Improving uptake of germline genetic testing amongst individuals at high-risk of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PC) is one of the most lethal cancers (1). Up to 1 in 10 PCs are due to familial risk and/or hereditary PC predisposition, including hereditary breast and ovarian cancer syndrome (BRCA1, BRCA2, ATM, PALB2), Lynch syndrome (MLH1, MSH2, EPCAM, MSH6, PMS2), Peutz-Jeghers syndrome (STK11), Li-Fraumeni syndrome (TP53), hereditary pancreatitis (PRSS1), and pathogenic germline variants (PGVs) in CDKN2A (2). Identification of individuals with hereditary PC predisposition syndromes is important since they may be eligible for PC surveillance, which has been shown to downstage PC diagnosis and improve PC survival (3). Additionally, PC susceptibility genes may also increase the risk of select cancers outside of the pancreas, leading to additional cancer screening and prevention recommendations.

In 2019, the National Comprehensive Cancer Network (NCCN) began recommending that all individuals with PC undergo germline genetic testing. Additionally, germline genetic testing is recommended for individuals with a first-degree relative (FDR) with PC who did not have genetic testing themselves (4). If a genetic predisposition is identified, cascade testing of other family members becomes the next important task, as those individuals may be eligible for PC surveillance and/or enhanced screening for cancers outside of the pancreas. However, despite the NCCN recommendations and the opportunity for potential lifesaving interventions that come with the identification of a cancer risk gene, the cancer genetics community has had longstanding challenges associated with the successful implementation of cascade testing (5). Thus, developing improved methods for increasing genetic testing uptake amongst high-risk individuals is needed, and therefore, it is with great interest that the Genetic Education, Risk Assessment, and Testing (GENERATE) study was conducted (6).

GENERATE study results

The GENERATE study was a randomized trial conducted using two methods of remote genetic education and testing in individuals at increased risk of PC. Initially, GENERATE was open to individuals with a family history of PC in an FDR or second-degree relative (SDR) who had a PGV identified in a PC risk gene, however, eligibility was later expanded to include individuals with an FDR with PC who had not undergone germline genetic testing. Participants were randomized to one of two arms. Arm 1 included video-based pretest education followed by a question-and-answer telemedicine session with a genetic counselor (GC), whereas Arm 2 utilized only online educational resources provided through the commercial laboratory website without interaction with a GC. Of note, participants in both Arms had the opportunity to request pre- or post-test counseling from a GC via telephone through the commercial laboratory.

In the GENERATE study, 601 participants were randomized, with 555 (92%) completing their assigned interventions. The majority of these participants (86%) enrolled after the start of the coronavirus disease 2019 (COVID-19) pandemic. Study-wide, an incredible 90% completed genetic testing, with a statistically significantly higher rate of genetic testing uptake amongst those receiving only online genetic education (93% in Arm 2 compared to 87% in Arm 1). The study team also scored anxiety, depression, and cancer worry, and importantly, 3 months after genetic testing was completed, no statistically significant differences between any of these scores were identified between study Arms. While this study demonstrates that remote genetic testing and education can be successfully implemented, there are multiple points that merit further discussion.

Diversity amongst study participants in genetic testing studies continues to be a limitation

The authors appropriately acknowledge that a significant limitation of the study is its homogeneous population. The study cohort was predominantly female (65%), non-Hispanic White (97%), and had at least a college education (79%). The mean Area Deprivation Index score of participants was 29 on a scale that ranges from 1 to 100, with 1 being the least deprived. The mean score of participants on the Rural Urban Commuting Areas Codes scale, which assesses the population density of zip codes on a scale of 1 to 10, was 1.7, with 1 being the most urban.

The population characteristics of the GENERATE study are not unique to this study and are unfortunately, representative of most similar studies of genetic testing uptake. The authors hoped to have a more diverse genetic testing cohort through their removal of geographic and cost barriers associated with genetic testing, however, despite these efforts, most study participants remained highly educated, wealthy, urban dwelling non-Hispanic White females. Some of this homogeneity may be explained by certain features of the study design, namely the requirement for internet access and recruitment methods outside of study sites that were primarily internet-based, as it is well-documented that broadband internet access is lower in rural communities, for individuals with low incomes, and for racial/ethnic minorities (7-9). Nonetheless, the cancer genetics community must continue to find novel and improved methods to meaningfully engage underrepresented individuals who have not historically been included in clinical- and research-based genetic testing. One option to accomplish this would be to conduct future studies through programs directly serving areas with under-represented populations. Another avenue would be for study investigators to partner with community organizations that have already built effective outreach programs to develop and disseminate information about the studies. We are looking forward to the data from the REGENERATE study, as well as other studies outlined in the thoughtful commentary by some of GENERATE study’s authors (10).

