Health Benefits and Cost-Effectiveness of Primary Genetic Screening for Lynch Syndrome in the General Population

Abstract

In current clinical practice, genetic testing to detect Lynch syndrome mutations ideally begins with diagnostic testing of an individual affected with cancer before offering predictive testing to at-risk relatives. An alternative strategy that warrants exploration involves screening unaffected individuals via demographic and family histories, and offering genetic testing to those individuals whose risks for carrying a mutation exceed a selected threshold. Whether this approach would improve health outcomes in a manner that is cost-effective relative to current standards of care has yet to be demonstrated. To do so, we developed a simulation framework that integrated models of colorectal and endometrial cancers with a 5-generation family history model to predict health and economic outcomes of 20 primary screening strategies (at a wide range of compliance levels) aimed at detecting individuals with mismatch repair gene mutations and their at-risk relatives. These strategies were characterized by (i) different screening ages for starting risk assessment and (ii) different risk thresholds above which to implement genetic testing. For each strategy, 100,000 simulated individuals, representative of the U.S. population, were followed from the age of 20, and the outcomes were compared with current practice. Findings indicated that risk assessment starting at ages 25, 30, or 35, followed by genetic testing of those with mutation risks exceeding 5%, reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%, respectively. For a population of 100,000 individuals containing 392 mutation carriers, this strategy increased quality-adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY. The cost-effectiveness of screening for mismatch repair gene mutations is comparable to that of accepted cancer screening activities in the general population such as colorectal cancer screening, cervical cancer screening, and breast cancer screening. These results suggest that primary screening of individuals for mismatch repair gene mutations, starting with risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost-effective manner relative to current practice.

Which Lynch syndrome screening programs could be implemented in the “real world”? A systematic review of economic evaluations

“…29,35,37,[40][41][42]44 Although to different degrees, most studies gave details of the modeling and parameters used. [26][27][28][30][31][32][33][34][35][36][37][38][39]42,43 The time horizon of the analysis was not always clearly defined, although it could be deduced from the model. 29,31,40,41,44 Sensitivity analysis was performed in all economic evaluations: [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] six studies used only univariate analysis, 25,28,31,...…”

“…[25][26][27][28][29][30][33][34][35][37][38][39][40][41][42][43][44] All economic evaluations provided an incremental analysis. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] Influential parameters and basic assumptions…”

“…43 Several studies reported percentages greater than 99% for both sensitivity and specificity of MMR genes sequencing 30,[38][39][40]43,44 (Supplementary Table S5), but a lower sensitivity was assumed by Ramsey (87%), 26,27 Dinh (90%), 31 and Snowsill (90%). 37 The sensitivity ranges of microsatellite instability (MSI) and immunohistochemistry (IHC) tests were respectively 76-91% 26,27,30,33,34,[37][38][39]42 and 77-92%, [30][31][32][33][34][37][38][39][40]42,43 whereas specificity ranges were 79-93% for MSI [26][27][28]30,33,34,[37][38][39]42 tests and 70-91% for IHC tests. [30][31][32][33][34][37]…”

“…37 The sensitivity ranges of microsatellite instability (MSI) and immunohistochemistry (IHC) tests were respectively 76-91% 26,27,30,33,34,[37][38][39]42 and 77-92%, [30][31][32][33][34][37][38][39][40]42,43 whereas specificity ranges were 79-93% for MSI [26][27][28]30,33,34,[37][38][39]42 tests and 70-91% for IHC tests. [30][31][32][33][34][37][38][39][40]42,43 Being context-specific, cost assumptions (Supplementary Table S6) are not directly comparable; single-gene sequencing costs ranged from 600 to 1,200 dollars in American studies, [30][31][32][33][34]39,…”

“…All studies included programs that considered CRC, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] while endometrial cancer and ovarian cancer were addressed respectively in nine [31][32][33][34]37,39,41,43,44 and in five studies. 33,34,39,41,43 Most studies focused on newly diagnosed CRC patients, [26][27][28]30,33,34,[36][37][38][39][41][42][43] but five additional different target populations were also considered.…”