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. 2026 Jun 30;9(6):e2621242. doi: 10.1001/jamanetworkopen.2026.21242

Differences in Cascade Genetic Testing Among Families With Hereditary Cancer Risk

Elia Namey 1,3, Carolyn Horton 2, Beth Dudley 1, Cassidy Carraway 2, Timothy Komala 2, Carrie Milliard 2, Tara Namey 2, Eve Karloski 1, Randall Brand 1,✉
PMCID: PMC13320652  PMID: 42377955

Key Points

Question

Are there differences in the uptake of cascade testing among relatives of individuals with hereditary cancer risk?

Findings

In this cross-sectional study including 22 932 probands with pathogenic or likely pathogenic variants, 5559 (24.24%) had at least 1 relative pursue cascade testing, with the highest rates among non-Hispanic White probands and significantly lower rates among African American or Black, Asian, Hispanic, and Middle Eastern probands, even when controlling for socioeconomic status. The availability of free familial variant testing was not associated with a meaningful increase in cascade testing.

Meaning

These findings suggest that cascade testing remains markedly underused, and persistent demographic disparities suggest additional factors at play beyond financial access.

This cross-sectional study examines how often family members undergo cascade testing and evaluates demographic, socioeconomic, and clinical factors associated with this process

Abstract

Importance

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.

Objective

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

Design, Setting, and Participants

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.

Exposure

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

Main Outcomes and Measures

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.

Results

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.

Conclusions and Relevance

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.

Introduction

Germline genetic testing can inform medical management among individuals with a hereditary cancer predisposition.1 While testing individuals affected by cancer may provide the most informative initial result, reducing cancer morbidity and mortality as a result of germline genetic testing can only be fully realized through robust uptake by family members. This practice, referred to as cascade testing, involves the testing of biological family members after the identification of a pathogenic or likely pathogenic variant (P/LPV) in a proband.2

Identifying an asymptomatic individual with an underlying cancer predisposition allows for the implementation of appropriate interventions, including cancer surveillance and risk-reducing surgical procedures.3,4,5 The enhancement of cancer surveillance in individuals with an identified P/LPV can lead to earlier-staged cancer diagnoses and an increase in overall survival rate.6,7,8,9,10,11

Several studies have assessed factors associated with adoption of genetic testing among index probands. Demographic factors, such as race, ethnicity, and socioeconomic status (SES), are relevant for probands. Probands who identify with a racial or ethnic minority group (eg, African American or Black or Hispanic individuals) or have a lower SES use genetic testing at lower rates.12,13,14,15,16 These disparities highlight missed opportunities for cancer prevention in vulnerable populations.17 Conversely, certain clinical factors appropriately impact the likelihood of receiving genetic testing; for example, a personal and strong family history of cancer often is associated with an increase in the use of genetic testing services.18,19

Studies to determine whether similar variables are associated with adoption of cascade testing in family members following identification of a P/LPV in a proband are extremely limited. Existing studies on cascade testing indicate that it is performed only for a minority of probands.20,21 Some testing laboratories have instituted policies offering free testing for familial variants to stimulate cascade testing rates. However, the impact of these policies has not been well studied. Data suggest that testing indication and demographic factors are associated with cascade testing, but a more in-depth examination of these variables is still needed.22 It was hypothesized that the uptake of cascade testing would vary by demographic, socioeconomic, and clinical factors, with lower uptake among racial and ethnic minority groups (eg, [placeholder]) and individuals with lower SES, and that uptake would increase in these populations with the availability of free testing. The aim of this study was to determine the overall cascade testing rates and identify factors associated with uptake. In addition to proband age at testing, sex, and self-reported race and ethnicity, the associations of SES and the availability of free testing on the uptake of cascade testing was examined.

