Breast Cancer Screening (PDQ®)–Health Professional Version - National Cancer Institute

Breast Cancer Screening (PDQ®)–Health Professional Version

Appendix of Randomized Controlled Trials

Health Insurance Plan, United States 1963 [1,2]

Age at entry: 40 to 64 years.
Randomization: Individual, but with significant imbalances in the distribution of women between assigned arms, as evidenced by menopausal status (P < .0001) and education (P = .05).
Sample size: 30,000 to 31,092 in study group and 30,565 to 30,765 in control group.
Consistency of reports: Variation in sample size reports.
Intervention: Annual two-view mammography (MMG) and clinical breast examination (CBE) for 3 years.
Control: Usual care.
Compliance: Nonattenders to first screening (35% of the screened population) were not reinvited.
Contamination: Screening MMG was not available outside the trial; frequency of CBE performance among control women is unknown.
Cause of death attribution: Women who died of breast cancer that had been diagnosed before entry into the study were excluded from the comparison between the screening and control groups. However, these exclusions were determined differently within the two groups. Women in the screening group were excluded based on determinations made during the study period at their initial screening visits. These women were dropped from all further consideration in the study. By design, controls did not have regular clinic visits, so the prestudy cancer status of control patients was not determined. When a control patient died and her cause of death was determined to be breast cancer, a retrospective examination was made to determine the date of diagnosis of her disease. If the date preceded the study period, the control patient was excluded from the analysis. This difference in methodology has the potential for a substantial bias when comparing breast cancer mortality between the two groups, and this bias is likely to favor screening.
Analysis: Follow-up.
External audit: No.
Follow-up duration: 18 years.
Relative risk of breast cancer death, screening versus control (95% confidence interval [CI]): 0.71 (0.55–0.93) at 10 years and 0.77 (0.61–0.97) at 15 years.
Comments: The MMGs were of poor quality compared with those of later trials, because of outdated equipment and techniques. The intervention consisted of both MMG and CBE. Major concerns about trial performance are the validity of the initial randomization and the differential exclusion of women with a prior history of breast cancer.

Malmo, Sweden 1976 [3,4]

Age at entry: 45 to 69 years.
Randomization: Individual, within each birth-year cohort for the first phase, MMG screening trial (MMST I). Individual for the entire birth cohort 1933 to 1945 for MMST II but with variations imposed by limited resources. Validation by analysis of age in both groups shows no significant difference.
Exclusions: In a Swedish meta-analysis, there were 393 women with pre-existing breast cancer excluded from the intervention group and 412 from the control group. Overall, however, 86 more women were excluded from the intervention group than from the control group.
Sample size: 21,088 study and 21,195 control.
Consistency of reports: No variation in patient numbers.
Intervention: Two-view MMG every 18 to 24 months × 5.
Control: Usual care, with MMG at study end.
Compliance: Participants migrating from Malmo (2% per year) were not followed. The participation rate of study women was 74% for the first round and 70% for subsequent rounds.
Contamination: 24% of all control women had at least one MMG, as did 35% of the control women aged 45 to 49 years.
Cause of death attribution: 76% autopsy rate in early report, lower rate later. Cause of death assessment blinded for women with a breast cancer diagnosis. Linked to Swedish Cause of Death Registry.
Analysis: Evaluation, initially. Follow-up analysis, as part of the Swedish meta-analysis.[5]
External audit: No.
Follow-up duration: 12 years.
Relative risk of breast cancer death, screening versus control (95% CI): 0.81 (0.62–1.07).
Comments: Evaluation analysis required a correction factor for the delay in the performance of MMG in the control group. The two Malmo trials, MMST I and MMST II, have been combined for most analyses.

