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Strategies to Identify the Lynch Syndrome Among Patients With Colorectal Cancer: A Cost-Effectiveness Analysis

Uri Ladabaum, MD, MS; Grace Wang, PhD, MPH; Jonathan Terdiman, MD; Amie Blanco, MS; Miriam Kuppermann, PhD, MPH; C. Richard Boland, MD; James Ford, MD; Elena Elkin, PhD; and Kathryn A. Phillips, PhD
[+] Article and Author Information

From Stanford University School of Medicine, Stanford, California; University of California, San Francisco, San Francisco, California; Baylor University Medical Center, Dallas, Texas; and Memorial Sloan-Kettering Cancer Center, New York, New York.


Grant Support: By grants NIH 1 P01 CA130818 and R01 CA72851 from the National Institutes of Health.

Potential Conflicts of Interest: Dr. Ladabaum: Grant: National Institutes of Health; Consultancy: Epigenomics, Quest Diagnostics, Abbott Molecular, Given Imaging, Roche Diagnostics, GE Healthcare; Grants/grants pending: Epigenomics, Abbott Molecular; Stock/stock options: GeneNews. Dr. Wang: Grant: National Institutes of Health; Grants/grants pending: National Cancer Institute. Dr. Kuppermann: Grant: University of California, San Francisco. Dr. Boland: Grant: National Cancer Institute; Support for travel to meetings for study or other purposes: University of California, San Francisco; Consultancy: Archimedes. Dr. Elkin: Grant: National Cancer Institute. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-0137.

Reproducible Research Statement:Study protocol: Available from Dr. Ladabaum (e-mail, uri.ladabaum@stanford.edu). Statistical code and data set: Availability by written agreement can be discussed with Dr. Ladabaum (e-mail, uri.ladabaum@stanford.edu).

Requests for Single Reprints: Uri Ladabaum, MD, MS, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 450 Broadway Street, Pavilion C, 4th Floor, MC 6341, Redwood City, CA 94063; e-mail, uri.ladabaum@stanford.edu.

Current Author Addresses: Dr. Ladabaum: Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 450 Broadway Street, Pavilion C, 4th Floor, MC 6341, Redwood City, CA 94063.

Drs. Wang and Phillips: Department of Clinical Pharmacy and School of Pharmacy, University of California, San Francisco, 3333 California Street, Suite 420, Box 0613, San Francisco, CA 94143.

Dr. Terdiman: Division of Gastroenterology, University of California, San Francisco, 2330 Post Street, Suite 610, San Francisco, CA 94115.

Ms. Blanco: University of California, San Francisco, Comprehensive Cancer Center, University of California, San Francisco, 2330 Post Street, Suite 610, San Francisco, CA 94115.

Dr. Kuppermann: Program in Clinical Perinatal and Comparative Effectiveness Research, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, 3333 California Street, Suite 335, San Francisco, California 94143-0856.

Dr. Boland: Gastrointestinal Cancer Research Laboratory H-250, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246.

Dr. Ford: Division of Oncology, Room 1115 CCSR, 269 Campus Drive, Stanford University School of Medicine, Stanford, CA 94305-5151.

Dr. Elkin: Health Outcomes Research Group, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 44, New York, NY 10021.

Author Contributions: Conception and design: U. Ladabaum, A. Blanco, M. Kuppermann, J. Ford, K.A. Phillips.

Analysis and interpretation of the data: U. Ladabaum, G. Wang, J. Terdiman, A. Blanco, M. Kuppermann, C.R. Boland, J. Ford, E. Elkin, K.A. Phillips.

Drafting of the article: U. Ladabaum, G. Wang.

Critical revision of the article for important intellectual content: U. Ladabaum, G. Wang, J. Terdiman, A. Blanco, M. Kuppermann, C.R. Boland, E. Elkin, K.A. Phillips.

Final approval of the article: U. Ladabaum, G. Wang, J. Terdiman, M. Kuppermann, C.R. Boland, J. Ford, E. Elkin, K.A. Phillips.

Provision of study materials or patients: U. Ladabaum, A. Blanco.

Statistical expertise: U. Ladabaum.

Obtaining of funding: U. Ladabaum, K.A. Phillips.

Administrative, technical, or logistic support: U. Ladabaum.

Collection and assembly of data: U. Ladabaum, G. Wang.


Ann Intern Med. 2011;155(2):69-79. doi:10.7326/0003-4819-155-2-201107190-00002
Text Size: A A A

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.

Figures

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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.

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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.

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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.

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Appendix Figure.
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.

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Summary for Patients

Comparing the Benefits and Costs of Testing for Genetic Causes of Colon Cancer

The full report is titled “Strategies to Identify the Lynch Syndrome Among Patients With Colorectal Cancer. A Cost-Effectiveness Analysis.” It is in the 19 July 2011 issue of Annals of Internal Medicine (volume 155, pages 69-79). The authors are U. Ladabaum, G. Wang, J. Terdiman, A. Blanco, M. Kuppermann, C.R. Boland, J. Ford, E. Elkin, and K.A. Phillips.

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