Approximately 10% of all cancers can be attributed to hereditary cancer syndromes1. Yet, they are underdiagnosed currently2,3. Hereditary cancer syndromes are a group of conditions which puts an individual at increased risk of developing certain tumors due to an inherited pathogenic variant/likely pathogenic variant (PV/LPV). Most hereditary cancer syndromes are autosomal dominant, where first-degree relatives of the affected patient (proband) have a 1 in 2 (50%) chance to inherit the familial PV/LPV in a cancer susceptibility gene4. The care of a patient with a hereditary cancer syndrome extends beyond the affected patient to the family members, as the genetic test results have implications on the rest of the family.

Cascade testing is the process of extending genetic testing to biologic relatives at risk for inheriting a PV/LPV previously identified in an affected patient. Patients are encouraged to discuss cascade testing with at-risk relatives (ARRs)5. ARRs can then see a genetic service to undergo germline genetic testing to ascertain if they carry the familial PV/LPV found in the proband. Family members who tested positive for the familial PV/LPV can be made aware of an increased risk of cancer. This allows for implementation of risk management strategies, such as intensive surveillance or risk-reducing procedures, which have the potential to reduce long term morbidity and mortality in this high risk population6,7,8. Over the years, there has been increasing emphasis on cascade testing to identify these ARRs9,10. The timely identification of individuals and families with hereditary cancer syndromes can enhance clinician’s suspicion of cancer in view of their inherent elevated risk11,12. This impacts surveillance, motivates lifestyle changes, improves personal health choices and affects management plans. Cascade testing for Hereditary Breast and Ovarian Cancer and Lynch syndrome is categorized as a ‘tier 1 genomic application’ by Centres for Disease Control and Prevention (CDC)13, which highlights its potential for significant positive impact on public health. International guidelines also encourage testing of ARRs based on its utility for improving health outcomes with early risk management10,14. Cascade testing allows the benefits of genetic testing to propagate beyond the affected patients15,16, and empower family members to understand their carrier status as well as take charge of their health17. Importantly, cascade testing has also been found to be cost-effective in hereditary cancer syndromes, especially with the addition of cascade testing of ARRs18,19.

Despite efforts targeted at improving cascade testing uptake, current literature continues to reflect poor rates of uptake, typically below 30%16,20. Communication of hereditary cancer syndrome frequently relies on the proband, which may not wish to pass on this personal medical information. Furthermore, poor comprehension of genetics, limited access and concerns about genetic discrimination may further hamper uptake of cascade testing15,21. Of note, studies conducted in Asian countries report notably lower rates of cascade testing compared to those in the global community15,22. Uptake can be as low as 13%21, leaving much room for improvement. In view of the potential benefits of cascade testing, multiple interventions have been attempted to increase referrals for cascade testing in cancer genetic services worldwide23,24,25. While many strategies have shown success in trials, most of these interventions are not integrated into routine practice, failing to achieve their primary endpoint of improving public health. This is commonly referred to as the research-to-practice gap26. To close this gap, advances have been made in implementation research, with various tools, checklists and frameworks designed to facilitate replication and ease of implementation27,28,29. An example is the 2011 paper by Proctor and colleagues which described a heuristic taxonomy of eight implementation outcomes to aid in conceptualizing and evaluating success of implementation processes and strategies27. A review by Srinivasan et al. discussed interventions, barriers and facilitators to enhance cascade testing, highlighting research gaps including a clear lack of how interventions are implemented, which is important for success of their future application in the public health setting30. It has been noted that some of these interventions may work in one healthcare context and not in another31. We lack comprehensive information about how these interventions are implemented, and whether these interventions can be applied to unique healthcare settings.

