Streamlined Genetic Education and Cascade Testing in Men from Hereditary Breast Ovarian Cancer Families: A Randomized Trial

Hereditary breast and ovarian cancer (HBOC) is most often caused by pathogenic variants (PVs) in the BRCA1 and BRCA2 (BRCA1/2) genes [1]. An estimated 1 in 200 people carry a PV in BRCA1 or BRCA2, which increases to 1 in 40 for individuals with Ashkenazi Jewish ancestry [2]. Women with a BRCA1/2 PV have a lifetime breast cancer risk as high as 70% and a lifetime ovarian cancer risk of 17%–44% [3, 4]. While these risks in women are well established, risks for other cancers, particularly in men, are less appreciated by many providers [5]. Both men and women with PVs in BRCA1/2 are at increased risk for pancreatic cancer, and men with PVs are at substantially increased risk for breast and prostate cancer [3, 6, 7]. Notably, male BRCA1/2 PV carriers have lifetime prostate cancer risks as high as 29% (95% CI: 17–45%) for BRCA1 and 60% (95% CI: 43–78%) for BRCA2 carriers [8, 9].

When a PV is identified in a family, cascade genetic testing, or informing and then offering testing to family members, is recommended. First- and second-degree relatives of PV carriers are at 50% and 25% risk, respectively, for carrying the familial PV. Identifying PVs in these relatives before a cancer diagnosis can significantly impact the trajectory of the disease by providing the opportunity to consider risk-reducing and early-detection strategies [10]. Mutation status can also influence prostate cancer treatment as men with BRCA1/2 PVs can benefit from targeted treatments such as PARP inhibitors [11]. Despite these benefits, rates of cascade testing in relatives from HBOC families have been reported to be less than 50%; and men are significantly less likely than women to pursue cascade genetic testing [12‒14].

Low rates of cascade genetic testing in at-risk men may be related to a lack of awareness both by healthcare providers and patients regarding the personal relevance of genetic testing [15]. This perception is reflected in lower rates of genetic counseling referrals for men compared to women [16]. This lack of awareness may be compounded by the paucity of educational materials addressing men’s specific questions about testing [12, 17]. Further, evidence suggests that female carriers of a PV may be less likely to communicate these results to male family members [18]. Even when referred, men are less likely than women to complete pretest genetic counseling [16]. However, among men who complete genetic counseling, the rates of genetic testing are comparable to those of women [19].

A recent review of interventions designed to facilitate familial communication and cascade screening found that cascade testing-focused interventions led to small but significant increases in testing [18]. However, these trials have focused primarily on women and typically involved individual genetic counseling. While there are ongoing trials and recently developed electronic tools focused on cascade testing [20‒23], to our knowledge, there have been no randomized controlled trials evaluating interactive digital interventions designed to increase the uptake of cascade testing among untested men from HBOC families.

In this randomized controlled trial, we sought to proactively address barriers related to awareness of personal risk, relevance of genetic testing, and personal and familial implications of genetic test results that prevent men from participating in cascade genetic testing. Given that men are less likely to attend genetic counseling when referred, we sought to streamline the testing process by eliminating the requirement for pretest genetic counseling. We developed an interactive Web-based genetic education tool to provide information comparable to traditional genetic counseling. After viewing the intervention, participants had the option to proceed directly to genetic testing, opt for individual genetic counseling, or decline counseling and testing. We compared this intervention to an enhanced usual care (EUC) condition in which men were notified of their increased risk and provided with a referral for traditional genetic counseling. We hypothesized that Web-based genetic education (WGE) would increase cascade genetic testing uptake compared to EUC.

From late 2018 to 2022, we recruited untested men from hereditary cancer families into a parallel group randomized controlled trial comparing proactive outreach with WGE to EUC. Eligible participants were cisgender men from BRCA1/2 positive families, aged 25–70, who were first-, second-, or third-degree relatives of a known PV carrier, were not diagnosed with cancer, had no prior genetic testing, could communicate in English, resided in the USA, and had the cognitive capacity to provide informed consent. They were not eligible if any of their children tested positive for a BRCA1/2 PV.

As displayed in Figure 1, we identified 317 potentially eligible index patients who had received a positive genetic test result for a BRCA1/2 PV. Of the 317 identified probands, we could not reach 108 (34.1%) after repeated attempts, 34 (10.7%) declined participation via telephone or mailed opt-out form, and 175 (55.2%) agreed to participate. Of the 175 participating probands, 73 reported no eligible relatives, and 15 declined to provide relative contact information. Thus, 87 probands provided contact information for 131 eligible relatives. Of the 131 eligible relatives, 63 (48.1%) completed the baseline survey and agreed to be randomized. Participants were randomized via computer-generated random number in a 1:1 ratio to WGE (N = 30) versus EUC (N = 33). Although blinding to study arm was not possible, we minimized bias through structured data collection via standardized measures.

