1. Agency for Healthcare Research and Quality Advancing Excellence in Health Care www.ahrq.gov US Preventive Services Task Force Diana Petitti, MD, MPH Arizona State University

2. Advancing Excellence in Health Care Today’s outline Background on the USPSTF Background on the USPSTF USPSTF Analysis and Recommendation on Breast Cancer Screening USPSTF Analysis and Recommendation on Breast Cancer Screening

3. Advancing Excellence in Health Care U.S. Preventive Services Task Force 16 member independent, volunteer panel convened by AHRQ 16 member independent, volunteer panel convened by AHRQ Non-Federal experts in clinical prevention and primary care Non-Federal experts in clinical prevention and primary care Use evidence to create new and updated recommendations on screening, counseling, and medications to prevent illness Use evidence to create new and updated recommendations on screening, counseling, and medications to prevent illness

4. Advancing Excellence in Health Care USPSTF Relevant to practice of primary care for asymptomatic persons AND average risk persons Relevant to practice of primary care for asymptomatic persons AND average risk persons Uses systematic, unbiased evidence reviews to gather data on both benefits and harms Uses systematic, unbiased evidence reviews to gather data on both benefits and harms

5. Advancing Excellence in Health Care USPSTF The USPSTF does not use cost or cost effectiveness data in making recommendations The USPSTF does not use cost or cost effectiveness data in making recommendations The USPSTF does not make insurance coverage or policy determinations The USPSTF does not make insurance coverage or policy determinations

6. Advancing Excellence in Health Care USPSTF New member nominations are sought each year from the public and from partner organizations through a Federal Register notice New member nominations are sought each year from the public and from partner organizations through a Federal Register notice – Requirements for nominees Expertise in prevention and primary care Expertise in prevention and primary care Strong experience in critical appraisal of evidence Strong experience in critical appraisal of evidence Primary care experience Primary care experience – New members are named by the AHRQ Director

7. Advancing Excellence in Health Care The making of a recommendation Each systematic review starts with an analytic framework and key questions Each systematic review starts with an analytic framework and key questions Project at this stage is informed by Project at this stage is informed by – Previous evidence review and recommendation (if an update) – Topic Prioritization workgroup of the USPSTF – 3-4 member topic workgroup of the USPSTF – Evidence-based practice center (EPC) Principal Investigator and team

8. Advancing Excellence in Health Care Analytic Framework on Screening for a Disease

9. Advancing Excellence in Health Care USPSTF Recommendations On Breast Cancer Screening

10. Advancing Excellence in Health Care Breast Cancer Screening Recommendation Update of 2002 recommendation begun in 2007 Update of 2002 recommendation begun in 2007 Two reports commissioned by AHRQ: Two reports commissioned by AHRQ: – An updated systematic review and meta- analysis of trial data, including new information from large databases – A collaborative modeling study from the Cancer Information and Surveillance Network (CISNET)

11. Advancing Excellence in Health Care Systematic Evidence Review

12. Advancing Excellence in Health Care Updated Systematic Evidence Review- (SER) PI: Heidi Nelson, Oregon Evidence-based Practice Center (EPC) PI: Heidi Nelson, Oregon Evidence-based Practice Center (EPC) Trials of screening with breast cancer mortality as outcome Trials of screening with breast cancer mortality as outcome – New trial from UK, updates from older trials Harms of screening: radiation exposure, pain, adverse psychosocial responses, overdiagnosis, false positive mammograms, additional imaging, biopsies Harms of screening: radiation exposure, pain, adverse psychosocial responses, overdiagnosis, false positive mammograms, additional imaging, biopsies – Using primary data from the Breast Cancer Surveillance Consortium (BCSC).

