AHRQ’s Effective Health Care Program: Applying Existing Evidence to Breast Cancer Prevention and Diagnosis

1. AHRQ’s Effective Health Care Program: Applying Existing Evidence to Breast Cancer Prevention and Diagnosis Friday, December 3, 2010 CALL-IN TELEPHONE NUMBER: (888) 632-5065 ACCESS CODE: 27294007#

2. Questions To submit a question: • Press the “Ask Question” button located at the bottom of the screen. • When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. • Once completed, press the “Submit” button. CALL-IN NUMBER: (888)-632-5065 ACCESS CODE: 27294007# 2

3. Agenda • Brief Overview of Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program- Deborah L. Rogal, Moderator • Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women- Heidi Nelson, M.D., M.P.H., FACP • Comparative Effectiveness of Core Needle and Open Surgical Biopsy for the Diagnosis of Breast Lesions- Karen Schoelles, M.D., S.M., FACP • Q&A from Audience CALL-IN NUMBER: (888)-632-5065 ACCESS CODE: 27294007# 3

4. Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program Deborah L. Rogal, M.P.P. AHRQ’s Office of Communications and Knowledge Transfer 4

5. Patient-Centered Outcomes Research • Also known as comparative effectiveness research • Unbiased and practical, evidence-based information • Compares drugs, devices, tests and surgeries, and approaches to health care • Benefits and harms • What is known and what isn’t • Descriptive, not prescriptive Harms Benefits 5

6. A Framework for Patient-Centered Outcomes Research Evidence Generation Strategies Interventions Conditions Populations Improvements in Health Care Horizon Scanning Evidence Need Identification Dissemination Translation Evidence Synthesis Research Platform Infrastructure – Methods Development – Training 6

7. Research Focus: 14 Priority Conditions Arthritis and nontraumatic joint disorders Cancer Cardiovascular disease, including stroke and hypertension Dementia, including Alzheimer’s disease Depression and other mental health disorders Developmental delays, ADHD and autism Diabetes mellitus Functional limitations and disability Infectious disease including HIV/AIDS Obesity Peptic ulcer disease and dyspepsia Pregnancy including preterm birth Pulmonary disease/asthma Substance abuse 7

8. Research Focus: Priority Populations • Low-income groups • Minority groups • Women • Children • The elderly • Individuals with special health-care needs, such as those with disabilities, those who need chronic care or end-of-life care, or those who live in inner-city and rural areas. 8

9. Effective Health Care Program Translation Products Patient Decision Aid (available soon) Executive Summary Web Site Systematic Review Report Clinician Guide Faculty Slides Consumer Guide Interactive Case Study Policymaker Summary 9 CE Modules

10. Breast Cancer Resources 10

11. Public Involvement Report Translation & Dissemination Topic Generation Topic Refinement Research Review Research Needs Development Topic Development During the Research Process Disseminating the Findings • Nominate topics using the online form • Participate in key question refinement • Comment via the Web on draft key questions and reports Web links Newsletter blurbs Articles or commentaries Web conferences Continuing education 11

12. Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women Heidi D. Nelson, M.D., M.P.H., FACP Research Professor Departments of Medical Informatics & Clinical Epidemiology and Medicine Oregon Evidence-Based Practice Center Oregon Health & Science University 12

13. Prevention strategies for breast cancer currently focus on early detection with screening mammography. Newer approaches target risk reduction: Identification of BRCA mutation carriers Prophylactic mastectomy/oophorectomy for high-risk women Medications Despite availability of medications that reduce risk of primary breast cancer: Not commonly used in the U.S. Unclear how to apply results of recently published trials in clinical practice Background 13

14. Comparative effectiveness review was commissioned by AHRQ for new USPSTF recommendations. Previous recommendations in 2002 include: B Recommendation for High Risk Clinicians should discuss chemoprevention with women at high risk for breast cancer and at low risk for adverse effects of chemoprevention. D Recommendation for Low Risk The USPSTF recommends against routine use of tamoxifen or raloxifene for the primary prevention of breast cancer in women at low or average risk for breast cancer. Background 14

