1. Advancing Health Economics, Services, Policy and Ethics Evidence-based marginal analysis: Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers Reka Pataky Priorities 2010, Boston

2. The BC Cancer Agency Evidence-based marginal analysis MRI screening study –Background –Model construction –Results Discussion and Conclusions 2 Outline

3. Provides a province-wide, publicly-funded, population-based cancer control program for British Columbia, Canada Prevention –Education and outreach in smoking cessation, sun protection Screening and early diagnosis –Cervical cancer screening, screening mammography program Treatment and supportive care –Sole provider of radiation therapy and drugs for systemic therapy Research –Basic science to cancer control –Registry and administrative data available 3 About the BC Cancer Agency

4. 4 Evidence-Based Marginal Analysis Define aim and scope Form Steering Committee Determine current program budget Establish decision- making criteria Identify areas for resource release Identify areas for new resource use Make allocation recommendations Validity check and final decisions For each area identified: Form Advisory Panel Collect local costs/outcomes Build Markov model Calculate cost- effectiveness EBMA PBMA Objective: to pilot innovations in the program budgeting and marginal analysis (PBMA) process, by generating program-specific empirical evidence and incorporating that evidence into decision-making for resource reallocation (EBMA). 5 areas identified: Adjuvant trastuzumab in breast cancer Bevacizumab in metastatic colorectal cancer Mammography for women with dense breast tissue PET for lung cancer staging MRI for breast cancer screening

5. Hereditary Cancer Program and MRI screening –Offers genetic counseling and mutation testing to referred patients –Confirmed BRCA1/2 mutation carriers (& family) are offered annual MRI screening and mammography 55% risk of breast cancer by age 70 MRI begins at age 25, or 5 years before earliest cancer in family; mammography begins at age 30 Continues until age 65 or first cancer –Annual mammography for others at high hereditary risk 5 Current Practice at the Agency

6. Objective: –Examine the cost effectiveness of MRI and mammography for breast cancer screening in high-risk women What is the cost-effectiveness of current practice? What would be the cost-effectiveness of expanding the program? How does preventive surgery fit within screening program? Rationale: –MRI screening for breast cancer is more sensitive than mammography, but less specific and more expensive Advisory Panel: –Genetic counselors from HCP; radiologist and oncologists from Breast Tumour Group; VP of Population Oncology 6 MRI for Breast Cancer Screening

7. 7 Markov Model Design Mammography Diagnostic work-up (screen-detected) Metastatic relapse Diagnostic work-up (non-detected) MRI screen Well DistantIn SituLocalRegional Dead false negatives false positives Mammography (2) MRI screen (2) true positives 1. Screening and Diagnostics 2. Treatment 3. Outcomes

8. 8 Local BRCA1/2 Population 98 with no cancer 68 patients with complete records 871 women with BRCA1/2 test results in 2002-2007 203 confirmed BRCA1/2 mutation positive 105 BRCA1/2 positive breast cancer cases 87 patients with first breast cancer 668 mutation negative or uninformative 18 with prior cancer or missing stage information 19 patients diagnosed before 1995

9. SensitivitySpecificity % (95% CI) MRI77 (70-84)86.3 (80.9-91.7) Mammography39 (37-41)94.7 (93.0-96.5) Combined94 (90-97)77.2 (74.7-79.7) 9 Screen Effectiveness Used pooled sensitivity to calculate conditional probabilities – sensitivity of either screen given false negative from the other Warner, 2008 (Ann Intern Med. 148: 671-679)

10. Pooled MRI- and mammography-detected cancers from 4 MRI screening studies Distribution of non-screen-detected cancers from US SEER data in pre- screening era 10 Stage Distribution Method of detection MRIMammographyNot screen-detec. (%, 95% CI) In Situ 16 (10-22)27 (17-38)5 (3-6) Local 68 (62-72)49 (38-58)48 (46-50) Regional 16 (10-22)22 (12-31)40 (37-42) Distant 1 (0-4)2 (0-11)8 (6-9) Kuhl, 2005 (J Clin Oncol. 23:8469-8476); Warner, 2004 (JAMA. 292:1317-1325); Leach, 2005 (Lancet. 365:1769-1788); Hagen, 2007 (Breast. 16:367-374); Lee, 2008 (Radiology. 246:763-771)

