1 Screening Mammography Update 2017Gaelyn Scuderi, M.D. Diagnostic Radiologist Breast Imaging and Intervention

2 Disclosures: I have no disclosures or conflicts of interest related to this presentation.

3 Objectives Summarize the current controversies surrounding screening mammography. Outline existing recommendations for screening mammography. Define parameters for usage of supplemental screening modalities.

4 Screening Mammography GuidelinesAmerican College of Radiology (ACR) Society of Breast Imaging (SBI) American Cancer Society (ACS) US Preventative Services Task Force (USPSTF) USPSTF ACS ACR/SBI More conservative At the current time there are three primary sets of guidelines regarding utilization of screening mammography for the early detection of breast cancer. While other professional societies also put forth additional guidelines (for instance the American Society of Breast Surgeons or the American Congress of Obstetrics and Gynecology), these other guidelines are in large part similar to one or multiple of the three major sets of guidelines put forth by our three major players: the ACR/SBI, the ACS, and the USPSTF. The classical approach to screening (annual mammography for women 40 and above) that has been employed up until the release of the initial USPSTF guidelines in 2009 is endorsed by the American College of Radiology and the Society of Breast Imaging, most updated version of which was published in 2010 in the JACR. The American Cancer Society published differing recommendations in October 2015 in JAMA. The USPSTF released initial recommendations in 2009 which have been reevaluated and re-released in January 2016 online and February 2016 in print in the Annals of Internal Medicine. These three sets of recommendations fall on a spectrum, with the USPSTF representing the least conservative approach in the early detection of clinically silent breast malignancy and the ACR/SBI representing the most conservative approach to screening mammography. Multiple Guidelines Less conservative

5 These three differing sets of guidelines have been formed because there has been a shift in consciousness within both the scientific community and in the larger public regarding screening mammography in the last 5-10 years. Whereas screening mammography was initially lauded from the public health perspective as a powerful tool in the general advancement of women’s health care, the conversation has shifted to a risk-benefit discussion, with many parties trying to nail down with statistical certainty the true benefits of screening mammography and weigh them against the potential risks inherent in looking for the presence of disease in otherwise asymptomatic women. RISK vs. BENEFIT

6 Controversies in Screening MammographyBENEFITS Mortality Reduction Since institution of widespread mammography screening in the 1980’s, US breast cancer death rate has declined by approximately 30% So let’s start on a high note and consider the benefits of screening mammography. Chief among these and the driving force behind the widespread institution of screening mammography are multiple powerful studies showing that screening mammography results in a substantial decrease in breast cancer mortality of approximately 30%. Two of the most referenced studies include: Hellquist (2011, Cancer) – largest RCT (620,000+ women) on breast cancer screening Tabar (2011, Radiology) – longest running (29 year f/u) RCT on breast cancer screening

7 Controversies in Screening MammographyBENEFITS Mortality Reduction Absolute mortality benefit is subject of hot debate American Cancer Society (ACS) and the American College of Radiology/Society of Breast Imaging (ACR/SBI) agree : Up to 48% in women actually screened Pooled mortality reduction 28-36% in trend studies 25% for invited and 38% for screened in cohort studies 31% for invited and 48% for screened in case-control studies Despite powerful data in support of this mortality benefit, there have been multiple studies in the last few years which have published more modest reductions in mortality with screening mammography. One of the most highly publicized of these was the Canadian National Breast Screening Study published Feb 2014 in the British Medical Journal which found no benefit at all to screening mammography above physical exam plus standard of care surgical and medical therapy. We don’t have time in todays talk to fully dissect the CNBSS study, however it should be known that this study’s methods have been contested, with egregious selection bias (pts with palpable masses were funneled into the screening arm) and substandard mammography practice representing the two biggest knocks on the validity of the study. Despite this controversy in absolute screening benefit, of the three major policy-makers, you should know that 2 out of 3 - the ACR/SBI and the ACS - are in agreement regarding the proven 30% mortality reduction associated with annual screening mammography.

