Title: Observational study of Age, test THreshold and frequency on English NAtional Mammography screening outcomes (ATHENA-M)
Funder: Department of Health and Social Care

Abstract: Background _x000D_ _x000D_ There is a lot of debate about whether the benefits of breast cancer screening outweigh the harms. Sir Michael Marmot estimated that Breast Cancer Screening in the UK saves 1300 women’s lives every year. However, 70,000 women get false positive test results, which means the screening test (mammography) shows signs of cancer, but the test is wrong. This can make them feel anxious. Another 4000 women receive unnecessary cancer treatment (overdiagnosis and overtreatment). This is because they have a cancer detected at screening that is so slow growing it never would have harmed her or given her any symptoms in her life. These are the best national estimates we have, but Sir Michael Marmot based his estimates on randomised controlled trials from the 1970s, using old tests and treatments. _x000D_ _x000D_ International Variation in Breast Screening _x000D_ _x000D_ Different countries give different versions of breast screening, because we are not sure which is best. In the UK we recall 4% of women for further tests because their mammograms show suspicious signs. Other countries recall as few as 2% (Denmark) or as many as 10% (USA). In the UK we offer screening every 3 years, which is the longest time between screens in the world. In the US it is every year or 2 years and in Europe every 2 years. Within England there is a lot of variability between centres, because we don’t know what is best to offer women. _x000D_ _x000D_ The research question_x000D_ _x000D_ We are interested in finding out which version of breast screening gives most benefit and least harm. By version we mean how often women are invited, at what ages, and how many are recalled for further tests. _x000D_ _x000D_ Our Approach _x000D_ _x000D_ We need to understand which version of screening offers the most benefit with the least harm. To do this we need a very large study. We suggest making use of the data we already have. We have records from offering different versions of breast screening to over 13 million women in England over the last 25 years. This is called ‘retrospective observational research’, meaning we look back at the different versions of breast screening women were offered in the past, and see which versions gave most benefit and least harm._x000D_ _x000D_ The Research Plan _x000D_ _x000D_ We will find the records for all women offered screening in England between 1990 and 2018. We will include information from the breast screening programme about what type of screening women had and when. We will add information about whether they got cancer and whether they died from the English Cancer Registry and Mortality and Births Information System. The benefits we will measure will include lives saved. The harms we measure will include numbers of false positive recalls, and overdiagnosed cases. We will also investigate how changes to number and type (grade, stage and size) of cancers detected at screening affect benefits and harms. We will explore how more or less detection of cell changes which look similar to cancer called Ductal Carcinoma in situ affect benefits and harms of screening. _x000D_ _x000D_ Patient and Public Involvement_x000D_ _x000D_ Two breast cancer patients are part of the research team. With the support of Independent Cancer Patient Voices they have helped design the study, and will be involved at every stage. _x000D_ _x000D_ Using Findings to Change NHS Practice _x000D_ _x000D_ We will use the findings to advise the UK National Screening Committee and suggest how to change the English quality assurance guidelines for breast cancer screening.

Lay abstract: Research Question_x000D_ _x000D_ How does age of eligibility, screening interval and recall threshold affect the benefits and harms of breast cancer screening?_x000D_ _x000D_ Background_x000D_ _x000D_ There debate about whether the benefits of breast cancer screening outweigh the harms. The UK Independent review estimated that Breast Cancer Screening in the UK has mortality benefit, but harms through overdiagnosis of disease that would never have become symptomatic within the woman’s lifetime, and through false positive recalls to assessment of women who do not have cancer. _x000D_ _x000D_ International Variation in Breast Screening_x000D_ _x000D_ Different countries give different versions of breast screening, due primarily to a lack of evidence about which gives most benefit and least harm to women screened. In the UK we recall 4% of women for further tests because their mammograms show suspicious signs, with other countries recalling as few as 2% (Denmark) or as many as 10% (USA). In the UK we offer screening every 3 years, which is the longest time between screens in the world. In the US it is every one or two years and in most of Europe every 2 years. Within England there is a lot of variability between centres, because we don’t know what is best to offer women. _x000D_ _x000D_ The Research Plan_x000D_ _x000D_ In this observational study we will analyse the records of women screened in England between 1990 and 2018, with follow up to whether they developed breast cancer (from the English cancer registry) and whether they died (from the Mortality and Births Information System). We will analyse how inviting women of different ages, with different frequencies, and recalling different proportions affects the benefits and harms of screening. Analysis methods are designed to allow causal inference, using Hernan’s target trial approach. For screening interval we will use the clone, censor and weight approach, and for age extension we will split into hypothetical weekly trials. Short term outcomes include false positive recalls, cancers detected at screening, and symptomatic cancer detection after screening. Long term outcomes will include mortality, breast cancer mortality, and overdiagnosis. We will also analyse the mechanism of action for any changes, how changes to number and type (grade, stage and size) of cancers detected at screening affect number and type of cancer detected symptomatically in the years after screening, numbers overdiagnosed and mortality. We will explore how more or less detection of Ductal Carcinoma in situ affects benefits and harms of screening. _x000D_ _x000D_ Using Findings to Change NHS Practice_x000D_ _x000D_ We will communicate findings to the UK National Screening Committee, feed into the process of redrafting the English quality assurance guidelines for breast cancer screening, and disseminate via national champions.

Research activity codes: 4.3 INFLUENCES AND IMPACT;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: CANCER AND NEOPLASMS