Breast Cancer Screening Modalities—Mammography
Mammography Description and Background
Benefit of Mammography
Randomized controlled trials
Summary of RCTs
Effectiveness of Population-Based Screening Programs
Statistical Modeling of Breast Cancer Incidence and Mortality in the United States
Mammography Description and Background
Mammography utilizes ionizing radiation to image breast tissue. The examination is performed by compressing the breast firmly between two plates. Such compression spreads out overlapping tissues and reduces the amount of radiation needed to image the breast. For routine screening in the United States, examinations are taken in both mediolateral oblique and craniocaudal projections. Both views should include breast tissue from the nipple to the pectoral muscle. Radiation exposure is 4 to 24 mSv per standard two-view screening examination. Two-view examinations are associated with a lower recall rate than are single-view examinations because they eliminate concern about abnormalities due to superimposition of normal breast structures.
Under the Mammography Quality Standards Act (MQSA) enacted by Congress in 1992, all U.S. facilities that perform mammography must be certified by the U.S. Food and Drug Administration (FDA) to ensure the use of standardized training for personnel and a standardized mammography technique utilizing a low radiation dose. (Refer to the FDA's Web page on Mammography Facility Surveys, Mammography Equipment Evaluations, and Medical Physicist Qualification Requirement under MQSA.) The 1998 MQSA Reauthorization Act requires that patients receive a written lay-language summary of mammography results.
On screening, the following Breast Imaging, Reporting and Data System (BI-RADS) assessments are used: 1, negative; 2, benign; or 0, incomplete with additional evaluation needed.
About 10% of women screened will be recalled for additional evaluation; more than 80% of these will be considered normal or benign after a full diagnostic workup, which may include additional mammographic views, ultrasound, or both. About 15% of women recalled will be recommended for biopsy, with 30% of cases assessed as BI-RADS 4, suspicious, yielding cancer; and 95% of cases assessed as BI-RADS 5, highly suggestive of malignancy, yielding cancer. About 2% of women screened will be recommended for short-interval follow-up, assessed as BI-RADS 3, probably benign, with fewer than 2% of such women ultimately found to have cancer.Benefit of Mammography
Randomized controlled trials
Randomized controlled trials (RCTs), with participation by nearly half a million women from four countries, examined the breast cancer mortality rates of women who were offered regular screening. One trial, the Canadian National Breast Screening Study (NBSS)-2, compared mammogram plus clinical breast examination (CBE) with CBE alone; the other eight trials compared screening mammogram with or without CBE to a control consisting of usual care.
The trials differed in design, recruitment of participants, interventions (both screening and treatment), management of the control group, compliance with assignment to screening and control groups, and analysis of outcomes. Some trials used individual randomization, while others used cluster randomization in which cohorts were identified and then offered screening; one trial used nonrandomized allocation by day of birth in any given month. Cluster randomization sometimes led to imbalances between the intervention and control groups. Age differences have been identified in several trials, although the differences were probably too small to have a major effect on the trial outcome. In the Edinburgh Trial, socioeconomic status, which correlates with the risk of breast cancer mortality, differed markedly between the intervention and control groups, so it is difficult, if not impossible, to interpret the results.
Breast cancer mortality is the major outcome parameter for each of these trials, so the methods used to determine cause of death are critically important. Efforts to reduce bias in the attribution of mortality cause have been made, including the use of a blinded monitoring committee (New York) and a linkage to independent data sources, such as national mortality registries (Swedish trials). Unfortunately, these attempts could not ensure a lack of knowledge of women’s assignments to screening or control arms. Evidence of possible misclassification of breast cancer deaths in the Two-County Trial with possible bias in favor of screening has been analyzed.
There were also differences in the methodology used to analyze the results of these trials. Four of the five Swedish trials were designed to include a single screening mammogram in the control group, timed to correspond with the end of the series of screening mammograms in the study group. The initial analysis of these trials used an "evaluation" analysis, tallying only the breast cancer deaths that occurred in women whose cancer was discovered at or before the last study mammogram. In some of the trials a delay occurred in the performance of the end-of-study mammogram, resulting in more time for members of the control group to develop or be diagnosed with breast cancer. Other trials used a "follow-up" analysis, which counts all deaths attributed to breast cancer, regardless of the time of diagnosis. This type of analysis was used in a meta-analysis of four of the five Swedish trials in response to concerns about the evaluation analyses.
The accessibility of the data for international audits and verification also varies, with formal audit having been undertaken only in the Canadian trials. Other trials have been audited to varying degrees, usually with less rigor.
