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


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-


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

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

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