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.

Figure 1

Cost-effectiveness of primary screening strategies for mismatch repair mutations in a simulated population of 100,000 individuals, representative of the general U.S. population. Risk thresholds representing the probability of carrying a mismatch repair gene mutation above which to initiate genetic testing: ◇ 0.0%, △ 2.5%, □ 5.0%, ○ 10%. Symbol color denoting screening initiation age: black ¼ age 20, red ¼ age 25, yellow ¼ age 30, blue ¼ age 35, white ¼ age 40. A, Increase in QALY versus increase in cost for 15 screening strategies for Lynch syndrome compared with current practice. Dashed line is the efficient frontier, representing sequential strategies, starting from the origin, with the greatest gain of QALYs per incremental cost. Strategies to the southeast of the efficient frontier are referred to as dominated. The inverse of the slope of the efficient frontier is the incremental cost-effectiveness ratio, representing the incremental cost per QALY compared with the next best strategy on the efficient frontier (see text). (◇ not shown in A due to scale, but data are reported in Table 3). B, average cost per QALY of 20 screening strategies for Lynch syndrome as functions of age, compared with current practice.

Figure 2

One-way sensitivity analysis of Strategy 13 (Tables 2–4). Sensitivity of the average cost-effectiveness ratio as each parameter varies within the specified range.