Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis

Abstract

Background: Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine.

Objective: To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives.

Design: Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers.

Data sources: Published literature.

Target population: All persons with newly diagnosed colorectal cancer and their relatives.

Time horizon: Lifetime.

Perspective: Third-party payer.

Intervention: Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery.

Outcome measures: Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios.

Results of base-case analysis: The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36,200 per life-year gained.

Results of sensitivity analysis: The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50,000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of $100,000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88,700 per incremental life-year gained compared with screening only up to age 70 years.

Limitation: Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered.

Conclusion: Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome.

Primary funding source: National Institutes of Health.

Model schematic of the strategies to identify persons with the Lynch syndrome and the management options based on risk stratification

IHC = immunohistochemistry. * Includes offering colonoscopy every 10 y starting at age 50 y for persons at average risk, with more frequent surveillance after adenoma detection and earlier and more frequent screening on the basis of family history. † Includes offering annual colonoscopy starting at age 25 y, annual gynecologic screening with transvaginal ultrasonography and endometrial sampling starting at age 35 y, and prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy at age 40 y.

Figure 1. Discounted life-years and costs per person for all strategies in the base case

When comparing 2 strategies, the one toward the right of the graph is more effective and the one toward the top of the graph is more costly. Tumor-testing strategies were more effective and more costly than clinical criteria strategies. The slope between 2 strategies represents the incremental cost-effectiveness ratio, with steeper slopes reflecting higher costs per life-year gained. The referent strategy reflects no active effort to diagnose the Lynch syndrome. IHC = immunohistochemistry; MSI = microsatellite instability.

Figure 2. Sensitivity analysis of number of relatives tested per proband

Among tumor-testing strategies, IHC with BRAF testing had an incremental cost-effectiveness ratio <$50 000 per life-year gained when 3 relatives but not when 2 relatives were tested per proband. IHC = immunohistochemistry.

Figure 3. Cost-effectiveness acceptability curves for all strategies, constructed from probabilistic sensitivity analyses

For any given strategy, a higher willingness to pay per life-year gained meant a higher probability that the strategy was considered cost-effective. All strategies are compared with the referent strategy. IHC = immunohistochemistry; MSI = microsatellite instability.