8 Controversies in Screening MammographyBENEFITS Mortality Reduction ACR/SBI, ACS, and USPSTF all cite data which shows that the most lives saved by screening mammography occur when women begin annual screening at age 40 Breast cancer incidence noticeably increases at age 40 Incidence of breast cancer at age 40 is 2x for ages 35-39 1 in 6 breast cancers occur in women in their 40’s Incidence continues to rise until age 80 Additionally, the ACR/SBI, ACS, and USPSTF all agree that absolute MOST lives saved occurs with annual screening of average risk women beginning at age 40. At this point, this remains a non-contested fact. What’s so special about the age of 40 years? Why do we send women for baseline mammography at age 40? *Read second part of slide*

9 Controversies in Screening MammographyRISKS Overdiagnosis False Positive Mammogram False Negative Mammogram

10 Controversies in Screening MammographyRISKS Overdiagnosis Detection of cancer by a screening methodology that would otherwise not have been detected within the person’s lifetime Excess incidence of breast cancer over time in a group exposed to screening versus a group not exposed to screening “Most serious concern” Moving on to a discussion of the Risks of screening mammography. One of the concepts garnering the most press in breast cancer early detection is that of overdiagnosis. What is overdiagnosis? *read slide* In other words, diagnosis of a cancer which would not have affected the person’s life in a clinically significant way How do we determine overdiagnosis? Clearly we cannot randomize patients diagnosed with breast malignancy either invasive or in situ to treatment or placebo. This would be highly unethical! We are left with a backprojection estimate of overdiagnosis, obtained by calculating excess breast cancer incidence over a period of time in a group exposed to screening to breast cancer incidence in a group that has not been screened. In a discussion about the risks of screening mammography, many, including the ACS, have dubbed overdiagnosis the “most serious concern” related to the screening mammography, because of its implications in breast cancer overtreatment, with overtreatment potentially resulting in excess patient morbidity and mortality.

11 Controversies in Screening MammographyRISKS Overdiagnosis Difficult to reliably quantify Invasive cancers only vs. invasive cancers + DCIS Adjust for lead time, trends in incidence, selection bias, etc. Reported rate is widely varied: 5-50% SBI: 10% ACS: it’s there, but no reliable data for magnitude USPSTF: 10-19%, possibly higher The problem with overdiagnosis is that it is really a guesstimate, and there is no single statistical method which is widely accepted as an accurate predictor of overdiagnosis. All statistical analysis methods require some or many presumptions in the calculation of overdiagnosis rates (i.e. “if interaction between region and period is assumed nonexistent….if incidence is assumed constant over time…..etc.“). So the proposed rates of overdiagnosis associated with screening mammography are highly varied, depending on which study you are reading.

12 Controversies in Screening MammographyThis includes a recent news making study published in the Annals of Internal Medicine on Jan 10 of this year 2017 authored by Dr. Karsten Jorgensen which used two different methods in which to calculate overdiagnosis in Denmark and came up with two conspicuously disparate rates. The first method of overdiagnosis projection yielded an overdiagnosis rate of approximately 24% (inclusive of DCIS) and 15% (excluding DCIS), while the second method yielded projected overdiagnosis rates between 39-48% (quite different from the first method’s calculation of 15-24%).

13 Controversies in Screening Mammography…….quite different than rates quoted in a study of Danish women published in February 2013 in the BMJ authored by public health statistician Sisse Njor. This paper used direct patient data to show overdiagnosis in two different Danish counties to be between 1% and 5%.

14 Controversies in Screening MammographyRISKS Overdiagnosis ACR/SBI and ACS agree: Overdiagnosis is real Reported rates of overdiagnosis are overinflated due to statistical and methodological flaws/inconsistencies DCIS accounts for most if not all overdiagnosed breast malignancies Currently, no prospective way for us to know which cancers will prove life threatening and which will not Thankfully, amongst the three major policymakers, there is some agreement between the ACR/SBI and the ACS regarding overdiagnosis. *Read 1st part of slide* As an important sidebar here, a perspective worth consideration is this: the point is often made in the breast imaging community that the problem of overdiagnosis isn’t solved by ceasing to look for the presence of malignancy. Just because some tumors will be more indolent in course doesn’t mean you stop looking for the lethal but still treatable tumors. Some say the problem of overdiagnosis and overtreatment of breast cancer are problems related to DIAGNOSIS and TREATMENT, not detection. Mammography has room to improve, but we have to look at the entire breast cancer care picture, from radiologic detection to histopathologic diagnosis, all the way through treatment and aftercare. *A major take home point to remember: read bottom of slide*