All of these studies are designed to study breast cancer mortality rather than all-cause mortality because of the infrequency of breast cancer deaths relative to the total number of deaths. When all-cause mortality in these trials was examined retrospectively, only the Edinburgh Trial showed a significant difference, which could be attributed to socioeconomic differences. The meta-analysis (follow-up methods) of the four Swedish trials also showed a small but significant improvement of all-cause mortality.
The trials are described in detail in the Appendix of Randomized Controlled Trials section of this summary.Summary of RCTs
Screening for breast cancer does not affect overall mortality, and the absolute benefit for breast cancer mortality is small.
A way to view the potential benefit of breast cancer screening is to estimate the number of lives extended because of early breast cancer detection.[7,8] One author estimated the outcomes of 10,000 women aged 50 to 70 years who undergo a single screen. Mammograms will be normal (true-negatives and false-negatives) in 9,500 women. Of the 500 abnormal screens, 466 to 479 will be false-positives, and 100 to 200 of these women will undergo invasive procedures. The remaining 21 to 34 abnormal screens will be true-positives, indicating breast cancer. Some of these women will die of breast cancer in spite of mammographic detection and optimal therapy, and some may live long enough to die of other causes even if the cancer had not been screen detected. The number of extended lives attributable to mammographic detection is between two and six. Another expression of this analysis is that one life may be extended per 1,700 to 5,000 women screened and followed for 15 years. The same analysis for 10,000 women aged 40 to 49 years, assuming the same 500 abnormal examinations, results in an estimate that 488 of these will be false-positives, and 12 will be breast cancer. Of these 12, there will probably be only one or two lives extended. Thus, for women aged 40 to 49 years, it is estimated that one or two lives may be extended per 5,000 to 10,000 mammograms.
While the numbers discussed above are from a single mammography exam, women undergo screening throughout their lifetimes, which can include 20 to 30 years of screening activity. A meta-analysis of RCTs conducted for the U.S. Preventive Services Task Force in 2009 (including the AGE Trial) found that the number needed to invite to screen for 10 years to avoid or delay one death from breast cancer was 1,904 for women in their 40s, 1,339 for women in their 50s, and 377 for women in their 60s. A 2009 combined analysis by six Cancer Intervention and Surveillance Modeling Network modeling groups found that screening every 2 years maintained an average of 81% of the benefit of annual screening with almost half the false-positive results. Screening biennially from age 50 to 69 years achieved a median 16.5% reduction in breast cancer deaths versus no screening. Initiating biennial screening at age 40 years (vs. age 50 years) reduced breast cancer mortality by an additional 3%, consumed more resources, and yielded more false-positive results.Effectiveness of Population-Based Screening Programs
Although the RCTs of screening have addressed the issue of screening efficacy (i.e., the extent to which screening reduces breast cancer mortality under the ideal conditions of an RCT), they do not provide information about the effectiveness of screening (i.e., the extent to which screening is reducing breast cancer mortality in the U.S. population). Studies that provide information about this issue include nonrandomized controlled studies of screened versus nonscreened populations, case-control studies of screening in real communities, and modeling studies that examine the impact of screening on large populations. An important issue in all of these studies is the extent to which they can control for additional effects on breast cancer mortality such as improved treatment and heightened awareness of breast cancer in the community.
Three population-based, observational studies from Sweden compared breast cancer mortality in the presence and absence of screening mammography programs. One study compared two adjacent time periods in 7 of the 25 counties in Sweden and concluded a statistically significant breast cancer mortality reduction of 18% to 32% attributable to screening. The most important bias in this study is that the advent of screening in these counties occurred over a period during which dramatic improvements in the effectiveness of adjuvant breast cancer therapy were being made, changes which were not addressed by the study authors. The second study considered an 11-year period comparing seven counties with screening programs to five counties without them. There was a trend in favor of screening, but again, the authors did not consider the effect of adjuvant therapy or differences in geography (urban vs. rural) that might affect treatment practices.
In part to account for the effects of treatment, the third study was a detailed analysis by county and concluded little impact of screening. These authors made the assumption that the annual decrease in mortality observed during the prescreening period would carry into the postscreening period, and any screening effect would result in an incremental decrease in mortality. Although no such incremental decrease in breast cancer mortality was observed after the introduction of screening, their assumption makes their conclusion weak. Comparisons across counties showed similar reductions in decreased breast cancer mortality regardless of when the counties’ screening programs were initiated; however, the authors carried out no formal cross-county analyses.
