MAMMOGRAPHY IN WOMEN 40-49yo


SUMMARY OF THE EVIDENCE:

The data on the clinical impact of screening for breast cancer with mammography in women in their 40's comes from 8 randomized controlled trials (RCTs). Most of these trials included women in other age groups and reported the results on women in their 40's as part of their subgroup analysis. Also, most of these trials reported their results in more than one publication, which makes it a little confusing to track down the primary literature. The table below lists the RCT's with bibliographic information and information about the study protocol and results.

One important issue here is formulating the proper clinical question and determining whether the design of the studies we're looking at, and particularly the outcomes measured, answer that question. The question here is NOT "what are the sensitivity and specificity of mammography for breast cancer in this age group" or even "does mammography result in earlier diagnosis of breast cancer in this age group than [for example] periodic breast exam" but rather, "what benefit in terms of clinically significant outcomes, e.g. mortality, ensues from mammography in women in this age group." In other words, what we want to know is whether mammography in women in their 40's detects curable cancers that would otherwise not be detected until they were incurable.

The main outcome reported by the RCTs was mortality from breast cancer (as opposed to incidence of breast cancer, or overall mortality). With some interventions that are highly risky (like, say, coronary angiography), it can be misleading to look at just disease specific mortality rather than overall mortality. However, it seems unlikely that mammography would affect non-breast-cancer mortality adversely (e.g., increased mortality from complications of local anesthesia used for breast biopsies), so the use of breast cancer mortality as an outcome seems reasonable.

Most of the individual RCTs showed a lower incidence of breast cancer mortality in women screened with mammography than in controls, but without reaching statistical significance. This could either be because mammography truly doesn't lower breast cancer mortality in these women or because the studies lacked the statistical power to detect a small difference with statistical significance. The latter, in turn, could be due to the fact that a) the number of subjects in these studies in the 40-49yo age group was small and b) the incidence of the outcome in being studied (breast cancer mortality) is in general low in that age group, so greater numbers of subjects are necessary to demonstrate a significance difference between intervention and control groups than in other age groups.

Meta-analyses, of course, are studies that combine data from multiple other studies in order to increase the statistical power of various analyses and in order to resolve conflicts between study findings. There are at least seven meta-analyses of the data on mammography screening in women age 40-49yo (listed with summary information below), and they almost all are based on the exact same eight RCTs. They all have slightly different results, either because they looked at different subsets of the published RCTs or different versions of the randomized trial data (depending on what was available when the meta-analysis was performed), or because they analyzed the data with slightly different techniques (there are lots of options as to how to combine the data when you're dong a meta-analysis).

In the list below, I have put the three meta-analyses that showed a significant benefit to mammography screening for women age 40-49 in BLUE. Of interest, all three were published in 1996 or later, whereas some of those which did not show a benefit were published earlier. So one reason for the difference might be that the later-published meta-analyses had data representing longer-term followup from the RCTs. In any case, the meta-analyses that showed a significant benefit found RR's for breast cancer mortality from 0.76-0.84. I have not been able to find much data on absolute risk reduction for this summary. One RCT reported a significant ARR of .0018 (number needed to screen = 1/.0018 = 555 patients). Neither of the meta-analyses that I found ARR data in found significant results, so it would seem illogical to use the ARR data from those (since the lack of statistical significance implies that the difference might really be zero).


THE CLINICAL TRIALS:

Location References Protocol Findings
MALMO, SWEDEN Andersson I, Janzon L. Reduced breast cancer mortality in women under age 50: updated results from the Malmo Mammographic Screening Program. Journal of the National Cancer Institute Monographs 1997;22:63-67.

Andersson I, Aspegren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: the Malmo mammographic screening trial. BMJ 1988; 297: 943-48.