15 Controversies in Screening MammographyRISKS False positive exam What constitutes a false positive? Screening diagnostic screening Screening diagnostic negative biopsy Concern raised for long-term psychosocial harm Ann Fam Med, 2013: up to 3 years of negative psychosocial consequences JAMA Intern Med, 2014: no significant long term anxiety A second risk of mammography screening for breast cancer which is currently a hot topic and influencing policies is the potential of screening mammography to result in a false positive exam. *Read slide*

16 Controversies in Screening MammographyRISKS False positive exam For a women undergoing screening from age yrs False positive recall 61.3% with annual mammography 41.6% with biennial mammography False positive biopsy 7% with annual mammography 4.8% with biennial mammography How big of a problem is false positivity? Recent 2011 study (Hubbard, Annals of Internal Medicine) suggests that for a women undergoing annual mammographic screening, the rates of a false positive study are as follows: (see data) This data suggests that the longer 2 year interval between screening exams significantly decreases the false positivity rate. This type of data has been a primary impetus driving current recommendations by the ACS and USPSTF for biennial mammography in women 55 and older (for the ACS) and women older than 50 (USPSTF).

17 Controversies in Screening MammographyRISKS False negative exam (“Happy Gram”) Increased breast density makes mammographic detection of malignancy more difficult Breast density = proportion of fat to gland Almost entirely fatty Scattered fibroglandular densities Heterogeneously dense which may obscure small masses Extremely dense A third major risk of screening mammography is the False Negative exam. The so-called Happy Gram (a term coined by the areyoudense advocacy group). This risk is real, and it’s the risk of mammography that I, as a breast imager whose clinical mission is to find breast cancer at as early a stage as possible so as to prevent a lethal process, most fear in my day to day practice. What you may or may not realize is that every pair of breasts is quite different. I like to tell my patients that their breasts are like their “feminine fingerprint.” No two pair are alike. Breasts differ of course in size and shape but also in density (proportion of fatty tissue to hormonally active glandular tissue) as well as parenchymal pattern. *Read slide*

18 Almost Entirely Fatty Here are some examples of the different breast densities, directly taken from the most recent BIRADS atlas. As you can see, these predominantly fatty breasts are very easy to see through. They are lucent. An invasive malignancy would be expected to be easily seen in these breasts, as very few malignancies are truly mammographically occult.

19 Scattered FibroglandularDensities In these breast tissues you can see a step-up in overall density related to a relative increase in proportion of hormonally active breast parenchymal tissue (white) relative to breast fat (grey/black).

20 Heterogeneously Dense

21 Extremely Dense

22 Controversies in Screening MammographyRISKS False negative exam (“Happy Gram”) Dense breasts Masking effect Digital Mammography improves false negative rate compared to screen film Increased risk of breast malignancy with increased breast density Heterogeneously dense: RR 1.2 Extremely dense: RR 2.1 Supplemental screening? So as you can see, detecting a subtle mass in the midst of a heterogeneously dense or extremely dense breast can prove quite challenging and the potential for oversight is higher than any of us (as practitioners or patients) would like to accept. This is the so-called “MASKING EFFECT” of breast density….the dense tissue masks or obscures an underlying cancer. Now the advent of digital mammography did improve upon screen film with regards to the masking effect in dense breasts, however remains, like most diagnostic imaging modalities, an imperfect test. A second important piece of this false negative-breast density discussion is the fact it turns out that increasing breast density is in and of itself an independent risk factor for breast malignancy. *read slide* The question has arisen, should we be performing supplemental screening for our women with heterogeneously or extremely dense breasts?

23 This is the most updated map from the areyoudense advocacy websiteThis is the most updated map from the areyoudense advocacy website. The states in pink have passed a breast density notification law, the states in red and blue have bills submitted or which are actively being worked at the state governmental level. In updating this talk and reviewing this most recent map, the advocacy website has now made this map interactive. When you click on each state it tells you where the state is in the process of breast density legislation and gives you a link to receive legislative updates. The areyoudense.org nonprofit has obviously been very influential. What about the stars? These represent states that have, in addition to breast density notification laws, also passed laws requiring insurance companies to provide coverage for supplemental breast cancer screening. Note that this means that in the states in pink which have no stars on thars, women are receiving letters which state that they may have had a noneffective breast cancer screen, that they should consider supplemental screening, but good luck getting that paid for!