Methods

Study Cohort

We confirm that we have adhered to all ethical regulations and that this cross-sectional study was carried out in accordance with the recommendations of the WGC IRB (formerly Western Institutional Review Board), which has granted an waiver of institutional review and informed consent because our research does not include human participants based on federal regulation 45 CFR 46.102(f) and associated “Guidance on Research Involving Coded Private Information or Biological Specimens,” determining that coded private information or biological specimens would not be considered to involve human participants. Individuals who declined participation in deidentified research were excluded from this study. All data presented were obtained as part of standard diagnostic testing. This study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

This retrospective, cross-sectional study of demographics, reported cancer history, genetic test results, and family member testing was conducted through a single diagnostic testing laboratory (Ambry Genetics; Aliso Viejo, California). Probands who underwent mutigene panel testing (MGPT) between December 2016 through August 2020 and who were found to have a P/LPV in Lynch syndrome (LS) genes (MLH1, MSH2, MSH6, PMS2, or EPCAM) or hereditary breast and ovarian cancer (HBOC) genes (ATM, BRCA1, BRCA2, CHEK2, or PALB2) were included in the study. This timeframe was selected to include data before and after the introduction of free single-site testing in June 2018, allowing assessment of uptake after this policy change while limiting the influence of longer-term changes in clinical practice or payer policies. The timeframe was also informed by data availability at the time of data analysis. Clinical information, including proband cancer history, was derived from test requisition forms, clinical documents, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes provided by the ordering clinician. Probands were defined as having familial cascade testing if at least 1 family member underwent genetic testing on any cancer platform (single-site analysis, single-gene testing, or MGPT), the family member testing included analysis of the known familial P/LPV, and the family member testing occurred after the proband’s positive result.

Cascade Testing Variables

The associations of several demographic, clinical, and economic variables with uptake of cascade testing were assessed. Demographic factors include the proband’s sex at birth, age at testing, and self-reported racial and ethnic group. Race and ethnicity were self-reported by probands at the time of test ordering using test requisition forms and recorded in the laboratory database. Racial and ethnic groups assessed were limited to African American or Black, Asian, Hispanic, Middle Eastern, multiple races or ethnicities, non-Hispanic White, and other (Alaska Native, American Indian or Native American, Assyrian, Brazilian, Creole, Jewish unspecified, Sephardic Jewish, Sudanese, or unknown). Clinical variables, including genes impacted, proband cancer history, and ordering clinician credentials (genetic counselor or geneticist, nurse practitioner or physician assistant, or physician), were also assessed. Lastly, we evaluated economic factors, such as availability of free cascade testing and residential zip code, as a surrogate for SES. The US Income by ZIP Code software23 was used to acquire US Census Bureau income statistics by zip code. Proband SES was designated as high (≥$86 000), medium ($50 000-$85 999), or low ($0-$49 999) based on zip-level median household income.24 Single-site cascade testing for family members within 90 days of a proband’s positive test result was free of charge beginning June 2018.

Statistical Analysis

Descriptive statistics summarized the demographic and clinical characteristics of the proband cohort, with counts and proportions provided for outcomes of categorical variables, such as uptake of cascade testing. The differences in the number of probands with positive results who had at least 1 family member pursue cascade testing, the number of family members who had cascade testing when it was performed, and the type of cascade testing performed based on each study variable were compared. To evaluate differences in cascade testing rates across demographic and clinical factors, 2-sided χ2 tests were performed to compare proportions across independent groups. All assumptions for the χ2 test were verified, including independence of observations and expected cell counts exceeding the minimum threshold of 5. Odds ratios (ORs) and 95% CIs were calculated directly from contingency tables to quantify the associations between proband characteristics and cascade testing uptake. No logistic regression was performed; however, the associations of race and ethnicity were evaluated through a stratified analysis that controlled for SES to account for potential confounding. For analysis of categorical variables, such as SES, missing values were kept as a separate category. All comparisons were 2-sided and P < .05 was considered statistically significant. Statistical analyses were conducted between June 2023 and March 2025 using Excel software version 16.0 (Microsoft).

