Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; National Cancer Registration and Analysis Service, NHS England, London, UK.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Lancet. 2023 Nov;402 Suppl 1:S54. doi: 10.1016/S0140-6736(23)02103-7.
Polygenic Risk Scores (PRSs) have been proposed as a mechanism for risk-stratification of screening, increasing efficiency and enabling extension of existing programmes to improve survival in our aging population. We sought to model the impact of three hypothetical programmes of annual breast cancer screening in women aged 40-49 years: screening the PRS-defined high-risk quintile, screening the oldest quintile, and screening the full population.
In this UK-based modelling study, we used the published estimate of the area under the curve (AUC) of a currently available breast cancer PRS (0·64) to calculate the proportion of cancers captured by the PRS-defined high-risk quintile. We used population size estimates from the Office for National Statistics alongside age-stratified incidence rates of breast cancer, and age or stage-specific survival data from the National Cancer Registry, to build our model. We used stage-specific route-to-diagnosis data to reassign stage-specific survival for screen-detected cancers. Ethics approval was not required.
The PRS-defined high-risk quintile, oldest quintile, and full population capture 37% (n=2811), 29% (n=2198), and 100% (n=7533) of breast cancers occurring in women aged 40-49 each year. Annual screening of each group using digital mammography (sensitivity 70%, specificity 92%) would identify 1968, 1538, and 5273 breast cancers per year, respectively. This corresponds to an improvement in survival of 1·4% (102 deaths averted), 1·1% (80 deaths averted) and 3·6% (274 deaths averted) compared with baseline (no screening). Full population screening would require 4 369 703 mammograms and 354 246 confirmatory tests (breast biopsies) every year, while screening the oldest quintile would require 937 850 mammograms and 76 390 biopsies. Screening the PRS-defined high-risk quintile would require 873 941 mammograms and 71 658 biopsies, in addition to a PRS for all women in the age group (4 369 703).
Under favourable assumptions, stratifying screening by PRS rather than age results in modest gains in survival but increases overdiagnoses, logistical complexity, and economic costs. Our study is limited by our modelling parameters (anticipated to maximise survival estimates), including complete uptake of PRS profiling and cancer screening, no interval cancers, and application of screening tools superior to those currently available in the UK. Only with randomised controlled trials, can the uptake, clinical impact, costs, and harms of PRS-stratified screening be definitively assessed.
The Wellcome Trust.
多基因风险评分（PRSs）被提议作为一种风险分层筛查的机制，提高效率，并使现有的项目得以扩展，以提高我们老龄化人口的生存率。我们试图对三种假设的 40-49 岁女性年度乳腺癌筛查计划进行建模：筛查 PRS 定义的高危五分位数、筛查最年长五分位数和筛查全人群。
在这项基于英国的建模研究中，我们使用目前可用的乳腺癌 PRS 的曲线下面积（AUC）的已发表估计值（0.64）来计算 PRS 定义的高危五分位数所捕获的癌症比例。我们使用来自国家统计局的人口规模估计值以及乳腺癌的年龄分层发病率数据，以及来自国家癌症登记处的年龄或分期特异性生存数据来构建我们的模型。我们使用分期特异性的诊断途径数据来重新分配筛查发现的癌症的分期特异性生存。不需要伦理批准。
PRS 定义的高危五分位数、最年长五分位数和全人群每年分别捕获 40-49 岁女性中发生的 37%（n=2811）、29%（n=2198）和 100%（n=7533）的乳腺癌。使用数字乳房 X 线摄影术（灵敏度 70%，特异性 92%）对每组进行年度筛查，每年将分别识别出 1968、1538 和 5273 例乳腺癌。与基线（无筛查）相比，这分别对应于 1.4%（102 例死亡避免）、1.1%（80 例死亡避免）和 3.6%（274 例死亡避免）的生存改善。全人群筛查每年需要进行 4369703 次乳房 X 线摄影和 354246 次确认性检查（乳房活检），而筛查最年长五分位数则需要进行 937850 次乳房 X 线摄影和 76390 次活检。筛查 PRS 定义的高危五分位数除了对该年龄段的所有女性进行 PRS 分析外，还需要进行 873941 次乳房 X 线摄影和 71658 次活检，外加 4369703 次乳房 X 线摄影和 71658 次活检。
在有利的假设条件下，按 PRS 而不是年龄对筛查进行分层可导致生存适度改善，但会增加过度诊断、后勤复杂性和经济成本。我们的研究受到模型参数的限制（预计会最大限度地提高生存估计值），包括 PRS 分析和癌症筛查的完全接受度、无间隔性癌症以及应用优于英国目前可用的筛查工具。只有通过随机对照试验，才能最终评估 PRS 分层筛查的采用率、临床影响、成本和危害。
惠康信托基金会。
