The Genetics Update

Genomic sequencing (GS) is a driver of precision medicine: Clinicians are using GS for precision medicine, to diagnose patients and tailor recommendations about their medical care. Germline GS offers increased sensitivity over classic genetic tests, decreasing time-consuming and costly diagnostic cascades.

Genomic test results can change over time: Variants are classified as pathogenic (P), likely pathogenic (LP), VUS, likely benign (LB), or benign (B) per guidelines. However, the evidence on variants in disease changes constantly. Over time, laboratories reanalyze variants and genes, taking into new evidence and updated standards for interpretation.4 Reanalysis may result in a variant being reclassified (e.g. from VUS to P, or LB to B). On average, reclassification takes between 6 months and 2 years after a variant is first identified.5 Ideally, people with reclassified variants should be recontacted as soon as possible within this time frame. Among cancer genes, as many as 38% of reanalyzed variants are reclassified, and this rate can be as high as 43% among VUS. Up to 25% of VUS are reclassified as LP/P, and the remaining 75% downgraded to LB/B. In the context of cancer, such reclassifications have the potential to bring relief to a patient with a VUS, or to indicate their need for more urgent care and/or a refined treatment pathway.

Reclassification can affect patients' care: Identification of novel genomic changes, discovery of novel gene-disease associations, and/or variant reclassifications, (e.g. changes to or from LP/P) can trigger significant changes to patients' management. These changes can include altered frequency and/or types of surveillance, modified surgical recommendations, cascade testing for relatives or removal from a clinical trial. Even reclassifications that typically will not modify management, such as from VUS to LB/B, have the potential to relieve patient and provider uncertainty, and to reduce the risk of inappropriate actions being taken on the basis of the VUS. All of these changes in care depend on timely awareness of the patient (and/or) provider of the reclassification and its implications, particularly when updated genomic results are expected to impact clinical management; all of which are reinforced by international guidelines.

Cancer is the most common condition for which patients will need to be recontacted: Oncologists use tumour and germline GS to identify therapies, and improve diagnosis and management. And as its cost decreases, GS is expected to replace single gene or multigene panel testing as standard of care.

Patients want to be recontacted but waiting for updates causes patient distress: Internationally, patients and providers agree that recontact is desirable, though practically challenging. Patients value reanalysis of their genomic results over time and want to be recontacted with updates to their genomic results, even those with no impact on their medical care. Some cancer patients have been found to experience intrusive thoughts and worry about their genetic cancer risk while waiting for genetic results. Patients who receive VUS report elevated genetic-test specific distress; waiting for updates about VUS may result in further distress. Patients who are recontacted have been found to experience relief from both upgraded and downgraded results, and have been found not to experience distress or reduced trust in medical genetics. Innovative approaches are needed to feasibly recontact patients to deliver updates.

Recontact poses health service delivery challenges: There are high resource impacts for clinicians to recontact patients, which will grow as the scope and volume of possible updates increases. The greatest obstacles include the time and resources required to identify patients whose results have been reclassified, maintain up-to-date contact information or track patients who have moved, consult with patients to deliver updated results, counsel patients about their results' implications and support patients' needs while they wait for their results or after they have received updates, all of which can impact providers' capacity to see new patients. Consequently, recontact practices vary between clinics; in some cases, patients are not recontacted with updated results, and they may not follow their providers' request to call and ask about updates. Approaches to recontact include registries or mailed letters. Neither is scalable or sustainable, and may miss a substantial proportion of patients. Without systematic practices, inequities can arise in information provision and health outcomes. Ultimately, this is a growing service delivery issue: with thousands of patients receiving genetic testing yearly in Ontario alone, the burden of recontacting patients with reinterpreted results is substantial. Genetics services are challenged to meet current demands; the added burden of recontacting patients is infeasible. New service delivery models are urgently needed.

Virtual care is now the norm: The COVID-19 pandemic catalyzed a rapid shift toward virtual healthcare delivery to in order to minimize interruptions in access to care. Digital health applications, such as patient platforms, are increasingly used across the continuum of genetics and genomics service delivery. Digital tools have been found to improve knowledge, reduce clinician time, and promote patient-centered care.

Digital platforms could deliver updates to patients' genomic results over time: Some Ontario hospitals and networks allow patients the option to access their results online. Platforms provide patients with timely access to, and control over their health information, increasing efficiency of service delivery. Patients and members of the public prefer to receive updates through a database compared to no updates, and reported that use of a database for updates would provide them with control over their medical information. We propose to develop a stand-alone platform to provide continual updates to results.

Digital platforms can reduce distress associated with waiting for results and empower patients to act on medical results: A systematic review of patient platforms found that they can improve psychological outcomes such as decision-making and self-efficacy. For patients with diabetes, patient platforms have been found to improve medication adherence, use of preventive services, and clinical outcomes. In interviews, cancer patients report that waiting for a verbal confirmation of results from a provider was more distressful than having control and accessing the results online through a platform. Among cancer patients, platforms reduced distress associated with waiting for pathology results related to a cancer diagnosis. Patient platforms to return genomic test results may provide better infrastructure to support patient-clinician communication, reduce resource burden, mitigate inequities in patients' access to updated health information and reduce distress. However, no tools exist for use in this context.

Inclusion criteria

• Adult patients who have had germline genome sequencing as part of the Incidental Genomics (CTO #0819), Genetics Adviser (CTO #3400), or GENCOV (CTO #3302) trials and consented to be re-contacted for related research.

Exclusion criteria

• Individuals who are unable to provide consent to participate in the study will not be eligible.
• Patients are unable to participate if they do not speak English or lack access to the internet or an electronic device.