Disparities in the Estimates of Benefits and Harms of Mammography: Are the Numbers Really Different?*

Robert A. Smith, American Cancer Society, Atlanta, GA 30345
Medical University of Vienna, Vienna, Austria
Key words: Breast cancer, Methodology, Modeling, biostatistics,
Cancer surveillance and screening

Financial support: American Cancer Society

Corresponding author: Robert A. Smith
American Cancer Society
250 Williams St, Suite 600
Atlanta, GA 30303
Phone: 404-329-7610
Fax: 404-327-6404
Email: robert.smith@cancer.org

Conflicts of interest: None
Tables and Figures: 1 table

This material in this paper was presented at the San Antonio Breast Cancer Symposium, San Antonio, December 11, 2013, and also derives from two subsequent publications.^1,2

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Abstract

In the mid-20^th century, experimental approaches with x-ray imaging eventually led to the initiation of randomized trials in North America and Europe, collectively establishing the efficacy of mammography screening in reducing deaths from breast cancer. Nevertheless, over the 40+ years since publication of the first experimental evidence on the efficacy of mammography, the value of breast cancer screening has been a source of on-going debates. At the extremes are estimates of absolute benefits of mammography that vary 20-fold in their estimates of the number needed to screen or invite to screening to prevent one breast cancer death. Since these estimates commonly derive from the same data sources, it is important to understand whether the differences in these estimates are real or artifactual. Here we show that when different estimates are adjusted to a common relative risk, a standard population, and similar numbers of screening rounds and duration of follow-up, differences in balance sheet estimates diminish from 20-fold to about 2-fold, demonstrating a substantial benefit from screening across all estimates.

Introduction

Various debates about the value of mammography have been a persistent presence in the medical and scientific literature.^3-8 Some of these debates have endured since the introduction of the earliest screening programs, such as when to begin screening, whether to screen annually or biennially, or to tailor the screening interval to a woman’s age or her risk factors. Some debates endure because they are difficult to resolve, such as the impact of various harms associated with screening. However, unlike the early debates, the modern debates are complex and very much defined by the data that are chosen to represent the magnitude of benefits and harms, i.e., the balance sheet.⁹ Benefits typically are expressed in terms of the number of women needed to invite to screening (or to be screened) to prevent one death vs. various harms that are estimated to occur as a result of screening, such as false positive findings and overdiagnosis. Commonly cited estimates of benefit vary 20-fold, and estimates of overdiagnosis and other harms are equally disparate. Since these estimates commonly derive from the same data or at least share some common data inputs, we sought to understand the underpinnings of the magnitude of the differences.

Supporting evidence for estimates of benefits and harms may rely on different methodologies applied to the same data or different data, and thus estimates may differ considerably. Modern examples include estimates of the mortality reduction associated with invitation or exposure to screening, the number needed to be invited or screened to save one life, the age to begin and end screening, and how to judge the downsides of screening, such as radiation exposure, false positive exams, and overdiagnosis and overtreatment. While conclusions about whether or not mammography screening can be recommended based on a balance sheet of estimated benefits and harms may seem to be uncomplicated, the underlying data supporting the estimates may not be evident, well understood, or scrutinized. Differences in the mortality reduction associated with screening can differ more than 4-fold,^10,11 the number needed to screen to save one life differs more than 20-fold,^1,12 and estimates of overdiagnosis range from 0% to greater than 50%.¹³ Taken together, the modern arguments against breast cancer screening emphasize an unfavorable balance of benefits and harms, stating that harms, principally false positive findings and overdiagnosis, significantly exceed the small absolute benefit, which is further diminishing due to progress in therapy and increased breast awareness.^6,11,14,15 Others looking at the same data conclude that screening is beneficial and that benefits outweigh harms.^14,16-18 Indeed, beyond favorable interpretation of the randomized controlled trial (RCT) evidence, there is a steadily growing body of literature of the evaluation of service screening showing breast cancer mortality reductions as great as and commonly greater than those observed in the RCTs.^10,19-24 These reports conclude that modern mammography and improvements in therapy are contributing to a decline in the breast cancer mortality rate, and while both are important, where robust screening programs exist, early detection is the more significant contribution.^19,25

Recent Reviews of Mammography Screening

In the last year there have been three evaluations of the effectiveness of mammography: (1) an update of the Nordic Cochrane Institute’s review;¹¹ the independent review of the UK’s National Health Service’s breast cancer screening program;¹² and the evaluation of the European breast cancer screening programs by the EUROSCREEN working group.²⁶ It is useful to examine these three recent evaluations of breast cancer screening, along with an earlier evaluation by the United States Preventive Services Task Force¹⁴ because they represent different approaches to the data, reach different conclusions about the benefits and harms of mammography screening, and whether or not the balance between benefits and harms is favorable.