42,283 women 45-69yo enrolled in the trial; screened with 2-view mammogram (then 1-view subsequently depending on parenchymal patterns) Q18-24mo RR for breast Ca mortality was 0.96 in the screening group (95% CI 0.68-1.35)
SWEDISH 2-COUNTY TRIAL: Kopparberg Tabar L, Fagerberg G, Chen HH, Duffy SW, Smart CR, Gad A, Smith RA. Efficacy of breast cancer screening by age. New results from the Swedish Two-County Trial. Cancer 1995 May 15;75(10):2507-2517

Tabar L, Duffy SW, Vitak B, et al. The natural history of breast carcinoma: What have we learned from screening? Cancer 1999;86(3):449-62

57,171 women 40-74yo at entry; screened w/1-view mammogram Q24-33mo Over avg. 12y f/u, RR for breast Ca mortality 0.58 (95% CI 0.45-0.76)
SWEDISH 2-COUNTY TRIAL: Ostergotland As above As above; 75,894 pts enrolled Over avg. 12y f/u, RR for breast Ca mortality 0.76 (95% CI 0.61-0.95)
STOCKHOLM, SWEDEN Frisell, J., Lidbrink, E., Hellstrom, L. and Rutqvist, L. E. Follow-up after 11 years--update of mortality results in the Stockholm mammographic screening trial. Breast Cancer Research & Treatment 45:263-70, 1997.

Frisell J, Lidbrik E. The Stockholm mammographic screening trial: risks and benefits in age group 40-49 years. Journal of the National Cancer Institute Monographs 1997;22:49-51.

Cohort study comparing 40,318 women 40-64yo at entry enrolled in a screening study (screened w/1-view mammogram Q28mo) with 19,943 women not enrolled in the study. Over 11y f/u, RR for breast Ca mortality was 0.73 (95% CI 0.50-1.06) in screened group. Among subgroups: RR1.08 for 40-49yo subgroup (95% CI 0.54-2.17) and 0.62 for 50-64yo group (95% CI 0.38-1.0). Absolute risk difference in the 40-49yo group was 12 deaths among 14,842 screened = .0008 increased chance of death among screened women.
GOTHENBURG, SWEDEN Bjurstam, N., Bjorneld, L., Duffy, S. W., Smith, T. C., Cahlin, E., Eriksson, O., Hafstrom, L. O., Lingaas, H., Mattsson, J., Persson, S., Rudenstam, C. M. and Save- Soderbergh, J. The Gothenburg breast screening trial: First results on mortality, incidence, and mode of detection for women ages 39-49 years at randomization. Cancer, 80:2091-9, 1997.

Bjurstam N, Bjorneld L, Duffy SW, et al. The Gothenburg breast cancer screening trial: preliminary results on breast cancer mortality for women aged 40-49. Journal of the National Cancer Institute Monographs 1997;22: 53-55.

25,941 women 39-59yo randomized to 2-view mammography (then 1-view subsequently depending on parenchymal patterns) Q18mos vs. none. Over avg. 11y f/u, RR of mortality was 0.55% in the screened group (95% CI 0.31-0.95). Absolute risk reduction = 22 deaths among 11,724 screened pts = .0018, NNS = 555)
CANADIAN NATIONAL BREAST SCREENING STUDY Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 1-breast cancer detection and death rates among women aged 40-49 years. Can Med Assoc J 1992; 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; 147: 1477-88

Miller AB, To T, Baines CJ, et al. The Canadian National Breast Screening Study: update on breast cancer mortality. Journal of the National Cancer Institute Monographs 1997;22:37-41.

J. Nat. Canc. Inst. 92:1490, 2000--A f/u study @ 13y showing no diff. in Breast Ca mortaity between the two groups for CNBSS-2

Milller AB et al. The Canadian National Breast Screening Study-1: Breast Cancer Mortality after 11 to 16 years of follow-up.  Ann. Int. Med. 137:305-12, 2002--JW

85,835 women 40-59yo (50,430 40-49yo) randomized to annual 2-view mammo + Px x 5y vs. usual care.  Note that the breast exam was very detailed in these women (took about 10min)  

Over avg. 10.5y f/u, RR for breast Ca mortality was 1.08 in the screened group (95% CI 0.84-1.40). Among women 40-49yo at randomization, over avg. 13y f/u, RR for breast Ca mortality was 0.97 in the screened group (nonsig.)

