Overdiagnosis of Breast Cancer: Myths and Facts

Transcription

1 Overdiagnosis of Breast Cancer: Myths and Facts Mark A. Helvie, MD Department of Radiology Comprehensive Cancer Center University of Michigan Health System April 7, 2016

2 Objectives Define overdiagnosis Contrast benefits of screening with harm of overdiagnosis Review assumptions inherent re overdiagnosis Estimate magnitude of overdiagnosis from mammographic screening

3 Overdiagnosis: Breast Cancer Screening Detection of a breast cancer at screening that would not have been diagnosed by usual care or become clinically evident in a woman s lifetime

4 Causes of Overdiagnosis Death due to other causes prior to impact of cancer diagnosis Non progressive invasive cancer or in-situ cancer In era of personalized medicine, desire to successfully treat those who will benefit most and cause minimal morbidity for those who may benefit the least

5 Why do we screen? To save lives from breast cancer

6 Female Cancer Estimates 2016 USA New Cases Deaths Breast 246,660 (+60,000 DCIS) 40,890 Colon 47,560 23,170 Cervical 12,990 4,120 Lung 106,470 72,160 Pancreas 25,400 20,330 ACS. Cancer Facts and Figures, 2016

7 Oeffinger et al. JAMA 2015;314(15): ; Siu et al Ann Intern Med 2016;164:

8 Mammographic Screening Benefit ( ACS and USPSTF) Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health ACS 2015 (IOM review) USPSTF found adequate evidence that mammography screening reduces breast cancer mortality in women aged USPSTF 2016 Oeffinger et al. JAMA 2015;314(15): ; Siu et al Ann Intern Med 2016;164:

9 USA Female Breast Cancer Mortality Rate is now declining = 36% 249,000 deaths averted due to Screening and Treatment Greater decline if Mortality trend used ACS 2014, SEER 2015, ACS 2016

10 Mortality Trend among African American and Hispanic women 1.5% per year seer.cancer.gov/laccessed July 2015

11 Mammographic Screening RCT: UK Review 20% mortality reduction Marmot et al British Journal of Cancer (2013) 108,

12 Case Control and Incidence-Based Mortality Studies American Cancer Society review 38-48% reduction 4 Oeffinger et al. JAMA 2015;314(15):

13 Screening outcomes CISNET: 2015 (median) Age Range LYG/1000 Mortality Reduction B % A % A NA NA Difference B50-74 vs A (57%) 12% (47%) Derived from :Mandelblatt et al. AHRQ Publication No EF-4, 2015

14 Overdiagnosis Over diagnosis = pathology Over detection = imaging, PE, genetic tests Over treatment = surgery, RT, oncology Assumes usual care = optimal level of diagnosis Usual care may be under diagnosis when early diagnosis results in improvement in morbidity or mortality

15 Any two levels of diagnosis will define over or under

16 Preference depends upon context of benefit and harm. Optimal level desried. No mortality reduction, some overdiagnosis or 45% mortality reduction, 6% more overdiagnosis

17 It has been clearly demonstrated that screening mammography does just what it is supposed to do: It has reduced death from breast cancer in populations that have routine screening The question is not whether we should find early, more easily treatable cases of breast cancer but rather how to treat early-stage cancer found on mammography. Kaplan et al January 2013 Annals of Internal Medicine Volume 158 Number 1

18 Consideration 1: Definition of disease Is usual care optimal? Is only symptomatic disease real or Is symptomatic disease a failure of modern medicine?

19 Moynihan et al BMJ 2012;344:

20 2014 ACC-AHA statin guidelines 87 % of males age >60 placed on statins most do not have symptomatic CV disease or would experience CV death Extreme case of labeling risk or life saving treatment? Pencina et al N Engl J Med 2014;370:

21 Consideration 2: Is overdiagnosis unique to mammo screening? Pre mammography trends USA Incidence>>mortality prior to mammographic screening. Incidence not constant : acutely or over time (about 1.1% per year) Cancer 1994;74:222-7.

22 Overdiagnosis Estimates: 0-54% (DCIS plus invasive Ca) EUROSCREEN (2012) 1-10% UK Panel (2013) 10.7% ACS (2015)?? USPSTF (2016)? 2-20% DCIS - % progressive (preventative) Older women

23 There is an estimate in the literature to support almost any position on overdiagnosis and, likewise, almost any percentage of DCIS that is nonprogressive. Oeffinger et al. JAMA 2015;314(15):

24 Excess incidence Methods to Estimate BC incidence with vs without screening Historic, non-screened, projections Lead time infers time cancer detection is advanced vs competing causes of death Strong opinions about the frequency of OD based upon existing studies are not warranted Etzioni et al JNCI J Natl Cancer Inst (2016) 108(3):

25 Malmo Trial Over diagnosis estimates ( over whole f/u time period ) Age % Lower for invasive cancer (10.5% for age 55-69) Zackrisson et al BMJ,(2006) 332 Marmot et al British Journal of Cancer (2013) 108

26 Overdiagnosis RCT : 10.7% Cancers (invasive +DCIS) diagnosed over whole follow up period among women invited to screening Marmot et al British Journal of Cancer (2013) 108,

