• Uri Ladabaum, Grace Wang, Jonathan Terdiman, Amie Blanco, Miriam Kuppermann, C Richard Boland, James Ford, Elena Elkin, and Kathryn A Phillips.
• Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA. uri.ladabaum@stanford.edu
• Ann. Intern. Med. 2011 Jul 19; 155 (2): 697969-79.

BackgroundTesting 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.ObjectiveTo 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.DesignMarkov model that incorporated risk for colorectal, endometrial, and ovarian cancers.Data SourcesPublished literature.Target PopulationAll persons with newly diagnosed colorectal cancer and their relatives.Time HorizonLifetime.PerspectiveThird-party payer.InterventionStrategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery.Outcome MeasuresLife-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios.Results Of Base Case AnalysisThe 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 AnalysisThe 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.LimitationOther types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered.ConclusionWidespread 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 SourceNational Institutes of Health.

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