Results

Proband Cohort Characteristics

Among 22 932 probands (18 949 [81.38%] female; mean [SD] age at testing. 51.6 [14.5] years) with test results positive for a P/LPV in LS or HBOC genes from December 2016 through December 2020, 1406 (6.13%) were African American or Black, 1853 (8.08%) were Ashkenazi Jewish, 875 (3.82%) were Asian, 1616 (7.05%) were Hispanic, 136 (0.59%) were Middle Eastern, 910 (3.97) reported multiple races or ethnicities, 13 846 (60.38%) were non-Hispanic White, and 2290 (9.99%) reported other race or ethnicity. Figure 1 and Table 1 provide detailed overviews of the cohort, summarizing the demographic and clinical characteristics observed in probands. Based on zip code, 3198 probands (13.95%) were assigned to the low SES group, while 9352 probands (40.78%) and 5956 probands (25.97%) were assigned to the medium and high SES groups, respectively; 4426 probands (19.30%) were excluded from SES analyses due to insufficient patient-reported data. Free single-site analysis became available in June 2018; 6664 probands (29.06%) were tested before this date, while 16 268 probands (70.94%) received testing after this time point. Most individuals were identified as having a personal history of cancer, with breast, ovarian, and colon cancers reported most frequently.

Figure 1. Study Population Flowchart .

Flowchart of probands split into familial testing versus none, with ethnicity counts. Light gray flowchart with black text and thin gray connector lines. A top, centered rectangular node reads 22932 Probands with B R C A 1 slash 2, L S, A T M, or C H E K 2, P A L B 2 P slash L P V s detected from December 2016 to December 2020. A single connector line descends and branches to two midlevel nodes. The left midlevel node reads 5559 greater than or equal to 1 Family member tested. The right midlevel node reads 17373 No familial testing. From the left midlevel node, a horizontal connector branches downward to six smaller nodes arranged across the lower left half: 175 Asian; 319 Hispanic; 17 Middle Eastern; 227 African American or Black; 396 Ashkenazi Jewish; 3762 Non-Hispanic White; and 663 Multiple or other. Each node is connected by a short vertical line from the shared branch line. From the right midlevel node, a similar horizontal connector branches downward to six smaller nodes arranged across the lower right half: 700 Asian; 1297 Hispanic; 129 Middle Eastern; 1179 African American or Black; 1458 Ashkenazi Jewish; 10072 Non-Hispanic White; and 2538 Multiple or other. No axes, legend, scale bar, or panel labels are present.

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Flow diagram of the probands analyzed for cascade genetic testing uptake among probands with pathogenic or likely pathogenic variants (P/LPVs) in BRCA1, BRCA2, Lynch Syndrome (LS) genes, ATM, CHEK2, and PALB2 in the study population.

Table 1. Cohort Description.

Category Probands, No. (%) (N = 22 932)
Race and ethnicity
African American or Black 1406 (6.13)
Ashkenazi Jewish 1853 (8.08)
Asian 875 (3.82)
Hispanic 1616 (7.05)
Non-Hispanic White 13 846 (60.38)
Middle Eastern 136 (0.59)
Multiple races or ethnicities 910 (3.97)
Othera 2290 (9.99)
SES
Low 3198 (13.95)
Medium 9352 (40.78)
High 5956 (25.97)
Not provided 4426 (19.30)
Sex at birth
Female 18 949 (81.38)
Male 3962 (18.52)
Not provided 21 (0.10)
Free testing implementation
Before 6664 (29.06)
After 16 268 (70.94)
Age, y
0-19 140 (0.61)
20-39 4957 (21.62)
40-59 10 420 (45.44)
60-79 6869 (29.95)
≥80 462 (2.01)
Not provided 84 (0.37)
Genes positive
BRCA1/2 9699 (42.71)
Lynch syndrome 3323 (14.63)
Other HBOCb 8852 (38.98)
BRCA1/2 and Lynch syndrome 75 (0.33)
BRCA1/2 and other HBOC 412 (1.81)
Lynch syndrome and other HBOC 345 (1.52)
BRCA1/2, Lynch syndrome, and other HBOC 1 (<0.01)
P/LPVs, No.
1 22 326 (97.36)
2 600 (2.62)
3 6 (0.03)
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Abbreviations: HBOC, hereditary breast and ovarian cancer; P/LPV, pathogenic or likely pathogenic variant; SES, socioeconomic status.