The MedStar-Georgetown University Oncology Institutional Review Board approved this study (2016-1162). Eligible index patients were recruited through the Familial Cancer Registry and the Nontherapeutic Subject Registry Shared Resource at Georgetown Lombardi Comprehensive Cancer Center (GLCCC), from the cancer genetics programs at GLCCC and MedStar Franklin Square Hospital, and from individuals who responded to emails sent to members of Facing our Risk of Cancer Empowered (FORCE). There were no restrictions on when index patients had received their genetic test results. After verifying that index cases had eligible male relatives, we mailed index cases an introductory letter describing the study, an opt-out postcard, an informed consent document, a study brochure, a USD 20 gift card incentive, and a family contact form on which index patients could identify and provide contact information for untested male blood relatives. Index patients were requested to seek permission from their at-risk relatives before providing their contact information. If no response was obtained from the index patient 3 weeks following this mailing, a research assistant (RA) made a follow-up call.

Based on the information provided on the family contact form, potentially eligible relatives were mailed a packet with an introductory letter, informed consent document, study brochure, and opt-out postcard. Upon receipt of a signed informed consent document or 3 weeks after each mailing, a research assistant (RA) called men who had not opted out and administered a baseline interview. Following the interview, the RA randomized participants to EUC or WGE via computer-generated random number, where family members were assigned to the same intervention to avoid contamination. Participants were contacted for follow-up surveys at 1 month and 6 months post-randomization. However, in this article, we focus on the uptake of genetic counseling and testing as measured through clinical records.

Men randomized to EUC received an email and letter informing them of their assignment along with a flyer from FORCE that provided information regarding hereditary cancer in men. They were also informed that if they were interested in genetic counseling and testing, they could contact the study team to schedule a free telephone genetic counseling session or receive a local referral for in-person genetic counseling. Participants in the EUC arm could not proceed to genetic testing without completing pretest genetic counseling.

Men randomized to WGE were informed of their assignment and told they would receive an express mail packet with the website/login information. After receiving the information, they were asked to review the genetic education website as soon as possible.

The WGE is described in detail in a prior report [24]. Briefly, the WGE included essential elements of informed consent for cancer genetic testing, providing an overview of BRCA1/2 and familial inheritance, cancer risks and management for men with a BRCA1/2 PV, implications for children and relatives, information about the process and logistics of genetic testing, pros and cons of testing, and considerations in making a testing decision. The WGE was individually tailored on the following variables: familial gene variant, closest relative identified with PV, family history of prostate cancer, sex of biological children or plans for future children, race, Ashkenazi Jewish ancestry, and genetic testing insurance status. The WGE included text, images, animations, tables, and graphics and took 20–30 min to review. Figure 2 contains representative screenshots from the WGE intervention.

After reviewing the WGE, participants had the option to proceed directly to genetic testing, decline genetic testing, schedule a free telephone genetic counseling session, or indicate that they had further questions about genetic testing, which prompted a study RA to follow up to respond to process-related questions.

All participants interested in proceeding with genetic testing received standard clinical genetic testing from Invitae, a CLIA-certified commercial laboratory not associated with GLCCC. At the time of the study, the standard of care for cascade testing was to test only the BRCA1 and BRCA2 genes rather than to offer multigene panel testing. However, men who were negative for their familial PV were offered the option to reflex test to the Invitae Common Hereditary Cancers Panel, which analyzed 47 genes in which PVs are associated with cancers of the breast, ovary, uterus, prostate, and gastrointestinal system. Men had the option to go through their insurance company or pay out of pocket for genetic testing.

All participants who received genetic testing received individual post-test genetic counseling by telephone from a board-certified genetic counselor. If participants did not undergo pretest genetic counseling, post-test counseling started with a brief medical and family history so that risk and management information could be individualized. For participants with a family history suggestive of other hereditary cancer syndromes, reflex testing to the multigene panel was offered free of charge within 90 days of their initial results.

We assessed age, education, income, race, ethnicity, marital status, and employment.

We assessed familial PV from medical records, cancer family history, and the number and biological sex of children via self-report.

We measured BRCA1/2 knowledge with an adapted version of the Breast Cancer Genetic Counseling Knowledge scale [25]. We have used similarly modified versions in prior research [26]. This 13-item scale assessed knowledge related to cancer genetic testing and hereditary cancer risks in men. Responses categories were true, false, and unsure. The total score was the percentage of correct responses. Cronbach’s alpha in this study was 0.77.

We assessed participation in genetic counseling via a review of clinical records. Participants who did not participate in genetic counseling during the study period were defined as decliners.

Participation in genetic testing was our primary outcome. We assessed participation in genetic testing via a review of clinical records. Participants who did not complete genetic testing during the study period (as indicated by a genetic testing result report) were considered genetic testing decliners. We confirmed these results via participant self-report.

