1. Methods Background Abstract Probability Parameters Selected References Genetic testing for BRCA mutations in high-risk women is cost-effective under base- case assumptions. High-risk 30-year-old women should be tested for BRCA mutations. The study cohort of hypothetical women had an incremental increase of nearly 150,000 QALYs. Based on the sensitivity analysis, the genetic testing would be cost-effective at the threshold of $50,000 per QALY 76% of the time. Under the base-case scenario, the cost per death averted falls below the range used by the federal government in estimating the value of a statistical life. Incidence Rate 117.7 per 100,000 for all races. Mortality Rate 24.4 per 100,000 for all races. 5-10% of cases are caused by hereditary mutations in BRCA gene. About 250,000 American women have mutated BRCA genes. Mutated BRCA genes increase chance of developing breast cancer between 40-90%. 2% of U.S. women are “high risk.” Background: Breast cancer is the leading cause of cancer deaths for women aged 40-59. A woman’s lifetime risk for breast cancer in America is 12%, but women with BRCA mutations are at substantially higher risk. Objective: To analyze the cost-effectiveness of screening high-risk women for mutations in the BRCA genes. Design: Cost-effectiveness study using Microsoft Excel to model a decision tree and Oracle Crystal Ball to run Monte Carlo simulations to test for sensitivity. Costs and outcomes discounted at 3%. Data Sources: American Cancer Society, National Cancer Institute, peer-reviewed cost-effectiveness studies. Target Population: Hypothetical cohort of 50,000 high-risk 30-year-old women with family history of breast cancer. Time Horizon: Cohort followed for duration of natural lifespan or until breast cancer death. Perspective: Societal Interventions: Cohort of high-risk women screened for BRCA gene; those with the gene proceed to have one of five interventions – surveillance, mastectomy, oophorectomy, tamoxifen chemopreventive therapy or both mastectomy and oophorectomy. Outcome Measures: Incremental cost, life-years saved, incremental quality adjusted life years (QALY), deaths averted, cost per life-year saved, cost per QALY. All costs measured in 2008 US$. Results of Base-Case Analysis: The Incremental Cost-Effectiveness Ratio (ICER) is $3,230 per QALY. Base-case is cost-effective at the threshold value of $50,000 per QALY. Results of Sensitivity Analysis: Probabilities for developing breast cancer with and without BRCA mutation have most effect on one-way sensitivity. Probabilistic sensitivity shows cost/QALY to be cost-effective 76% of the time. Limitations: Relapse is not considered in the model. Branches in the decision-tree with three or more options were not tested for sensitivity. Conclusions: Genetic screening for high-risk women should be undertaken, provided that the test results are confidential. Cost-Effectiveness of Testing High-Risk Women for Mutations in the BRCA 1 and BRCA 2 Genes: Does Early Detection Lead to Better Health and Economic Outcomes? Michelle Sonia Wilkinson, MSPH Department of Health Policy and Management University of North Carolina Gillings School of Global Public Health Hypothesis Decision Tree Limitations Acknowledgements Conclusions Cost and Outcome Parameters Base-Case Results Sensitivity Analysis Results Thank you to my academic advisor, Andrea Biddle, PhD, Associate Professor in the Department of Health Policy and Management, UNC Gillings School of Global Public Health, for her guidance in completing this research project. Special thanks to the Theta Chapter of the Delta Omega Society and the Office of Research at the UNC Gillings School of Global Public Health for their support and assistance. Genetic testing for BRCA mutations will be cost-effective for high-risk women. Genetic testing will lead to an increase in quality-adjusted life years, more deaths averted and more life-years saved. High-risk women may develop breast cancer before the median age (61 years) of diagnosis in general population. Costs to treat localized and regional disease assumed to be the same. Relapse is not part of the model. Branches in the decision tree with three or more options were not subject to sensitivity analysis. It was assumed that high-risk women with unknown status would have the same decremented utility value as women who knew they had a BRCA mutation. Who is High Risk?  Two first-degree relatives (mother, sisters, daughters) with breast cancer or three or more first- or second-degree relatives (grandmothers, aunts, cousins) diagnosed with breast cancer.  Both breast and ovarian cancer among first- and second-degree relatives or two or more first- or second-degree relatives with ovarian cancer.  A first-degree relative diagnosed with breast cancer in both breasts or a male relative with breast cancer.  