Breast Cancer Screening: A Summary of the Evidence for the U.S. Preventive Services Task Force

Breast cancer is the second leading cause of cancer death among North American women. Approximately 1 in 8.2 women will receive a diagnosis of breast cancer during her lifetime, and 1 in 30 will die of the disease (1). Breast cancer incidence increases with age (1), and although significant progress has been made in identifying risk factors and genetic markers, more than 50% of cases occur in women without known major predictors (2-5). This review was commissioned to assist the current U.S. Preventive Services Task Force (USPSTF) in updating its recommendations on breast cancer screening. We focus on information that was not available in 1996, when the second USPSTF examined the issue (6). Our goal was to critically appraise and synthesize evidence about the overall effectiveness of breast cancer screening, as well as its effectiveness among women younger than 50 years of age. Methods The analytic framework, literature search, and data extraction are described in detail in the Appendix. Briefly, we searched the Cochrane Controlled Trials Registry, MEDLINE, PREMEDLINE, and reference lists (6-8) for randomized, controlled trials of screening with death from breast cancer as an outcome. In all, we reviewed 154 publications from eight eligible randomized trials of screening mammography and two trials of breast self-examination (BSE). We abstracted details about patient population, design, quality, data analysis, and published results at each reported length of follow-up. We also evaluated previous meta-analyses of these trials and of screening test characteristics and studies evaluating the harms associated with false-positive test results. We used predefined criteria developed by the current USPSTF to assess the internal validity of the trials (9). Two authors rated the internal validity of each study as good, fair, or poor. Disagreements were resolved by further review and discussion. In the USPSTF system, a study that meets all the criteria for internal validity is rated as good quality (9). The rating reflects a judgment that the results of the study are very likely to be correct. The fair-quality rating is used for studies that have important but not major flaws and implies that the findings are probably valid. A study that has a major flaw in design or executionone that is serious enough to invalidate the results of the studyis rated as poor quality. We based our quality ratings on the entire set of publications from a trial rather than on individual articles. The USPSTF criteria for internal validity are listed in Appendix Table 1. All of the mammography trials met the first three criteria: They clearly defined interventions, measured important outcomes, and used intention-to-treat analysis. Therefore, our quality ratings reflect differences among the studies on the remaining criteria: 1) initial assembly of comparable groups; 2) maintenance of comparable groups and minimization of differential loss to follow-up or overall loss to follow-up; and 3) use of outcome measurements that were equal, reliable, and valid. The Appendix describes our approach to applying these criteria in more detail. We conducted new meta-analyses to incorporate new information about the quality of the trials and longer follow-up results. Breast cancer is known for its biological heterogeneity (10) as well as for late recurrences (10). Thus, longer follow-up is relevant in evaluating mortality rates, particularly in younger women. In addition, for several of the trials, the most recent analyses correct flaws in earlier reports. Six of the eight mammography trials were designed to assess the effectiveness of mammography over a broad age range, rather than its comparative effectiveness in various age subgroups. One trial specifically examined women 40 to 49 years of age because the earliest trial seemed to show no benefit in this subgroup. The USPSTF posed these questions for the meta-analysis: 1) Does mammography reduce breast cancer mortality rates among women over a broad range of ages when compared with usual care? and 2) If so, does mammography reduce breast cancer mortality rates among women 40 to 49 years of age when compared with usual care? We answered each question in two parts. First, using WinBUGS software (MRC Biostatistics Unit, Cambridge, United Kingdom), we constructed a two-level Bayesian random-effects model to estimate the effect size from multiple data points for each study and to derive a pooled estimate of relative risk reduction and credible intervals (CrIs) for a given length of follow-up (11). Second, we pooled the most recent results of each trial to calculate the absolute and relative risk reduction, using the results of the first analysis to estimate the mean length of follow-up. To avoid bias that could result from excluding any data from valid studies, we included the results of all trials of fair quality or better in the base-case analysis. The disadvantage of this approach is that it combines results from two distinct types of studies. The six population-based trials randomly assigned women to an invitation-to-screening group or to a control group that received usual care and was followed passively. In these trials, women who were invited to screening but chose not to be screened were included in the analysis of the screened group. Two trials from Canada, the Canadian National Breast Cancer Screening Study-1 (CNBSS-1) and the Canadian National Breast Cancer Screening Study-2 (CNBSS-2), differed from the other six trials. First, the Canadian trials used mass media to recruit a sample of volunteers, and all women randomly assigned to mammography had mammography at least once (12, 13). Second, in CNBSS-2, the control group was screened periodically with clinical breast examination (CBE). To estimate the relative risk reduction and the number needed to invite to screening to prevent one breast cancer death compared with usual care, we reanalyzed the data excluding the results of the Canadian studies. This study was funded by the U.S. Agency for Healthcare Research and Quality. Agency staff and members of the USPSTF reviewed and made substantive recommendations about the analyses and final manuscript. Agency approval was required before the manuscript could be submitted for publication. Results Description of Trials The eight randomized trials of mammography identified in our review (12-23) varied in recruitment of participants, mammography protocol, control groups, and size (Table 1). Six trials examined the effectiveness of screening among women between 40 and 74 years of age; one trial enrolled women in their 40s, and one enrolled only women in their 50s. Four trials from Sweden tested mammography only (14-17, 23-26), and the other four, from Canada, New York, and Edinburgh, Scotland, tested mammography and CBE (12, 13, 18-22, 27). Table 1. Controlled Trials of Mammography and Clinical Breast Examination Study Quality We found important methodologic limitations in all of the trials and rated all but one as fair, using USPSTF criteria. Table 1 lists the flaws of each trial and indicates how they influenced the overall ratings. The two reviewers rated the Swedish and Canadian trials as fair. Their initial ratings for the Edinburgh study and for the Health Insurance Plan of Greater New York (HIP) study differed. After extensive peer review, and detailed review of these trials' associated publications, the reviewers reached a consensus that the HIP study should be rated as fair and the Edinburgh study should be rated as poor. The HIP trial (conducted from 1963 to 1966) was the first trial of breast cancer screening. It is difficult to critically appraise because publications that describe it differ in detail from more recent publications. We found several limitations of this trial, including inadequate description of allocation concealment and poor reporting of intervention and control group numbers. In addition, we found better ascertainment of clinical variables (including previous mastectomy) among the invitation-to-screening cohort than among the passively followed control group. However, we viewed this as an expected consequence of a study design in which a control group receives usual care and is not contacted. The screening and control groups differed from each other slightly in education, menopausal status, and previous breast lumps; however, the differences were not systematic and did not favor one group over the other. The strengths of the trial included intention-to-treat analysis, little contamination, and blind review of deaths. We did not find the faults severe enough to rate the study as poor quality and rated it as fair, which signifies that the results were probably valid at the time the study was conducted. The Canadian trials met all of the USPSTF criteria for a rating of good quality, except for adequacy of allocation concealment. They differed from the other trials because all participants had a history and physical examination before randomization. This design permitted exclusion of patients who had a history of breast cancer and extensive examination of the baseline differences between groups. The Swedish trials all had limitations that resulted in a rating of fair rather than good. The Stockholm and Malm trials, which were individually randomized, did not report whether allocation was concealed. The Gothenburg trial and Swedish Two-County Study, which were cluster randomized trials, had small differences in mean age between the invited and control groups. Such differences are expected to occur in a cluster-randomized trial, do not indicate failure of randomization or a problem in the trial execution, and can be adjusted for in statistical analyses (28). Both the Gothenburg trial and the Swedish Two-County Trial provided insufficient data to determine whether randomization distributed other important confounders equally among the groups, but comparison of overall mortality rates in the