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Editorial

Section Editor’s Notebook: Breast Cancer Screening and Overdiagnosis Unmasked

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arly breast cancer detection and treatment must be weighed against any harm [1]. Successful screening must be safe, effective, and well tolerated and have low false-positive and false-negative rates. The intense debate about breast cancer screening and overdiagnosis is a messy one that cannot go far without a serious discussion of methodology, statistics, and the public trust. The debate has spread well past scientific circles and into the media in the public domain where politics and sensationalism are all too common. It has gone well beyond healthy disagreements over how data should be interpreted. Controversies are raging over which conclusions are best supported by the available evidence and over which research agendas are worth investigating further. The question of whether screening mammography does more harm than good has the potential to shake up the state of medical knowledge, alter our views of ethical practice, and alter our application of screening principles. The stakes are high in this discourse because women’s lives hang in the balance. How important is breast cancer screening? Breast cancer is the second most common cause of cancer death after lung cancer in women. The incidence has stabilized recently and mortality has decreased by 31% since 1989. In 2013, an estimated 232,340 new cases of invasive breast cancer in women and 39,620 breast cancer deaths are expected in women in the United States [2]. After a 7% decrease in incidence rate from 2002 to 2003 (likely due to reduced use of hormone replacement therapy for menopause after publication of the results of the Women’s Health Initiative in 2002), the breast cancer incidence rates have been stable between 2005 and 2009 [2]. If the incidence of breast cancer is really decreasing, can this improvement be attributed to screening with earlier detection, to improved treatment, or both? What are the potential harms of screening mammography? Recently, attention has been drawn to radiation exposure, pain from breast compression, patient anxiety and psychologic responses, false-positive and false-negative results, and overdiagnosis [1]. Measuring the true impact and import of these harms is difficult. Because the absolute radiation exposure of mammography is low, the radiation risk is also low. Patient responses to the procedure, such

as pain and anxiety, are most likely transient. More worrisome are the specters of overdiagnosis and missed cancers. Overdiagnosis means that lesions are detected that are noninvasive and unlikely to become clinically evident in the absence of screening. Overdiagnosis can only be estimated at the population-based level over years of screening, not individually [3]. Length-time bias can result in overdiagnosis if there is unnecessary treatment of detected indolent or slow-growing tumors. Wide-ranging rates of overdiagnosis have been reported, from less than 1% to 50% [1, 4–11]. However, those studies that accounted for cancer incidence during screening and for lead time have estimated overdiagnosis at only 1% to 10% [3–6, 12–19]. These estimates are nonuniform in methodology (incident, prevalent, or cases by age) and differ in their endpoints (invasive cancer vs ductal carcinoma in situ [DCIS]). These heterogeneous methodologies and nonuniform study designs make statistical modeling difficult. Meta-analysis is also challenging because nonuniform data cannot be easily combined. Other factors are also confounding. Because breast cancer is not a single disease but rather a spectrum of histopathology, growth rate, aggressiveness, and responsiveness to therapy, weighing choices regarding screening and treatment against overdiagnosis and other harms is problematic. DCIS detected at screening may be a cause of overdiagnosis [5, 6]. In 2013, 64,640 new cases of in situ breast cancer are expected in women, of which about 85% will be DCIS [2]. It is noteworthy that in situ breast cancer incidence rates increased 2.8% per year from 2005 to 2009 [2]. About 25% of cancers detected at screening are DCIS [20]. The prevalence of DCIS in autopsy series in women without breast cancer has been reported between 9% and 14% [21, 22]. The prevalence at first screening is usually much lower, at about 0.1% [5]. No one knows whether the lesions found at autopsy would be detectable by mammographic screening. Little hard data are available regarding the behavior of DCIS if untreated. Is the risk of having DCIS the same as that of women with no breast carcinoma? The estimates of DCIS detection versus that of invasive cancer come from lesions detected at screening and interval cancer incidence. Whether or not a particular case of untreated DCIS will progress to in-