We characterized participants in terms of their clinical and sociodemographic characteristics, baseline levels of knowledge, and attitudes toward genetic testing. Next, we characterized the sample overall and by randomization group in terms of the proportion of participants who opted for genetic counseling and genetic testing. Finally, we utilized χ² analysis to compare the impact of WGE versus EUC on the uptake of genetic testing. Despite conducting randomization by family, we elected not to account for this in our analyses due to the small number of families (n = 10) with more than one participant – resulting in an extremely low average cluster size of ≤1.2 in both arms.

Table 1 displays the baseline sociodemographic characteristics of the study sample.

Overall, 27% (n = 17) of participants completed genetic counseling and 19% (n = 12) completed genetic testing. Participants in the WGE arm were more likely to complete genetic testing (n = 9, 30.0%) compared to EUC participants (n = 3, 9.1%; χ² (n = 63, df = 1) = 4.46, p = 0.03; OR = 4.29, 95% CI = 1.04, 17.74).

Of the 30 participants in the WGE arm, 24 (80%) logged into the WGE and 23 (76.7%) completed the full intervention. Six WGE participants (20%) did not access the WGE intervention.

WGE participants had the option to proceed directly to genetic testing after completing web-based genetic education, request a pretest genetic counseling session, or decline genetic testing and genetic counseling. Overall, 56.7% (n = 17) of WGE participants declined both genetic counseling and genetic testing, 13.3% (n = 4) proceeded to genetic testing without pretest genetic counseling, 16.7% (n = 5) completed pretest genetic counseling followed by genetic testing, and 13.3% (n = 4) completed pretest genetic counseling but declined genetic testing.

Among EUC participants – who were required to complete pretest genetic counseling prior to genetic testing – 87.9% (n = 29) declined genetic counseling, 9.1% (n = 3) completed pretest genetic counseling and genetic testing, and 3.0% (n = 1) completed genetic counseling but declined testing. Overall, 43% (n = 13) of WGE participants opted for pretest genetic counseling and/or testing compared to only 12.1% (n = 4) of EUC participants (χ² [n = 63, df = 1] = 7.77, p = 0.005; OR = 5.54, 95% CI = 1.56, 19.75). Of the 12 men who were tested, 5 (41.7%; n = 1 in EUC, n = 4 in WGE) were found to carry a PV in BRCA1 (n = 4) or BRCA2 (n = 1).

In this randomized controlled trial, we compared two strategies for increasing the uptake of cascade genetic testing among untested men from families with a previously identified PV in the BRCA1 or BRCA2 genes. Specifically, we compared a clinical referral letter and informational flyer that informed men of their increased risk and provided contact information for scheduling pretest genetic counseling to a streamlined approach that included proactively delivered web-based genetic education with the option to proceed directly to genetic testing in lieu of pretest genetic counseling. Proactive genetic education plus streamlined genetic testing led to a 30% rate of cascade genetic testing compared to 9.1% in standard genetic counseling referral.

The 30% genetic testing uptake rate in the WGE arm is noteworthy because the families in this study were long aware of their BRCA1/BRCA2 status. The mean time between the proband’s positive test result and the untested relatives’ study enrollment was 101.5 months. Thus, the men in this study had not pursued genetic testing despite previous opportunities to do so. These men may not have pursued testing at the time the PV was identified in their family for a variety of reasons including not having children of their own, being too young to consider testing, or being unaware of the potential benefits of testing. Regardless, these data suggest that proactive outreach with streamlined genetic education has the potential to facilitate testing among men who might not otherwise pursue it.

We cannot disentangle the relative contributions of the proactive delivery of digital genetic education and the streamlined genetic testing process. However, it is likely that both contributed to increased testing. Nearly half of those who were tested in the WGE arm proceeded without pretest genetic counseling, suggesting that the elimination of required genetic counseling likely contributed to increased uptake. This finding is consistent with recent studies that have found that eliminating pretest genetic counseling can yield increased genetic testing uptake [27], is acceptable to patients, and noninferior to traditional genetic counseling in terms of patient-reported psychosocial outcomes [28, 29].

In the WGE arm, nine (30%) participants completed pretest genetic counseling compared to four (12.1%) in EUC. Thus, WGE participants were not only more likely to be tested but were also more likely to receive pretest genetic counseling. Thus, proactively delivering genetic education might raise questions for some men who had not previously considered genetic testing – prompting them to seek additional information through genetic counseling. However, in the current study, seven of the nine WGE participants who opted for pretest genetic counseling were required by their insurers to complete pretest counseling prior to authorizing genetic testing. If not for this requirement, it is likely that some of these participants would have opted to proceed directly with testing. It is also likely that some participants may have been dissuaded from pursuing genetic testing due to insurance requirements for genetic counseling – potentially reducing the overall uptake in the WGE arm. As additional evidence emerges regarding the safety and efficacy of proceeding with genetic testing without pretest genetic counseling, insurers might reconsider these requirements.