Östergötland (County E of Two-County Trial), Sweden 1977 [6-8]

Age at entry: 40 to 74 years.
Randomization: Geographic cluster, with stratification for residence (urban or rural), socioeconomic factors, and size. Baseline breast cancer incidence and mortality were comparable between the randomly assigned geographic clusters. The study women were older than the control women, P < .0001, which would not have had a major effect on the outcome of the trial.
Exclusions: Women with pre-existing breast cancer were excluded from both groups, but the numbers were reported differently in different publications. The Swedish meta-analysis excluded all women with a prior breast cancer diagnosis, regardless of group assignment.
Sample size: Variably reported, ranging from 38,405 to 39,034 in the study and from 37,145 to 37,936 in the control.
Consistency of reports: Variable.
Intervention: Three single-view MMGs every 2 years for women younger than 50 years and every 33 months for women 50 years and older.
Control: Usual care, with MMG at study end.
Compliance: 89% screened.
Contamination: 13% of women in the Two-County trial had MMG as part of routine care, mostly in 1983 and 1984.
Cause of death attribution: Determined by a team of local physicians. When results were recalculated in the Swedish meta-analysis, using data from the Swedish Cause of Death Registry, there was less benefit for screening than had been previously reported.
Analysis: Evaluation initially, with correction for delay in control group MMG. Follow-up analysis, as part of the Swedish meta-analysis.[5]
External audit: No. However, breast cancer cases and deaths were adjudicated by a Swedish panel that included the trial's investigators.[9]
Follow-up duration: 12 years.
Relative risk of breast cancer death, screening versus control (95% CI): 0.82 (0.64–1.05), Östergötland.
Comments: Concerns were raised about the randomization methodology and the evaluation analysis, which required a correction for late performance of the control group MMG. The Swedish meta-analysis resolved these questions appropriately.

Kopparberg (County W of Two-County Trial), Sweden 1977 [6-8]

Age at entry: 40 to 74 years.
Randomization: Geographic cluster, with stratification for residence (urban or rural), socioeconomic factors, and size. The process for randomization has not been described. The study women were older than the control women, P < .0001, but this would not have had a major effect on the outcome of the trial.
Exclusions: Women with pre-existing breast cancer were excluded from both groups, but the numbers were reported differently in different publications.
Sample size: Variably reported, ranging from 38,562 to 39,051 in intervention and from 18,478 to 18,846 in control.
Consistency of reports: Variable.
Intervention: Three single-view MMGs every 2 years for women younger than 50 years and every 33 months for women aged 50 years and older.
Control: Usual care, with MMG at study end.
Compliance: 89% participation.
Contamination: 13% of women in the Two-County trial had MMG as part of routine care, mostly between 1983 and 1984.
Cause of death attribution: Determined by a team of local physicians (see Östergötland).
Analysis: Evaluation.
External audit: No. However, breast cancer cases and deaths were adjudicated by a Swedish panel that included the trial's investigators.[9]
Follow-up duration: 12 years.
Relative risk of breast cancer death, screening versus control (95% CI): 0.68 (0.52–0.89).

Edinburgh, United Kingdom 1976 [10]

Age at entry: 45 to 64 years.
Randomization: Cluster by physician practices, though many randomization assignments were changed after study start. Within each practice, there was inconsistent recruitment of women, according to the physician’s judgment about each woman’s suitability for the trial. Large differences in socioeconomic status between practices were not recognized until after the study end.
Exclusions: More women (338) with pre-existing breast cancer were excluded from the intervention group than from the control group (177).
Sample size: 23,226 study and 21,904 control.
Consistency of reports: Good.
Intervention: Initially, two-view MMG and CBE; then annual CBE, with single-view MMG in years 3, 5, and 7.
Control: Usual care.
Compliance: 61% screened.
Contamination: None.
Cause of death attribution: Cancer Registry Data.
Analysis: Follow-up.
External audit: No.
Follow-up duration: 10 years.
Relative risk of breast cancer death, screening versus control (95% CI): 0.84 (0.63–1.12).
Comments: Randomization process was flawed. Socioeconomic differences between study and control groups probably account for the higher all-cause mortality in control women compared with screened women. This difference in all-cause mortality was four times greater than the breast cancer mortality in the control group, and therefore, may account for the higher breast cancer mortality in the control group compared with screened women. Although a correction factor was used in the final analysis, this may not adjust the analysis sufficiently.