vasive cancer is uncertain [5]. It is likely that some DCIS may progress to invasive cancer [7, 23], and up to 30% of DCIS treated by local excision alone can recur [12]. How can overdiagnosis be quantified? Estimating overdiagnosis can be done by comparing screened and unscreened cohorts, but there are many sources of error. The risks of breast cancer must be similar in both cohorts. Excess incidence from overdiagnosis must be differentiated from that due to lead-time bias. Lead-time bias without overdiagnosis results in an initial increase in screening detected breast cancers that persists during screening but results in a compensatory drop in incidence in older age groups after screening ends. Overdiagnosis will be overestimated unless there is sufficient follow-up after screening stops [3]. Statistical correction can be made if the follow-up period is short or none. Lead-time bias can be adjusted statistically by postponing the dates of screening-detected cancers for a period equal to the estimated lead-time bias [3]. Even the calculation of overdiagnosis is controversial. Data on incidence, distribution of stages at diagnosis, and numbers of screening-detected and interval cancers must be known to account for the effects of lead-time bias. Measures adjusted for lead-time bias and breast cancer risk are usually compared with cases expected in the absence of screening in the same time period and in a given age range. In comparing screened and unscreened cohorts, the denominator defines the population at risk. However, denominators are nonuniform (e.g., cases expected in the defined screened age range, lifetime expected cases, observed cases in the screened cohort or the invitedto-screen cohort, or screening-detected cancers) [3]. Overestimation of overdiagnosis occurs if no adjustments are made for lead-time bias and breast cancer risk. Further confounding the estimation of overdiagnosis is the wide difference in screening programs nationally and internationally. Screening recommendations by age and frequency are nonuniform. Screening age ranges and compliance for eligible women vary. Lengths of the screening period in various studies differ. The attendance rates for screening tend to decrease with patient age [13, 14]. What effect does this contentious debate about benefit versus harm have on the doctor-patient

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Editorial partnership during counseling about screening mammography? In this era of social media and lightning-fast digital access to information, it is imperative that physicians take responsibility for engaging with patients to discuss screening. Patients are entitled to make an informed decision about screening and deserve to hear a balanced discussion of the possible harm and benefit. How should this discussion of benefit versus harm be communicated to our patients when even the experts disagree? In counseling patients, some have advocated for a discussion of how many women must be screened per life saved compared with how many women are screened for each case of overdiagnosis. Another approach to offering informed consent is to consider the individual risk in the absence of screening. These concepts are complicated and may not be grasped by our patients. Moreover, the ground is constantly shifting because breast cancer incidence and mortality rates can change due to variations in the prevalence of risk factors and advances in treatment. Patients want to know whether screening mammography results in a decreased death rate from breast cancer. Several observational studies have attributed the decreased death rate from breast cancer to mammographic screening [16, 24–27]. There have been eight population-based randomized controlled trials of breast cancer screening and two that randomized volunteers [28–41]. Meta-analyses of randomized controlled trials with women invited to screening after age 40 years show a 20–25% decrease in breast cancer deaths [42, 43], which would be even higher for women who actually undergo screening [16, 23–25]. This is strong evidence that screening mammography reduces breast cancer mortality. Each patient ultimately decides whether or not to undergo screening mammography. A flint-eyed look at the available data shows that population-based mammographic screening saves lives. This conclusion is reached if the following key elements are accounted for: use of data from patients actually receiving screening, evaluation of long-term follow-up showing that the initial excess of cases is compensated for by a later drop in incidence and changes in incidence independent of screening [15]. The bottom line is that the probability of prevention of breast cancer death exceeds the risk of overdiagnosis. Breast imaging has improved since the first randomized controlled mammographic screening began in 1963. Quality is better ow-