24 Controversies in Screening MammographyBreast Density Relative risk of breast density is much smaller than other major risk factors for breast cancer Age Family history Reproductive history Known genetic mutations Mammography is a keystone imaging modality Supplemental screening modalities should never substitute for screening mammography In the question of breast density and how to manage screening there are a couple of issues to consider. First of all, it turns out that, in the big picture, the increased risk of malignancy associated with breast density really isn’t that great when compared to other more common risk factors such as *read slide* Also, regardless of breast density, mammography is still a keystone imaging modality – it provides our road map so to speak of the “feminine fingerprint” upon which breast ultrasound and breast MRI (which are more correlative modalities) are interpreted. Since the breast density issue has become more widely discussed, there has been a substantial uptick (at least from my end as a breast imager) of women requesting to forgo mammography entirely, wanting whole breast ultrasound or breast MR in lieu of mammography. What do I tell my patients? The short answer is NO – a negative MRI or whole breast ultrasound may provide a false sense of security…which brings us back to the risk of having a false negative exam…..which is the whole reason that breast density came up as an issue in the first place. Even the areyoudense group advocates in favor of screening mammography first for women with dense breasts.

25 Controversies in Screening MammographyBreast Density High risk women (>20% lifetime risk) Supplemental screening with annual breast MRI, regardless of breast density Performed at six month intervals to screening mammography Endorsed by multiple groups: American Cancer Society (ACS) National Comprehensive Cancer Network (NCCN) American College of Radiology/Society of Breast Imaging (ACR/SBI) American Society of Breast Surgeons (ASBS) So here are some guidelines, well summarized in a recent Radiographics article written by Phoebe Freer in 2015 regarding supplemental breast cancer screening. *read slide* PLEASE NOTE – there is no guidance on this slide on the performance of supplemental screening whole breast ultrasound…….more to come on that in a couple slides.

26 Controversies in Screening MammographyBreast Density Intermediate-risk women 15-20% lifetime risk ACS: Not enough information to recommend for or against yearly supplemental screening MRI Average-risk women Supplemental screening in women who are of average or low risk is not currently recommended by most major medical societies or evidence-based review studies, regardless of breast density *Read slide*

27 Controversies in Screening MammographyBreast Density Whole breast screening ultrasound No additional value added in high-risk women who can undergo supplemental screening breast MRI If breast MRI contraindicated (pacemaker, contrast allergy, lack of vascular access), then whole breast supplemental screening ultrasound may be considered Incremental cancer detection rate /1000 PPV3 is extremely low: 6-7% Recall rate estimated 2x compared to mammography Biopsy rate 3x compared to mammography A quick word or two about whole breast screening ultrasound which you may pass on to your patients: *read slide* PPV3 - positive predictive value for malignancy of biopsied lesions detected at screening

28 Screening Mammography GuidelinesAmerican College of Radiology (ACR) Society of Breast Imaging (SBI) American Cancer Society (ACS) US Preventative Services Task Force (USPSTF) USPSTF ACS ACR/SBI More conservative Multiple Guidelines Less conservative

29 Screening Mammography GuidelinesAmerican College of Radiology and Society of Breast Imaging Yearly screening beginning at age 40 for average risk females Remember that the ACR/SBI guidelines are based on MAXIMAL MORTALITY BENEFIT

30 Screening Mammography GuidelinesAmerican College of Radiology and Society of Breast Imaging Yearly screening beginning at age 40 for average risk females Yearly screening beginning at age 30 for females with 20% or greater lifetime risk BRCA 1 or 2 positive family history risk calculation premenopausal first degree relative or ten years earlier than the youngest family member diagnosed with breast malignancy, not before age 25 Yearly within 8 years of mantle irradiation (≥ 25 yrs) Yearly in all women with biopsy-proven breast cancer or ovarian cancer

31 Screening Mammography GuidelinesAmerican College of Radiology and Society of Breast Imaging Continue screening indefinitely as long as: 5-7 years of remaining life expectancy Willing to undergo additional testing (biopsy) and at least limited treatment How long should screening continue?