27 Canadian National Breast Screening Study During entire period, excess of 3.8% cancers in screened arm Miller et al. BMJ 2014;348

28 40s 50s RED=Invited Cancer 2012;118: s 70s Yen et al Cancer 2012;118:

29 AGE trial yrs: 0.7% ( %) overdiagnosis Gunsoy et al. Breast Cancer Res 2012;14(6):R152

30 Key considerations Estimating magnitude Complex, multiple methods ( any estimate will therefore be, at best, provisional UK Panel 2013*) Age of population Lead time (decade) Temporal trends in incidence Risk level of population screened ( family history, HT, risk factors) Inclusion or exclusion of in situ cancer *Marmot et al British Journal of Cancer (2013) 108

31 Sweden age Overdiagnosis 1% in situ plus invasive negative 5% invasive Hellquist et al. J Med Screen 2012; 19(1):14-19

32 Denmark overdiagnosis = 33% Nordic Cochrane Centre (NOTE: incidence trend) Jorgesen et al BMC Women's Health 2009, 9:36

33 Denmark overdiagnosis = 2.3% (-3 to 8%) Department of Public Health, University of Copenhagen, Importance of prevalent vs incidence and lead time Njor et al BMJ 2013;346:

34 Iceland screening : Begins 1987 Incidence of invasive cancer 11% Reduction of invasive cancer Sigurdsson and Ólafsdóttir, Breast Cancer: Targets and Therapy (2013):

35 UK screening: incidence trends age Marmot et al British Journal of Cancer (2013) 108,

36 Incidence Trends pre-mammography US 1.1% per year UK 1-2% per year DOI: /bjc

37 Mortality Trend estimates: NCI-CISNET Model Mortality rate was predicted to have increased 1.2% per year due to increasing incidence and demographic trends Berry et al N Engl J Med 2005;353:

38 From 2008 to 2012, Breast Cancer Worldwide: 1. Incidence increased 20% (4% per year) 2. Mortality increased 14% (3% per year) 3. Most Common female cancer death: 522,000

39 Minimal stage shift 31% overdiagnosis - Mammography use not assessed % background incidence trend based upon age <40 trend Bleyer et al N Engl J Med 2012;367:

40 Annual % Change: Helvie et al Cancer Sep1;120(17):

41 Observed vs projected incidence /yr) rate/100,000 % change re projected DCIS % early Localized % 48% Regional 77-39% late Distant 18-26% -37% Total Invasive cancer 276-9% Total breast cancer 7% Helvie et al Cancer Sep1;120(17):

42 Less than expected invasive cancer at APC 1% and higher Helvie et al Cancer Sep1;120(17):

43 Historic APC=1.1% 36yrs Siu et al Ann Intern Med 2016;164:

44 Pro program screened no mammogram No mammogram vs mammogram 0.93 ( ) With risk factor adjustment : 0.97 ( ) Lund et al BMC Cancer ,614

45 Overdiagnosis in mammographic screening Europe (16 estimates, 7 countries) Adjusted vs not adequately adjusted estimates 1-10% Adjusted Not adequately Adjusted Puliti, et al. J Med Screen 2012;19 Suppl1:42 56

46 CISNET 2015 (median) DCIS vs Invasive Cancer Overdiagnosis Screen Intervals All DCIS +Invasive Invasive* B % 2.3% A % 2.8% Mandelblatt et al. AHRQ Publication No EF-4, 2015 (* derived )

47 F/U of misdiagnosed DCIS with later invasive cancer development (initially interpreted as benign, had excision) Rosen 53% developed cancer 10 yrs Eusebi 18% developed cancer 18 yrs Sanders 39% developed cancer 28 yrs Collins 46% developed cancer 9 yrs

48 Progressive DCIS Prevalent screen 63% Incident screen 96% Yen et al Eur. J Cancer (2003)

49 Netherlands - overdiagnosis 1 million annual invitations Micro simulation models Peak at implementation 11.4% Steady State (2006) 2.8% (upper estimate 9.7% screening age only) DeGelder et al, Epidemiol Rev 2011;33:

50 Remember the baseline: Pre mammography trends USA Incidence>>mortality prior to mammographic screening. Cancer 1994;74:222-7.

51 Optimal level of Diagnosis 1000 women age Biennial screening Usual care: 19 deaths/ 67 cases Screen: deaths/ 71 cases Screened to usual care: 6% (4/71) fewer cancer diagnosis 73% (8/11) more cancer deaths Pauci Cancer Epidemiol Biomarkers Prev; 23(7);

52 Overdiagnosis by screening mammography RCT, observational, and computer models show mortality reduction among screened women age 40 and older Screening is associated with some degree of overdiagnosis which must be placed in context of benefit achieved

53 Overdiagnosis is lower for young women, at incident screen, and when restricted to invasive cancer Our future goals should be to optimize treatment of screen detected cancer, some of which may not require aggressive treatment

54 When you improve cancer survival even by a few % points, you re talking about thousands of lives Allen Lichter, MD ASCO President

