Final results of the UK Age trial on breast cancer screening age

Abstract

In The Lancet Oncology, the findings from a 23-year follow-up of the UK Age trial are presented by Stephen Duffy and colleagues.1Duffy SW Vulkan D Cuckle H et al.Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial.Lancet Oncol. 2020; (published online Aug 12.)https://doi.org/10.1016/S1470-2045(20)30398-3Summary Full Text Full Text PDF PubMed Scopus (65) Google Scholar No difference in mortality from breast cancer was found between the group that began yearly mammography screening at age 39–41 years until they entered the National Health Service (NHS) Breast Screening Programme at age 50–52 years, and a group that did not begin mammography screening until they entered the NHS Breast Screening Programme (126 deaths vs 255 deaths occurring after more than 10 years of follow-up; relative rate 0·98 [95% CI 0·79–1·22]; p=0·86). The trial was well conducted, utilising the facilities of the centres already participating in the NHS Breast Screening Programme that had the capacity to screen additional women. As participating women were flagged with the NHS Central Register, mortality from breast cancer in the compared groups could be accurately ascertained. Unfortunately, the debate over whether to initiate breast screening at age 40 or 50 years will not have been resolved by the UK Age trial, as the lack of a control group who were not offered screening at any age precluded determining whether either group in the trial derived any benefit. Although there is the possibility that in the intervention group (screening initiated at age 39–41 years) some person-years were saved by the earlier detection of breast cancer than in the control group, overall there was no mortality reduction in the intervention group compared to the control group by the end of follow-up. Those who favour screening will be left with a conundrum, but those who believe that mammography screening has little or no benefit will feel their views have been justified. One surprising aspect of the report by Duffy and colleagues is the conclusion that no overdiagnosis of breast cancer occurred in either group beyond that which would occur when screening those aged 50 years and older. Because overdiagnosis appears to increase with age, it is possible that overdiagnosis occurred in both groups after the age of 50 years, but could not be detected because of the design of the trial. The UK programme for breast cancer screening began after the early results of the Swedish Two-County trial and the US HIP trial had been reviewed in the Forrest report.2Forrest APM Aitken RJ Mammography screening for breast cancer.Annu Rev Med. 1990; 41: 117-132Crossref PubMed Scopus (18) Google Scholar Unfortunately, neither the Forrest report authors, nor the later report by Marmot and colleagues,3Marmot MG Altman DG Cameron DA Dewar JA Thompson SG Wilcox M The benefits and harms of breast cancer screening: an independent review.Br J Cancer. 2013; 108: 2205-2240Crossref PubMed Scopus (605) Google Scholar recognised the serious flaws in the design and conduct of the Two-County trial that casts considerable doubt on their conclusions, including the cluster randomisation, the inability to confirm that the two groups were comparable, and the lack of use of adjuvant chemotherapy.4Tabar L Chen HH Duffy SW Krusemo UB Primary and adjuvant therapy, prognostic factors and survival in 1053 breast cancers diagnosed in a trial of mammography screening.Jpn J Clin Oncol. 1999; 29: 608-616Crossref PubMed Scopus (24) Google Scholar By contrast, in the Canadian National Breast Screening study,5Miller AB To T Baines CJ Wall C 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. 2002; 137: 305-312Crossref PubMed Google Scholar we were able to publish detailed data on the comparability of the study groups because the participants were randomly assigned after completing a questionnaire on risk factors for breast cancer. We also confirmed that adjuvant chemotherapy was used, but found no benefit from mammography screening,6Miller AB Wall C Baines CJ Sun P To T Narod SA Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial.BMJ. 2014; 348: g366Crossref PubMed Scopus (520) Google Scholar and instead found a harmful effect, especially from overdiagnosis.7Baines CJ To T Miller AB Revised estimates of overdiagnosis from the Canadian National Breast Screening Study.Prev Med. 2016; 90: 66-71Crossref PubMed Scopus (32) Google Scholar Thus, although Duffy and colleagues should be commended for providing long-term data from a well conducted study, it could be argued that breast screening with mammography should not be initiated at any age, but rather women should be encouraged to practise breast awareness, with mammography used as a diagnostic test, while always remembering that in young women mammography can be negative even in the presence of physically detectable breast cancer. This approach is akin to the WHO recommendations on cancer early diagnosis.8WHOGuide to cancer early diagnosis. World Health Organization, Geneva2017Google Scholar This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on September 1, 2020 This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on September 1, 2020 I declare no competing interests. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trialYearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality. Full-Text PDF Open AccessCorrection to Lancet Oncol 2020; 21: 1125–26Miller AB. Final results of the UK Age trial on breast cancer screening age. Lancet Oncol 2020; 21: 1125–26—In this Comment, the fourth paragraph should read "One surprising aspect of the report by Duffy and colleagues is the conclusion that no overdiagnosis of breast cancer occurred in either group beyond that which would occur when screening those aged 50 years and older. Because overdiagnosis appears to increase with age, it is possible that overdiagnosis occurred in both groups after the age of 50 years, but could not be detected because of the design of the trial." This correction has been made as of Sept 1, 2020, and the printed version is correct. Full-Text PDF Recommendations for breast cancer screeningIn his Comment, Anthony Miller1 asserted that his trials showed "comparability of the study groups". Although Miller states that women were randomly assigned in the Canadian National Breast Screening Studies, he did not mention that all women had a clinical breast examination before allocation and study coordinators with this information could assign women out of random order. Significantly more women with palpable, advanced cancers were allocated to the screening group than to the control group of the Canadian National Breast Screening Study-1. Full-Text PDF Recommendations for breast cancer screening – Author's replyLászló Tabár and Peter Dean, Martin Yaffe and colleagues, and Daniel B Kopans have used my commentary1 on the UK Age trial as a means to comment adversely on the Canadian National Breast Screening Study. Tabár and Dean rely on the International Agency for Research on Cancer 2016 evaluation of breast screening2 to support their arguments, yet that evaluation did not consider the Canadian National Breast Screening Study. Yaffe and colleagues were impressed with the 25% reduction in breast cancer mortality at 10 years of follow-up in the UK Age trial (relative rate 0·75 [95% CI 0·58–0·97]), but acknowledge that this was attenuated on longer follow-up (0·98 [0·79–1·22]). Full-Text PDF Recommendations for breast cancer screeningDespite evidence confirming the benefits of detecting breast cancer before it becomes palpable, in his Comment, Anthony Miller1 advocates that women should not have mammography screening, but instead could wait until their breast cancers have grown large enough to become palpable. Contrary to his closing statement, Miller's argument against earlier diagnosis of breast cancer through mammography screening is not supported by the WHO recommendations, which review various methodologies available to bring care to patients as early as possible. Full-Text PDF Recommendations for breast cancer screeningIn his Comment on the UK Age trial, Anthony Miller1 stated that it could be argued that breast cancer screening with mammography should not be initiated at any age. We disagree with this assertion, given the overwhelming evidence from multiple randomised trials and observational studies showing the lifesaving benefits of mammography screening—benefits that have been acknowledged by guideline-setting bodies in several countries.2 Furthermore, recent publications have shown a reduced need for mastectomy, chemotherapy, and axillary dissection when breast cancers are detected by mammography screening. Full-Text PDF

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