Cascade Testing for Hereditary Cancer Syndromes: Should We Move Toward Direct Relative Contact? A Systematic Review and Meta-Analysis

Abstract

PURPOSE Evidence-based guidelines recommend cascade genetic counseling and testing for hereditary cancer syndromes, providing relatives the opportunity for early detection and prevention of cancer. The current standard is for patients to contact and encourage relatives (patient-mediated contact) to undergo counseling and testing. Direct relative contact by the medical team or testing laboratory has shown promise but is complicated by privacy laws and lack of infrastructure. We sought to compare outcomes associated with patient-mediated and direct relative contact for hereditary cancer cascade genetic counseling and testing in the first meta-analysis on this topic. MATERIALS AND METHODS We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO No.: CRD42020134276). We searched key electronic databases to identify studies evaluating hereditary cancer cascade testing. Eligible trials were subjected to meta-analysis. RESULTS Eighty-seven studies met inclusion criteria. Among relatives included in the meta-analysis, 48% (95% CI, 38 to 58) underwent cascade genetic counseling and 41% (95% CI, 34 to 48) cascade genetic testing. Compared with the patient-mediated approach, direct relative contact resulted in significantly higher uptake of genetic counseling for all relatives (63% [95% CI, 49 to 75] v 35% [95% CI, 24 to 48]) and genetic testing for first-degree relatives (62% [95% CI, 49 to 73] v 40% [95% CI, 32 to 48]). Methods of direct contact included telephone calls, letters, and e-mails; respective rates of genetic testing completion were 61% (95% CI, 51 to 70), 48% (95% CI, 37 to 59), and 48% (95% CI, 45 to 50). CONCLUSION Most relatives at risk for hereditary cancer do not undergo cascade genetic counseling and testing, forgoing potentially life-saving medical interventions. Compared with patient-mediated contact, direct relative contact increased rates of cascade genetic counseling and testing, arguing for a shift in the care delivery paradigm, to be confirmed by randomized controlled trials.

What happens in the long term: Uptake of cancer surveillance and prevention strategies among at‐risk relatives with pathogenic variants detected via cascade testing

“…[32][33][34][35] Interestingly, although several prior studies have demonstrated that females are more likely to complete cascade testing than males, we found no difference in rates of testing by sex in our cohort In summary, our long-term follow-up study demonstrates that clinician-facilitated cascade testing can result in the successful completion of genetic testing and utilization of genetically targeted primary disease prevention through screening and risk-reducing surgery with a positive patient-reported experience. These results, supported by a recent meta-analysis, 16 suggest that health care systems should consider supporting clinician-facilitated direct contact cascade testing programs, and this is to be confirmed by larger randomized controlled trials. Notably, 67% of relatives did not complete all of the NCCN-recommended cancer screening interventions, and this suggests that future strategies to promote care for families with hereditary cancer syndromes must focus not just on access to genetic testing but also on supporting engagement with the medical system after the identification of a germline pathogenic variant.…”

“…The clinician‐facilitated strategy yielded promising results and achieved cancer genetic testing for 58% of total identified relatives and for 70% of relatives who were able to be reached by the research team. These results have been confirmed by a systematic review and meta‐analysis, which demonstrated cascade testing completion for 36% of relatives with patient‐mediated relative contact versus 63% of relatives when relatives are directly contacted by the medical team or testing laboratory 16 . Although this increased utilization of genetic testing is exciting, it is only clinically meaningful if action is taken in response to positive genetic testing results.…”

“…These results have been confirmed by a systematic review and meta-analysis, which demonstrated cascade testing completion for 36% of relatives with patient-mediated relative contact versus 63% of relatives when relatives are directly contacted by the medical team or testing laboratory. 16 Although this increased utilization of genetic testing is exciting, it is only clinically meaningful if action is taken in response to positive genetic testing results. To promote a paradigm shift whereby clinicians and medical centers embrace the responsibility of cascade testing, data on long-term health and quality-of-life implications for at-risk relatives are needed.…”

An approach to genetic testing in patients with metastatic castration-resistant prostate cancer in Singapore

“…Moreover, male relatives show higher reluctance towards cascade testing than their female counterparts. [56][57][58][59] This lack of cascade testing is a concern in view of the missing opportunity to detect and prevent hereditary cancers.…”

Direct letters to relatives at risk of hereditary cancer – study protocol for a multi-centre randomised controlled trial of healthcare-assisted versus family-mediated risk disclosure at Swedish cancer genetics clinics (DIRECT-study)

“…In most countries, the current standard approach for risk disclosure is to rely on the proband to pass on information to relatives, so called family-mediated risk disclosure. Recently, the rst meta-analysis showed that 35% [95% CI, 24 to 48] of ARRs underwent genetic counselling with family-mediated risk disclosure (2). With healthcare-assisted risk disclosure using direct contact with ARRs the uptake almost doubled to 63% [95% CI, 49 to 75].…”