Supplemental file: Appendix

Appendix Table 1. Sensitivity Analysis: Reducing the costs of MRI by 10%-90%.

Mutation / Effect / Incremental Cost Effectiveness of MRI with complete screening compared to Mammogram alone
BRCA1 / LYs / At 30% reduction, MRI is costeffective compared to mammography alone; at ≥70% reduction, MRI dominates.
BRCA2 / LYs / At >10% reduction, MRI is costeffective; at ≥70% reduction, MRI dominates.
BRCA1 / QALYs / MRI is not costeffective compared to mammography but is costeffective compared to bilateral mastectomy,
BRCA2 / QALYs / At >50% reduction, MRI is costeffective compared to mammography alone; at >60% reduction, MRI dominates; at >10% reduction, MRI is costeffective compared to bilateral mastectomy.

MRI is sensitive to changes in costs and becomes cost effective as the price falls.


Appendix Table 2. Sensitivity Analysis: Varying the Penetrance of Breast and Ovarian Cancer

Average lifetime risk of breast cancer = 12.5%; average lifetime risk of ovarian cancer = 1.5%
Mammography dominates MRI and BSO/MRI in all categories at average lifetime risk of breast and ovarian cancer because of its decreased cost compared to other imaging strategies.
BRCA1: Basecase penetrance of ovarian cancer = 54%.
Sensitivity analysis variations using rate reductions of 50%, 25%, 12.5%, 1.5%
LY / At all penetrance levels > 50%, mastectomy and BSO together dominate BSO alone, but at 1.5% the cost effectiveness ratio is > than $76,211 compared to prophylactic oophorectomy.
QALY / At ≥ 25% penetrance, prophylactic oophorectomy is cost effective at $2,218 compared to both surgeries
BRCA2: Basecase penetrance of ovarian cancer = 23%.
Sensitivity analysis variations 50%, 25%, 12.5%, 1.5%
LY / At < 25% penetrance of ovarian cancer, both surgeries are costeffective compared to mastectomy. Otherwise both surgeries dominate over mastectomy and all other strategies.
QALY / At 25% penetrance of ovarian cancer with QALYs, mastectomy dominates both surgeries. For > 25%, mastectomy or oophorectomy are cost effective compared to both surgeries.
BRCA1: Basecase penetrance of breast cancer = 81%.
Sensitivity analysis variations 50%, 25%, 12.5%
LY / Both surgeries dominate prophylactic oophorectomy and all other strategies, including imaging. At 50% penetrance, both surgeries are expensive, compared to BSO.
QALY / BSO dominates all other strategies including both surgeries but is cost effective compared to both surgeries when the penetrance of breast cancer is 81%.
BRCA2: Basecase penetrance of breast cancer 85%;
sensitivity analysis variations 50%, 25%, 12.5%
LY / BSO dominates all strategies when the penetrance is < 50% . If the penetrance is > 50% both surgeries are cost effective compared to BSO. At 81% penetrance of breast cancer, both surgeries dominate all other interventions including annual imaging.
QALY / As breast cancer penetrance falls, BSO dominates all strategies except mammography, which among women with a 12.5% life-time normal risk of breast cancer is cost-effective compared to prophylactic oophorectomy.

This set of analyses demonstrates the benefit of interventions depending on the penetrance of the population at risk.

Appendix Table 3: Sensitivity Analysis: Varying the Discount Rate 1%–5%

BRCA1
LY / At 0% discount rate, survival is similar for bilateral mastectomy and oophorectomy compared to mammography alone for BRCA1, 2.15 years, and for BRCA2, 1.68 years. At a discount rate of 1–3%, both surgeries dominate all other interventions. At 5%, prophylactic oophorectomy is costeffective compared to both surgeries at $11,090.
QALY / Prophylactic oophorectomy is more cost-effective ($4,842) than both prophylactic oophorectomy and mastectomy surgeries at a 1% discount rate. It is less so, $1,741/QALY at 3%, and at 5% prophylactic oophorectomy dominates both surgeries.
BRCA2
LY / At 0% discount rate BRCA2 is similar to BRCA1 but has less of a survival advantage because of the decreased risk of ovarian cancer among BRCA2 carriers. At 1–3%, both surgeries dominate. At 5%, both surgeries are costeffective compared to mastectomy at $4,211/LY).
QALY / From 1-3%, mastectomy is more costeffective than both surgeries. At 1% it is $6,170/QALY and at 3%, $2,679/QALY. At 5%, mastectomy dominates both surgeries.

Varying the discount rate has a large effect on outcomes as can be seen by Table 3.

Appendix Table 4: Sensitivity Analysis: Increasing the Age of Participants to 50-100 Years

BRCA1
LY / At all ages, both surgeries dominate all other strategies.
QALY / At all ages, bilateral salpingooophorectomy is costeffective compared to both surgeries and dominates all other strategies.
BRCA2
LY / At all ages, both surgeries dominate all other strategies. Mastectomy becomes the second-best strategy.
QALY / At all ages, both mastectomy alone and BSO alone are cost-effective compared to both surgeries.

Ages have a similar effect on all interventions. BRCA1 and BRCA2 differ due to differences in rates of either breast, ovarian, or both cancers.


Figures 2 and 3 are of comparative effectiveness and show 25,000 Monte Carlo simulations of prevention and screening strategies with their costs and effectiveness for BRCA1 and BRCA2 carriers. The effectiveness is measured as quality-adjusted life years among healthy women between the age of 25-65 (Medicare age). Costs range from $139,000 to $212,000 for BRCA1 and from $127,000 to $197,000 for BRCA2. The QALYS are relatively close together and range between 8 and 22.