We had three aims for this project. First, to systematically review current literature on intervention strategies to improve cascade testing for hereditary cancer syndromes regarding the quality of intervention descriptions and implementation outcomes of stated interventions. Second, to report the effectiveness of the strategies in measurable clinical outcomes, where available, including number of ARRs referred for genetic counseling and subsequent cascade testing uptake. Lastly, to assess the implementation strategies used to enhance referrals for cascade genetic testing and success of these strategies in terms of implementation outcomes.


The database search identified a total of 2606 studies. After title and abstract screening, 63 studies were assessed in full-text screening. Twenty-seven studies were included in the final review (Fig. 1).

Fig. 1: PRISMA 2020 flow chart.
figure 1

Reports excluded (36): wrong study design (9), no interventions (5), duplicates (5),conference abstracts (17).

Study characteristics

Study designs in this review include 17 prospective studies, five cross-sectional studies and five retrospective studies. Publication dates ranged from 2013 to 2023 and spanned nine countries. Study characteristics are shown in Table 1. Of the 27 studies included, 17 studies (63.0%) were from the USA, 5 studies (18.5%) did not specify the genes evaluated, and a range of interventions were used. Eight studies (29.6%) evaluated only BRCA1 and BRCA2 PV/LPV, three studies (11.1%) looked at Lynch syndrome genes MLH1, MSH2, MSH6, PMS2 and EPCAM PV/LPV, whereas 11 studies (40.7%) evaluated broader gene panels.

Table 1 Characteristics of 27 studies included in systematic review

Taxonomy of health systems interventions

Intervention components were mapped to an adapted EPOC taxonomy. Some studies described multicomponent interventions without differentiating between individual components’ efficacy. We ascertained the primary intervention as the intervention of interest. Out of 27 studies, proposed interventions in 20 studies (74.1%) were classified into delivery arrangements, of which 11 were categorized under “Information and communication technology” and nine under “Coordination of care and management of care processes”. Four studies (14.8%) evaluated implementation strategies, of which all four were categorized into interventions targeted at healthcare workers. Three studies (11.1%) attempted to address financial arrangements, of which all fall under the category of collection of funds. A summary is presented in Table 2.

Table 2 Classification of interventions reported in included studies based on EPOC taxonomy strategies and categories and reported rate of uptake of genetic testing for the post-intervention and control group

Among the 20 studies under delivery arrangements, two studies reported uptake rates of genetic testing pre- and post-intervention. Dilzell et al. evaluated the use of educational materials which led to a higher uptake post-intervention (51%) as compared to control, where no materials were used (19%)32. On the other hand, Katz et al. investigated on the effect of free genetic testing which reflected a lower rate of uptake post-intervention (83.3%) as compared to control which received low-cost testing (94.4%)33. Nine studies reported rate of uptake of genetic testing post-intervention only, of which six reported uptake rates of 70% and above, reflecting relatively high rates of genetic testing.

Among the four studies under implementation strategies, one study reported rate of genetic testing uptake post-intervention and control. Garcia et al. evaluated the use of communication aids which reported a higher uptake post-intervention (4.5%) as opposed to control (0%)34. One other study reported rate of genetic testing uptake post-intervention only. This study by Menko et al. investigated the outcomes from implementation of guidelines by the Dutch Society for Clinical Genetics on proband-mediated dissemination of genetic information via proband education, family letters and follow-up phone call. The study reported a 43% uptake rate for genetic testing35.

Among the three studies targeting financial arrangements, two studies reported rate of genetic testing uptake post-intervention and control. Courtney et al. studied the impact of free cascade testing while Li et al. looked at the efficacy of subsidy schemes18,21. Both studies reported a higher uptake post-intervention as opposed to control, with the former reporting rates of 21.6% vs 6.1%, and the latter 53.3% vs 47.5%.