a

Includes Alaska Native, American Indian or Native American, Assyrian, Brazilian, Creole, Jewish unspecified, Sephardic Jewish, Sudanese, and unknown.

b

ATM, CHEK2, and PALB2.

Overall Cascade Testing Rate

Among all 22 932 probands with a P/LPV, 5559 (24.24%) had at least 1 family member undergo testing for the same genetic variant. The mean (SD) age at testing for probands whose family used cascade testing was 54.2 (13.5) years.

Proband Variables Associated With Cascade Testing

Age and Sex

Comparisons in the uptake of cascade testing showed significant differences between age groups. All age group cascade testing rates were compared to the group aged 20 to 39 years, which had 869 of 4957 probands (17.53%) with at least 1 family member undergoing cascade testing. Cascade testing occurred for 2587 of 10 420 probands aged 40 to 59 years (24.83%) (P vs age 20-39 years < .001), 1960 of 6869 probands aged 60 to 79 years (28.53%) (P vs age 20-39 years < .001), and 129 of 462 probands aged 80 years or older (27.92%) (P vs age 20-39 years < .001). Of 140 probands aged 0 to 19 years, 13 (9.29%) had a family member use cascade testing (P vs age 20-39 years = .01). Female probands were more likely than male probands to have familial cascade testing, with respective rates of 4740 of 18 948 female probands (25.02%) vs 817 of 3963 male probands (20.62%) (P < .001).

Race and Ethnicity

Non-Hispanic White individuals were most likely to have at least 1 relative pursue cascade testing, with 3762 probands (27.19%) having at least 1 family member undergo cascade testing. Rates of cascade testing were significantly lower in all other racial and ethnic groups (Table 2). The lowest rates of cascade testing were observed for African American or Black probands (227 individuals [16.15%]) and Middle Eastern probands (17 individuals [11.64%]).

Table 2. Utilization of Cascade Testing Based on Proband Race and Ethnicity and SES.
Race and ethnicity Cascade testing total, No./No. of probands (%) OR (95% CI) P value
No SES adjustment (N = 22 932)
African American or Black 227/1406 (16.15) 0.52 (0.45-0.60) <.001
Ashkenazi Jewish 396/1854 (21.36) 0.73 (0.65–0.82) <.001
Asian 175/875 (20.00) 0.67 (0.57-0.79) <.001
Hispanic 319/1616 (19.74) 0.66 (0.58-0.75) <.001
Middle Eastern 17/146 (11.64) 0.35 (0.21-0.57) <.001
Multiple 215/911 (23.60) 0.82 (0.71-0.97) .02
Non-Hispanic White 3762/13 834 (27.19) 1 [Reference] NA
Othera 448/2290 (19.56) 0.65 (0.58-0.73) <.001
Low SES (n = 3198)
African American or Black 82/500 (16.40) 0.53 (0.41-0.69) <.001
Ashkenazi Jewish 21/96 (21.88) 0.78 (0.46-1.24) .27
Asian 11/49 (22.45) 0.78 (0.40-1.54) .48
Hispanic 72/375 (19.2) 0.64 (0.49-0.85) .002
Middle Eastern 3/3 (100) NA NA
Multiple 36/141 (25.53) 0.93 (0.63-1.37) .71
Non-Hispanic White 480/1778 (27.00) 1 [Reference] NA
Othera 43/256 (16.8) 0.55 (0.39-0.77) <.001
Medium SES (n = 9352)
African American or Black 91/523 (17.4) 0.53 (0.42-0.67) <.001
Ashkenazi Jewish 98/486 (20.16) 0.64 (0.51-0.81) <.001
Asian 46/239 (19.25) 0.60 (0.44-0.84) .002
Hispanic 136/695 (19.57) 0.62 (0.51-0.75) <.001
Middle Eastern 3/29 (10.34) 0.29 (0.09-0.97) .03
Multiple 76/376 (20.21) 0.64 (0.50-0.83) <.001
Non-Hispanic White 1725/6100 (28.28) 1 [Reference] NA
Othera 196/904 (21.68) 0.70 (0.59-0.83) <.001
High SES (n = 5956)
African American or Black 20/166 (12.05) 0.39 (0.24-0.63) <.001
Ashkenazi Jewish 171/761 (22.47) 0.83 (0.69-1.00) .04
Asian 58/303 (19.14) 0.68 (0.50-0.91) .009
Hispanic 40/236 (16.95) 0.58 (0.41-0.82) .002
Middle Eastern 6/62 (9.68) 0.31 (0.13-0.71) .004
Multiple 44/219 (20.09) 0.72 (0.51-1.01) .05
Non-Hispanic White 929/3577 (25.97) 1 [Reference] NA
Othera 127/632 (20.09) 0.72 (0.58-0.88) .002
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Abbreviations: NA, not applicable; OR, odds ratio; SES, socioeconomic status.