In Nijmegen, the Netherlands, where a population-based screening program was undertaken in 1975, a case-cohort study showed that screened women have decreased mortality (odds ratio [OR] = 0.48). However, a subsequent study comparing Nijmegen breast cancer mortality rates with neighboring Arnhem in the Netherlands, which had no screening program, showed no difference in breast cancer mortality.
A community-based case-control study of screening as practiced in excellent U.S. health care systems between 1983 and 1998 found no association between previous screening and reduced breast cancer mortality. Mammography screening rates, however, were generally low. The association among women at increased risk due to a family history of breast cancer or a previous breast biopsy (OR = 0.74; 95% confidence interval [CI], 0.50–1.03) was stronger than that among women at average risk (OR = 0.96; 95% CI, 0.80–1.14), but the difference was not statistically significant (P = .17).
A well-conducted ecologic study compared three pairs of neighboring European countries, matched on similarity in health care systems and population structure, one of which had started a national screening program some years earlier than the others. The investigators found that each country had experienced a reduction in breast cancer mortality, with no difference between matched pairs that could be attributed to screening. The authors suggested that improvements in breast cancer treatment and/or health care organizations were more likely responsible for the reduction in mortality than was screening.
A systematic review of ecologic and large cohort studies published through March 2011 compared breast cancer mortality in large populations of women aged 50 to 69 years who started breast cancer screening at different times. Seventeen studies met inclusion criteria. All studies had methodological problems, including control group dissimilarities, insufficient adjustment for differences between areas in breast cancer risk and breast cancer treatment, and problems with similar measurement of breast cancer mortality between compared areas. There was great variation in results among the studies, with four studies finding a relative reduction in breast cancer mortality of 33% or more (with wide CIs) and five studies finding no reduction in breast cancer mortality. Because only a part of the overall reduction in breast cancer mortality could possibly be attributed to screening, the review concluded that any relative reduction in breast cancer mortality due to screening would likely be no more than 10%, less than predicted by the RCTs.
A U.S. ecologic analysis conducted between 1976 and 2008 examined the incidence of early-stage versus late-stage breast cancer for women aged 40 years and older. To find a screening effect, the authors compared the magnitude of increase in early-stage cancer with the magnitude of an expected decrease in late-stage cancer. Over the study period, the absolute increase in the incidence of early-stage cancer was 122 cancers per 100,000 women, while the absolute decrease in late-stage cancers was 8 cases per 100,000 women. After adjusting for changes in incidence due to hormone therapy and other undefined causes, the authors concluded that the screening effect on breast cancer mortality reduction (28% during this period) was small, and that overdiagnosis of breast cancer was likely between 22% and 31% of all diagnosed breast cancers. Most of the reduction in breast cancer mortality, the authors concluded, was probably because of improved treatment rather than screening. To make these adjustments, the authors made uncertain assumptions about the effects of other factors on incidence, and made no mention of the effects of changing treatment over time. Ecologic studies are difficult to interpret because of this type of potential uncontrolled confounding, as well as these types of unfair comparisons. However, this study largely agrees with some similar analyses from other countries (see studies discussed above). A major limitation of this and other ecologic studies is the failure to account for actual exposure to screening. Most late-stage breast cancer occurs in women not exposed to screening.Statistical Modeling of Breast Cancer Incidence and Mortality in the United States
The optimal screening interval has been addressed by modelers. Modeling makes assumptions that may not be correct; however, the credibility of modeling is greater when the model produces overall results that are consistent with randomized trials overall and when the model is used to interpolate or extrapolate. For example, if a model’s output agrees with RCT outcomes for annual screening, then it has greater credibility in comparing the relative effectiveness of biennial versus annual screening.
In 2000, the National Cancer Institute formed a consortium of modeling groups (Cancer Intervention and Surveillance Modeling [CISNET]) to address the relative contribution of screening and adjuvant therapy to the observed decline in breast cancer mortality in the United States. (Refer to the Randomized controlled trials section of this summary for more information.) These models gave reductions in breast cancer mortality similar to those expected in the circumstances of the RCTs but updated to the use of modern adjuvant therapy. In 2009, CISNET modelers addressed several questions related to the harms and benefits of mammography, including comparing annual versus biennial screening. The proportion of reduction in breast cancer mortality maintained in moving from annual to biennial screening for women aged 50 to 74 years ranged across the six models from 72% to 95%, with a median of 80%.References
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