Genetic testing is becoming increasingly used in oncology because of its potential to inform surgical decisions and chemotherapy. The complexity of this testing has also increased, however, with the growing number of genes and variants now being detected, coupled with a limited understanding of the implications of specific test results. At the National Comprehensive Cancer Network (NCCN) 2022 Annual Conference, a panel of experts discussed the latest evidence and recommendations regarding genetic testing and risk assessment.
Genetic Testing in Breast Cancer
Julie S. Mak, MS, MSc, CGC, Genetic Counselor Supervisor, Hereditary Cancer Clinic, Cancer Genetics and Prevention Program, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, began the session with a discussion on genetic testing in breast cancer.
Many genes other than BRCA1 and BRCA2 are known to be associated with an inherited risk for breast cancer. Although BRCA1 and BRCA2 constitute approximately 50% of the pathogenic variants in inherited breast cancer, a PALB2 variant accounts for 10% and TP53 for 9%, with several other variants responsible for 1% to 4% of cases. “We are also seeing genes that we are still learning about, such as RAD51D and RAD51C,” she said.
Different genes vary in the spectrum of cancer risks. The presence of a RAD51D variant, for example, is associated with an absolute risk for breast cancer of 15% to 40% and an absolute risk for ovarian cancer of >10%. With the identification of a pathogenic variant, testing of family members can identify those at increased risk; however, both family history and test results should be considered as women with several affected relatives may not have a RAD51D variant but may still be at elevated risk for breast cancer, Ms Mak said.
Women with a RAD51D variant who have female relatives with the RAD51D pathogenic variant are at an increased risk for ovarian cancer. It is recommended that these women consider surgery to remove the fallopian tubes and ovaries (ie, a bilateral salpingo-oophorectomy) between the ages of 45 and 50 years.
Patients who have had previous negative genetic test results may need to be retested, as testing technology and availability have improved over time, Ms Mak added.
“When you’re seeing a family with what looks like hereditary breast cancer, you should be thinking about multiple genes,” she said. A panel of genes is efficient in terms of cost and time, and most insurance carriers will pay for a one-time panel test for a specific indication. A panel of a few high-risk, well-known genes will result in fewer variants of unknown significance and fewer findings with unclear clinical applicability, she explained, but a large panel provides the most complete genetic risk assessment and the most reassurance in ruling out inherited risk.
Value of RNA Genetic Studies
RNA genetic studies as a supplement to DNA genetic testing can increase the yield and affect medical management, said Tuya Pal, MD, Associate Director, Cancer Health Disparities, Vanderbilt-Ingram Cancer Center, Nashville, TN.
In a 2019 study, performing RNA studies clarified 88% of inconclusive genetic results evaluated. In 47%, there was a molecular diagnosis of hereditary cancer predisposition and 41% were clarified as negative. Of the 307,812 patients who underwent DNA genetic testing for hereditary cancer, splicing variants were identified in 7265, and this is a population that could benefit from RNA studies.
Barriers to Genetic Testing and Counseling
Sue Friedman, DVM, Founder and Executive Director at FORCE: Facing Our Risk of Cancer Empowered, said that policy barriers and a patchwork of policies may prevent insurance coverage for genetic counseling and testing. Currently, Medicare will pay for these services only when patients are under active treatment.
“FORCE, NCCN, and other partners are trying to change this Medicare statute so that they will start covering genetic counseling and testing for patients not in treatment,” she said.
Concerns regarding genetic discrimination is a barrier to cascade testing (ie, testing of family members). The Genetic Information Nondiscrimination Act (GINA) bans genetic discrimination in health insurance and employment, but this does not apply to life insurance, long-term care insurance, or disability insurance, she pointed out. Furthermore, GINA does not apply to members of the US military, veterans obtaining healthcare through the Veterans Administration, individuals using the Indian Health Service, or federal employees enrolled in the Federal Employees Health Benefits Program. Recently, Florida passed legislation prohibiting genetic discrimination in life, long-term care, or disability income insurers.
“Most states do not have laws like this,” she said. The FORCE website should be consulted for legislation in various states.