The study design and conduct make these results difficult to assess or combine with the results of other trials.

National Breast Screening Study (NBSS)-1, Canada 1980 [11]

Age at entry: 40 to 49 years.
Randomization: Individual volunteers, with names entered successively on allocation lists. Although criticisms of the randomization procedure have been made, a thorough independent review found no evidence of subversion and that subversion on a scale large enough to affect the results was unlikely.[12]
Exclusions: Few, balanced between groups.
Sample size: 25,214 study (100% screened after entry CBE) and 25,216 control.
Consistency of reports: Good.
Intervention: Annual two-view MMG and CBE for 4 to 5 years.
Control: Usual care.
Compliance: Initially 100%, decreased to 85.5% by screen five.
Contamination: 26.4% in usual care group.
Cause of death attribution: Death certificates, with review of questionable cases by a blinded review panel. Also linked with the Canadian Mortality Data Base, Statistics Canada.
Analysis: Follow-up.
External audit: Yes. Independent, with analysis of data by several reviewers.
Follow-up duration: 25 years.
Relative risk of breast cancer death, screening versus control (95% CI): 1.09 (0.80–1.49).
Comments: This is the only trial specifically designed to study women aged 40 to 49 years. Cancers diagnosed at entry in both study and control groups were included. Concerns were expressed before the completion of the trial about the technical adequacy of the MMGs, the training of the radiologists, and the standardization of the equipment, which prompted an independent external review. The primary deficiency identified by this review was the use of the mediolateral view from 1980 to 1985 instead of the mediolateral oblique view, which was used after 1985.[13] Subsequent analyses found the size and stage of the cancers detected mammographically in this trial to be equivalent to those of other trials.[14] This trial and NBSS-2 differ from the other RCTs in the consistent use of adjuvant hormone therapy and chemotherapy following local breast cancer therapy in women with axillary node-positive disease.

NBSS-2, Canada 1980 [15]

Age at entry: 50 to 59 years.
Randomization: Individual volunteer (see NBSS-1).
Exclusions: Few, balanced between groups.
Sample size: 19,711 study (100% screened after entry CBE) and 19,694 control.
Intervention: Annual two-view MMG and CBE.
Control: Annual CBE.
Compliance: Initially 100%, decreased to 86.7% by screen five in the MMG and CBE group. Initially 100%, decreased to 85.4% by screen five in the CBE only group.
Contamination: 16.9% of the CBE only group.
Cause of death attribution: Death certificates, with review of questionable cases by a blinded review panel. Also linked with the Canadian Mortality Data Base, Statistics Canada.
Analysis: Follow-up.
External audit: Yes. Independent with analysis of data by several reviewers.
Follow-up duration: 25 years.
Relative risk of breast cancer death, screening versus control: 1.02 (95% CI, 0.77–1.36)
Comments: This trial is unique in that it compares one screening modality to another and does not include an unscreened control. Regarding criticisms and comments about this trial, see NBSS-1.

Stockholm, Sweden 1981 [16]

Age at entry: 40 to 64 years.
Randomization: Cluster by birth date. There were two subtrials with balanced randomization in the first and a significant imbalance in the second, with 508 more women in the screened group than the control.
Exclusions: Inconsistently reported.
Sample size: Between published reports, the size declined from 40,318 to 38,525 in the intervention group and rose from 19,943 to 20,978 in the control group.
Consistency of reports: Variable.
Intervention: Single-view MMG every 28 months × 2.
Control: MMG at year 5.
Compliance: 82% screened.
Contamination: 25% of women entering the study had MMG in the 3 years before entry.
Cause of death attribution: Linked to Swedish Cause of Death Registry.
Analysis: Evaluation, with 1-year delay in the post-trial MMG in the control group. Follow-up analysis as part of the Swedish meta-analysis.[5]
External audit: No.
Follow-up duration: 8 years.
Relative risk of breast cancer death, screening versus control (95% CI): 0.80 (0.53–1.22).
Comments: Concerns exist about randomization, especially in the second subtrial, exclusions, and the delay in control group MMG. Inclusion of these data in the Swedish meta-analysis resolves many of these questions.