a

Includes Alaska Native, American Indian or Native American, Assyrian, Brazilian, Creole, Jewish unspecified, Sephardic Jewish, Sudanese, and unknown.

Clinical Characteristics and Testing Rates

Results were compared to determine whether cascade testing rates varied by the genes in which probands carried a P/LPV. Rates were similar between individuals with P/LPVs in BRCA1 or BRCA2 and LS genes, but individuals with P/LPVs in other HBOC genes (ATM, CHEK2, or PALB2) were less likely to have familial testing compared with probands with P/PLVs in BRCA1 or BRCA2 (Figure 2). This trend was consistent when stratifying by sex. Males with BRCA1 or BRCA2 and LS P/LPVs had similar rates of familial testing (333 of 1563 probands [21.31%] vs 223 of 1034 probands [21.57%]; P = .12) while uptake was lower among male probands with HBOC P/LPVs (218 of 1231 probands [17.71%]) (P = .001). While female probands with LS P/LPVs were less likely to have familial testing compared with female probands with BRCA1 or BRCA2 P/LPVs (576 of 2283 probands [25.23%] vs 2228 of 8134 probands [27.38%]; P = .04), this gap was more pronounced among females with other HBOC P/LPVs (1700 of 7739 probands [21.97%]) (P < .001). Finally, probands who had multiple P/LPVs were more likely to have family members undergo cascade testing compared with those who had a single P/LPV (Figure 2).

Figure 2. Bar Graph of Associations of Clinical Variables With Cascade Testing Rates.

Horizontal bar chart of cascade testing rate percent by cancer and gene groups. Single-panel horizontal bar chart with light blue bars and thin black error bars. Horizontal axis label at bottom: Cascade testing rate, percent, with tick marks at 0, 10, 20, 30, 40, 50, and 60; faint vertical gridlines align with these ticks. Left side contains grouped row labels in dark text. Group header Cancer status near the upper left, followed by two rows: Any cancer with a bar ending near 39 percent and an error bar extending roughly from 37 to 41 percent; No cancer with a bar ending near 16 percent and an error bar roughly from 14 to 18 percent. Next group header Cancer type, followed by paired rows: Breast cancer near 44 percent with error bar about 42 to 46; No breast cancer near 27 percent with error bar about 25 to 29. Ovarian cancer near 48 percent with error bar about 46 to 50; No ovarian cancer near 32 percent with error bar about 30 to 34. Colon cancer near 39 percent with error bar about 38 to 41; No colon cancer near 32 percent with error bar about 30 to 34. Prostate cancer near 34 percent with error bar about 32 to 36; No prostate cancer near 24 percent with error bar about 22 to 26. Next group header Proband gene, with three rows: B R C A 1 slash 2 near 27 percent with error bar about 25 to 29; L S near 26 percent with error bar about 24 to 28; Other H B O C a comma b near 23 percent with error bar about 21 to 25. Next group header P slash L P V s, with two rows: Single near 26 percent with error bar about 24 to 28; Multiple near 31 percent with error bar about 29 to 33. Final group header G C involvement, with two rows: G C a near 26 percent with error bar about 24 to 28; No G C near 22 percent with error bar about 20 to 24.

