Canada–National Breast Screening Study 1
The Canadian randomized trial of the efficacy of breast cancer screening in women aged 40 to 49 was initiated in 1980. It was designed to specifically test the efficacy of breast cancer screening in women in their 40s and consisted of four to five rounds of annual CBE and mammography, depending on time of entry into the study. After a physical examination that included CBE, women were invited to participate in the study, and volunteers were then randomized into a study group or control group.

Approximately 50,000 women participated in the study, with virtually equal numbers randomized to study and control groups. At 7 years of follow-up, approximately 36% more breast cancer deaths had occurred in the study group than in the control group. At 10.5 years of follow-up, the rate of excess mortality had declined to 14%. This study and its conclusions have been controversial for a number of reasons, including study design (all study participants received a high-quality CBE before randomization), questions about the randomization process, the quality of mammography, and the observation that there was a significant excess of patients with advanced tumors in the group invited to screening compared with the usual care group.

More specifically, Tarone has shown that the excess of patients in the National Breast Screening Study 1 (NBSS-1) who had four or more positive nodes in the screening arm is statistically significant and inconsistent with the stage distribution of disease in other trials, both in the first round and at the conclusion of the study. There is no known explanation for the excess of advanced tumors in the group invited to the screening, and a review of the randomization process did not uncover any irregularities. However, it is apparent that this yet unexplained excess of advanced cancers accounts for the higher breast cancer death rate in the screening arm.

Canada–National Breast Screening Study 2
The National Breast Screening Study 2 (NBSS-2) was also initiated in 1980 and was a trial of the efficacy of breast cancer screening in women aged 50 to 59. It was designed to test specifically the efficacy of breast cancer screening in this age group with mammography and CBE versus CBE alone and consisted of four rounds of annual examinations in the study and control groups.

As with the NBSS-1, after a physical examination that included CBE, women were invited to participate in the study. Volunteers were then randomized into a study group or control group. Approximately 39,000 women participated in the study, with virtually equal numbers randomized to study and control groups. At 7 years of follow-up, only 3% fewer deaths had occurred from breast cancer in the study group than in the control group. This particular study has received less attention than the study of women aged 40 to 49, but many of the same critiques apply.

Metaanalyses
Before 1997 both the HIP study and the Swedish Two-County study provided clear and early evidence that mammography could reduce breast cancer mortality in women aged 50 and older, providing a sound basis for the promotion of screening for this age group. Evidence supporting the value of screening for women in their 40s was less clear. Although there was indirect evidence of a benefit both from the trials and observational studies, until recently no single trial had shown a statistically significant reduction in breast cancer deaths among women randomized to an invitation to screening in their 40s.

Whereas the absence of definitive evidence of a benefit was troubling to some, especially in light of early findings of an excess of breast cancer deaths in the NBSS-1, others were persuaded that the absence of a benefit was an artifact of methodologic shortcomings, in particular low statistical power in the trials for subgroup analysis.

To overcome the limits of small sample sizes, investigators began to conduct meta-analyses of trial data, combining age-specific results from the various studies to overcome the limits of small sample sizes. There are two important observations about these meta-analyses. First, as was the case with individual trials, benefits for women aged 50 and older appear early in the follow-up period, whereas they occur later for women aged 40 to 49. Second, with accumulating years of follow-up in the 40 to 49 group, the relative risk of mortality steadily improved.