Women of Ashkenazi (Eastern European) Jewish descent. Cost-effectiveness study with decision tree to show linear progression of disease. Costs and QALYs discounted at 3%. Study uses gross-costing. Societal perspective with lifelong time horizon. Costs are all presented in 2008 US$ and have been inflated using the Consumer Price Index (CPI) Medical Care Component. Sensitivity Analysis Methods Microsoft Excel 2007 used to model base case; Oracle Crystal Ball v. 11.1 used for Monte Carlo simulation (1,000 iterations) and one-way sensitivity analysis. Costs parameterized as triangular distributions. Event probabilities and outcomes (QALYs) parameterized as beta distributions. Branches with 3 or more options were held constant. Using the Gold et al. (1996) standard of $50,000 per QALY, the base case scenario is cost-effective. Genetic testing resulted in an incremental increase of 148,049 quality-adjusted life years and saved 6,722 life years. Sensitivity analysis was conducted on all three outcomes; results for cost per QALY are shown because there is no standard thresholds for cost per death averted or life-year saved. One-way sensitivity analysis changing one input at a time. The variable with the biggest effect on cost per QALY is the utility of being well with a BRCA+ test result. Probabilistic sensitivity analysis conducted using 1,000 Monte Carlo simulations. At a threshold level of $50,000 per QALY, the probability that genetic testing for BRCA mutations is cost-effective is 0.76. 85.3% of the points fall in the northeast quadrant. In this quadrant, costs are higher and outcomes are improved. 14.5% of the points fall in the northwest quadrant. These are dominated; costs increase but outcomes are worse. 0.2% of the points fall in the southeast quadrant. This is cost-saving, as costs decrease and QALYs increase. $50,000/QALY Anderson K, Jacobson J, Heitjan D, Zivin JG, Hershman D, Neugut A and Grann V. Cost-effectiveness of preventive strategies for women with a BRCA1 or BRCA2 mutation. Annals of Internal Medicine 2006; 164(6): 397-407. Grann V, Jacobson J, Whang W, Hershman D, Heitjan D, Antman K et. Al. Prevention with tamoxifen or other hormones versus prophylactic surgery in BRCA1/2 positive women: a decision analysis. Cancer J Sci Am 2000;(6): 13-20. Grann V, Panageas K, Whang W, Antman K and Neugut A. Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients. Journal of Clinical Oncology 1998; 16(3): 979-985. SEER Fact Sheet on Breast Cancer. Surveillance, Epidemiology and End Results (SEER) Program. National Cancer Institute. [Online] http://seer.cancer.gov/statfacts/html/breast.html Accessed 10/23/08. http://seer.cancer.gov/statfacts/html/breast.html Sprecher Institute for Cancer Research. Cornell University. Fact Sheet #48: Family History, Inheritance and Breast Cancer Risk. [Online] http://envirocancer.cornell.edu/FactSheet/General/fs48.inheritance.cfm Accessed 9/25/08. http://envirocancer.cornell.edu/FactSheet/General/fs48.inheritance.cfm Each chance node has an associated probability of occurrence as well as a cost and outcome parameter. The study consists of a hypothetical cohort of 50,000 high-risk 30-year-old women with a family history of breast cancer. The parameters were derived from a literature review. Data comes from the National Cancer Institute SEER Project, previous peer-reviewed journal articles on BRCA testing, the American Cancer Society and the Tufts-New England Medical Center Cost-Effectiveness Analysis Registry. $50,000/QALY Costs (in 2008 US$)Base-CaseMinMaxSource Surveillance$2,814$1,021$4,239Grann et al. 1999; Grann et al. 2000; Anderson et al. 2006 Oophorectomy$7,965$4,691$10,264Grann et al. 1999; Grann et al. 2000; Anderson et al. 2006 Oophorectomy Follow-up$666$606$1,410Grann et al. 1999; Grann et al. 2000; Anderson et al. 2006 Mastectomy$13,305$11,649$25,826Grann et al. 1999; Grann et al. 2000; Anderson et al. 2006 Mastectomy Follow-up$1,477$915$2,040Grann et al. 1999; Grann et al. 2000; Anderson et al. 2006 Oophorectomy and Mastectomy$20,755$16,340$36,090Grann et al. 1999; Grann et al. 2000; Anderson et al. 2006 Oophorectomy and Mastectomy Follow-up$550$501$1,212Grann et al. 1998; Grann et al. 1999; Grann et al. 2000 Tamoxifen Chemoprevention$1,271$733$1,809Grann et al. 2000; Anderson et al. 2006 Tamoxifen Follow-up$1,021$919$1,123Grann et al. 2000 Genetic test from Myriad$745$331$3,973Grann et al. 2000; Anderson et al. 2006 Cancer Treatment, 1st year after Diagnosis$31,091$27,982$34,200Anderson et al. 2006 Cancer Treatment, 2nd year onward$7,986$7,187$8,784Anderson et al. 2006 Treating Metatastic Disease$19,101$18,338$19,866Grann et al. 1998; Grann et al. 1999; Grann et al. 2000 End of life care$45,829$41,246$50,412Anderson et al. 2006 Mammogram$100$50$150National Cancer Institute Pr(Event)Base-CaseMinMaxSource Having BRCA gene, given a family history20%15%87%Sprecher Institute for Cancer Research Average woman's lifetime probability of breast cancer diagnosis12%11%13%American Cancer Society Developing breast cancer, given the presence of BRCA gene80%40%90%National Cancer Institute Localized stage at time of cancer diagnosis61% SEER 17 Incidence (2000 - 2005) Regional stage at time of cancer diagnosis31% SEER 17 Incidence (2000 - 2005) Distant stage at time of cancer diagnosis6% SEER 17 Incidence (2000 - 2005) 5-Year Survival if diagnosed with localized disease98%88%107%Foley and Lordell, 2005 5-Year Survival if diagnosed with regional disease80%72%88%Foley and Lordell, 2005 5-Year Survival if diagnosed with distant disease26%23%28%Foley and Lordell, 2005 Cancer diagnosis after surveillance only62%60%76%Anderson et al. 2006 Cancer diagnosis after prophylactic mastectomy10%3%50%Schrag et al, 2000 Cancer diagnosis after oophorectomy50%40%100%Schrag et al. 2000; Grann et al. 1998 Cancer diagnosis after 5 years of daily tamoxifen chemo-preventive therapy53%40%75%Schrag et al. 2000 Cancer diagnosis after both mastectomy and oophoretcomy22%20%24%Anderson et al. 2006 Choosing Mastectomy as intervention11% Uyei et al. 2006 Choosing Oophorectomy as intervention14% Uyei et al. 2006 Choosing Tamoxifen as intervention5% Uyei et al. 2006 Choosing Mastectomy and Oophorectomy14% Uyei et al. 2006 Choosing Surveillance Only57% Uyei et al. 2006