Is immunohistochemistry-based screening for Lynch syndrome in endometrial cancer effective? The consent's the thing

To investigate the plausible failure rate of the immunohistochemistry (IHC)-based screening protocol to identify Lynch syndrome (LS) index cases among endometrial cancer (EC) patients. We developed a simulation model of the IHC protocol in this context. The model was populated from systematic and focused reviews, augmented with local data and expert opinion. The virtual cohort represents the number of women expected to be diagnosed with EC in the U.S. in 2018. The outcomes include protocol failure rates and LS cases missed in a variety of hypothetical scenarios. The best estimate of failure rate of the IHC protocol is 58%; minimum and maximum estimates are 33% and 80%, respectively. These failure rates are driven primarily by the high rates of failure to obtain consent from patients for sequencing (25% to 80%). The multiple imperfect tests and potential failure points in this protocol, collectively, make up 7% to 20% of the total failure rate. When consent for sequencing was fixed in the model at 25%, 50%, and 80%; the expected ranges for index case identification failure are 78%–82%, 57%–64%, and 29%–42%, respectively. The primary driver of failure to identify index cases remains consent for sequencing. Consent rates have shown little improvement since LS screening programs were instituted in the U.S., leaving us to conclude these high failure rates are resistant to substantial improvement. These missed opportunities will be magnified because cascade screening for carrier status among family members will not be pursued. [Display omitted] •In routine clinical settings, the tumor/immunohistochemistry (IHC)-based Lynch syndrome (LS) screening protocol often fails.•In endometrial cancer (EC) populations, the protocol will likely fail to identify 33% to 80% of LS index cases.•The dominant factor in failure of the protocol is non-consent for sequencing among screen positive patients.•Even under the most optimistic consent scenario (e.g., 80%), this protocol will miss between 29% and 42% of index cases.•There is considerable evidence suggesting that many LS screening programs in the U.S. have consent rates below 50%.