13. Advancing Excellence in Health Care SER Results Film Mammography 8 screening trials for age 39 – 49 year olds indicate reduced breast cancer mortality in screened women 8 screening trials for age 39 – 49 year olds indicate reduced breast cancer mortality in screened women 1 screening trial for ages 70-74 years indicates no mortality reduction 1 screening trial for ages 70-74 years indicates no mortality reduction

14. Advancing Excellence in Health Care SER Results New evidence for women 40-49 Age Trial, in United Kingdom Age Trial, in United Kingdom Annual mammography to age 48 yrs vs. ‘usual care’ Annual mammography to age 48 yrs vs. ‘usual care’ Results Results – Breast cancer mortality RR 0.83 (0.66- 1.04) – Number needed to invite 2,512 (1,1,49- 13,544)

15. Advancing Excellence in Health Care SER results New Evidence for Women 40-49 Additional follow-up for the Gothenburg trial Additional follow-up for the Gothenburg trial RCT of mammography among women aged 39-59 in Gothenburg, Sweden in 1982 RCT of mammography among women aged 39-59 in Gothenburg, Sweden in 1982 Results Results – Breast cancer mortality RR 0.69 (0.45- 1.05)

16. 0.2 0.5 1 2 5 34/11,724 59/14,217 22/9,582 16/5,031 53/13,568 66/12,279 64/13,740 82/13,740 105/53,884 251/106,956 105/25,214 108/25,216 31/10,285 30/10,459 34/14,303 13/8,021 437/152,300 615/195,919 Gothenburg (2003) Kopparberg (1995) Malmo (2002) HIP (1986) Age (2006) CNBSS-1 (2002) Ostergotland (2002) Stockholm (2002) Total 0.69 (0.45, 1.05) 0.72 (0.38, 1.37) 0.73 (0.51, 1.04) 0.78 (0.56, 1.08) 0.83 (0.66, 1.04) 0.97 (0.74, 1.27) 1.05 (0.64, 1.73) 1.47 (0.77, 2.78) 0.85 (0.75, 0.96) Favors screening Favors control Screened Control Relative Risk for Breast Cancer Death (95% CI) Cases/N Study (yr) Meta-analysis of Screening Trials of Women Age 39 to 49 Years Meta-analysis of Screening Trials of Women Age 39 to 49 Years 16 SER Results

17. Summary of Meta-analyses of Screening Trials For All Age Groups Summary of Meta-analyses of Screening Trials For All Age Groups Age Groups Number of trials RR for Breast Cancer Death (95% CI) NNI to Prevent 1 Breast Cancer Death (95% CI) 39-4980.85 (0.75-0.96)1,904 (929-6,378) 50-5960.86 (0.75-0.99)1,339 (322-7,455) 60-6920.68 (0.54-0.87)377 (230-1,050) 70-7411.12 (0.73-1.72)Not available Trials and their acronyms are discussed in the text. Abbreviations: RR, relative risk; CI, confidence interval; NNI, number needed to invite to screening. 17 SER Results SER Results

18. Advancing Excellence in Health Care SER Results Harms of Screening Mammography Radiation – per study very low Radiation – per study very low Pain – common, transient Pain – common, transient Adverse psychosocial responses – anxiety, distress, worry Adverse psychosocial responses – anxiety, distress, worry Overdiagnosis Overdiagnosis – estimates vary - 9 European studies from 1 to 10%

19. Advancing Excellence in Health Care SER Results Illustration of Overdiagnosis: Rates of Invasive Cancer and DCIS Invasive cancer 2.74.56.37.8 DCIS0.91.41.61.6 19 Age (yrs) Invasive Cancer DCIS Number per 1000 Women Screened

20. SER Results: Harms of Screening- Rates of False Positive and False Negative Mammograms False Pos9.88.77.96.6 False Neg0.1 0.2 20 False Positive False Negative Age (yrs) Rates (%) 12 10 8 6 4 2 0

21. Advancing Excellence in Health Care SER results Breast Self Examination Benefits: Two trials conducted in countries (China, Russia) without mass mammography screening Benefits: Two trials conducted in countries (China, Russia) without mass mammography screening – No mortality reduction in either trial Harms Harms – Increased benign biopsy rates in the BSE group compared to controls

22. Advancing Excellence in Health Care SER Results Clinical Breast Examination RCTs in countries without mass mammography screening (one discontinued, two underway) RCTs in countries without mass mammography screening (one discontinued, two underway) Canadian trial from the 1980’s compared mammography plus CBE plus BSE versus CBE plus BSE and found no difference in mortality between groups. Canadian trial from the 1980’s compared mammography plus CBE plus BSE versus CBE plus BSE and found no difference in mortality between groups. Harms- inconclusive data, potential harms include false positives, anxiety, excess imaging and benign biopsies Harms- inconclusive data, potential harms include false positives, anxiety, excess imaging and benign biopsies