55 Level of Diagnosis 1000 women age Biennial screening 71 cancers diagnosed 7-9 lives saved (19 deaths w/o screening) 4 (6%) Excess diagnoses Usual care: 19 deaths/ 67 cases Screen: 10 deaths/ 71 cases Pauci Cancer Epidemiol Biomarkers Prev; 23(7);

56 Consideration 3 excess level of diagnosis/treatment most important when benefit is nil Conversely, excess level of diagnosis/treatment is least important when benefit is great Cost of doing business

57 US Females: Incidence vs Mortality seer.cancer.gov/statfacts/html/breast.html Accessed Sept 2015

58 Lake Michigan

59 Acad Radiol 2015; 22:

60 % Change in Cancer incidence by APC estimates

61 10 observational studies: Meta-analysis 49% Mortality Reduction = 96% increase mortality from screen level Nickson C et al. Cancer Epidemiol Biomarkers Prev 2012;21: by American Association for Cancer Research

62 Swedish 2 County RCT 29 year update: Age Cumulative mortality from breast cancer Not Invited InviInvited Significant reduction of BC deaths in invited group means: Excess BC deaths in non invited groups: 45% (harm) Tabár L et al. Radiology 2011;260: by Radiological Society of North America

63 BMJ 2012

64 DCIS Progressive? Precursor (non-obligatory) to invasive cancer Progressive 18-96% Focus of attention and research

65 USA Pre Mammo Screen: Annual Incidence Trend: 1.1% (1-5% worldwide) JNCI, 1997

66 World wide Breast Cancer Incidence Trends preceded mammography Breast Cancer Res. 2004; 6(6):

67 SEER unadjusted: marked increase in localized, 8% decrease in late stage Bleyer, NEJM 2012

68 Change in Disease Stage over 30 yrs Early 48% Late -37% Invasive -9% All CA 7%

69 Research Support: NIH US Army GE Healthcare (DBT) Disclosures Relevant Panels NCCN breast screening and diagnosis Michigan Cancer Control

70 Malmo Trial Over diagnosis estimates (during screen period alone) Age 45-69=15.5% (18.7% for age 55-69) Zackrisson et al BMJ,332, 2006 British Journal of Cancer (2013) 108,

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73 JAMA Oncol. doi: /jamaoncol Published online August 20, 2015.

74 Obamacare Architect Announces The Optimal Age Of Death And You re NOT Going To Like It I think this manic desperation to endlessly extend life is misguided and potentially destructive. For many reasons, 75 is a pretty good age to aim to stop, writes the chief architect of Obamacare Ezekiel Emanuel in The Atlantic. It.

75 2015 CISNET Models

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77 Analysis of survival curves of women with breast cancer suggests that two or more populations exist, with about 40% suffering fatal outcome unaffected by treatment. The remaining 60% exhibit a relative mortality only modestly different from that of women of similar ages without evidence of disease. JAMA 241: , 1979)

78 Female Cancer Estimates 2014 USA New Cases Deaths Breast 232,670 (+67,570 in situ) 40,000 Colon 48,380 24,040 Cervical 12,360 4,020 Lung 108,210 72,330 Pancreas 22,840 19,420 ACS. Cancer Facts and Figures, 2014

79 Harms of Screening 1. Overdiagnosis 2. FP - recalls extra views 3. FP - Biopsy 4. Anxiety/Discomfort 5. Radiation

80 NNS as key metric USPSTF The USPSTF emphasizes the adverse consequences for most women who will not develop breast cancer and therefore use the number needed to screen to save 1 life as its metric. USPSTF 2009, Annals of IM

81 CISNET (USPSTF) data: NNS vs NNI Age Range NNS Annual Screening NNI (Nelson et al) Not Available Overall Not available Hendrick, Helvie AJR 2012

82 2012 CISNET Annual Digital Mammography age / deaths averted = 588 NNS LYG =51 LYG = 20 NNS Biennial to Annual: +42% van Ravesteyn, Ann Intern Med. 2012;156(9):

83 JAMA. 2015;314(15): Ann Intern Med. 2016;164:

84 Mammographic Screening Benefit ( ACS and USPSTF) Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health ACS 2015 (IOM review) USPSTF found adequate evidence that mammography screening reduces breast cancer mortality in women aged USPSTF 2016 JAMA. 2015;314(15): Annals of IM 2016:

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86 Breast Cancer Continuum Normal High Risk In Situ Invasive Micrometast ic Detectable Metastatic Death Normal Duct Intraductal Hyperplasia Atypical Ductal Hyperplasia Ductal Carcinoma In Situ Invasive Ductal Cancer Pre-malignant condition Disease (morbidity & mortality) Screening Palliative Therapy From D Hayes MD

87 From 2008 to 2012, Breast Cancer Worldwide: 1. Incidence increased 20% (4% per year) 2. Mortality increased 14% (3% per year) US data is divergent from overall world trends

88 Overdiagnosis in mammographic screening in Europe ( 16 estimates, 7 countries) Adjusted vs not adequately adjusted estimates 1-10% Adjusted Not adequately Adjusted Puliti, et al. J Med Screen 2012;19 Suppl1:42 56 DOI: /jms