Elsevier

The Lancet Oncology

Volume 16, Issue 9, September 2015, Pages 1123-1132
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(15)00128-XGet rights and content

Summary

Background

Age-specific effects of mammographic screening, and the timing of such effects, are a matter of debate. The results of the UK Age trial, which compared the effect of invitation to annual mammographic screening from age 40 years with commencement of screening at age 50 years on breast cancer mortality, have been reported at 10 years of follow-up and showed no significant difference in mortality between the trial groups. Here, we report the results of the UK Age trial after 17 years of follow-up.

Methods

Women aged 39–41 from 23 UK NHS Breast Screening Programme units years were randomly assigned by individual randomisation (1:2) to either an intervention group offered annual screening by mammography up to and including the calendar year of their 48th birthday or to a control group receiving usual medical care (invited for screening at age 50 years and every 3 years thereafter). Both groups were stratified by general practice. We compared breast cancer incidence and mortality by time since randomisation. Analyses included all women randomly assigned who could be traced with the National Health Service Central Register and who had not died or emigrated before entry. The primary outcome measures were mortality from breast cancer (defined as deaths with breast cancer coded as the underlying cause of death) and breast cancer incidence, including in-situ, invasive, and total incidence. Because there is an interest in the timing of the mortality effect, we analysed the results in different follow-up periods. This trial is registered, number ISRCTN24647151.

Findings

Between Oct 14, 1990, and Sept 25, 1997, 160 921 participants were randomly assigned; 53 883 women in the intervention group and 106 953 assigned to usual medical care were included in this analysis. After a median follow-up of 17 years (IQR 16·8–18·8), the rate ratio (RR) for breast cancer mortality was 0·88 (95% CI 0·74–1·04) from tumours diagnosed during the intervention phase. A significant reduction in breast cancer mortality was noted in the intervention group compared with the control group in the first 10 years after diagnosis (RR 0·75, 0·58–0·97) but not thereafter (RR 1·02, 0·80–1·30) from tumours diagnosed during the intervention phase. The overall breast cancer incidence during 17 year follow-up was similar between the intervention group and the control group (RR 0·98, 0·93–1·04).

Interpretation

Our results support an early reduction in mortality from breast cancer with annual mammography screening in women aged 40–49 years. Further data are needed to fully understand long-term effects. Cumulative incidence figures suggest at worst a small amount of overdiagnosis.

Funding

National Institute for Health Research Health Technology Assessment programme and the American Cancer Society. Past funding was received from the Medical Research Council, Cancer Research UK, the UK Department of Health, and the US National Cancer Institute.

Introduction

Population-based screening for breast cancer by mammography is well established in many countries, although the target age range for invitation varies and the appropriate age range at which to invite women for screening continues to be an area of debate. Although some service screening programmes begin offering screening at age 40 or 45 years,1 most begin offering it from age 50 years.1 In England, the lower age limit for invitation is being reduced to 47 years, which means that when this extension is complete, all women will receive their first invitation before the age of 50 years. This change is being made with an experimental design that will allow assessment of its effect in the service screening environment,2 but the results will not be available for many years.

A recent review3 by the International Agency for Research on Cancer concluded that there was limited evidence for the efficacy of screening women aged 40–49 years by mammography. However, it has been argued that evidence4 from randomised controlled trials does not provide a strong basis for determining the effectiveness of mammography in women in their 40s compared with that in older women, and evidence5, 6 from service screening programmes supports a more optimistic view of the benefits of mammography in women aged 40–49 years. Although most US organisations recommend annual mammography for women in their 40s, in 2009, the US Preventive Services Task Force (USPSTF) revised its 2002 recommendations that women in their 40s should undergo mammography screening every 1–2 years, and now recommends against routine screening mammography for women in this age group based mainly on what it judged to be an uncertain balance of benefits and harms.7 Its systematic review8 noted that although the relative risk reductions in women aged 50–59 years (14%) and 40–49 years (15%) were similar, the absolute risk reduction was greater for women aged 50–59 years than for those aged 40–49 years, leading to a number needed to invite to screening of 1339 compared with 1904 for the younger age group.