32 Screening Mammography GuidelinesAmerican Cancer Society Yearly screening from ages 45-54 for average risk females Access to annual screening for women years Why start at 45? The ACS looked at multiple sources of data and considered women not just in terms of decades but broken down into groups separated at 5 year intervals (i.e , 45-49, 50-54, etc.). They found the incidence of breast cancer in women was similar to women 50-54, but about a third greater than in women Also used to derive the age 45 starting point was the large scale Hellquist study that was noted at the beginning of this talk as one of the keystone studies showing mortality benefit of screening mammography. This study examined outcomes of women ages exposed vs not exposed to screening over a 16 year follow-up interval: women had a 32% mortality reduction while women had an 18% mortality reduction. Data such as this in combination with the inverse relationship of age at screening to rate of false positive biopsy informed the ACS guidelines recommending initiation of screening mammography at age 45.

33 Screening Mammography GuidelinesAmerican Cancer Society Biennial screening in women >55 years for average risk females OR Access to annual screening Remember our previous discussion regarding false positivity rates and annual vs. biennial screening? It is this concept which influenced the biennial periodicity in this older age group. The ACS also took into consideration data from a 2009 article published in the Annals of Internal Medicine written by the Breast Cancer Working Group of the CISN (Cancer Intervention and Surveillance Modeling Network) showing that relative benefits of annual vs biennial screening are less after menopause and as women get older. The ACS did acknowledge, however, that in the same very CISN study, it was demonstrated that annual screening resulted in higher reduction in breast cancer mortality than biennial screening….hence the recommendation for continued access to annual screening. They also acknowledged that the determination of age 55 as the starting point for biennial exam was somewhat arbitrary, with 55 considered “the age at which the large majority of women are postmenopausal.”

34 Screening Mammography GuidelinesAmerican Cancer Society Continue screening indefinitely as long as life expectancy is 10 years or longer Not much different from ACR/SBI which recommends continuation of screening until 5-7 yrs life expectancy

35 Screening Mammography GuidelinesUSPSTF Biennial screening mammography for women years. Grade B USPSTF has excluded all women yrs from the screening pool.

36 Screening Mammography GuidelinesUSPSTF High risk women (known first degree relative with breast cancer) may consider initiating screening at age earlier than 50 years. Grade C

37 Screening Mammography GuidelinesUSPSTF Current evidence is insufficient to assess balance of benefits versus harms of screening mammography in women ≥ 75 yrs Grade I

38 Controversies in Screening MammographyWhy do the USPSTF recommendations matter? Intense criticism of USPSTF methodology No clinician involved in women’s breast health or cancer care was on the panel Decisions were made on a limited number of selected studies, many of which were contested by contrast, ACS used widely accepted IOM guideline development process Development and revision process was closed to input from all stakeholders *read slide* Contested studies include the 2014 CNBSS (Canadian National Breast Screening Study) published in the British Medical Journal

39 Controversies in Screening MammographyWhy do the USPSTF recommendations matter? Hendrick and Helvie, 2011, AJR Preventable loss of life Annual screening at age 40 saves 6,500 more lives a year in the US than USPSTF’s proposed biennial screening beginning at age 50 But even more important than the insurance coverage issues, in the bigger picture here, is the risk to the average American woman. The USPSTF recommendations support a practice which results in otherwise preventable loss of life. In a study authored by Hendrick and Helvie and published in the AJR in 2011….*read slide*

40 Controversies in Screening MammographyHow will USPSTF impact patient care? Women’s Preventative Services Initiative (WPSI) Recommendations Begin screening no earlier than 40 and no later than 50 At least biennial and up to annual frequency Continue screening until at least age 74 Age alone should not determine cessation of screening Recommendations apply only to women of average risk High risk screening considered beyond scope of the WPSI 2019 Released December 20, 2017 the WPSI (Health Resources and Services Administration HRSA + American Congress of Obstetricians and Gynecologists ACOG) recommendations are as follows: *read slide* As these recommendations are reviewed biennially, this guarantees that (click to show year) private insurers must offer coverage for screening mammography with no copay for women age 40 and older.