EDINBURGH, SCOTLAND Alexander, F. The Edinburgh randomised trial of breast cancer screening. Journal of the National Cancer Institute Monographs, 22: 31-5, 1997.

Alexander FE, Anderson TJ, Brown HK, et al. 14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999;353(9168):1903-08

34,268 women 45-64yo randomized to mammography (2-view Q2y) + clinical exam vs. "regular care." Over 14y f/u, RR for breast Ca mortality was 0.87 (99% CI 0.70-1.08) in the screened group. Among women 45-49yo, RR was 0.83 (95% CI 0.54-1.21; absolute risk reduction = 6 deaths among 11479 women screened = .00052, NNS = 1923)
HIP (NEW YORK) Chu KC, Smart CR, Tarone RE. Analysis of breast cancer mortality and stage distribution by age for the Health Insurance Plan clinical trial. J Natl Cancer Inst 1988; 80: 1125-32

Shapiro, S. Periodic screening for breast cancer: the HIP Randomized Controlled Trial. Health Insurance Plan. Journal of the National Cancer Institute Monographs, 22: 27-30, 1997.

60,696 women 40-64yo randomized to clinical exam + 2-view mammography Q1y vs. usual care. Over 18y f/u, RR for breast Ca mortality was 0.79 (95% CI 0.64-0.98) in mammography group. To a large extent the difference among the pts 40-49yo at study entry occurred among women who had their breast cancer diagnosed after age 50.
UK CCCR Wald, N., Murphy, P. and Major, P. UK CCCR multicentre randomised controlled trial of one and two view mammography in breast cancer screening. BMJ, 311:1189-93, 1995 STUDY UNDERWAY as of 2001. Will recruit women on their 40th birthday into a large RCT.  
SINGAPORE Ng EH, Ng FC, Tan PH, Low SC, Chiang G, Tan KP et al. Results of intermediate measures from a population-based, randomized trial of mammographic screening prevalence and detection of breast carcinoma among Asian women: the Singapore Breast Screening Project. Cancer 1998;82(8):1521-8 STUDY UNDERWAY as of 2001.  Randomized 166,600 women 50-64yo to 2-view mammography vs. observation.  

In addition-


META-ANALYSES ADDRESSING EFFECT OF SCREENING ON WOMEN 40-49yo:

Anonymous. Breast-cancer screening with mammography in women aged 40-49 years. Swedish Cancer Society and the Swedish National Board of Health and Welfare. International Journal of Cancer 68:693-9, 1996.

Meta-analysis of 8 RCT's and 4 cohort studies involving mammography for women 40-49yo; found no sig. breast cancer mortality reduction in mammography group (0.85, 95% CI 0.71-1.01) BUT the reduction WAS significant when only RCT data was used (0.76, 95% CI 0.62-0.93).

 

Demissie, K., Mills, O. F. and Rhoads, G. G. Empirical comparison of the results of RCTs and case-control studies in evaluating the effectiveness of screening mammography. Journal of Clinical Epidemiology, 51:81-91, 1998.

Meta-analysis of 8 RCT's and 5 case-control studies of screening mammography. RR for breast Ca mortality was 0.76 (sig.) from RCT's and 0.44 (sig.) from case-control studies. For women > 65yo the RR from RCT's was 0.7 (sig.). For women 40-49yo, the RR for breast Ca mortality was 0.95 (95% CI 0.75-1.14) using data from the RCT's and 0.88 (95% CI 0.47-1.63) for the case-control studies. This paper did NOT report any data on absolute risk reduction.

 

Glasziou P P, Woodward A J, Mahon C M. Mammographic screening trials for women aged under 50: a quality assessment and meta-analysis. Medical Journal of Australia1995, 162(12), 625-629.

Meta-analysis of 7 RCT's of mammography involving women 40-49yo. RR of breast Ca mortality was 0.95 (95% CI 0.77-1.18)

Glasziou P, Irwig L. The quality and interpretation of mammographic screening trials for women ages 40-49. Journal of the National Cancer Institute Monographs 1997;(22):73-77.