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GC indicates genetic counselor; HBOC, hereditary breast and ovarian cancer; P/LPV, pathogenic or likely pathogenic variant.

aStatistically significant.

bATM, CHEK2, and PALB2.

The proband’s impacted gene also was associated with the type of cascade testing performed, such that probands with BRCA1 or BRCA2 P/LPVs were least likely to have a family member undergo expanded cascade testing (959 of 2614 probands [36.69%]), compared with individuals with P/LPVs in other HBOC (821 or 2015 probands [40.74%]) (P = .005) and probands with P/LPVs in LS genes (363 of 850 probands [42.71%]) (P = .002).

Individuals with a personal history of cancer were more likely to have a family member pursue cascade testing compared to those without (Figure 2). This was most remarkable when comparing individuals with any cancer with those with no cancer, but was also significant when comparing specifically for breast, ovarian, prostate, and colon cancers (Figure 2).

Overall assessment of ordering clinician credentials found that 13 846 probands (60.38%) had a genetic counselor listed as the ordering clinician or primary contact on the test requisition form. Of these, 3614 of 13 846 individuals (26.10%) had at least 1 family member with cascade testing use compared with probands without apparent involvement of genetics professionals (1948 of 7140 individuals [21.43%]) (P < .001) (Figure 2).

Socioeconomic Status

Among probands with available SES data, 748 of 2450 probands (23.39%) in the low SES group, 2371 of 6981 probands (25.35%) in the medium SES group, and 1395 of 5956 probands (23.42%) in the high SES group had a family member undergo cascade testing (medium vs low SES: P = .03; high vs low SES: P = .97). Lower familial cascade testing rates were still present among racial and ethnic minority groups when examining rates within each SES group (Table 2). Even for probands with the highest SES, all racial and ethnic minority groups had lower adoption of cascade testing compared with non-Hispanic White individuals, with African American or Black and Middle Easter probands having the lowest rates (Table 2).

Free Cascade Testing

Cascade testing uptake occurred among family members of 1559 of 6665 probands (23.39%) before the implementation of free family variant testing and 4000 of 16 268 probands (24.59%) after free testing (P = .06) (Table 3). The mean (SD) number of family members tested before gratis testing was 1.98 (1.67), compared with 2.11 (1.82) after free testing implementation (P = .07). The association of free single-site testing with the type of cascade testing ordered was also evaluated. Expanded cascade testing of multiple genes was more common after institution of free familial testing (524 tests [41.38%]) rather than before (1655 tests [33.61%]) (P < .001), indicating that when testing was pursued, it was not restricted to the free offering. Free testing was not associated with the rates of cascade testing within racial and ethnic groups (Table 3). The low and high SES groups showed an increase in cascade testing rates after the implementation of free testing, while the medium SES group showed no significant change (Table 3).

Table 3. Uptake of Cascade Testing Before and After Free Family Variant Testing.