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ing to digital imaging, nationally mandated minimum quality standards, double readings, and computer-aided diagnosis, to name a few advances. Innovative new technologies, such as tomosynthesis, digital mammography, MRI, and whole-breast ultrasound, hold promise to advance the screening agenda, but the data are lacking. Perhaps these advances may enable earlier detection of breast cancer and offer advantages to women with dense breasts, but will they have more potential for overdiagnosis? To date, no large-scale studies can verify the validity of these newer techniques as comprehensive, unqualified, cost-effective, or safe for routine screening of asymptomatic women at average risk. Achieving tailored patient management is the new frontier. Multispecialty teams of health care providers treating breast cancer have a favorable impact on the management and treatment of this disease. Individual risk profiles; genetic testing; and tumor grade, type, and receptor status as indicators of tumor aggressiveness are empowered by imaging-guided biopsy. In this highlighted Women’s Imaging issue, we intend to offer practical perspectives about breast cancer screening and overdiagnosis. We will consider risk stratification, technical advances, and new technologies for screening that are promising future pathways to combat breast cancer. In summary, the weight of methodologically sound evidence suggests that cancer mortality reduction from breast cancer screening outweighs the potential harms of false-positive screening and overdiagnosis. The potential benefits of mammography are the reduced risk of dying from breast cancer, the earlier detection of breast cancer, appurtenant breast-conserving surgery with decreased disfigurement, less-aggressive adjuvant therapy, and a wider range of treatment options. In this dedicated Women’s Imaging issue, the screening versus overdiagnosis controversy is unmasked. Once tissue signatures and imaging fingerprints of aggressive breast cancers that are distinct from indolent lesions are revealed through future research, the conversation will be even more brief and to the point: Breast cancer screening saves lives—no “ifs, ands, or buts.” Marcia C. Javitt AJR Section Editor for Women’s Imaging Uniformed Services University of the Health Sciences [email protected] DOI:10.2214/AJR.13.12052

References 1. Nelson HD, Tyne K, Naik A, et al. Screening for breast cancer: systematic evidence review update for the U.S. Preventive Services Task Force. Ann Intern Med 2009; 151:727–737 2. American Cancer Society website. Cancer facts and figures 2013. www.cancer.org/acs/groups/ content/@epidemiologysurveilance/documents/ document/acspc-036845.pdf. Accessed May 8, 2013 3. Puliti D, Duffy SW, Miccinesi G, et al. Overdiagnosis in mammographic screening for breast cancer in Europe: a literature review. J Med Screen 2012; 19(suppl 1):42–56 4. Paci E, Broeders M, Hofvind S, et al. Summary of the evidence of breast cancer service screening outcomes in Europe and first estimate of the benefit and harm balance sheet. J Med Screen 2012; 19(suppl 1):5–13 5. Yen MF, Tabár L, Vitak B, et al. Quantifying the potential problem of overdiagnosis of ductal carcinoma in situ in breast cancer screening. Eur J Cancer 2003; 39:1746–1754 6. Duffy SW, Agbaje O, Tabár L, et al. Overdiagnosis and overtreatment of breast cancer: estimates of overdiagnosis from two trials of mammographic screening for breast cancer. Breast Cancer Res 2005; 7:258–265 7. Cuzick J, Sestak I, Pinder SE, et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol 2011; 12:21–29 8. Zahl PH, Strand BH, Maehlen J. Incidence of breast cancer in Norway and Sweden during introduction of nationwide screening: prospective cohort study. BMJ 2004; 328:921–924 9. Jørgensen KJ, Gøtzsche PC. Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends. BMJ 2009; 339:b2587 10. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012; 367:1998–2005 11. Mandelblatt JS, Cronin KA, Bailey S, et al. Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med 2009; 151:738–747 12. de Roos MA, van der Vegt B, de Vries J, et al. Pathological and biological differences between screendetected and interval ductal carcinoma in situ of the breast. Ann Surg Oncol 2007; 14:2097–2104 13. Matson S, Andersson I, Berglund G, et al. Nonattendance in mammographic screening: a study of intra-urban differences from the city of Malmö in Sweden 1990-94. Cancer Detect Prev 2001; 25:132–137