11. MRI scan: $277 –Average of estimates from BCCA and 2 regional health authorities –Includes radiologist cost, other staff costs (technologist and clerical), supplies and support costs Bilateral Mammogram: $95 Average diagnostic work-up: $175 –Mix of diagnostic mammograms, ultrasound, biopsies and consults –Used individual-level data from screening mammography program, and provincial insurance fee schedule 11 Screen Costs

12. Mammography Only (%) MRI & Mammography (%) Incidence 45.4 Program sensitivity 71.092.7 Average specificity 92.486.7 Stage Distribution In Situ 20.918.2 Local 48.861.0 Regional 26.819.1 Distant 3.61.7 Survival 83.785.1 Increment Cost ($) 3,7877,7493,962 Effectiveness (QALY) 17.23017.2880.058 Cost-Effectiveness ($/QALY) 22044868,498 12 Cost-Effectiveness of MRI

13. VariableRangeICER range MRI sensitivity0.85-0.7056,414-84,972 MRI specificity0.95-0.8058,257-77,809 In Situ0.20-0.1060,491-82,411 Local0.75-0.6059,571-80,874 Regional0.10-0.2052,388-88,017 Distant0.005-0.0263,839-80,986 Cost of MRI200-70048,790-176,420 Discount rate0-0.0532,569-68,498 13 One-way Sensitivity Analysis

14. 25%Median75% Incremental cost ($) 3,4533,9314,451 Incr. effectiveness (QALY) 0.0470.0640.082 ICER ($/QALY) 43,38159,31383,461 14 Probabilistic Sensitivity Analysis

15. Annual screening of BRCA1/2 mutation carriers with MRI and mammography, compared to mammography alone, is cost- effective, given the low cost of MRI –ICER of $68,500 is within Agency’s generally accepted range –For current program size (approx. 200 women), incremental cost of MRI screening is $800,000, for 12 QALYs gained Limitations: –Assumes full participation starting at age 25, with no movement into/out of screening program –Variability in current practice due to geography, wait times, etc. –Data: used BRCA1/2-specific local data where possible, but it was often not possible 15 Conclusions – MRI Model

16. Comparable to findings from studies in US and UK: –$55,500/QALY for BRCA1 and $130,500/QALY for BRCA2 (Plevritis, 2006) around $86,000 for population mix seen at BC Cancer Agency –£13,500/QALY (Norman, 2007) screening for 10-year intervals (30-39, 40-49 yrs) only –$180,000/QALY (Moore, 2009) sensitive to cost of MRI; decreased to <$50,000/QALY when cost of MRI $315 –$69,000/QALY for BRCA1 carriers (Lee, 2010) Conclusions – MRI Model 16

17. Engagement of MRI Advisory Panel been good throughout –Interested in development of model; provided valuable direction and feedback at each stage –Challenge to communicate between disciplines Interest in further modeling –Recommended ages for MRI screening –Expanding to lower risk groups: BRCA1/2 mutation negative or unconfirmed –Incorporation of preventive mastectomy and/or oophorectomy Cost-effectiveness evidence being used in evaluation of screening program 17 Conclusions – EBMA Process

18. Steering Committee and BC Cancer Agency Executive also committed to process –Combination of top-down and bottom-up engagement is necessary Participant interviews and qualitative analysis –Variety of perspectives on priority-setting Future direction for EMBA project –Levels of evidence required to support decision-making –When to build new models and when to use existing evidence 18 Conclusions – EBMA Process

19. Acknowledgements 19 Stuart Peacock, Lindsay Hedden and Elena Papadakis Advisory Panel members: Linlea Armstrong, Stephen Chia, Andrew Coldman, Barbara McGillivray, Charmaine Kim- Sing, Jenna Scott and Christine Wilson BC Cancer Agency Provincial Systemic Therapy Program Canadian Institutes for Health Research