Research in context

Evidence before this study

Several previous randomised trials of mammographic screening included women aged younger than 50 years. A meta-analysis including these studies done for the US Preventive Services Task Force (USPSTF), published in 2009, identified a relative risk reduction in breast cancer mortality of 15% in women, aged 39–49 at randomisation, invited for screening, similar to that for older women, but a lower absolute reduction and greater number needed to invite. This meta-analysis included the first mortality results of the UK Age trial, and also the results of the Canadian trial (NBSS-1), the only other trial designed to study women younger than 50 years. A Cochrane review published in 2013 identified a 13% reduction in mortality in an analysis of only three of the eight trials included in the USPSTF meta-analysis, and a 16% reduction including all eight trials at 13 years of follow-up. Evidence from some service screening programmes supports a benefit of mammography in women younger than 50 years.

Estimates of overdiagnosis as a result of mammographic screening vary widely, largely because of differences in the methods used. Particularly, failure to allow for adequate follow-up will lead to an overestimate of overdiagnosis because of lead time. As a result, little reliable evidence exists about the extent of overdiagnosis in this age group.

Added value of this study

The UK Age trial is the only trial designed specifically to study the effect of mammographic screening starting at age 40 years. This study reports breast cancer mortality and incidence at a median of 17·7 years of follow-up, an increase of 7 years from the previous publication.

Implications of all the available evidence

The evidence supports a reduction in breast cancer mortality as a result of mammographic screening in women younger than 50 years at least in the first 10 years of follow-up. Further analysis of all the trials might clarify the long-term effects of early screening. No evidence for an increased amount of overdiagnosis in this age group was noted.

The USPSTF meta-analysis7 included the first mortality results from the UK Age trial,9 which were based on breast cancer mortality at a mean of 10·7 years (SD 1·6) of follow-up and showed a non-significant reduction in women invited to screening (relative risk 0·83, 95% CI 0·66–1·04), with an absolute risk reduction of 0·40 per 1000 women invited, equivalent to a number needed to invite of 2512. The UK Age trial was a randomised screening trial established in 1991 to determine the effectiveness of annual mammographic screening commencing at age 40 years compared with the UK national policy at the time, which was to commence from age 50 years. The UK Age trial is unique in that it included women aged 39–41 years at entry and is the only trial of mammography specifically designed to study the effectiveness of commencing screening at age 40 years. We aimed to assess the effect on breast cancer incidence and breast cancer mortality after long-term follow-up of the UK Age trial.

Section snippets

Study design and participants

The design of the UK Age trial has been described elsewhere.10 Briefly, women aged 39–41 years from 23 UK NHS Breast Screening Programme (NHSBSP) units (appendix) were identified from the general practitioners' (GP) lists of patients held in health authority databases. Women in the intervention group received an information leaflet about the trial with their letter of invitation and acceptance of the invitation to attend screening was taken to be informed consent to participate. The uninvited

Results

Between Oct 14, 1990, and Sept 24, 1997, 160 921 women were randomly assigned to the intervention and control groups. More than 99·9% of women were successfully identified by the NHSCR; 85 women (31 in the intervention group and 54 in the control group) were excluded from the analysis because they either could not be traced by the NHSCR, they had died or emigrated before entry, or were mistakenly identified men (figure 1). Four women have been identified as having emigrated or died before date

Discussion

The long-term results from the UK Age trial presented here show a significant reduction in the risk of breast cancer mortality in the intervention group compared with the control group in the first 10 years, followed by no difference between the groups thereafter, when analysis was restricted to breast cancers diagnosed during the intervention phase. The absolute effect of mammographic screening in this age group is difficult to assess when we include deaths from cancers diagnosed after the

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