OBJECTIVES: Between 2%-6% of endometrial cancer (EC) cases are attributable to Lynch syndrome (LS). Although universal tumor screening for LS among patients with EC is recommended by professional societies, implementation remains suboptimal. Our objective is to compare the relative performance, costs, and efficiency of different LS screening protocols among newly diagnosed EC patients from a U.S. healthcare system perspective.

METHODS: We developed decision analytic models representing seven LS screening protocols for a hypothetical cohort of 1,000 patients. Model assumptions and parameter values were extracted from literature, supplemented by input from clinical experts and public sources such as Medicare fee schedules for costs. All costs were reported in 2021 USD.

RESULTS: The direct germline sequencing (DGS) protocol provided the best performance for identifying LS cases (sensitivity 99.90%, 95% CI: 99.55-99.95%) and similar specificity (99.50%, 95.47-99.53%) compared to the immunohistochemistry (IHC) (sensitivity 92.59%, 88.27-97.24%; specificity 99.98%, 99.78-99.98%), microsatellite instability (MSI) to germline sequencing (sensitivity 89.48%, 86.63-93.86%; specificity 99.91%, 99.00-99.90%), and MSI (sensitivity 80.53%, 77.16-85.46%; specificity 100.00%, 99.96-100.00%) protocols. The IHC protocol was most cost efficient at $12,992 ($8,378-$24,362) per LS case identified compared to $19,179 ($12,749-$33,542), $19,948 ($13,089-$37,671), and $20,521 ($10,315-$50,301) for the MSI, MSI to germline sequencing, and DGS protocols respectively. Adding double somatic testing to the IHC, MSI and MSI to germline sequencing protocols reduced the number of unexplained cases by 99%-100% and increased costs by 1%-18%. Threshold analysis showed that the cost of germline sequencing would need to be $251.44 for DGS to be as efficient as the IHC protocol.

CONCLUSIONS: The DGS protocol had the best performance for identifying LS cases. The IHC protocol was most efficient but missed more LS cases. DGS would be as efficient as the IHC protocol if the cost of germline sequencing continues to decline and is already at similar efficiency to the MSI protocol.