Nordic Cochrane Institute

The Nordic Cochrane Institute’s report is the most recent update of their first assessment of the RCT evidence for the effectiveness of mammography in 2001.^11,27 Then and now, the conclusion of the report is that the evidence does not support mammography screening. The Cochrane authors argue that: (1) the absolute benefit of mammography screening today is smaller due to advances in treatment and women’s increased awareness, and (2) that the harms of screening, principally overdiagnosis, exceed the benefit.¹¹ The most current Cochrane estimate of the breast cancer mortality reduction associated with an invitation to screening is 19%, but this estimate arbitrarily is then adjusted to 15% based on then the author’s judgment that suboptimal randomization biases the true estimate upward.¹¹ For the balance sheet, the authors estimate that the rate of overdiagnosis is 30%, and that 2,000 women must be screened for 10 years to save one life, at a cost of 10 overdiagnosed cases of breast cancer.

Independent UK Panel on Breast Cancer Screening

In 2011, the leadership of the UK National Health Service and Cancer Research UK asked Professor Sir Michael Marmot to assemble and chair a small group of independent exerts (with no prior published work on breast cancer screening) to review the evidence related to the benefits and harms of breast cancer screening in the UK. The Panel concentrated their analysis on the RCTs of breast cancer screening and applied their findings to the UK breast cancer screening program. The Panel’s meta-analysis observed 20% fewer breast cancer deaths comparing invited vs. control women. For the balance sheet, the Panel based their estimates on 10,000 women aged 50 years invited to screening every 3 years for a 20 year period (ages 50-69), with the cumulative risk of breast cancer mortality measured from age 55-79. Based on that scenario, the Panel estimated that 1 breast cancer death would be prevented for every 235 women invited to screening, or for every 180 women who attended screening.¹² The Panel based their estimate of overdiagnosis (19%) on the excess proportion of cancers diagnosed among women invited to screening compared with the control group in the Malmö and Canadian trials. Thus, according to the scenario above, 1 in 77 women invited to screening would be diagnosed with an overdiagnosed cancer, or 3 cancers overdiagnosed for every 1 life saved. In the summary of their report published in The Lancet, the Panel acknowledged that mammography screening was associated with both benefits and harms, but concluded, “the UK breast screening programmes confer significant benefit and should continue.”¹²

The EUROSCREEN working group

The EUROSCREEN working group consists of 30 experts involved in the planning and evaluation of cancer screening programs in the European Screening Network.^28,29 Unlike the two reports described above, the EUROSCREEN Working Group’s report, published in a supplement to the Journal of Medical Screening,²⁶ was both an evaluation of the European breast cancer screening programs and a review of the methodologic issues involved in the evaluation of observational data of mammography screening,^10,26,30,31 including trend studies, case-control studies, and incidence-based mortality studies (IBM).^10,30,31 IBM studies offer advantages over trend studies because the analysis is restricted to deaths arising from cases that were diagnosed after the first invitation to screening. Among the several strengths of this approach is avoiding the sizeable contamination in the post-screening period by breast cancer deaths among women diagnosed before the introduction of screening. Based on 7 incidence based mortality studies that had the strongest designs, the EUROSCREEN Working Group estimated a 25% breast cancer mortality reduction associated with an invitation to screening and a 38% mortality reduction associated with exposure to screening. Among the case control studies, the mortality reductions were 31% and 48% respectively. Given the limited opportunity to address the question of overdiagnosis with RCT data, Puliti and colleagues sought to evaluate the growing number of estimates of overdiagnosis in the service screening setting. To avoid bias, estimates of overdiagnosis must compare incidence rates over time in screened and unscreened populations that are equivalent with respect to the underlying risk of disease, and the effects of lead time. The EUROSCREEN Working Group divided 13 studies based on whether or not overdiagnosis estimates were adjusted for lead time associated with screening, and contemporaneous trends in incidence. Failure to adjust for these influences on incidence rates largely accounts for the wide range in the estimates of overdiagnosis (0% to 57%), in particular extraordinary large estimates.³² Among the reliable estimates of overdiagnosis, i.e., those that did adjust for lead time and changing risk over time, the investigators estimated overdiagnosis of invasive and in situ cancers at 6.5%. From the above, the Group estimated that among 1,000 women aged 50 years screened every 2 years until age 69 (and followed to age 79) 7-9 lives are saved (out of 30 deaths expected in the absence of screening) and 4 women are overdiagnosed (out of 67 incident cases expected in the absence of screening).²⁶ Unlike the balance sheets described above, the EUROSCREEN Working Group estimates that more lives are saved due to screening compared with cancers overdiagnosed.