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Breast Cancer Screening and Overdiagnosis 14. Zackrisson S, Andersson I, Manjer J, et al. Nonattendance in breast cancer screening is associated with unfavourable socio-economic circumstances and advanced carcinoma. Int J Cancer 2004; 108:754–760 15. Duffy SW, Tabár L, Olsen AH, et al. Absolute numbers of lives saved and overdiagnosis in breast cancer screening, from a randomized trial and from the Breast Screening Programme in England. J Med Screen 2010; 17:25–30 16. Duffy SW, Tabár L, Chen HH, et al. The impact of organized mammography service screening on breast carcinoma mortality in seven Swedish counties. Cancer 2002; 95:458–469 17. Zackrisson S, Andersson I, Janzon L, et al. Rate of over-diagnosis of breast cancer 15 years after end of Malmö mammographic screening trial: follow-up study. BMJ 2006; 332:689–692 18. Olsen AH, Agbaje OF, Myles JP, et al. Overdiagnosis, sojourn time, and sensitivity in the Copenhagen mammography screening program. Breast J 2006; 12:338–342 19. Puliti D, Zappa M, Miccinesi G, et al. An estimate of overdiagnosis 15 years after the start of mammographic screening in Florence. Eur J Cancer 2009; 45:3166–3171 20. Allegra CJ, Aberle DR, Ganschow P, et al. National Institutes of Health State-of-the Science Conference statement: diagnosis and management of ductal carcinoma in situ—September 22–24, 2009. J Natl Cancer Inst 2010; 102:161–169 21. Welch HG, Black WC. Using autopsy series to estimate the disease “reservoir” for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med 1997; 127:1023–1028 22. Nielsen M, Thomsen JL, Primdahl S, et al. Breast cancer and atypia among young and middle-aged women: a study of 100 medicolegal biopsies. Br J Cancer 1987; 56:814–819 23. Kopans DB, Smith RA, Duffy SW. Mammographic screening and “overdiagnosis.” Radiology 2011; 260:616–620 24. Swedish Organised Service Screening Evaluation

Group. Reduction in breast cancer mortality from organized service screening with mammography. I. Further confirmation with extended data. Cancer Epidemiol Biomarkers Prev 2006; 15:45–51 25. Tabár L, Vitak B, Chen HH, et al. Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality. Cancer 2001; 91:1724– 1731 26. Hellquist BN, Duffy SW, Abdsaleh S, et al. Effectiveness of population-based service screening with mammography for women ages 40 to 49 years: evaluation of the Swedish Mammography Screening in Young Women (SCRY) cohort. Cancer 2011; 117:714–722 27. Otto SJ, Fracheboud J, Looman CW, et al. Initiation of population-based mammography screening in Dutch municipalities and effect on breastcancer mortality: a systematic review. Lancet 2003; 361:1411–1417 28. Smith RA, Duffy SW, Tabár L. Breast cancer screening: the evolving evidence. Oncology 2012; 26:471–475 29. Shapiro S, Venet W, Strax P, et al. Ten- to fourteen-year effect of screening on breast cancer mortality. J Natl Cancer Inst 1982; 69:349–355 30. Shapiro S. Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore, MD: Johns Hopkins University Press, 1988 31. Andersson I, Aspegren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: the Malmö mammographic screening trial. BMJ 1988; 297:943–948 32. Nyström L, Rutqvist LE, Wall S, et al. Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet 1993; 341:973–978 33. Nyström L, Andersson I, Bjurstam N, et al. Longterm effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 2002; 359:909–919 34. Tabár L, Fagerberg CJ, Gad A, et al. Reduction in mortality from breast cancer after mass screening

with mammography: randomised trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1985; 325:829–832 35. Tabár L, Fagerberg G, Duffy SW, et al. Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 1992; 30:187–210 36. Tabár L, Fagerberg G, Duffy SW, et al. The Swedish two county trial of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Community Health 1989; 43:107–114 37. Roberts MM, Alexander FE, Anderson TJ, et al. Edinburgh trial of screening for breast cancer: mortality at seven years. Lancet 1990; 335:241–246 38. Miller AB, To T, Baines CJ, et al. The Canadian National Breast Screening Study. 1. Breast cancer mortality after 11 to 16 years of follow-up: a randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med 2002; 137:305–312 39. Miller AB, Baines CJ, To T, et al. Canadian National Breast Screening Study. 2. Breast cancer detection and death rates among women aged 50 to 59 years. CMAJ 1992; 147:1477–1488 40. Frisell J, Eklund G, Hellström L, et al. Randomized study of mammography screening: preliminary report on mortality in the Stockholm trial. Breast Cancer Res Treat 1991; 18:49–56 41. Moss SM, Cuckle H, Evans A, et al. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years’ follow-up: a randomized controlled trial. Lancet 2006; 368:2053–2060 42. Smith RA, Duffy S, Tabár L. Screening and early detection. In: Barbiera GV, Esteva FJ, Skoracki R, eds. Advanced therapy of breast disease, 3rd ed. Shelton, CT: People’s Medical Publishing House, 2011 43. Humphrey LL, Helfand M, Chan BK, et al. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002; 137:347–360

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Section editor's notebook: breast cancer screening and overdiagnosis unmasked.

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