23. Advancing Excellence in Health Care SER Results Digital Mammography and MRI No studies of MRI screening in average risk women No studies of MRI screening in average risk women No trials of digital mammography for screening average risk women. Studies of diagnostic accuracy suggest similar to film mammography and more accurate in younger women and those with dense breasts. No trials of digital mammography for screening average risk women. Studies of diagnostic accuracy suggest similar to film mammography and more accurate in younger women and those with dense breasts.

24. Advancing Excellence in Health Care CISNET Modeling Data

25. Advantages of (Collaborative) Modeling Models can “test” strategies not feasible in the population Models can “test” strategies in large samples Models can ask “what if” questions Multiple models can use common data (“experimental conditions”) and: –“Replicate” experiments –Control the experimental conditions –Provide sense of qualitative ranking –Provide range of plausible quantitative effects Results can inform practice and policy debates

26. Predicted Mortality Dissemination of Adjuvant Therapy Dissemination of Mammography Change in Background Risk Mortality from Other Causes Population Inputs (Common to all models) Efficacy of Treatment Tumor Growth Rates & Metastatic Spread Operating Characteristics of Screening (e.g., sensitivity, lead time) Consequences of Screening (e.g., stage shift, over diagnosis) Post Diagnosis Survival by Tumor Characteristics Model Specific Inputs and Assumptions For: Treatment Alone Screening Alone Treatment and Screening Overview of CISNET Breast Cancer Models Original Objective: Assess Impact of Screening and/or Adjuvant Therapy on Breast Cancer Mortality

27. Outcome Measures -Benefits Two primary measures of benefit of screening (vs. no screening): –% reduction in breast cancer mortality –Life years gained (per 1000 women) Secondary metrics: –Additional change in effect for screening at ages younger or older than 50 to 69..

28. Outcome Measures- Resources and Harms Resources required: –Number of screening mammograms Exposure to harms: –False positive screens –Number of un-necessary biopsies –Detection of tumors never destined to cause breast cancer death (“over diagnosis”) –(NO measure of morbidity or decrement in QOL)

29. % Benefit Maintained Moving from Annual to Biennial Screening by Strategy and Model Screening Strategy Models WMGDSE 50-6968%93%85%75%74%75% 40-6967%97%86%75%73% 45-6970%96%91%78% 74% 40-7970%98%87%78%76%75% 40-8471%97%88%81%77%75% 55-6971%92%91%80% 75% 60-6970%93%86%74% 73% 50-7472%94%89%80%79%76% 50-7970%94%88%78%85%75% 50-8473%95%89%81%79%76% ~70 to 98% of benefit maintained screening biennial

30. Efficiency Frontier Non-dominated Strategies (% Mortality Decline)– Exemplar Model B 60-69 B 50-79 B 50-84 A 50-84 A 40-84 Model S A 50-79 B 50-69 B 50-74 B 40-79 A 40-79

31. Harms: Screen Detection of Invasive Tumors Never Destined to Cause Cancer Death by Age Model assumes that all invasive cancers progress with different age-specific lead times Percent dying in lead time increases steeply in older age due to: –High rate of death from other illnesses –Longer lead time in older age Annual Screening Ages 40-84 Model D

32. Harms: Screen Diagnosis of Tumors Never Destined to Cause Cancer Death Two models (E, W) include: –Some DCIS/small local tumors that never progress (“low malignant potential”) –Screen detection of progressive invasive cancers where death occurs in the lead time from other illness These models project “over-diagnosis” rates several orders of magnitude higher than models without “low malignant potential” tumors Overall, there is uncertainty for this potential harm due to limited primary data upon which to base models

33. Potential Harms: False Positive Results, Unnecessary Biopsies False positives increase in linear fashion with number of mammograms performed (~8.3% rate; varies by age) –If 9 screens  ~0.8 false + per woman –If 18 screens  ~1.5 false + –If 36 screens  ~3.0 false + Adding 10 years screening in younger women adds > 2x as many false positives as adding 10 years at older ages. ~ 7% of false positives lead to “unnecessary” biopsy Based on published age-specific specificity in BCSC:

34. Balance Sheet of Potential Benefits & Harms Starting Ages Shaded =dominated by other strategies *% over-diagnosed invasive cancers within the strategy divided by all cancer cases occurring over life time from age 40. Probability of over-diagnosis is ~10 times higher in models E and W with explicit LMP Model S Potential Benefits (vs. no screening)Potential Harms StrategyAverage Screens per 1000 % Mortality Reduction Breast Cancer Deaths Averted per 1000 Life Years Gained per 1000 # False positives per 1000 # of unnecessary biopsies per 1000 Over diagnosis of invasive cancer* Biennial B 40-691370016%6.11201250880.8% B 45-691180017%6.21161050740.8% B 50-69 890015%5.499780550.7% B 55-69 690013%4.980590410.8% B 60-69 4200 9%3.452340240.6% Annual A 40-692760022%8.316422501581.0% A 45-692260022%8.015218001260.9% A 50-691780020%7.31321350 950.9% A 55-691300016%6.1102 950 670.9% A 60-69 840012%4.6 69 600 420.8%

35. Balance Sheet of Potential Benefits & Harms Stopping Ages *% over-diagnosed invasive cancers within the strategy divided by all cancer cases occurring over life time from age 40. Probability of over-diagnosis is ~10 times higher in models E and W with explicit LMP. Shaded=dominated by other strategies Model SPotential Benefits (vs. no screening) Potential Harms StrategyAverage Screens per 1000 % Mortality Reduction Breast Cancer Deaths Averted per 1000 Life Years Gained per 1000 # False positives per 1000 # of unnecessary biopsies per 1000 Over diagnosis- invasive* Biennial B 50-69 890015%5.4 99 780550.7% B 50-741110020%7.5121 940661.5% B 50-791230025%9.41301020712.1% B 50-841380026%9.61381130793.3% Annual A 50-691780020%7.31321350950.9% A 50-742140026%9.515615701101.7% A 50-792440030%11.117017401222.6% A 50-842690033%12.217818801323.7%

36. CertaintySubstantialModerateSmall Zero or negative HighABCD ModerateBBCD LowInsufficient USPSTF Assessment- Grades Net Benefit (Benefit – Harms)

37. Advancing Excellence in Health Care Summary of New USPSTF recommendations Biennial screening mammography between 50 and 74 years (B grade) Biennial screening mammography between 50 and 74 years (B grade) The decision to start regular screening before the age of 50 should be an individual one and take into account patient context, including values regarding specific benefits and harms (C grade) The decision to start regular screening before the age of 50 should be an individual one and take into account patient context, including values regarding specific benefits and harms (C grade) Previous recommendation was to screen women 40 and older every 1 to 2 years Previous recommendation was to screen women 40 and older every 1 to 2 years

38. Advancing Excellence in Health Care Summary of New USPSTF recommendations The USPSTF concludes evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older (I statement) The USPSTF concludes evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older (I statement) Previous recommendation had no ending date (applied to women 40 and older) Previous recommendation had no ending date (applied to women 40 and older) Insufficient evidence on the additional benefits and harms of clinical breast examination beyond mammography in women 40 or older (I statement) Insufficient evidence on the additional benefits and harms of clinical breast examination beyond mammography in women 40 or older (I statement) This is unchanged from previous This is unchanged from previous

39. Advancing Excellence in Health Care Summary of New USPSTF recommendations USPSTF recommends against clinicians teaching women how to perform breast self- examination (D grade) USPSTF recommends against clinicians teaching women how to perform breast self- examination (D grade) Previous recommendation: teaching BSE was given an Insufficient Evidence rating Previous recommendation: teaching BSE was given an Insufficient Evidence rating Insufficient evidence to assess additional benefits and harms for Insufficient evidence to assess additional benefits and harms for – digital mammography or – magnetic resonance imaging (I statement) These new modalities were not mentioned in the 2002 recommendation These new modalities were not mentioned in the 2002 recommendation

40. Advancing Excellence in Health Care Questions and Discussion Questions and Discussion