Gothenburg, Sweden 1982

Age at entry: 39 to 59 years.
Randomization: Complex; cluster randomly assigned within birth year by day of birth for older group (aged 50–59 years) and by individual for younger group (aged 39–49 years); ratio of study to control varied by year depending on MMG availability (randomization took place, 1982–1984).
Exclusions: A similar proportion of women were excluded from both groups for prior breast cancer diagnosis (1.2% each).
Sample size: Most recent publication: 21,650 invited; 29,961 control.
Consistency of reports: Variable.
Intervention: Initial two-view MMG, then single-view MMG every 18 months × 4. Single-read first three rounds, then double-read.
Control: Control group received one screening exam approximately 3 to 8 months after the final screen in study group.
Cause of death attribution: Linked to Swedish Cause of Death Registry; also used an independent endpoint committee.
Analysis: Both evaluation and follow-up methods.[5]
External audit: No.
Follow-up duration: 12 to14 years.
Relative risk of breast cancer death, screening versus control (95% CI): Aged 39 to 59 years: 0.79 (0.58–1.08) [evaluation]; 0.77 (0.60–1.00) [follow-up].
Comments: No reduction for women aged 50 to 54 years, but similar reductions for other 5-year age groups.
Conclusions: Delay in the performance of MMG in the control group and unequal numbers of women in invited and control groups (complex randomization process) complicates interpretation.

AGE Trial [17,18]

Age at entry: 39 to 41 years.
Randomization: Individuals from lists of general practitioners in geographically defined areas of England, Wales, and Scotland; allocation was concealed.
Exclusions: Small (n = 30 in invited group and n = 51 in not invited group) number excluded in each group because individuals could not be located or were deceased.
Sample size: 160,921 (53,884 invited; 106,956 not invited).
Consistency of reports: Not applicable.
Intervention: Invited group aged 48 years and younger were offered annual screening by MMG (double-view first screen, then single mediolateral oblique view thereafter); 68% accepted first screening and 69% to 70% were reinvited (81% attended at least one screen).
Control: Those who were not invited received usual medical care, unaware of their participation, and few were screened before randomization.
Cause of death attribution: From the National Health Service (NHS) central register, death certificate code accepted.
Analysis: Follow-up method was intention-to-treat (although all women aged 50 years would be offered screening by NHS).
External audit: None.
Follow-up duration: 10.7 years.
Relative risk of breast cancer death, screening versus control (95% CI): 0.83 (0.66–1.04).
Conclusions: Not a statistically significant result, but fits with other studies.
Follow-up duration: Restricted to 10 years from randomization.
Relative risk of breast cancer death, screening versus control (95% CI): 0.75 (0.58–0.97).
Conclusions: A statistically significant result.
Follow-up duration: Median 17.7 years.
Relative risk of breast cancer death, screening versus control (95% CI): 0.88 (0.74–1.04).
Conclusions: Not a statistically significant result.
Follow-up duration: Median 17.7 years.
Relative risk of all-cause mortality, screening versus control (95% CI): 0.98 (0.93–1.03).
Conclusions: Not a statistically significant result.

The reduction in breast cancer mortality at a median follow-up of 17.7 years corresponds to an absolute risk reduction of 0.1 of 1,000 (or 1 of 10,000) fewer deaths.