Estimating the Absolute Benefits and Harms of Mammography

In meta-analyses of the RCTs conducted to date, the relative risks of dying from breast cancer have been consistent, varying only on the basis of which RCT data are included in the analysis. This also is the case in the two most recent meta-analyses conducted as part of the systematic reviews described above. In contrast, absolute risk estimates derived from the various systematic reviews vary by orders of magnitude. How do we explain that the UK Panel and the Nordic Cochrane Institute each estimated a 20% and 19% (respectively) reduction in breast cancer deaths associated with an invitation to screening, ^11,12 but then differed nearly 10 fold in their estimate of the number of women who needed to be invited (NNI) to screening to save one live (1/250 vs. 1/2000, respectively)? The United States Preventive Services Task Force estimates of the NNI to screening to save one life for women ages 50-59 and 60-69 (respectively, 1 in 1339 and 1 in 377) also are considerably different than the UK Panel and the Nordic Cochrane Institute estimates, although their estimates are for narrower age groups.³³ Each of these, in turn, is different from the estimates from the EUROSCREEN Working Group, which estimated both NNI and NNS from observational data. Closer examination reveals that each measure of absolute risk differs in terms of the reference population, mortality benefit (originally a 19% mortality reduction became 15% in the Nordic Cochrane Institute’s estimate), duration of screening and follow-up, and whether invitation or exposure to screening is being compared. In particular, the most extreme estimate of the NNI to save one life is from the Nordic Cochrane Institute, which is influenced by the shortest observation period (a fixed 10 years of screening and follow-up) and an absolute benefit estimated from a subset of the RCTs that are dominated by women in their 40s.¹ In an effort to understand the disparity between estimates in absolute benefit, given the similarity of the common relative risk estimates derived from the RCTs, Duffy, et al. standardized the Nordic Cochrane Institute, USPSTF, and EUROSCREEN estimate of absolute benefit to a common scenario, i.e., the recent UK Independent Panel estimate of the effect of screening every 3 years in women ages 50-69 on breast cancer mortality from ages 55-79. This is fairly straightforward, i.e., and involves applying the Nordic Cochrane estimate of benefit to the estimated cumulative mortality in the UK screening program. For example, as Duffy, et al. have shown, in the UK the cumulative breast cancer mortality among women ages 55-79 is 17 per 1,000. From the perspective of the Nordic Cochrane review’s claim of a 15% mortality reduction associated with an invitation to screening, the breast cancer mortality rate in the absence of screening would be 20 per 1,000 (17/0.85), with the effect of an invitation to screening being 3 deaths prevented per 1,000 women invited. Since the attendance rate to screening in the UK is 77%, the effect of being screened would be 3.89 breast cancer deaths avoided per 1,000 women invited (3/0.77), or 257 women needed to screen to prevent one breast cancer death (1000/3.89).¹

When the 4 leading estimates (Nordic Cochrane Institute, UK Independent Review Panel, USPSTF, and EUROSCREEN Working Group) of absolute benefit are adjusted to the screening scenario used by the UK Independent Review Panel (the effect of screening every 3 years for a 20 year period beginning at age 50 on breast cancer mortality between ages 55-79), the difference in the estimates of absolute benefit are substantially reduced from 20 fold to 4 fold (Table 1), and thus are not as disparate as the original estimates, especially when considered over a 25 year period. ¹ Duffy et al. also converted the (NNI estimates to the number needed to screen (NNS) since the NNI is artificially inflated by breast cancer deaths in the invited group among women who were non-adherent to the invitation to screening, which is non-trivial across all rounds of screening and all RCTs. The NNI is not generalizable, and has no meaning to a woman contemplating screening or having already attended screening. It should not be used in a balance sheet to communicate benefits and harms.

Table 1: Original and Adjusted Estimate of the Absolute Benefit of Breast Cancer Screening from 4 Systematic Reviews
Systematic Review Group	Age Group	Intervention	Screening Period/Years of Follow-up	Mortality Reduction	Original NNS/NNIb	Adjusted NNSc
UK Independent Panela	50-69	Screening	20 yrs. ages 50-69/ 25 yrs. ages 55-79	20%	180	180
USPSTFd	50-59 60-69	Invitation Invitation	Avg. 7 years, ages 50-59/ Avg. 14, ages 50-59 Combined Avg. 7 years, ages 60-69/ Avg. 14, ages 60-69	14% 19% 32%	1,339 337	193
EUROSCREEN Working Group	50-69	Screening	20 yrs., ages 50-69/ 30 yrs., ages 50-79	38-48%	111 - 143	64-96
Nordic Cochrane Institute	40-74	Invitation	10 yrs., ages 40-74/ 10 yrs., ages 40-74	15%	2,000	257

