Screening Overdiagnosis. Archie Bleyer, MD Department of Radiation Medicine Knight Cancer Institute at the Oregon Health & Science University

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1 Screening Overdiagnosis Archie Bleyer, MD Department of Radiation Medicine Knight Cancer Institute at the Oregon Health & Science University

2 NNS Bottom Line I To prevent 1 death from breast cancer, 2, y/o women in the U.S. undergo screening mammography every year for 10 years (22,500 mammograms) Screening Overdiagnosis Archie Bleyer, MD Department of Radiation Medicine Knight Cancer Institute at the Oregon Health & Science University 1,250 have >1 false alarm" (more mammograms) 500 undergo a biopsy, 30 are diagnosed to have breast cancer 29 do not have their life saved as a result of screening are overdiagnosed NNS Bottom Line II The (of 30) who are overdiagnosed will be treated needlessly with: Mastectomy or lumpectomy and radiation, to which are currently added: 5 10 years of hormone therapy if ER+ or PR+ a year's worth of IV trastuzumab if her2neu+ chemotherapy if triple neg, non DCIS (local+) Overdiagnosis Reported in 12 Prior Studies NEJM Supplemental Appendix OD Rate 2004 Zahl 2006 Anderson WF, et al Zackrisson 2008 Zahl PH, et al Jørgensen KJ, et al Jørgensen KJ, et al Morrell S, et al Martinez-Alonso M 2012 Hellquist BN, et al Kalager M, et al Zahl PH, et al Puliti D, et al. Norway and Sweden Connecticut, U.S. Malmö, Sweden Four counties in Norway Denmark Various New S. Wales, Australia Catalonia, Spain Two counties in Sweden Entire country of Norway Seven counties in Norway Florence, Italy One-third 40% 24% ** 22% 33% ** One-third 30-42% 47% 5% 15-25% ** ~75% 10% Mean 31.5% U.S. (NEJM) 31% **of screen-detected cancers (other reports are of all breast cancer)

3 Local Magnitude of the Problem Central Oregon (St. Charles) Cancer Registry includes 3000 cases of newly-diagnosed breast cancer since 2000 (after full implementation of screening mammography) implying that Central Oregon has 1000 women who have been treated for breast cancer that wasn t Comparison of Old vs USPSTF Guidelines ACS, NCCN, 40+ Mammograms 30+ msv 1983 Most aggressive worldwide as long as healthy USPSTF, Mammograms Age Heidi Nelson, MD, MPH OHSU Pop Health Metrics 2011;9:16 21 Organizations Weighed In on USPSTF Breast Cancer Screening Guidelines In alphabetical order For (N = 13) Amer. Academy of Family Physicians Amer. Academy of Nurse Practitioners Amer. Academy of Physician Assistants American College of Ob/Gyn American College of Physicians Amer. College of Preventive Medicine Amer. Public Health Association Breast Cancer Action National Association County and City Health Officials National Breast Cancer Coalition National Women's Health Network Partnership for Prevention Public Health Institute Trust for America s Health Against (N = 9) American Cancer Society American College of Radiology American College of Surgeons American Medical Association Society of Clinical Oncology National Cancer Institute National Comprehensive Cancer Network Society for Breast Imaging Susan G. Komen for The Cure September 2011 Central Oregon Medical Society Comparison of USPSTF, Canadian and UK Guidelines UK Canada 2011 USPSTF Mammograms (q3y) 10 ± 2 Mammograms (q2-3y) 13 Mammograms (q2y) 2012: Affirmed by Independent UK Panel on BrCa Screening Age

4 NEJM Report Thanksgiving Day 2012 Comprehensive Critique and Defense of NEJM report Overdiagnosis (U.S.) Best Guess 2008 Rate (of all breast cancer) 31% Number of women 74,000 Number of women since Million % 71, Million The Oncologist early Randomized Trials of Screening Mammography 30 to 50 Years Ago Trial Health Insurance Plan of New York, 1963 Country U.S. Breast Cancer Mortality Benefit 23% (15y) Malmo Study, 1976 Sweden 19% (12y) Two-County Trial, 1977 Sweden 17% (12y) Gothenburg Breast Screening Trial, 1982 Sweden 21% (13y) Stockholm Trial, 1982 Sweden 20% ( 8y) Edinburgh Trial, 1976 Scotland 16% (10y) Natl. Breast Screening Trial 1 (Age 40-49), 1980 Natl. Breast Screening Trial 2 (Age 50-59), 1980 Canada Canada None None 30 years required to eliminate lead time bias [Duffy SL, Parmar D, Br Ca Res. May 2013] Screening included clinical breast exam (15% dx d solely by mammography) No external audit (DSMB) Cause of death biased in favor of screening Randomization flawed actually worse in screened groups Most experts judge the mortality benefit = 10 15% 8 Randomized Trials of Screening Mammography 30 to 50 Years Ago Breast Cancer Trial Country Mortality Benefit Health Insurance Plan of New York, Cochrane U.S. 23% (15y) 1963 Collaboration Analysis, 2011 Malmo Breast Study, cancer 1976 mortality Sweden was an 19% (12y) unreliable outcome biased in favor of Two-County Trial, 1977 Sweden screening, mainly because of differential 17% (12y) Gothenburg misclassification Breast of cause of death Sweden 21% (13y) Screening 3 trials Trial, with 1982 adequate randomization did Stockholm not find Trial, cancer 1982mortality Sweden benefit : 20% ( 8y) Edinburgh Either Trial, breast 1976 cancer, Scotland after 10 years 16% (10y) (RR=1.02, 95% CI ), or Natl. Breast All cause Screening mortality Canada after 13 years None Trial 1 (Age (RR=0.99, 40-49), % CI 0.95 to 1.03) Natl. Breast Screening Canada None Trial 2 (Age 50-59), 1980 How not to design and conduct a randomized clinical trial All cause mortality unaffected Therapy has improved so much in years that: 1) 10 15% screening benefit is not currently applicable 2) Little of the survival progress is due to screening