41 Screening Mammography Update 2017Take Home Points for the Primary Care Physician Screening mammography like all medical tests has RISKS and BENEFITS Major benefit: 30% reduction in death from breast cancer Risks: Overdiagnosis (mostly DCIS) False Positive (diagnostic workup or biopsy that is neg for cancer) False Negative (HappyGram aka breast density) Risk stratification of patients is KEY High risk patients need annual mammography and supplemental screening Maximum mortality reduction benefit = annual screening beginning at age 40 Tradeoff = potential increase in false positive exams Pivot points (in addition to perfecting breast imaging modalities) include continued improvement in characterization of cancer at the pathologic and molecular levels, development of accurate prognostic factors that will help us to predict which malignant lesions will become threatening, and continued refinement of minimally morbid, maximally effective multidisciplinary treatment plans.

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43 References Smith, R.A. Counterpoint: overdiagnosis in breast cancer screening. J Am Coll Radiol. 2014;11:648–652. Hubbard  RA, Kerlikowske  K, Flowers  CI,  et al.  Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study. Ann Intern Med. 2011;155(8): Broderson J and Siersma VD. Long-Term Psychosocial Consequences of False-Positive Screening Mammography. Ann Fam Med. March/April 2013; 11: ; doi: /afm.1466. Tosteson AA, Fryback DG, Hammond CS, et al. Consequences of False-Positive Screening Mammograms. JAMA Intern Med. 2014;174(6): doi: /jamainternmed Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA ;311(24):2499–507. Rose SL, Tidwell AL, Bujnoch LJ, et al. Implementation of breast tomosynthesis in a routine screening practice: an observational study. AJR Am J Roentgenol. 2013;200(6):1401–8. Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population- based screening program. Radiology. 2013;267(1):47–56. Freer PE. Mammographic breast density: impact on breast cancer risk and implications for screening. RadioGraphics 2015; 35:302–315 Mandelblatt  JS, Cronin  KA, Bailey  S,  et al; Breast Cancer Working Group of the Cancer Intervention and Surveillance Modeling Network.  Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med. 2009;151(10):

44 References "Are You Dense Advocacy | D.E.N.S.E.®." Are You Dense Advocacy | D.E.N.S.E.®. Web. 14Jan2017. Surveillance, Epidemiology, and End Results Program. (n.d.). Retrieved April 23, 2016, from "Provider Resources. End The Confusion ACR/SBI Talking Points: ACS Mammography Guidelines.” Society of Breast Imaging. retrieved 23 Apr from "Provider Resources. ACR Mammography Study Brief.” Society of Breast Imaging. retrieved 25 Apr from https://www.sbi- online.org/Portals/1/Position%20Statements/ACS/ACR%20Mammography%20Study%20Brief.pdf. Evidence Summary: Harms of Screening for Breast Cancer. (n.d.). Retrieved April 23, 2016, from Women’s Preventative Services Guidelines. Retrieved 14 Jan 2017 from https://www.hrsa.gov/womensguidelines2016/. HRSA Takes Next Step in Updating the Women’s Preventative Services Guidelines. 20 Dec Retrieved 14 Jan 2017 from https://www.hrsa.gov/about/news/pressreleases/161220womensguidelinesupdates.html. ACR and SBI Support Mammography Insurance Coverage Required by New HRSA Breast Cancer Screening Guidelines. 22 Dec Retrieved 14 Jan 2017 from https://www.sbi-online.org/Portals/0/Position%20Statements/HRSA%20Requires%20Mammo%20Coverage.pdf. Conant, Emily and Philpotts, Liane. September White Paper, Digital Breast Tomosynthesis for Screening and Diagnostic Imaging. Retrieved 16 Jan 2017 from Diagnostic%20Imaging-September% pdf.

45 References Berg, Wendie and Harvey, Jennifer. September White Paper, Breast Density and Supplemental Screening. Retrieved 14 Jan 2017 from Women’s Preventative Services Initiative (WPSI). Retrieved 14 Jan 2017 from Womens-Health-Care/Womens-Preventive-Services-Initiative. Jørgensen KJ, Gøtzsche PC, Kalager M, Zahl P. Breast Cancer Screening in Denmark: A Cohort Study of Tumor Size and Overdiagnosis. Ann Intern Med. [Epub ahead of print 10 January 2017] doi: /M Njor, SH, Olsen AH, Blichert-Toft M, et al. Overdiagnosis in Screening Mammography in Denmark: Population Based Cohort Study. BMJ 2013;346:f1064.