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Therapeutics

Mortality was not reduced by screening women aged 40 to 44 years with an annual breast exam and mammography or by adding mammography to an annual breast exam for women aged 50-59 years

ACP J Club. 1993 Mar-April;118:40-1. doi:10.7326/ACPJC-1993-118-2-040


Source Citations

Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years. Can Med Assoc J. 1992 Nov 15;147:1459-76.

Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. Can Med Assoc J. 1992 Nov 15;147:1477-88.


Abstract

Objectives

1. To compare the efficacy of annual mammography screening and physical examination of the breasts with a single physical examination of the breasts and annual follow-up through a mailed, self-administered questionnaire in reducing mortality from breast cancer among women aged 40 to 49 years on entry.

2. To compare the efficacy of annual mammography screening and physical examination of the breasts with annual physical examination only in reducing mortality from breast cancer among women aged 50 to 59 years on entry.

Design

Randomized controlled trial with a mean follow-up of 8.4 years. Randomization was stratified by center and 5-year age group.

Setting

15 urban centers in Canada with expertise in mammography and in the diagnosis and treatment of breast cancer.

Participants

50 430 women aged 40 to 49 years on entry and 39 405 women aged 50 to 59 years on entry were enrolled from January 1980 through March 1985. Other eligibility criteria were no mammography in the past 12 months, no history of breast cancer, and no current pregnancy. Over 90% of women aged 40 to 49 years attended the screening sessions or returned the annual questionnaires from years 2 to 5. Over 85% of women aged 50 to 59 years attended the screening sessions after the first screen.

Intervention

25 214 women aged 40 to 49 years were assigned to annual mammography screening and physical examination of the breasts (MP group), and 25 216 women aged 40 to 49 years were assigned to a single physical examination of the breasts and annual follow-up through a mailed, self-administered questionnaire (UC [usual care] group). 19 711 women aged 50 to 59 years were assigned to annual mammography and physical examination of the breasts (MP group), and 19 694 women aged 50 to 59 years were assigned to annual physical examination only (PO group). All women were taught breast self-examination.

Main outcome measures

Rates of detection of histologically confirmed breast cancer from screening and community care, nodal status, tumor size, and rates of death from breast cancer. Data were collected from the participants by initial and annual self-administered questionnaires, screening examinations, and the patients' physicians, and from the provincial cancer registries and the Canadian National Mortality Data Base. Death certificates were obtained for women who died in Canada.

Main results

The rate of screen-detected breast cancer, including in-situ and invasive cancer, among women aged 40 to 49 years on first examination was 3.89/1000 per y in the MP group and 2.46/1000 per y in the UC group; the rate among women aged 50 to 59 years at entry was 7.20/1000 per y in the MP group and 3.45/1000 per y in the PO group (in both cases this difference was not statistically significant). More node-positive tumors were found in the MP groups than in the control groups. During years 2 through 5 among women aged 40 to 49 years, the cumulative ratio of observed to expected rates of invasive breast cancer was 1.26 (95% CI 0.98 to 1.59) in the MP group compared with 1.02 (CI 0.78 to 1.33) in the UC group. The corresponding ratios for women aged 50 to 59 years were 1.28 (CI 1.05 to 1.56) in the MP group and 1.18 (CI 0.96 to 1.45) in the PO group. Of women aged 40 to 49 years with invasive breast cancer through 7 years of follow-up, 191 and 157 women in the MP and UC groups, respectively, had no node involvement; 55 and 43 had 1 to 3 nodes involved; 47 and 23 had ≥ 4 nodes involved; and 38 and 49 had an unknown nodal status. Of women aged 50 to 59 years with invasive breast cancer through 7 years of follow-up, 217 in the MP group and 184 in the PO group had no node involvement; 66 and 56 had 1 to 3 nodes involved; 32 and 34 had ≥ 4 nodes involved; and 55 and 46 had an unknown nodal status. For both age groups, the MP groups had more small invasive tumors detected compared with the control groups (women aged 40 to 49 years 156 vs 116, women aged 50 to 59 years 202 vs 144). The number of deaths from breast cancer were similar in the 2 treatment groups for both age groups {P = 0.22 for women aged 40 to 49 y P = 0.91 for women aged 50 to 59 y}* (Table). The 7-year survival rates were similar in the 2 treatment groups for both age groups (women aged 40 to 49 y 90.2% in the MP group vs 89.9% in the UC group, women aged 50 to 59 y 91.2% in the MP group vs 86.8% in the PO group).

