Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial.

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.

Risk-stratified faecal immunochemical testing (FIT) for urgent colonoscopy in Lynch syndrome during the COVID-19 pandemic.

BACKGROUND: Lynch syndrome is a hereditary cancer disease resulting in an increased risk of colorectal cancer. Herein, findings are reported from an emergency clinical service implemented during the COVID-19 pandemic utilizing faecal immunochemical testing ('FIT') in Lynch syndrome patients to prioritize colonoscopy while endoscopy services were limited. METHODS: An emergency service protocol was designed to improve colonoscopic surveillance access throughout the COVID-19 pandemic in England for people with Lynch syndrome when services were extremely restricted (1 March 2020 to 31 March 2021) and promoted by the English National Health Service. Requests for faecal immunochemical testing from participating centres were sent to the National Health Service Bowel Cancer Screening South of England Hub and a faecal immunochemical testing kit, faecal immunochemical testing instructions, paper-based survey, and pre-paid return envelope were sent to patients. Reports with faecal haemoglobin results were returned electronically for clinical action. Risk stratification for colonoscopy was as follows: faecal haemoglobin less than 10 µg of haemoglobin/g of faeces (µg/g)-scheduled within 6-12 weeks; and faecal haemoglobin greater than or equal to 10 µg/g-triaged via an urgent suspected cancer clinical pathway. Primary outcomes of interest included the identification of highest-risk Lynch syndrome patients and determining the impact of faecal immunochemical testing in risk-stratified colonoscopic surveillance. RESULTS: Fifteen centres participated from June 2020 to March 2021. Uptake was 68.8 per cent amongst 558 patients invited. For 339 eligible participants analysed, 279 (82.3 per cent) had faecal haemoglobin less than 10 µg/g and 60 (17.7 per cent) had faecal haemoglobin greater than or equal to 10 µg/g. In the latter group, the diagnostic accuracy of faecal immunochemical testing was 65.9 per cent and escalation to colonoscopy was facilitated (median 49 versus 122 days, χ2 = 0.0003, P < 0.001). CONCLUSION: Faecal immunochemical testing demonstrated clinical value for Lynch syndrome patients requiring colorectal cancer surveillance during the pandemic in this descriptive report of an emergency COVID-19 response service. Further longitudinal investigation on faecal immunochemical testing efficacy in Lynch syndrome is warranted and will be examined under the 'FIT for Lynch' study (ISRCTN15740250).

Impact of changes to cervical screening guidelines on age and interval at which women are tested: Population-based study.

BACKGROUND: English cervical screening programme guidelines changed between 2009 and 2012. We explore the impact on the age and intervals at which women receive a cytology test. METHODS: Eligible women were controls from a population-based case-control study in England. Tests taken between 1980 and 2017 were extracted from the call/recall database. Using the Kaplan-Meier estimator by birth cohort and age at (or time since) last test, we explore proportions tested since or prior to a given age, years since previous test, and interval following a negative test. RESULTS: Screening histories from 46,037 women were included. Proportion tested by age 26 has increased from 55% among birth cohorts 1978-1979 to 67% among those born 1990-1991, despite more recent cohorts only having received one invitation (instead of two) prior to age 26. The proportion of women tested at aged 28 with a test three years earlier increased by 20% (from 36% in 1997-2006 to 56% in 2012-2017) whereas the proportion tested at ages 23-27 without a prior test increased from 34% to 80%. The age at last test prior to exiting the programme has decreased: among those born 1928-1931 86% had a test aged 60-65, but only 71% of those born 1947-1951. CONCLUSION: Clear programme guidance alongside quality assurance has improved the cervical screening programme by standardising the age and intervals at which women are screened.

Annual mammographic screening to reduce breast cancer mortality in women from age 40 years: long-term follow-up of the UK Age RCT.