The Enduring, but Limited Value of the RCTs of Mammography Screening

Relying on the RCTs to measure the effectiveness of screening is conservative and based principally on the hierarchy of evidence. This is the logic advanced by the USPSTF, the UK Independent Review Panel, and the Nordic Cochrane Center for only considering RCT evidence in their systematic reviews. However, with the efficacy of breast cancer screening established more than 4 decades ago, does it make sense to rely on these data to estimate the effectiveness of modern mammography? The RCTs varied considerably on important protocol factors (i.e., 1 vs. 2-view mammography, the screening interval, etc.) number of screening rounds, adherence with the invitation to screening, and control group contamination. Duration of follow-up also is highly variable, and lack of long-term follow-up reduces the ability to measure the absolute benefit of screening, as was just shown in the example above, and also recently in the 29-year follow-up of the Swedish Two County Trial.³⁴ In the Two County Trial, based on the local endpoint committee assessment, an invitation to screening was associated with a 31% reduction in breast cancer deaths over the 29 year period. However, the NNS to save one life became steadily more favorable over the duration of the follow-up period. According to the trial protocol, the NNS for 7 years (~ 2-3 rounds) to save 1 life with 10 years of follow-up was 922. At 29 years of follow-up, the NNS to screen to save 1 life had dropped to 414. The investigators estimated that if screening had continued for 10 years, the NNS to prevent 1 breast cancer death would be 300. The follow-up data also reveal that fewer than half of the deaths prevented were observed in the first 10 years. These observations reinforce that 10-15 years of follow-up should be regarded as the minimum needed to measure the benefit of screening mammography, and 20+ years is preferable. Indeed, as shown in Table 1, failing to allow for longer follow-up accounts for a great deal of the difference between estimates of absolute risk, as does measuring absolute risk in terms of NNI vs. NNS. Understanding the underpinnings of these estimates is important since they contribute to substantial differences in the summary judgments about the balance of benefits and harms, and also to screening recommendations.

Meta-analysis of the RCTs further underestimates the true effectiveness of screening. As would be expected, there are differing opinions over which among the RCTs best reveals the true association between an invitation to screening and breast cancer death, and these judgments figure heavily into meta-analysis inclusion and exclusion decisions. What is often overlooked among the RCT findings is that the relative risk of being diagnosed with an advanced breast cancer is strongly associated with the relative risk of dying from breast cancer.³⁵ Thus, to argue that it is inappropriate to pick winners and losers among the RCTs and rely instead on meta-analysis of all trials as a more credible estimate of benefit ignores this important and consistent pattern, which more than any other observation explains why some trials demonstrated reduced breast cancer mortality and some did not. This pattern of more favorable tumor characteristics associated with exposure to screening is also evident in the evaluation of service screening,³⁶ lending further support for moving beyond the RCTs to estimate the effectiveness of modern mammography.

Many of the key methodological imperatives for the proper evaluation of mammography service screening programs have been understood for some time, but they are commonly neglected, leading to erroneous conclusions about the value of breast cancer screening. For example, trend analyses of breast cancer mortality or incidence contemporaneous with the introduction of screening are deceptively attractive due to their simplicity. After all, once mammography

screening is introduced, shouldn’t breast cancer death rates begin to fall? However, these analyses are not well suited to measuring the effectiveness of screening.³⁰ For example, in the first decade after the introduction of screening, usually more than half of the breast cancer deaths are attributable to diagnoses that occurred before screening was introduced, highlighting the need to censor deaths in the post screening era attributable to diagnoses in the pre-screening era.³⁷ Deaths from breast cancer among women not invited to screening, and among those who are invited but do not attend screening can also account for a significant fraction of deaths after screening is introduced. There also is a need to appreciate that it takes time to launch a screening program and invite and screen the target population, a process that can take several years, and long follow-up also is needed. Trends in the death rate also can be influenced by cohort effects on incidence over time, and by improvements in therapy. For these reasons, the most valid designs for the evaluation of service screening are those in which individual longitudinal data linking screening history and cause of death are evaluated with either an incidence-based mortality (IBM) or case control approach.¹⁰ In Norway, failure to attend to methodological imperatives has led to erroneous conclusions about the limited impact of mammography screening programs,^38,39 in contrast with the substantial 43% fewer deaths after 15 years of follow-up associated with exposure to screening demonstrated in a recent IBM analysis.⁴⁰

Conclusion

The weight of the conclusions of the recent systematic reviews provide strong support for the importance of mammography screening in the control of breast cancer, and sweep aside alarmist claims that the benefits of mammography in the era of adjuvant therapy are few, and the harms unacceptably high. While continued analysis of the RCT databases will remain fruitful, especially where contemporary question can be addressed with the benefit of decades of follow-up, it is time to move beyond the RCTs and use modern service screening data evaluated with appropriate methodology to inform screening policy, a sentiment echoed by others.²⁸ It also is important to insist on standardized approaches to measuring the absolute benefit of mammography, preferably based on modern estimates of the reduced risk of dying from breast cancer based on exposure to screening, and with sufficient follow-up to measure that benefit.

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