Differences in Cascade Genetic Testing Among Families With Hereditary Cancer Risk

Performing germline genetic testing of family members following the identification of an individual with a pathogenic variant in a cancer predisposition gene, a process known as cascade testing, is a critical step in maximizing the preventive benefit of genetic testing for hereditary cancer.

To determine how often family members undergo cascade testing and to evaluate demographic, socioeconomic, and clinical factors associated with this process.

This retrospective cross-sectional study analyzed demographics, cancer history, genetic test results, and cascade testing data from probands who underwent multigene panel testing between December 2016 and August 2020 at a single diagnostic laboratory. The study cohort included probands found to have a pathogenic or likely pathogenic variant (P/LPV) in Lynch syndrome (MLH1, MSH2, MSH6, PMS2, or EPCAM) or hereditary breast and ovarian cancer (ATM, BRCA1, BRCA2, CHEK2, or PALB2) genes. Statistical analyses were conducted between June 2023 and March 2025.

Identification of a P/LPV in a cancer predisposition gene.

Variables assessed included proband age, sex, race and ethnicity, socioeconomic status (SES), availability of free testing for family members, cancer history, type of test ordered, and clinician credentials. Differences in cascade testing rates were calculated via 2-sided χ2 test.

Of 22 932 probands (18 949 [81.38%] female; mean [SD] age at testing. 51.6 [14.5] years), 5559 (24.24%) had at least 1 family member who underwent cascade testing. Higher rates of cascade testing were seen in individuals aged 40 to 79 years compared with those aged 20 to 39 years (age 40-59 years: 2587 of 10 420 probands [24.83%]; P < .001; age 60-79 years: 1960 of 6869 probands [28.53%]; P < .001; age ≥80 years: 129 of 462 probands [27.92%]; P < .001), women (4740 of 18 948 female probands [25.02%] vs 817 of 3963 male probands [20.62%]; P < .001), non-Hispanic White individuals (3762 of 13 834 probands [27.19%]), those with a personal cancer history vs those without (4712 of 16 674 probands [39.43%] vs 847 of 6261 probands [15.64%]; P < .001), and those whose care involved genetic counselors vs those whose did not (3614 of 13 847 probands [26.10%] vs 1948 of 9088 probands [21.43%]; P < .001). People with BRCA1 or BRCA2 variants had higher cascade testing rates compared with those with ATM, CHEK2, or PALB2 variants (2614 of 9699 probands [26.95%] vs 2015 of 8973 probands [22.46%]; P < .001). Several disparities were identified, including lower rates of cascade testing among male probands and probands from racial or ethnic minority groups compared with non-Hispanic White probands (227 of 1406 African American or Black probands [16.15%]; P < .001; 175 of 875 Asian probands [20.00%]; P < .001; 319 of 1616 Hispanic probands [19.74%]; P < .001; 17 of 146 Middle Eastern probands [11.64%]; P < .001). SES had minimal associations with testing rates, and free family testing was not associated with boosting participation.

In this retrospective cross-sectional study, cascade testing was underused, especially among specific demographic groups, with clinical and cultural factors appearing to play a larger role than financial barriers. These findings may guide efforts to address barriers preventing wider uptake of cascade testing and improve cancer prevention efforts, particularly among racial and ethnic minority groups.