From a practical perspective, while this study suggests that proactive genetic education and streamlined genetic testing yields increased uptake of cascade genetic testing, questions remain regarding the efficiency of this approach in clinical practice. In order to identify untested men, we conducted outreach to previously tested probands. Overall, 44.8% of probands we attempted to contact could not be reached or declined to participate. Of those we contacted, nearly 20% declined to provide contact information for their relatives. Of those probands who provided their relatives’ contact information, we identified 131 eligible relatives, of whom 52.6% could not be reached or declined to participate. Thus, our identification and attempted outreach to 317 probands resulted in only 12 of their relatives completing genetic testing and the identification of 5 PVs – raising questions about the feasibility and efficiency of this approach outside of the research setting. However, it is likely that proactive outreach to relatives for cascade testing closer to the time of an initial positive test result would be more efficient and yield higher genetic testing uptake.

Despite these caveats, it is important to consider several unique aspects of this study. First, we targeted untested men from hereditary cancer families. Substantial evidence documents that men are much less likely to participate in cascade testing compared to women [14, 30, 31]. It is also noteworthy that we targeted men who had not proceeded with genetic testing despite the presence of a PV in the family for more than 9 years on average. This suggests that our target population may have been particularly resistant or unmotivated to pursue genetic testing. Further, the time between the proband’s genetic test result and our attempts at contact likely made contact more difficult.

The small sample size obviously limits the conclusions that can be drawn from this study. This is especially true given that we initially anticipated a much larger trial [24]. However, as discussed above, the low overall yield limited our ability to enroll a larger sample for a more definitive study. The low yield and small sample size meant we were not powered to conduct multivariate analyses or identify other factors that might have contributed to uptake. Further, although our effect sizes were large, the wide confidence intervals highlight the need to replicate these findings with a larger sample size. In addition to the small sample size, there was also a lack of diversity in the sample. As displayed in Table 1, our sample was primarily non-Hispanic white, well educated, and employed. In addition, about 60% reported a family history of prostate cancer. These percentages are likely higher than the general population of men from hereditary cancer families. This raises questions about the generalizability of this study, but also may indicate characteristics of those men most likely to respond to proactive and streamlined genetic education and testing.

Despite the small sample size, the results of this trial indicate that proactively delivered streamlined genetic education and testing has the potential to increase the uptake of cascade testing among men from hereditary cancer families. However, further research with larger and more diverse samples is needed to determine the best approach for facilitating cascade genetic testing – both prospectively in families with a new PV and retrospectively among untested members of previously identified hereditary cancer families.

The authors are grateful to all the men who participated in this study. The authors would like to acknowledge the contributions of Hannah Segal and Rachel Kritzik for conducting study surveys.

The study protocol was reviewed and approved by the MedStar Health Research Institute-Georgetown University Oncology Institutional Review Board. All procedures performed in studies involving human participants were in accordance with the ethical standards of Georgetown University (IRB 2016–1162) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.

Ms. Peshkin is a paid consultant for Clear Genetics, San Francisco, CA. Dr. Isaacs has received consulting fees from Pfizer and Astra Zeneca. Ms. Ladd, Ms. Segal, Ms. Jacobs, Ms. Sorgen, Ms. Binion, Ms. Tynan, Ms. Kuchinsky, Mr. Grisham, Mr. Kim, and Drs. Taylor, Graves, O’Neill, Friedman, and Schwartz declare that they have no conflict of interest.

The study was supported by Grant R21 CA185808 from the National Cancer Institute (Dr. Marc Schwartz, PI) and by the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. This study was also supported by the Georgetown Lombardi Comprehensive Cancer Center’s Survey, Recruitment, and Biospecimen Collection Shared Resource which is partially supported by NIH/NCI grant P30 CA051008. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Conceptualization: M.D.S., B.N.P., C.I., K.L.T., K.G., and S.O. Data collection: M.D.S., B.N.P., C.G., L.S., M.K.L., A.J., S.B., M.T., E.K., and S.F. Data analysis: M.D.S., B.N.P., C.G., L.S., and D.K. Manuscript preparation and review: M.D.S., C.G., B.N.P., L.S., C.I., M.K.L., A.J., S.B., M.T., E.K., S.F., K.L.T., K.G., S.O., and D.K.

Clinical Trial Registration: NCT02957981.

The data that support the findings from this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (MDS; Georgetown Lombardi Comprehensive Cancer Center, 2115 Wisconsin Ave, NW, Suite 300, Washington DC 20007, schwartm@georgetown.edu upon reasonable request).