Variable No. with cascade testing/proband total No. (%) P value OR (95% CI)
Before free testing implementation After free testing implementation
All probands 1559/6664 (23.39) 4000/16 268 (24.59) .06 NA
Race
African American or Black 72/424 (16.98) 155/982 (15.78) .58 0.92 (0.68-1.24)
Ashkenazi Jewish 129/603 (21.39) 266/1250 (21.28) .96 0.99 (0.78-1.26)
Asian 54/290 (18.62) 121/585 (20.68) .47 1.14 (0.80-1.63)
Hispanic 95/494 (19.23) 224/1122 (19.96) .73 1.05 (0.80-1.37)
Middle Eastern 5/45 (11.11) 12/91 (13.19) .73 1.22 (0.40-3.69)
Multiple 99/429 (23.08) 115/481 (23.91) .77 1.05 (0.77-1.42)
Non-Hispanic White 1004/3800 (26.42) 2760/10 046 (27.47) .21 1.06 (0.97-1.15)
Othera 101/579 (17.44) 347/1711 (20.28) .14 1.20 (0.94-1.54)
SES
Low 195/926 (21.06) 553/2272 (24.34) .05 1.21 (1.00-1.45)
Medium 638/2612 (24.43) 1733/6740 (25.71) .20 1.07 (0.96-1.19)
High 368/1696 (21.70) 1027/4260 (24.11) .05 1.15 (1.00-1.31)
Not provided 358/1430 (25.03) 687/2996 (22.93) .12 NA
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Abbreviations: NA, not applicable; OR, odds ratio; SES, socioeconomic status.

a

Includes Alaska Native, American Indian or Native American, Assyrian, Brazilian, Creole, Jewish unspecified, Sephardic Jewish, Sudanese, and unknown.

Discussion

This cross-sectional study found that approximately 1 in 4 probands with a P/LPV in HBOC or LS genes had at least 1 family member undergo cascade testing. The overall cascade testing rate of 24.24% is consistent with the findings of other studies. In a 2021 study in which MGPT was performed on unselected individuals with any type of solid tumor, only 18% of probands with a positive result had a family member pursue genetic testing.20 Another study found that probands with HBOC or LS P/LPVs reported a cascade testing rate of 40% for eligible first-degree relatives.21 Both studies highlight underutilization of cascade testing despite recommendations in published guidelines.25

Our data show similar patterns across SES levels and that availability of free familial testing was not associated with a significant increase in cascade testing, suggesting economic factors may not be the primary driver of cascade testing. At the population level, cascade testing uptake remains low across studies, even in settings where testing is offered at no cost, suggesting that removal of financial barriers alone may be insufficient to increase uptake.26,27 One possible explanation is that nonfinancial barriers, including psychosocial, communication, and systemic factors, may play a more substantial role, which aligns with previous literature identifying these barriers.27,28

We used zip code–based indicators to determine SES for our probands; area-based SES indicators have been developed and used in prior studies.29 Specifically, median household income and percentage of living below the poverty line were deemed the best zip code–level proxies for SES.30,31 Contrary to our hypothesis, cascade testing rates differed only slightly by SES. The statistically significant difference between low and medium SES probands reflects the larger medium SES group. The lack of a trend suggests limited clinical significance.

Existing data suggest that cost is not the primary barrier to genetic testing among probands referred for genetic counseling, with a 2021 study finding that only 1% of the population that declined genetic testing did so because of cost.32 Our data support this finding in the setting of cascade testing, as overall rates did not change after free testing was implemented or vary meaningfully across SES. We initially hypothesized that the removal of this cost barrier would increase the overall uptake of cascade testing, especially among individuals in the low SES group. However, our analysis showed that the difference was minimal. Additionally, there were no significant differences by racial or ethnic groups before vs after the implementation of free testing.

While these data do not support our initial hypotheses about the association of SES and the availability of free testing with cascade testing, there were several demographic and clinical factors that were associated with cascade testing, including proband sex, age, race and ethnicity, impacted gene, number of P/LPVs detected, cancer history, and clinician type. Family members of male probands underwent cascade testing at a significantly lower rate than those of female probands. Barriers to cascade testing among family members of male probands may include reduced family communication, differences in perception of risk, and differing social roles.33 Relatives of younger probands were also less likely to undergo cascade testing, possibly due to fewer available at-risk relatives, as testing typically is not done before age 18 years.

