Opportunistic Genomic Screening for a Broad Range of Medically Relevant Secondary Findings: Molecular Findings, Clinical Utility, and Cost-Effectiveness

Background: When used as a diagnostic test, genomic sequencing can also be used to opportunistically screen for secondary findings (SFs) – medically relevant variants that are unrelated to the primary indication for testing. However, there is scarce evidence on the outcomes or costs of screening for SFs to inform decisions about whether, and which, secondary findings should be offered to patients. Through a randomized controlled trial (Incidental Genomics RCT; NCT03597165) we aimed to evaluate the clinical, economic, and laboratory outcomes of opportunistic screening for a broad range of medically relevant SFs, encompassing risks for medically actionable and non-medically actionable monogenic disorders, carrier status for recessive disorders, pharmacogenomic variants, and risk variants for common multifactorial disease.Methods: Adult cancer patients received germline exome sequencing with primary cancer findings only (control arm), or primary cancer findings and a choice of secondary findings (intervention arm). Through a chart review and patient-reported outcomes, the yield of reportable secondary findings was characterized, as well as the impact on patients’ medical management and correlations with clinical features and family history. Data from the RCT were linked to healthcare administrative databases, and cost-utility and cost-effectiveness analyses were performed. Laboratory exome analysis logs were analyzed to characterize all variants requiring manual curation, and the resources required for exome analysis. The time horizon for all analyses was the first year after return of exome sequencing results. Results: From the diagnostic laboratory perspective, analyzing all types of secondary findings required substantial effort. Across all intervention arm participants, in the monogenic secondary finding genes there were 4,441 unique variants, 5.0% (221) of which were classified as P/LP and were reportable, and 81.4% (3615) were classified as VUS and not reportable. There were on average 2.6 (SD 1.66, range 0-9) P/LP variants per case in the intervention arm, and 29.5 VUS (SD 13.2, range 2-74). Filtration, variant classification and report generation were substantially more time consuming in the intervention arm compared to the control arm given the greater number of variants being analyzed. All participants who elected to learn SFs had ≥1 variant reported (100% [139/139]). SFs across all categories prompted changes in management among 28.1% of participants, including SFs not a priori categorized as medically actionable. Moreover, a considerable proportion of participants had suggestive clinical features (49.0% [24/49]) or family history (21.7% [27/124]) potentially related to their SFs. Overall costs (costs associated with genomic sequencing, plus downstream healthcare costs) were on average $1290CAD higher per participant in the intervention arm, at $12,965 (SD$20,038) in the intervention arm compared to $11,676 (SD$21,776) in the control arm. However, we did not find strong evidence that these were statistically different (ratio of geometric means: 1.27, 95% CI 0.98 to 1.65, p=0.0652). QALYs were higher for participants in the intervention arm than in the control arm (β=0.04, 95% CI 0.01-0.06, p=0.005), and the odds of having a GS-informed change in management were substantially higher among participants in the intervention arm compared to the control arm (OR 11.2, 95% CI 4.3 to 29.5, p<0.0001). The ICER was $34,929CAD/QALY, falling below commonly accepted cost-effectiveness thresholds. Conclusions: This thesis provides evidence on the laboratory, clinical and health system outcomes of opportunistic screening for a broad range of secondary findings. While secondary findings were associated with higher costs, these may be justified in light of the associated benefits, namely, clinical utility and quality of life.

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