5 Coakley F, 12/20/13 Annual Breast Cancer Mortality Rate U.S., Deaths per 100,000 Log Scale % decrease Annual Breast Cancer Mortality Rate by 10 Year Age Intervals U.S., Age (Years) Deaths per 100,000 Log Scale Includes Screened Population 80% Dx d before Age Not Screened Not Screened SEER: 224, y/o s diagnosed during Observed Survival (95% CI) 10 year: 80.5% ( ) year: 70.4% ( ) % Females Age Participated in Screening Mammography Annual Age Adjusted Breast Cancer Death Rate Relative to Autier P, et al, BMJ. 2011;343: d4411 ^Bleyer A. BMJ 2011; 343:d5630 *Ireland estimated from Autier s starting dates **Norway relative to Sweden U.S Netherlands Norway Northern Ireland* Republic of Belgium Ireland* and Flanders 0.6 United States^ Netherlands Belgium and Flanders 0.4 Sweden Norway** 0.2 Republic of Ireland Northern Ireland

6 Coakley F, 12/20/13 Pseudodisease Microscopic cancer is common Cancer Autopsy + Prostate cancer 40% Renal cell carcinoma 22% Thyroid cancer 6-36% Breast cancer 5 Autopsy Series: largest 14% 207 consecutive autopsies of women dying of other causes Low grade tumors or DCIS could be slower growing, but we don t know how to predict which ones will eventually become deadly. Estimated to be 0.5%-52% Oh KY, 12/20/13 DCIS: 20 Year Estimate <5% Bhathal PS, et al. (Melbourne) Br J Cancer. 1985;51: Trauma -64, drug overdose -13, sudden natural cause -92, chronic illness -18, surgical or post-surgical death deaths in year-olds Observed and Relative Survival of 149,520 Females Diagnosed with DCIS, , SEER 100% 90% 80% 70% 60% Survival 50% 40% 30% 20% 10% 0% Relative Survival Observed Survival Years after Diagnosis Harms of mammography Psychological harms Unnecessary imaging tests Unnecessary biopsies in women without cancer Pain associated with procedure Inconvenience due to false-positive screening results These factors have been shown to have minimal effect on patients returning to screening Armstrong et al. Ann Intern Med, 2007 Oh KY, 12/20/13 Biopsy negative women suffer psychological stress for at least 6 months that is equivalent to those diagnosed with and treated for breast cancer Brodersen J, Siersma VD. Ann Fam Med. 11(2);106 15, 2012

7 Failure Analysis 70.8% of breast cancer deaths occurred among unscreened women Webb ML, et al. Cancer. Sep 9, [Epub ahead of print] Oh KY, 12/20/13 Letters to the Editor Multiple reasons other than failure to be screened for unscreened women to be more likely to die after breast cancer diagnosis: lower educational and socioeconomic status lack of or compromised health insurance Continued Unscreened women: limited access to healthcare resources less availability for and adherence to diagnostic and therapy recommendations: further from medical center, limited transportation, less family support [and pressure], less ability to take time off from work less participation in clinical trials less motivation to undergo diagnostic, staging, and posttherapy evaluations less use of supportive care including access to psychologists, psychiatrists, and social workers more use of hormone replacement therapy more overweight or obese less likely to be sufficiently active of racial/ethnic minority or unidentified race/ethnicity more often non English speaking or recent immigrant Screening for cancer is widely assumed to be highly effective In fact, screening is based on an imperfect concept and requires rigorous cancer specific mortality based evaluation all-cause For now, screening remains of limited but proven benefit for selected cancers For breast cancer, the limitations are Coakley F, 12/20/13 greater and the benefit much smaller than generally recognized Screening Mammography Good News Breast cancer treatment is better than assumed Randomized trials and advocate organizations have successfully raised awareness Less therapy is being administered to Stage 0 patients IDLE catching on Genomics will ultimately identify who is overdiagnosed Individual coercion ( pinking ) can abate Screening mammography need not be a public mandate Annual national cost ($7.9B/year) can be reduced to as little as $2.4B (Triple Aim 3)