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Duffy 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 Sep;21(9):1165-1172. doi: 10.1016/S1470-2045(20)30398-3. Epub 2020 Aug 12. (Original study)

BACKGROUND: The appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40-48 years on breast cancer mortality.

METHODS: We did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39-41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant's first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151.

FINDINGS: 160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8-24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58-0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79-1·22]; p=0·86).

INTERPRETATION: Yearly 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.

FUNDING: National Institute for Health Research Health Technology Assessment programme.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 7 / 7
General Internal Medicine-Primary Care(US) 7 / 7
Oncology - Breast 7 / 7
Gynecology 6 / 7
Public Health 6 / 7
Internal Medicine 6 / 7
Comments from MORE raters

General Internal Medicine-Primary Care(US) rater

Useful quantitative information regarding the benefits and harms of beginning mammography around age 40. Readers would benefit from knowing both the relative and absolute risk reductions as well as the harms associated with beginning mammography at 40.

Gynecology rater

This manuscript deals with a topic (age to initiate mammographic screening) in a well-structured and rigorous manner. The conclusions reveal a clear benefit of initiating screening at the age of 40. This important article deserves reading by all relevant physicians.

Gynecology rater

This is a controversy that never seems to end. The best solution is having adequate informed consent for all ages of women prior to their choosing to undergo a mammogram.

Internal Medicine rater

Need to screen 1000 women to prevent one death. 18% false-positive rate during the time frame of age 40-50.

Internal Medicine rater

This important randomized controlled trial of breast cancer screening in women 40 to 49 just released its 20-year follow-up. This is a very important trial because there was some controversy at one time about breast cancer screening for women 40 to 49. There was also concern that early identification of cancers may lead to other treatment-related effects such as radiation-induced coronary disease that would have made early identification more morbid in the longer term. In this study, women in the screened intervention arm had a significant reduction in breast cancer death, but no difference in long-term follow-up. I believe this study strongly supports starting breast cancer screening at age 40.

Internal Medicine rater

Long-term follow-up suggesting that mammography during ages 40-49 has very modest benefit and very modest harm. The number-needed-to-invite to screening was well over 1,000, there was no signal for improvement in overall mortality, and the benefits are likely even lower with modern therapy vs that available in the 1990s. On the harm side, about 18% of invited women had at least one false-positive result during the 10 years - this was presumably higher in those who complied with screening. Surprisingly, there was no evidence of over-diagnosis in this group, contrary to almost all other published data.

Oncology - Breast rater

An update on a long-running RCT (now at 26 y post-initiation; last published update 6 y ago). Unfortunately, the large n (>160K women) is still under-powered due to low baseline incidence of breast cancer in the target population (age 40-49). Randomisation in the 1990s was for screening mammography from recruitment (aged 39-41) vs usual care, which is screening mammography from age 50 in the UK. So, the 2 arms were receiving the same care after the first 10 y. In this regard, the results are unsurprising- a 25% reduction in breast cancer mortality in the first 10 y of the trial and no difference thereafter. Given the low breast cancer incidence in this age group, the absolute decrease in death is small, and given improvements in breast cancer treatment and survival since the first 10 y the trial, it is difficult to put these results into the current context, especially when balanced against the 18% in the early screening group who experienced a false-positive result during the trial.

Oncology - Breast rater

Great to see data shed light on such a controversial topic.

Public Health rater

The results of 23-year follow-up from this landmark RCT are important, but they did not differ from the 17-year follow-up. Importantly, women who were recruited to this study were 39-41 years of age at the outset, so screening was completed prior to age 50 and showed a breast cancer mortality benefit. In the sense that the absolute mortality benefit did not change after 10 years, this study was most useful in highlighting the validity of the original study.
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