Conclusions

Among women aged 40 to 49 years, screening with yearly mammography and physical examination of the breasts had no effect on the rate of death from breast cancer for up to 7 years of follow-up. In women aged 50 to 59 years, the addition of annual mammography to annual breast examination had no effect on the rate of death from breast cancer for up to 7 years of follow-up.

*P value calculated from data in article.

Sources of funding: Canadian Cancer Society; Department of National Health and Welfare; National Cancer Institute of Canada; Alberta Heritage Fund for Cancer Research; Manitoba Health Services Commission; Medical Research Council of Canada; le Ministère de la Santé et des Services sociaux du Québec; Nova Scotia Department of Health; Ontario Ministry of Health.

For article reprint: Dr. A.M. Miller, Department of Preventive Medicine and Bio-statistics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. FAX 416-978-8299.


Table. Deaths in women (age 40 to 49 y) allocated to mammography and physical breast examination or usual care and in women (age 50 to 59 y) allocated to mammography and physical breast examination or physical breast examination alone

Patient group Mammography and breast exam Control RRI (95%) NNH (CI)
Age 40 to 49 years 0.15% 0.11% 36% (-16 to 120) Not significant
RRR (CI) NNT (CI)
Age 50 to 59 years 0.19% 0.20% 3% (52 to 37) Not significant

*Abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from data in article.


Commentary

Before the Canadian studies by Miller and colleagues, 5 randomized trials (1-5) had included breast cancer mortality results for women in their 40s screened with routine mammograms alone or in combination with physical examination (6). For women in their 40s, only 1 trial (the Health Insurance Plan) showed a slowly occurring 25% reduction in mortality after 18 years of follow-up, which was not statistically significant and which occured in the context of a higher-than-expected mortality rate among women with node-negative cancers in the control group (5). Also, several women who developed breast cancer entered the trial in their 40s but were diagnosed with breast cancer in their 50s. Results from the other 4 trials for women in their 40s (1-4), after 7 to 11 years, varied from a 2% reduction in mortality to a 29% increase in mortality after screening, with no result being statistically significant. For women aged 50 and over, all 5 trials showed a reduction in breast cancer mortality, ranging from 20% to 39%.

With these results, expert groups that require rigorous evidence before making recommendations have not recommended routine mammography in women younger than age 50. Others were more optimistic. All hoped the Canadian trial, the largest to date of women aged 40 to 49 years, would demonstrate benefit.

The Canadian study results for women 40 to 49 years of age are similar to those of previous studies. The group that was offered yearly physical examinations and mammograms had more breast cancers detected, both node-negative and node-positive, than the control group. After 7 years, however, mortality did not decrease; in fact, the point-estimate of the relative risk was 1.36 favoring the control group. This disturbing result has generated criticism about the quality of mammography used in the study. Perhaps just as important, 25% of patients in the control group had received at least 1 mammogram by the end of the study.

Updates of the previous studies, especially 4 studies in Sweden, are in the offing. The National Cancer Institute and the American Cancer Society plan to consider all new reports. Meanwhile, it is clear that effectiveness of breast cancer screening varies by age, with quicker and greater effects in older women. This finding should not be surprising, given the biologic differences in breast cancers and breast tissue in women of different ages. The irony is that more women in their 40s have routine mammograms than in any other age group. The older the woman, the less likely she is to receive screening mammography.

Screening for breast cancer involves 3 different tests—a physical examination by a health care professional, mammography, and breast self-examination. The incremental value of these tests is not known. The Canadian report by Miller and colleagues for women in their 50s asks how much mammography adds to a careful annual physical examination. Mammography detected more breast cancers, both node-negative and node-positive, than did a careful physical examination. After 7 years, however, breast cancer mortality was the same in both groups, with a relative risk of 0.97. Again, the study has been criticized for poor-quality mammograms. Another possible explanation for the results is that a careful physical examination may be more important in breast cancer screening than previously thought.

With the intensive scientific study of breast cancer screening, it is discouraging that so much controversy remains. Large investments have been made to establish breast cancer screening programs in developed countries. Based on the cumulative evidence to date, concerned physicians should encourage breast cancer screening for all of their women patients aged 50 to 74 years; sadly, fewer than half currently receive regular mammography. Most important, women need to learn that 75% of breast cancers occur after the age of 50.

Suzanne W. Fletcher, MD
American College of Physicians Philadelphia, Pennsylvania, USA