GCs are an invaluable part of the cancer genetics community

The GENERATE study showed that genetic testing uptake was significantly higher in Arm 2, where discussion with a GC was not required. In this study, the main metric was completion of genetic testing. Although there was a statistical difference between the two study arms, the clinical relevance of this finding is uncertain, as there were exceptionally high rates of genetic testing completion in both arms, with rates higher than what is typically seen in the literature (11,12). The high rate of genetic testing uptake could be in part because study activities, including genetic testing, were completed at no charge for study participants. A more diverse population may also result in different genetic testing uptake rates. We look forward to additional research comparing these methods of genetics education in broader populations and in real-world settings to determine if the magnitude or direction of uptake changes.

Until such data is available, we caution non-genetics providers not to infer that the statistical significance of this finding means that GCs are a hindrance to pursuing genetic testing. In reality, there are many situations where having a GC involved is incredibly important in the pre- and post-testing setting, separate from whether or not an individual ultimately pursues genetic testing. GCs provide invaluable information about test selection, as well as billing and discrimination considerations that should be addressed prior to moving forward with genetic testing. Additionally, GCs are important for result interpretation, including management of variants of uncertain significance (VUSs), whose implications may not be understood by non-genetics providers, which can lead to unnecessary cancer screening and/or risk-reducing surgeries (13).

Additionally, GCs have the potential to provide long-term benefits to individuals who undergo genetic testing. Most concretely, GCs are experienced with managing variant reclassifications and providing updates to patients, which will inevitably occur in the future (14). Although the study found no difference in anxiety, depression, and cancer worry between the two Arms at baseline and 3 months after genetic testing, the outcomes over the 5-year study period will be more important. Having this longitudinal follow-up with participants will allow assessment of the long-term impact of the intervention in this study, and similar follow-up with both participants as well as cascade-tested family members should be a part of all future studies in this area. The full impact of genetic testing and the level of counseling that was provided may not be recognized for years and could manifest not only psychologically, but also in other ways, including rates and stages of cancer diagnoses, reproductive decision making, and the ability to obtain life, long-term care, and disability insurance policies.

Genetic testing is only the first step for pancreatic cancer risk management in high-risk individuals

Stratifying risk for individuals with a family history of PC through genetic testing is the first step in improving outcomes for individuals with a hereditary predisposition to PC. To reach the vast number of people who need to be offered testing, it is not feasible for all genetic testing to be coordinated by GCs and other specialized providers alone. Thus, the ability to roll out genetic testing on a large scale through methods like the ones used in the GENERATE study is needed. It is understandable that the GCs in the GENERATE study had limitations placed on their interactions with Arm 1 study participants in an effort to mimic real world scenarios that would arise when testing is coordinated by non-genetics professionals. However, an inability to provide personalized management recommendations for individuals with a predisposition to PC creates challenges as PC surveillance is nuanced.

The US Preventive Services Task Force recommends against screening for PC in the general population (15). Recommendations for surveillance eligibility and modality in high-risk individuals have been published by the International Cancer of the Pancreas Screening Consortium (16), the American College of Gastroenterology (17), NCCN (4), and others. Surveillance recommendations from these groups vary somewhat, but there is general agreement that the primary surveillance tool is imaging through endoscopic ultrasound (EUS) and/or magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) and that individuals who undergo surveillance should be encouraged to participate in research studies to contribute data about surveillance outcomes given the rarity of hereditary PC. As imaging with MRI/MRCP or EUS is costly, time-intensive, and has small but tangible risks, there has also been a longstanding interest in identifying blood-based or other non-imaging testing for PC early detection. While no tests outside of MRI/MRCP or EUS are currently recommended for high-risk individuals, there has been extensive work examining the utility of other tests, such as monitoring for diabetes mellitus with hemoglobin A1C/fasting blood glucose or trending CA19-9, in high-risk individuals undergoing pancreatic cancer surveillance (18). With additional research, these less expensive non-invasive surveillance options will hopefully become a reality, allowing for broader access.

Until then, there are multiple barriers to PC surveillance that high-risk individuals must overcome, and direct contact with a cancer genetics professional, such as a GC, may help these individuals overcome these barriers:

• Lack of provider awareness. We are unaware of published data regarding primary care provider (PCP) awareness of or attitudes towards PC surveillance. Given the wide range of health topics that PCPs need to address during short appointments, it is not feasible to expect that they have the bandwidth to delve into the nuances of who should be offered PC surveillance and how it should be performed.
• Lack of patient awareness. Since PC screening is not performed in the general population, many high-risk individuals who are eligible for PC surveillance are unaware of their options. Everett et al. reported that even among family members of individuals who undergo high-risk surveillance, a third of at-risk relatives were unaware that surveillance was available (19).
• Lack of access to specialized care. As with access to genetic counseling, individuals who live in rural areas, who have low incomes, or who are part of racial/ethnic minorities may be less likely to be able to access PC surveillance and surveillance research studies, as most participants in PC research are White, non-Hispanic females (20).