Meta-analysis of 8 RCTs of mammography screening in women 40-49yo (all of the RCT's in table above). Overall RR of breast Ca mortality was 0.85 (nonsig.) over avg. 13y of f/u. Absolute risk difference was 0.0004 (95% CI 0-0.0009). This is an update of the 1995 MJA article.

 

Hendrick, R. E., Smith, R. A., Rutledge, J. H., 3rd and Smart, C. R. Benefit of screening mammography in women aged 40-49: a new meta-analysis of RCTs. Journal of the National Cancer Institute. Monographs 22:87-92, 1997.

Meta-analysis of 8 RCT's (all of the RCT's in table above, including updated data presented at an NIH conference) of mammography in women 40-49yo; RR for breast Ca mortality was 0.82 (95% CI 0.71-0.95) over avg. 12.7y of f/u.

 

Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VL. Efficacy of screening mammography. JAMA 1995 Jan 11;273(2):149-154.

Meta-analysis of 9 RCT's and 4 case-control studies. RR for breast Ca mortality in pts 50-74yo was 0.74 (95% CI 0.66-0.83); for women 40-49yo, RR of breast Ca mortality was 0.93 (95% CI 0.76-1.13). Several sub-group analyses for pts 40-49yo (e.g. looking just at studies that used 2-view mammography) failed to show any sig. reduction in breast Ca mortality among any subgroup of studies.

Kerlikowske K. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. Journal of the National Cancer Institute Monographs 1997;22:79-86.

Meta-analysis of mammography screening in women 40-49yo; 8 RCT's (all of the RCT's in the table above). RR for breast Ca mortality was 0.84 (sig.) over 10-14y of f/u. This is an update on the 1995 JAMA article.

 

Larsson LG, Nystrom L, Wall S, Rutqvist L, Andersson I, Bjurstam N, Fagerberg G, Frisell J, Tabar L. The Swedish randomised mammography screening trials: analysis of their effect on the breast cancer related excess mortality. J Med Screen 1996;3(3):129-132

Meta-analysis of 5 RCTs of mammography screening (Malmo, Kopparberg, Ostergartland, Stockholm, Gothenburg) over median f/u of 12.8y showing RR for breast Ca mortality 0.76 in overall group (40-74yo at randomization). For women 40-49yo at randomization, RR of breast Ca mortality was 0.94 (nonsig.)

Larsson LG, Andersson I, Burstam N, et al. Updated overview of the Swedish Randomized Trials on breast cancer screening with mammography: age group 40-49 at randomization. Journal of the National Cancer Institute Monographs 1997;22:57-61.

This appears to be an update of the 1996 J. Med. Screen. paper. Compiling data up to 1993 f/u from 4 randomized trials (median f/u 12.8y), the authors found a RR of breast Ca mortality of 0.77 (95% CI 0.59-1.01, absolute risk reduction 7 deaths among 48,569 screened women = .00014, NNS = 7143)

 

Nystrom L, Rutqvist LE, Walls S, et al. Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet 1993; 341: 974-78.

Meta-analysis of an update of the 5 Swedish trials (Malmo, Kopparberg, Ostergartland, Stockholm, Gothenburg). Among all pts (40-74yo at randomization), RR of breast Ca mortality was 0.77 (95% CI 0.67-0.88, absolute risk reduction 7 deaths per 156911 women screened = 0.00004, NNS = 25,000). For women 50-69yo at randomization, RR of breast Ca mortality was 0.71 (95% CI 0.57-0.89). For women 40-49yo at randomization the RR for breast Ca mortality was 0.87 (95% CI 0.63-1.20, I couldn't calculate absolute risk reduction b/c the total # of pts in this age range wasn't reported)


SUMMARIES OF META-ANALYSES:

Hilder P, Nicholas B. The early detection and diagnosis of breast cancer: a literature review. New Zealand Health Technology Assessment Report. 2(2). 1999. 1-150. Available on the WWW at http://nzhta.chmeds.ac.nz/breast_cancer.htm

"Mammography screening: mortality rate reduction and screening interval "--Alberta Heritage Foundation for Medical Research, June 2000 at http://www.ahfmr.ab.ca/hta/hta-publications/reports/HTA21.FINAL.pdf