BACKGROUND: There remains disagreement on the long-term effect of mammographic screening in women aged 40-49 years. OBJECTIVES: The long-term follow-up of a randomised controlled trial that offered annual mammography to women aged 40-49 years. The estimation of the effect of these mammograms on breast cancer and other-cause mortality, and the effect on incidence, with implications for overdiagnosis. DESIGN: An individually randomised controlled trial comparing offering annual mammography with offering usual care in those aged 40-48 years, and thus evaluating the effect of annual screening entirely taking place before the age of 50 years. There was follow-up for an average of 23 years for breast cancer incidence, breast cancer death and death from other causes. We analysed the mortality and incidence data by Poisson regression and estimated overdiagnosis formally using Markov process models. SETTING: Twenty-three screening units in England, Wales and Scotland within the NHS Breast Screening Programme. PARTICIPANTS: Women aged 39-41 years were recruited between 1990 and 1997. After exclusions, a total of 53,883 women were randomised to undergo screening (the intervention group) and 106,953 women were randomised to have usual care (the control group). INTERVENTIONS: The intervention group was invited to an annual breast screen with film mammography, two view at first screen and single view thereafter, up to and including the calendar year of their 48th birthday. The control group received no intervention. Both groups were invited to the National Programme from the age of 50 years, when screening is offered to all women in the UK. MAIN OUTCOME MEASURES: The main outcome measures were mortality from breast cancers diagnosed during the intervention phase of the trial (i.e. before the first National Programme screen at 50 years), mortality from all breast cancers diagnosed after randomisation, all-cause mortality, mortality from causes other than breast cancer, and the incidence of breast cancer. RESULTS: There was a statistically significant 25% reduction in mortality from breast cancers diagnosed during the intervention phase at 10 years' follow-up (relative rate 0.75, 95% confidence interval 0.58 to 0.97; p = 0.03). No reduction was observed thereafter (relative rate 0.98, 95% confidence interval 0.79 to 1.22). Overall, there was a statistically non-significant 12% reduction (relative rate 0.88, 95% confidence interval 0.74 to 1.03; p = 0.1). The absolute benefit remained approximately constant over time, at one death prevented per 1000 women screened. There was no effect of intervention on other-cause mortality (relative rate 1.02, 95% confidence interval 0.97 to 1.07; p = 0.4). The intervention group had a higher incidence of breast cancer than the control group during the intervention phase of the trial, but incidence equalised immediately on the first National Programme screen at the age of 50-52 years. LIMITATIONS: There was 31% average non-compliance with screening and three centres had to cease screening for resource and capacity reasons. CONCLUSIONS: Annual mammographic screening at the age of 40-49 years resulted in a relative reduction in mortality, which was attenuated after 10 years. It is likely that digital mammography with two views at all screens, as practised now, could improve this further. There was no evidence of overdiagnosis in addition to that which already results from the National Programme carried out at later ages. FUTURE WORK: There is a need for research on the effects of modern mammographic protocols and additional imaging in this age group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24647151. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 55. See the NIHR Journals Library website for further project information. Other funding in the past has been received from the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, the US National Cancer Institute and the American Cancer Society.

It is known that breast cancer screening with mammography (i.e. X-ray of the breasts) in women aged ≥ 50 years leads to a reduction in the number of deaths from breast cancer. In the UK, the NHS Breast Screening Programme offers regular screening to women aged 50­70 years. There is still some disagreement about the effect of such screening on the risk of death from breast cancer for those aged 40­49 years. There is also concern about overdiagnosis, that is, the finding of breast cancer that would not have been diagnosed in a woman's lifetime if she had not been screened. This study recruited 160,921 women aged 39­41 years and randomly assigned one in three of the women to be offered annual mammographic screening from age 40 to 48 years. The women were followed up for occurrence of breast cancer, death from breast cancer and death from all other causes. We found that the women who were offered the screening were 25% less likely to die of breast cancer in the first 10 years in the trial. This mortality reduction was reduced with later follow-up, with a 12% reduction after an average of 23 years. There was no effect of offering screening on death from other causes. During the early years of the trial, the women offered screening had larger numbers of breast cancers diagnosed, but this excess disappeared after the first National Programme screen. This suggests that there is no overdiagnosis from screening those aged 40­49 years over and above that which already results from screening those aged ≥ 50 years.