Quality of description of intervention strategies

The mean TIDieR score for the 27 included studies was 7.3 out of 12. Six items were reported in more than 80% of the studies; these include (1) brief name of intervention (100%), (2) intervention rationale (96.3%), (3) intervention providers (88.9%), (4) description of procedures (85.2%), (5) description of materials (85.2%), (6) frequency/ timing, dose, duration (85.2%). Fewer than 20% of studies reported these items: (1) modifications (18.5%), (2) plans to assess adherence/fidelity (7.4%), (3) actual assessment of fidelity/adherence (7.4%). None of the studies provided detailed descriptions of all 12 items on the TIDieR checklist. A summary is presented in Table 3.

Table 3 Quality of description of intervention strategies based on the TIDieR checklist

Implementation outcomes

Of the eight aspects of implementation, an average of 2.9 aspects were evaluated. No single study evaluated all eight implementation outcomes - acceptability, adoptions, appropriateness, feasibility, fidelity, implementation cost, penetration and sustainability. Majority of the studies reported on feasibility (21/27, 77.8%), appropriateness (18/27, 66.7%) and penetration (16/27, 59.1%) of the interventions. Slightly below half studied acceptability (12/27, 44.2%). The least commonly reported outcomes were cost, fidelity and sustainability, with only 3.7% (1/27) of studies reporting them.

The penetration of the intervention, defined as the proportion of participants who took part in the intervention with respect to the total eligible population, varied widely from 10% to 100%, with an average penetration of 52.4% amongst the studies. A summary is presented in Table 4.

Table 4 Implementation outcomes based on Proctor’s Implementation Outcomes Framework


Our study systematically evaluated interventions to enhance cascade testing, ascertained rates of improved uptake and assessed them based on implementation outcomes. This systematic review highlights the success of several intervention efforts to increase cascade testing for hereditary cancer syndrome in family members, but also a clear lack of an implementation science approach in propagation of these successful interventions.

Genetic testing has become mainstream, with increasing number of patients being referred for genetic testing for treatment indications36,37. In the same vein, with more patients identified with hereditary cancer syndromes, there ought to be a corresponding increase in identification of ARRs. Overall, most interventions have demonstrated success in improving cascade testing uptake. This success is seen across the different EPOC taxonomy strategies. Amongst the studies that provided uptake information, the mean uptake is 41% in the intervention group compared with 33% in the control group. Uptake of cascade testing was highest with delivery arrangement (68%), compared to financial arrangement (37%) and implementation strategies (24%). There is a large difference in uptake as the success of an intervention does not just depend on the intervention, but also its implementation. Studies that have shown prominent success of more than 90% uptake post intervention often incorporate a multi-tiered approach with appropriate facilitation to ensure optimal implementation. Donenberg et al. integrated a local management team with the genetics team and ensured that the family counseling session occurred within two weeks, with free predictive testing38. Tone et al. used a two pronged approach with both outreach to the general public and direct recruitment of patients via their physician to achieve testing rates of 93.3%39. Sermijin utilized a three-step approach to inform ARRs via the proband, sending letters and a telephone call to follow up by the genetics team40. Furniss et al. improved genetic testing through convenience, allowing remote genetic education with a telemedicine platform and saliva-based genetic testing coordinated by the genetics team41. On the other hand, interventions with poor success rates were often one-dimensional, with use of a single genetic counseling session or providing supplementary educational materials with no further input from the genetics team. The distribution across the taxonomy strategies was largely in favor of delivery arrangements (20/27, 74%), while implementation strategies and financial arrangements formed 15% (4/27) and 11% (3/27) of the studies respectively. This suggests that most studies focus on individual tools such as educational materials, websites, targeted at individual patients or healthcare providers to improve cascade testing uptake. Generally, information and communication technology was most frequently used since technology-enabled care has been shown to be noninferior to in-person counseling, and is in fact more accessible and cost-effective42. Technology-enabled care requires an appropriate infrastructure12,43, which may be feasible in developed countries with a well-established communication network. There is minimal focus on how interventions can be integrated within existing healthcare pathways. Healthcare systems may need to adapt the intervention to suitably assimilate into the local setting, with follow up to ensure appropriate improved outcomes44. Further exploration of factors such as implementation and cost may allow more seamless integration of interventions within healthcare organizations.