15. Develop & prioritize topic Develop key questions Collect abstracts and papers by searching for published and unpublished studies and registries; and soliciting information from drug companies (to January 2009) Select studies based on predetermined eligibility criteria: Efficacy: RCTs Harms: RCTs, observational studies Risk Models: discriminatory and diagnostic accuracy studies Comparative Effectiveness Review Summary of Available Scientific Evidence 15

16. Abstract data from studies meeting eligibility criteria Evaluate studies for quality and applicability using predefined criteria Statistically combine results of trials in meta-analyses for major health outcomes Evaluate strength of evidence for each comparator and outcome using GRADE criteria Interpret results in the context of strengths and limits of evidence Identify future research needs Comparative Effectiveness Review Summary of Available Scientific Evidence 16

17. Dissemination 17

18. 1: In adult women without pre-existing breast cancer, what is the comparative effectiveness of selective estrogen receptor modulators (SERMs) tamoxifen citrate and raloxifene, and the selective tissue estrogenic activity regulator (STEAR) tibolone, when used to reduce risk for primary breast cancer on improving short-term and long-term outcomes including: Invasive Breast Cancer Noninvasive Breast Cancer including Ductal Carcinoma in situ (DCIS) Breast Cancer Mortality All-Cause Mortality Osteoporotic Fractures Key Questions 18

19. Thromboembolic Events Cardiovascular Events Metabolic Disorders Musculoskeletal Symptoms Genitourinary Outcomes Breast Outcomes Other Malignancies Ophthalmologic Disorders Gastrointestinal/ Hepatobiliary Disorders Others Impacting Quality of Life Key Questions 2: What is the evidence for harms? 19

20. 3: How do outcomes vary by heterogeneity in subpopulations? 4: What methods, such as clinical risk assessment models, have been used to identify women who could benefit from medications to reduce risk of primary breast cancer? Key Questions • Age • Menopausal Status • Use of Exogenous Estrogen • Risk of Breast Cancer • Ethnicity and Race 20

21. Drugs to Reduce Breast Cancer Risk 21 21

23. 0.125 0.25 1 2 Meta-Analysis of Placebo-Controlled TrialsInvasive Breast Cancer Favors Drug Favors Placebo 23 0.5

24. Summary of BenefitsEvents Prevented in Placebo-Controlled Trials *Per 1000 women-years assuming 5 years of treatment. 24

25. Summary of BenefitsEvents Prevented in STAR Head-to-Head Trial 25

26. Outcomes in Subgroups Tamoxifen Reduces breast cancer: Age (≤50/>50) Pre/post menopausal Estrogen use (yes/no) Family history of breast cancer (with/without) LCIS or atypical hyperplasia In National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1, cancer rates were highest and risk reduction greatest: Prior atypical hyperplasia Highest modified Gail model risk category (>5%) Raloxifene Reduces breast cancer: Age (≤60/>60 or ≤65/>65) Age at menarche Parity Age at first live birth Body mass index (≤25/>25) 26

27. Summary of HarmsEvents Caused in Placebo-Controlled Trials *Per 1000 women-years assuming 5 years of treatment. **Results from NSABP P-1 trial. 27

28. Summary of HarmsEvents Caused in STAR Head-to-Head Trial 28

29. Common Side Effects Tamoxifen Hot Flashes Vaginal Symptoms (discharge, dryness) Leg Cramps Bladder Control Problems Raloxifene Hot Flashes Leg Cramps MusculoskeletalProblems Weight Gain Lasofoxifene Leg Cramps Hot Flashes Vaginal Candidiasis Tibolone • Vaginal Bleeding • Reduces Hot Flashes 29