In the traditional model of pre-test genetic counseling and post-test result disclosure by a GC, patients have the opportunity to receive tailored education about their cancer risk and surveillance options. Some patients may receive this counseling in specialized high-risk PC clinics, while others can be referred post-counseling to such clinics or other PC specialists for further discussion, coordination of surveillance, and enrollment in research studies. If we remove the ability of a GC to help provide and guide personalized care, we need to have a plan in place to ensure that high-risk individuals are still provided with the tools they need to pursue PC surveillance if desired.

Barriers to the inclusion of GCs in routine clinical care persist

Although we recognize that alternate models of genetic testing are necessary, the cancer genetics community also stands to benefit from an expansion of GCs’ purview and increased access to genetic counseling services. Due to a lack of recognition at national and state levels, GCs’ scope of practice and ability to obtain reimbursement for their services are limited. Many GCs need to partner with a physician to order genetic testing and to bring in revenue. Some states with licensure for GCs allow them to order genetic testing themselves, but most states are vague about its legality, and Pennsylvania explicitly prohibits it (21).

The federal government currently does not allow coverage of services provided by GCs to patients with Medicare Part B. However, Medicare does provide coverage of services billed by physical therapists, occupational therapists, audiologists, marriage and family therapists, mental health counselors, and even physical and occupational therapy assistants in its fee schedule (22). While all of these services are important and should be reimbursed, they are provided by health care professionals with similar and in some cases less education, training, and certification as GCs. Furthermore, since Medicare does not reimburse GCs, many private insurers follow suit. Consequently, without a mechanism to bring in revenue to offset their costs, many hospitals cannot afford to have a GC on staff, which in turn exacerbates the historical problem of access to care by patients from underserved communities. In 2020, only 17% of counties in the US had at least one GC and 98.7% of GCs were centered within geographic areas with at least 50,000 occupants (23). Access to National Cancer Institute (NCI)-designated cancer facilities can act as a surrogate to measure access to cancer genetic counseling services since these sites are required to have a GC on staff, whereas other hospital systems are not; in a review of access under the Affordable Care Act, only 41% of insurance policies offered through federal exchange networks had an in-network NCI-designated cancer facility (24). Previous research has also shown that individuals from racial and ethnic minority groups are less likely to be referred for genetic counseling (25).

Improved reimbursement is an important step in improving access to genetic counseling as it would increase the number of GCs providing services, potentially in more varied geographic locations. It may also allow for an expansion of service delivery methods to further improve the reach of GCs, like telephone counseling or telehealth appointments coordinated at local hospitals, that could disproportionately improve access for individuals in underserved areas, where specialized care and internet access are more limited.

Conclusions

The GENERATE study was an incredibly important study demonstrating that remote genetic education, as well as remote genetic testing, can be successfully implemented for the evaluation of individuals at increased risk of PC. However, this study also highlights the numerous barriers and challenges that the field still faces, including limited diversity amongst individuals undergoing genetic testing, barriers to increasing access to genetic counseling services, and need to improve awareness of PC risk management in at-risk individuals and their providers.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-152/prf