Increasing specialization in the medical field has resulted in fragmented care for the patient45, and in this case, his/ her family. Based on our study, coordination of care and management of care processes is the best form of intervention to improve cascade testing rates for families with hereditary cancer syndromes, with three studies showing post intervention uptake rates above 90%. It is important to recognize the importance of healthcare infrastructure on coordinated intervention efforts46, and the success of interventions may not be portable across health systems without adaptation. Several included studies incorporated direct contact of relatives by healthcare staff, but in practice this is limited by privacy laws prohibiting disclosure of genetic information to a third party without proband consent47. Families desire support from healthcare professionals in conveying hereditary genetic risk information, and this direct approach is acceptable to relatives25. This was echoed in a recent meta-analysis which confirmed that direct relative contact increases rates of cascade genetic counseling and testing20, and argued for current privacy laws and infrastructure to be revisited. Future studies may consider breaking down these groups of healthcare professionals to better understand the impact on uptake of cascade testing when facilitated by different types of healthcare professionals. We observed that most studies evaluated at-risk relatives as a congregate, without differentiating into first- or second-degree relatives. Such information could potentially be useful for informing future implementation studies. While no included studies evaluated government interventions, the effects of legalizing disclosure to ARRs even without probands’ consent as in New South Wales, Australia should be monitored48, bearing in mind the ongoing debate between healthcare professionals’ duty of care to ARRs and duty of confidentiality to the proband.

Our review also illustrates that implementation outcomes are often selectively evaluated. Feasibility, appropriateness and penetration are outcomes most frequently examined, while cost, fidelity and sustainability are often overlooked. Cost is often a factor that is cited by studies as a barrier to cascade testing18,49. Three out of 27 studies evaluated cost and showed that offering free cascade testing can remove a significant barrier, but this requires either further investment in a budget-constrained healthcare system or third-party payers. Additionally, the cost of implementation in the real world is not reported in the majority of included studies. A previous review by Allen et al. reported feasibility and appropriateness as the most frequently measured outcomes50. Another review by Proctor also reported cost and sustainability to be the least studied. Hence, the findings from our review largely supports prevailing literature51. Notably, sustainability was evaluated in only one study. This was likely due to the high cost of maintaining data collection beyond the study period. However, sustainability is a key aspect of implementation52, as it ascertains if the intervention was integrated into practice, the primary end goal for most interventions. The omission of key aspects underscores the need for increased utilization of implementation science frameworks in the evaluation of outcomes to increase cascade testing uptake. Formal assessment of implementation outcomes can aid stakeholders in making fair comparisons among interventions and ultimately adopt the one most relevant to their population. Given such varying extents of implementation outcome reporting, further work is needed to educate healthcare professionals on applying methods for implementing and reporting novel interventions. Implementation outcomes should be formally assessed to ensure these interventions have meaningful, long-lasting impact on the care of patients and ARRs at increased risk of cancer.

Our review highlights the lack of standardization in the reporting of interventions, as shown by inadequate intervention description. The mean TIDieR score for the 27 included studies was 7.3 out of 12, implying only slightly above half of the intervention characteristics were described adequately. This is concerning as it has been well-documented that poor descriptions of interventions may pose a serious challenge to the scientific community in the replication of interventions53,54. In this review, one of the most commonly omitted item was modifications made. The reporting of modifications is undeniably important given that certain alterations may have been made during the study to overcome an unexpected difficulty or to achieve better recruitment. Consequently, it appears that there was little tailoring to individuals or modification in a vast majority of the included trials. Tailoring during the study, which may be necessary in cascade testing where relative’s knowledge of hereditary cancer syndrome may not be uniform and will likely require bespoke communication strategies to best fit the participant55. Failure to report these details may affect the replication and implementation downstream, preventing the implemented interventions from achieving their desired outcomes. Hence, further work is needed to encourage more widespread adoption of standardized guidelines in reporting of interventions.