30. Age Age at Menarche Age at First Birth Family History of Breast Cancer in First Degree Relative History of Atypical Hyperplasia Prior Breast Biopsies cancer.gov/bcrisktool/ Selecting Candidates for Therapy Risk Based on Gail Model (≥1.67% 5-year Risk) 30

31. Summary of Risk Model Results Discriminatory Accuracy (16 studies of 9 models) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Excellent Good Worthless 0.55-0.66 True Positive Rate (Sensitivity) 0 .1 .2 .3 .4 .5 .6 .7 .8 .9 1.0 False Positive Rate (1-Specificity) 31

32. Questions To submit a question: Press the “Ask Question” button located at the bottom of the screen. When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. Once completed, press the “Submit” button. 32

33. Comparative Effectiveness of Core Needle and Open Surgical Biopsy for the Diagnosis of Breast Lesions Karen Schoelles M.D., S.M., FACP Director, ECRI Institute Evidence-based Practice Center 33

34. Objectives To describe the process of developing this comparative effectiveness review To describe the findings of the review To describe the implications of the review 34

35. Analytic Framework 35

36. Population Asymptomatic women with an abnormality identified on self-exam or by clinician exam Asymptomatic women with an abnormality identified by screening imaging Ultrasound – solid or mixed Mammography – typically BI-RADS® 4 36

37. ACR Breast Imaging Reporting and Data System (BI-RADS®) 0: Need additional imaging evaluation and/or prior mammograms for comparison 1: Negative 2: Benign finding 3: Probably benign; initial short-interval follow-up suggested 4: Suspicious abnormality. Biopsy should be considered 5: Highly suggestive of malignancy. Appropriate action should be taken 6: Known biopsy-proven malignancy 37

38. Intervention: Core Needle Biopsy (CNB) Hollow core needle inserted percutaneously Usually 11-, 14-, or 16-gauge needles Lesion located by palpation or imaging (stereotactic mammography, ultrasound, or MRI) during the procedure May be inserted multiple times or only once if using vacuum assistance 38

39. Comparator: Open Surgical Biopsy Excisional: Attempted complete removal of abnormality Incisional: Sample of the abnormality Nonpalpable lesions: May first use imaging to place marking wire, carbon particles, dye, etc. which is then used by the surgeon to identify the lesion in the operating room 39

40. Comparator: Clinical Follow-Up Clinical and imaging followup for at least 6 months 40

41. Methods 41

42. Evaluation of the Risk of Bias in Individual Studies Based on the QUADAS tool: BMC Med Res Methodol 2003 Nov 10;3(1):25. PMID: 14606960 42

43. Test Characteristics Sensitivity, specificity – commonly understood Sensitivity = TP/(TP+FN) Specificity = TN/(FP+TN) Predictive values – incorporates prevalence Positive predictive value = TP/(TP+FP) Negative predictive value = TN/(FN+TN) Likelihood ratios – independent of prevalence, but clinical use requires assessment of pre-test probability 43

44. Test Characteristics Likelihood ratio – useful for comparing tests Positive likelihood ratio = (TP/(TP+FN))/(FP/(FP+TN)) Negative likelihood ratio = (FN/(TP+FN))/(TN/(FP+TN)) For this evaluation, not missing a cancer was considered the most important outcome, reflected by: Sensitivity, Negative Predictive Value and Negative Likelihood Ratio 44

45. Fagan’s Nomogram Fagan TJ Letter: Nomogram for Bayes theorem. N Engl J Med 1975; 293:257. Interactive version: http://www.cebm.net/index.aspx?o=1161 45

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48. DCIS: Ductal carcinoma in situ 48

49. ADH: Atypical ductal hyperplasia 49

50. Overall Strength of Evidence for Each Question-Outcome Pair Risk of bias in the studies included to answer the question Quantity of evidence (number of studies and patients) Consistency of the findings across and within studies Robustness of the results (sensitivity analyses) Possible grades: high, moderate, low, or insufficient 50