Mammogram screening study supports the exclusion of low-risk women

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MammogramA UK modelling study concluded that excluding the screening of low risk women would improve the quality of life gained, reduce over-diagnosis and save resources, while maintaining the benefits of screening.

The study was funded by Cancer Research UK and led by the University College London (UCL) department for applied health research, with support from the University of Cambridge.

Lead author Dr Nora Pashayan (UCL department of applied health research) said: “Breast screening has both benefits and harms: It can reduce death from breast cancer in some women while others may have unnecessary diagnosis and treatment of breast cancer.

“Offering screening according to women’s risk level could improve the efficiency of the screening programme and reduce its harms.”

In the UK the NHS Breast Screening Programme (NHSBSP) invites women aged 50-69, for a digital mammogram every three years. However, numerous studies have shown that the risk of developing breast cancers varies significantly among women, with genetic, lifestyle and reproductive factors increasing an individual’s susceptibility.

The research simulated three hypothetical cohorts of women, aged 50 and free of cancer, followed up over 35 years. Each cohort consisted of 364,500 women – the 2009 population of women aged 50 in England and Wales. The first group received no screening, the second received a mammography at age 50, and for every three years thereafter – simulating the NHSBSP – while for the third cohort, a risk estimation was carried out and only those with a risk score greater than the threshold (low) risk, were offered screening every three years from 50 until aged 69.

In the modelling study, researchers used a number of accepted parameters, including predicted rates of age-specific breast cancer, breast cancer-specific mortality in screened and unscreened populations and the over-diagnosis estimate developed by the UK Independent Panel on Breast Cancer Screening. To model cost effectiveness of age-based and risk-based approaches to screening, along with no screening, researchers used NHS costs for the screening programme and costs of breast cancer treatment. The benefit to harm balance was measured as the ratio of over diagnoses to breast cancer deaths prevented. The researchers simulated 100 different risk-based screening scenarios.

In a risk-targeted screening, if screening is not offered to women at the lowest 30% of the risk distribution, there could be 27% fewer overdiagnoses, 3% fewer breast cancer deaths avoided and cost the NHS £20,000 less. With increasing the risk threshold, for example, so that screening is targeted to 30% of the highest risk women, then there could be 71% fewer overdiagnoses, 10% less breast cancer deaths avoided and cost the NHS £538,000 less.

Pashayan said: “The take-up of breast screening is currently around 72%. If we maintain this take-up but in a way that women who would benefit more from screening attend and women who would be more harmed from screening are spared, then the cost-effectiveness and benefit to harm balance of the NHSBSP could be improved.

“There are now more than 300 known variants within the human genome, which increase a women’s risk to breast cancer, and with genotype analysis feasible from cheek swabs, it may be possible for more targeted screening which will both reduce the detriment caused by over diagnosis and increase the chances of early diagnosis for those at risk.

“However, we recognise implementing an initiative of this nature raises challenges – not least defining those women deemed low risk and making any screening based on risk acceptable to the public, health professionals and regulators.”

Professor Fiona Gilbert, a co-author of the study from the University of Cambridge, said: “We need to change the model of delivery of breast screening and recognise that women are individuals with different risks and lifestyles. They should be offered screening tailored to their own profile.”

*Over diagnosis is the detection by screening of tumours that would not have been diagnosed in a woman’s lifetime if she had not had screening.

Importance: The age-based or “one-size-fits-all” breast screening approach does not take into account the individual variation in risk. Mammography screening reduces death from breast cancer at the cost of overdiagnosis. Identifying risk-stratified screening strategies with a more favorable ratio of overdiagnoses to breast cancer deaths prevented would improve the quality of life of women and save resources.
Objective: To assess the benefit-to-harm ratio and the cost-effectiveness of risk-stratified breast screening programs compared with a standard age-based screening program and no screening.
Design, Setting, and Population: A life-table model was created of a hypothetical cohort of 364 500 women in the United Kingdom, aged 50 years, with follow-up to age 85 years, using (1) findings of the Independent UK Panel on Breast Cancer Screening and (2) risk distribution based on polygenic risk profile. The analysis was undertaken from the National Health Service perspective.
Interventions: The modeled interventions were (1) no screening, (2) age-based screening (mammography screening every 3 years from age 50 to 69 years), and (3) risk-stratified screening (a proportion of women aged 50 years with a risk score greater than a threshold risk were offered screening every 3 years until age 69 years) considering each percentile of the risk distribution. All analyses took place between July 2016 and September 2017.
Main Outcomes and Measures: Overdiagnoses, breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, costs in British pounds, and net monetary benefit (NMB). Probabilistic sensitivity analyses were used to assess uncertainty around parameter estimates. Future costs and benefits were discounted at 3.5% per year.
Results: The risk-stratified analysis of this life-table model included a hypothetical cohort of 364 500 women followed up from age 50 to 85 years. As the risk threshold was lowered, the incremental cost of the program increased linearly, compared with no screening, with no additional QALYs gained below 35th percentile risk threshold. Of the 3 screening scenarios, the risk-stratified scenario with risk threshold at the 70th percentile had the highest NMB, at a willingness to pay of £20 000 (US $26 800) per QALY gained, with a 72% probability of being cost-effective. Compared with age-based screening, risk-stratified screening at the 32nd percentile vs 70th percentile risk threshold would cost £20 066 (US $26 888) vs £537 985 (US $720 900) less, would have 26.7% vs 71.4% fewer overdiagnoses, and would avert 2.9% vs 9.6% fewer breast cancer deaths, respectively.
Conclusions and Relevance: Not offering breast cancer screening to women at lower risk could improve the cost-effectiveness of the screening program, reduce overdiagnosis, and maintain the benefits of screening.

Nora Pashavan, Steve Morris, Fiona J Gilbert, Paul DP Phoroah

University College London material
JAMA Oncology abstract
JAMA Oncology editorial

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