Our review has several limitations. The EPOC taxonomy uses categories with some overlap so some interventions could fit into multiple categories, a limitation recognized by its authors. In these circumstances, we chose the classification that best fit the intent of the intervention in the context of our research question, i.e. the means by which the intervention aimed to increase uptake of cascade testing or genetic counseling. A majority of the studies included were targeted at participants in the USA, hence the findings may not be generalizable to Asian countries, where the rates of genetic testing and disclosure to family members have been reported to be significantly lower compared to European families18,56,57. Application of insights should be guided by knowledge of cultural and societal factors. Future reviews can consider evaluating the success of intervention strategies trialed and tested solely among Asian populations.

In conclusion, while there are many potentially efficacious strategies devised, further improvement in the reporting quality of studies in this field may be crucial to close the research-to-practice gap. Applying implementation science is therefore essential to ensure effective translation of intervention strategies that increase cascade testing from the experimental to public health setting. This review revealed that while interventions demonstrate effectiveness in experimental settings, we lack robust evaluation of implementation of interventions to optimize uptake of cascade testing. Moving forward, standardized reporting guidelines such as Standards for Reporting Implementation Studies (StaRI) should be used and implementation outcomes formally assessed to ensure interventions have meaningful, lasting impact on patients and relatives, within and beyond cancer genetics.


We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for good reporting58.

Search strategy

We searched PubMed, Embase (Elsevier), Web of Science, Cochrane Library, CINAHL, PsycINFO, and Google scholar using keywords and subject headings including “cascade testing” or synonymous terms. Search strategies were refined in consultation with a university librarian. Complete search strategy for PubMed and other databases are available (Supplementary Table 1). Peer-reviewed articles published in English between 1 January 2010 and 30 June 2022 were selected. This timeframe reflects current interventions as panel genetic testing has become more common in the past decade59, with increasing public acceptance60 and new genetic privacy laws47. Backward and forward reference searching was conducted for included studies. References were uploaded to Covidence (, a systematic review management software. All procedures followed were in accordance to the Declaration of Helsinki.

Eligibility criteria

Study selection is summarized in Fig. 1. We included studies on interventions that target patients with a hereditary cancer syndrome, harboring a PV/LPV in a cancer susceptibility gene. These studies included interventions aimed at improving cascade testing uptake or genetic counseling referral rates. Interventions with multiple components were included. Our review included original papers with quantitative, qualitative and mixed methods study designs and excluded non-English, and non-peer reviewed publications (Supplementary Table 2).

Study extraction and synthesis

Two reviewers (JC, ZC) separately screened each title and abstract for eligibility after duplicates were removed. These reviewers were blinded to the screening decisions made by the other and could only view their own screening decisions. Disagreements were resolved through discussion between reviewers with adjudication by a third senior reviewer (JN) when a consensus could not be reached. The same process was performed for the full-text review. A data extraction form was developed by the author (JC), then reviewed by all the members of the study team. The standardized form was used for data extraction by three reviewers (CJY, AAS, LWH). Reviewers piloted data extraction using two papers to ensure consistency in approach prior to full data extraction.

Study appraisal and assessment

Interventions proposed in each study were grouped based on the Effective Practice and Organization of Care (EPOC) taxonomy and the rate of uptake of genetic testing were recorded to determine the efficacy of interventions. The 12-item Template for Intervention Description and Replication (TIDieR) checklist was used to evaluate quality and completeness of intervention description in the included studies. The TIDieR score was calculated for each intervention by summing the number of items reported. Proctor’s Implementation Outcomes Framework was used to assess the implementation outcomes27. The eight outcomes assessed include acceptability, appropriateness, adoption, feasibility, fidelity, cost, penetration and sustainability.