Funding: This work was supported by The Smith Family Research Fund (B.W.K.), The Berg Family BRCA Pancreatic Cancer Research Fund (B.W.K.), the Ann and Richard Frankel Fund for Pancreatic Cancer Research (B.W.K.), the Susan and David Wolk Fund for Pancreatic Cancer Research (B.W.K.), Basser Center for BRCA (B.W.K.), and the Basser Men & BRCA Program (B.W.K.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-152/coif). B.D. is the current President of CGA-IGC, an organization focused on advancing the science and clinical management of hereditary GI cancer syndromes, including pancreatic cancer. It is a volunteer role. B.W.K. is a compensated advisory board member for Immunovia and has received clinical research funding paid to the institution from Janssen, Immunovia, Freenome, Guardant, Epigenomics, Universal Diagnostics, and Recursion. He receives support for his pancreatic cancer early detection research from multiple philanthropic and institutional sources. He currently serves as the Past President of CGA-IGC, which is a volunteer role. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12-49. [Crossref] [PubMed]
2. Seppälä TT, Burkhart RA, Katona BW. Hereditary colorectal, gastric, and pancreatic cancer: comprehensive review. BJS Open 2023;7:zrad023. [Crossref] [PubMed]
3. Dbouk M, Katona BW, Brand RE, et al. The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival. J Clin Oncol 2022;40:3257-66. [Crossref] [PubMed]
4. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Version 2.2025. Accessed 11/21/2024.
5. Levine R, Kahn RM, Perez L, et al. Cascade genetic testing for hereditary cancer syndromes: a review of barriers and breakthroughs. Fam Cancer 2024;23:111-20. [Crossref] [PubMed]
6. Rodriguez NJ, Furniss CS, Yurgelun MB, et al. A Randomized Trial of Two Remote Health Care Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study. Gastroenterology 2024;166:872-885.e2. [Crossref] [PubMed]
7. Li Y, Spoer BR, Lampe TM, et al. Racial/ethnic and income disparities in neighborhood-level broadband access in 905 US cities, 2017-2021. Public Health 2023;217:205-11. [Crossref] [PubMed]
8. Federal Communications Commission Fourteenth Broadband Deployment Report, released 1/19/2021. Available online: https://docs.fcc.gov/public/attachments/FCC-21-18A1.pdf. Accessed 10/18/2024.
9. Swenson K and Ghertner R. People in Low-Income Houses Have Less Access to Internet Services-2019 Update. US Department of Health and Human Services, March 2021. Available online: https://aspe.hhs.gov/sites/default/files/private/pdf/263601/internet-access-among-low-income-2019.pdf. Accessed 10/18/2024.
10. Rodriguez NJ, Ricker C, Stoffel EM, et al. Barriers and Facilitators to Genetic Education, Risk Assessment, and Testing: Considerations on Advancing Equitable Genetics Care. Clin Gastroenterol Hepatol 2023;21:3-7. [Crossref] [PubMed]
11. Cheng HH, Sokolova AO, Gulati R, et al. Internet-Based Germline Genetic Testing for Men With Metastatic Prostate Cancer. JCO Precis Oncol 2023;7:e2200104. [Crossref] [PubMed]
12. Morgan KM, Hamilton JG, Symecko H, et al. Targeted BRCA1/2 population screening among Ashkenazi Jewish individuals using a web-enabled medical model: An observational cohort study. Genet Med 2022;24:564-75. [Crossref] [PubMed]
13. Farmer MB, Bonadies DC, Pederson HJ, et al. Challenges and Errors in Genetic Testing: The Fifth Case Series. Cancer J 2021;27:417-22. [Crossref] [PubMed]
14. Makhnoon S, Davidson E, Shirts B, et al. Practices and Views of US Oncologists and Genetic Counselors Regarding Patient Recontact After Variant Reclassification: Results of a Nationwide Survey. JCO Precis Oncol 2023;7:e2300079. [Crossref] [PubMed]
15. US Preventive Services Task Force. Screening for Pancreatic Cancer: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA 2019;322:438-44. [Crossref] [PubMed]
16. Goggins M, Overbeek KA, Brand R, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 2020;69:7-17. [Crossref] [PubMed]
17. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015;110:223-62; quiz 263. [Crossref] [PubMed]
18. Heller M, Mann DA, Katona BW. Current Approaches of Pancreatic Cancer Surveillance in High-Risk Individuals. J Gastrointest Cancer 2025;56:61. [Crossref] [PubMed]
19. Everett JN, Burgos G, Chun J, et al. Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma. Cancer 2021;127:2271-8. [Crossref] [PubMed]
20. Katona BW, Klute K, Brand RE, et al. Racial, Ethnic, and Sex-based Disparities among High-risk Individuals Undergoing Pancreatic Cancer Surveillance. Cancer Prev Res (Phila) 2023;16:343-52. [Crossref] [PubMed]
21. National Society of Genetic Counselors - Policy. Available online: https://www.nsgc.org/POLICY/State-Licensure. Accessed 11/11/2024.
22. Centers for Medicare and Medicaid Services Fee Schedule. Available online: https://www.cms.gov/medicare/payment/fee-schedules. Accessed 10/18/2024.
23. Triebold M, Skov K, Erickson L, et al. Geographical analysis of the distribution of certified genetic counselors in the United States. J Genet Couns 2021;30:448-56. [Crossref] [PubMed]
24. Kehl KL, Liao KP, Krause TM, et al. Access to Accredited Cancer Hospitals Within Federal Exchange Plans Under the Affordable Care Act. J Clin Oncol 2017;35:645-51. [Crossref] [PubMed]
25. Dharwadkar P, Greenan G, Stoffel EM, et al. Racial and Ethnic Disparities in Germline Genetic Testing of Patients With Young-Onset Colorectal Cancer. Clin Gastroenterol Hepatol 2022;20:353-361.e3. [Crossref] [PubMed]