The evidence is inadequate to support the conclusion of a clinically significant breast cancer mortality reduction attributable to initiation of screening mammography among women aged 39 to 49 years. The reported mortality reduction is a very small, transient reduction in breast cancer mortality based on a nonstandard imaging schedule, nonstandard imaging protocol, and nonstandard threshold for biopsy; therefore, it is of uncertain relevance to the general population. In absolute terms, it corresponds to an absolute risk reduction of 0.1 of 1,000 (or 1 of 10,000) fewer deaths. Additionally, the mortality reduction is based on a re-analysis of the original data set, which was not statistically significant, and the recalculation of breast cancer mortality in a subgroup restricted to 10 years of follow-up. At 20 years of follow-up, there was no statistically significant decrease in risk of breast cancer or all-cause mortality.[18]

The evidence is inadequate to make a clear determination of the magnitude of overdiagnosis. Because the evidence is based on subgroup analysis and nonstandard imaging schedule, nonstandard imaging protocol, and a nonstandard threshold for biopsy with uncertain relevance to the general population, it does not support the investigators' conclusion of “at worst a small amount of overdiagnosis."[18]

References

Shapiro S, Venet W, Strax P, et al.: Ten- to fourteen-year effect of screening on breast cancer mortality. J Natl Cancer Inst 69 (2): 349-55, 1982. [PUBMED Abstract]
Shapiro S: Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore, Md: Johns Hopkins University Press, 1988.
Andersson I, Aspegren K, Janzon L, et al.: Mammographic screening and mortality from breast cancer: the Malmö mammographic screening trial. BMJ 297 (6654): 943-8, 1988. [PUBMED Abstract]
Nyström L, Rutqvist LE, Wall S, et al.: Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet 341 (8851): 973-8, 1993. [PUBMED Abstract]
Nyström L, Andersson I, Bjurstam N, et al.: Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 359 (9310): 909-19, 2002. [PUBMED Abstract]
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 1 (8433): 829-32, 1985. [PUBMED Abstract]
Tabàr L, Fagerberg G, Duffy SW, et al.: Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 30 (1): 187-210, 1992. [PUBMED Abstract]
Tabar 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 43 (2): 107-14, 1989. [PUBMED Abstract]
Holmberg L, Duffy SW, Yen AM, et al.: Differences in endpoints between the Swedish W-E (two county) trial of mammographic screening and the Swedish overview: methodological consequences. J Med Screen 16 (2): 73-80, 2009. [PUBMED Abstract]
Roberts MM, Alexander FE, Anderson TJ, et al.: Edinburgh trial of screening for breast cancer: mortality at seven years. Lancet 335 (8684): 241-6, 1990. [PUBMED Abstract]
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 137 (5 Part 1): 305-12, 2002. [PUBMED Abstract]
Bailar JC, MacMahon B: Randomization in the Canadian National Breast Screening Study: a review for evidence of subversion. CMAJ 156 (2): 193-9, 1997. [PUBMED Abstract]
Baines CJ, Miller AB, Kopans DB, et al.: Canadian National Breast Screening Study: assessment of technical quality by external review. AJR Am J Roentgenol 155 (4): 743-7; discussion 748-9, 1990. [PUBMED Abstract]
Fletcher SW, Black W, Harris R, et al.: Report of the International Workshop on Screening for Breast Cancer. J Natl Cancer Inst 85 (20): 1644-56, 1993. [PUBMED Abstract]
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 147 (10): 1477-88, 1992. [PUBMED Abstract]
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 18 (1): 49-56, 1991. [PUBMED Abstract]
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 randomised controlled trial. Lancet 368 (9552): 2053-60, 2006. [PUBMED Abstract]
Moss SM, Wale C, Smith R, et al.: Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial. Lancet Oncol 16 (9): 1123-32, 2015. [PUBMED Abstract]

Changes to This Summary (12/18/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Description of the Evidence

Revised text to state that women with inherited risk, including BRCA1 and BRCA2 gene carriers, comprise approximately 5% to 10% of breast cancer cases.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about breast cancer screening. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Breast Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389344]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.