancreatic cancer, the rate of genetic testing increased from 1.2% in 2013 to 18.6% in 2019, the year that universal testing for this tumor type was first recommended. Previously, testing was recommended only for patients meeting specific family history criteria, or with specific ancestries known to be associated with higher rates of genetic susceptibility. Because tumor registries do not record family histories, the number of people with cancer who met practice guideline criteria but who did not undergo genetic testing could not be evaluated. Some cancer patients may have obtained genetic testing through direct-to-consumer laboratories and would not have been counted among the patients with genetic testing in the analyses. Nonetheless, the low rates of cancer genetic testing reported by Kurian et al11 raise concern and should stimulate interventions to increase rates of genetic testing with the goal of reducing cancer burden.

A strength of the study by Kurian et al11 was measurement of testing at the population level using the California and Georgia statewide tumor registries. When the results were analyzed by race and ethnicity, 22% of Asian patients, 25% of Black patients, and 23% of Hispanic patients underwent genetic testing for male breast cancer, female breast cancer, or ovarian cancer compared with 31% of non-Hispanic White patients with these cancer types. Uncertain genetic test results (defined as a result that could not clearly indicate whether the variant was related to cancer), which can result in suboptimal clinical management and increased patient anxiety,¹² were significantly more common in non-White patients. The combination of low genetic testing and more frequent identification of variants of uncertain clinical significance can perpetuate existing disparities.¹³

The analyses by Kurian et al11 did not identify reasons for underuse of genetic testing. Potential explanations can be divided into at least 2 categories. First, there are health care system–related barriers (eg, lack of timely access to genetic counseling). Many health systems do not employ genetic counselors and there is a US shortage of these professionals. Second, there are patient factors, such as preoccupation with coping with cancer treatment, lack of awareness or interest, mistrust, or fear of the potential consequences of testing, which may contribute to low genetic testing rates. These health care system–related and patient-related factors are even greater in vulnerable populations, including racial and ethnic minority groups, residents of rural regions, and patients with low health literacy.¹⁴

An alternative to the traditional genetic counseling pretesting visit is a point-of-care testing approach, also known as mainstreaming. In this model, nongenetic health care clinicians (usually surgeons or oncologists) provide a brief educational session, obtain consent, and order genetic testing during a single medical center visit. Several studies of patients with breast, ovarian, pancreatic, and prostate cancer demonstrated excellent feasibility and acceptability for this approach.15^,16 The results (especially for positive or uncertain test results) can also be delivered by a genetic counselor or other clinicians trained in cancer genetics.

Identification of gene variants associated with increased cancer susceptibility can improve outcomes for both cancer patients and family members. As data from Kurian et al11 highlight, genetic cancer susceptibility testing is underused, and this is a missed opportunity to decrease the population-level burden of cancer. With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented.

Corresponding Author: Deborah Schrag, MD, MPH, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (schragd@mskcc.org).

Published Online: June 5, 2023. doi:10.1001/jama.2023.9474

Conflict of Interest Disclosures: Dr Stadler reported that an immediate family member serves as a consultant in ophthalmology for Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals. Dr Schrag reported receiving grants from GRAIL and that a family member receives personal fees from Merck with equity shares.