Our findings indicate that probands with P/LPVs in other HBOC genes were significantly less likely to have family members undergo familial testing compared with those with P/LPVs in BRCA1 or BRCA2 and LS genes. Findings of multiple P/LPVs in probands were associated with higher cascade testing rates among family members. The type of cascade testing also varied by gene, with probands with BRCA1 or BRCA2 P/LPVs showing the lowest rates of expanded testing. These variations indicate that the proband’s result was taken into account when familial testing was pursued and ordered and may reflect a higher likelihood of testing with higher perceived risk.

Our study found that probands with a personal history of cancer were approximately twice as likely to have at least 1 family member undergo cascade testing. This result is expected, since cancer in a close relative often motivates relatives to clarify their own risk. Additionally, family members of probands without cancer may not experience the same urgency to undergo genetic testing or may have the false perception that their cancer risk is lower.34,35 We also found that probands with a genetics professional involved in ordering genetic testing were more likely to have a family members pursue cascade testing. This finding underscores the important role of genetics professionals, such as genetic counselors, in promoting cascade testing. Genetic counselors, with their specialized training in genetic risk assessment and patient communication, are instrumental in ensuring that patients understand the implications of a P/LPV finding and in providing guidance on sharing genetic test results with all at-risk family members.

The rates of cascade testing for racial and ethnic minority groups in this study ranged from 11.64% to 23.60%, while non-Hispanic White probands had a cascade testing rate of 27.19%. These results indicate a significant disparity in cascade testing rates based on proband race and ethnicity. Lower referral rates for patients in a racial or ethnic minority group who meet genetic testing criteria for HBOC and LS has been well documented in previous literature.16,36,37 A study by Chapman-Davis et al32 found that Black individuals were tested at the highest rates after their own breast cancer diagnosis even if they previously met criteria for testing based on family history alone. Disparities have been attributed to physician recommendation patterns, differences in available family history, medical mistrust, and communication barriers.38,39,40 Which barriers most affect cascade testing remains unclear.

Limitations

This study has limitations. Although our cohort is derived from a single laboratory, its demographics are broadly similar to those reported in prior hereditary cancer testing studies.41,42 However, because testing depends on referral patterns and laboratory use, it may not fully represent all individuals undergoing cascade testing. While previous literature shows that communication of genetic testing results to at-risk family members is high,43 we cannot determine whether low cascade testing rates reflect failure to share positive test results or family members’ unwillingness or inability to undergo testing. Awareness of free testing among probands and relatives is also unknown. This study could not account for testing of family members through a different testing laboratory or for unlinked testing at the same laboratory. Therefore, the reported cascade testing rate uptake observed within this dataset may not represent the total uptake of cascade testing across all testing platforms. However, because the cohort is similar to populations undergoing hereditary cancer genetic testing in prior studies, the differences observed in cascade testing across demographic, socioeconomic, and clinical subgroups remain informative despite this limitation. This study did not include the total number of at-risk relatives for each proband, so the rate of cascade testing for each proband and the overall family communication of results are unknown. Furthermore, although validated, using zip code as a surrogate for SES has limitations, as zip codes can encompass diverse populations with varying SES, potentially leading to misclassification.

Conclusions

In this retrospective, cross-sectional study of cascade testing utilization, the overall uptake was low among family members of probands. Disparities were observed across demographic and clinical subgroups and did not appear to be primarily driven by financial barriers. Our study adds to the medical literature documenting barriers to cascade and genetic testing. Better understanding these and other barriers may be instrumental in identifying opportunities for improved adoption of cascade testing, allowing for targeted strategies to increase the use of cascade testing, especially in underserved populations.

Supplement.

Data Sharing Statement

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