Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; National Cancer Registration and Analysis Service, National Health Service (NHS) England, London, UK.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Lancet Oncol. 2023 Jun;24(6):658-668. doi: 10.1016/S1470-2045(23)00156-0. Epub 2023 May 10.
It is proposed that, through restriction to individuals delineated as high risk, polygenic risk scores (PRSs) might enable more efficient targeting of existing cancer screening programmes and enable extension into new age ranges and disease types. To address this proposition, we present an overview of the performance of PRS tools (ie, models and sets of single nucleotide polymorphisms) alongside harms and benefits of PRS-stratified cancer screening for eight example cancers (breast, prostate, colorectal, pancreas, ovary, kidney, lung, and testicular cancer).
For this modelling analysis, we used age-stratified cancer incidences for the UK population from the National Cancer Registration Dataset (2016-18) and published estimates of the area under the receiver operating characteristic curve for current, future, and optimised PRS for each of the eight cancer types. For each of five PRS-defined high-risk quantiles (ie, the top 50%, 20%, 10%, 5%, and 1%) and according to each of the three PRS tools (ie, current, future, and optimised) for the eight cancers, we calculated the relative proportion of cancers arising, the odds ratios of a cancer arising compared with the UK population average, and the lifetime cancer risk. We examined maximal attainable rates of cancer detection by age stratum from combining PRS-based stratification with cancer screening tools and modelled the maximal impact on cancer-specific survival of hypothetical new UK programmes of PRS-stratified screening.
The PRS-defined high-risk quintile (20%) of the population was estimated to capture 37% of breast cancer cases, 46% of prostate cancer cases, 34% of colorectal cancer cases, 29% of pancreatic cancer cases, 26% of ovarian cancer cases, 22% of renal cancer cases, 26% of lung cancer cases, and 47% of testicular cancer cases. Extending UK screening programmes to a PRS-defined high-risk quintile including people aged 40-49 years for breast cancer, 50-59 years for colorectal cancer, and 60-69 years for prostate cancer has the potential to avert, respectively, a maximum of 102, 188, and 158 deaths annually. Unstratified screening of the full population aged 48-49 years for breast cancer, 58-59 years for colorectal cancer, and 68-69 years for prostate cancer would use equivalent resources and avert, respectively, an estimated maximum of 80, 155, and 95 deaths annually. These maximal modelled numbers will be substantially attenuated by incomplete population uptake of PRS profiling and cancer screening, interval cancers, non-European ancestry, and other factors.
Under favourable assumptions, our modelling suggests modest potential efficiency gain in cancer case detection and deaths averted for hypothetical new PRS-stratified screening programmes for breast, prostate, and colorectal cancer. Restriction of screening to high-risk quantiles means many or most incident cancers will arise in those assigned as being low-risk. To quantify real-world clinical impact, costs, and harms, UK-specific cluster-randomised trials are required.
The Wellcome Trust.
有人提出，通过对高风险人群的限制，多基因风险评分（PRS）可能使现有的癌症筛查计划更有效地针对特定人群，并能将其应用范围扩展到新的年龄范围和疾病类型。为了验证这一假设，我们对 PRS 工具（即模型和单核苷酸多态性集合）的性能进行了概述，并对 8 种癌症（乳腺癌、前列腺癌、结直肠癌、胰腺癌、卵巢癌、肾癌、肺癌和睾丸癌）的 PRS 分层癌症筛查的危害和益处进行了分析。
在这项建模分析中，我们使用了英国国家癌症登记数据集（2016-18 年）中按年龄分层的癌症发病率，以及当前、未来和优化的每个癌症类型的 PRS 下的受试者工作特征曲线下面积的已发表估计值。对于每个 PRS 定义的高风险五分位数（即前 50%、20%、10%、5%和 1%）和 8 种癌症的三种 PRS 工具（即当前、未来和优化）中的每一种，我们计算了癌症发生的相对比例、与英国人口平均水平相比癌症发生的优势比以及终生癌症风险。我们通过将 PRS 分层与癌症筛查工具相结合，检查了通过年龄分层达到最大癌症检测率的可能性，并对假设的英国 PRS 分层筛查新计划对癌症特异性生存的最大影响进行了建模。
估计 PRS 定义的高风险五分位数（20%）人群中约 37%为乳腺癌病例，46%为前列腺癌病例，34%为结直肠癌病例，29%为胰腺癌病例，26%为卵巢癌病例，22%为肾癌病例，26%为肺癌病例，47%为睾丸癌病例。将英国的筛查计划扩展到包括年龄在 40-49 岁的乳腺癌、50-59 岁的结直肠癌和 60-69 岁的前列腺癌的 PRS 定义的高风险五分位数，每年分别有可能避免最多 102、188 和 158 例死亡。对年龄在 48-49 岁的所有女性进行无差别乳腺癌筛查、58-59 岁的所有男性进行无差别结直肠癌筛查和 68-69 岁的所有男性进行无差别前列腺癌筛查，每年分别预计最多可避免 80、155 和 95 例死亡。这些最大的模型数字将因 PRS 分析和癌症筛查、间隔性癌症、非欧洲血统以及其他因素的人群接受程度不完全而大大降低。
在有利的假设条件下，我们的建模表明，对于假设的新 PRS 分层筛查计划，在乳腺癌、前列腺癌和结直肠癌方面，癌症检测病例的检测效率和死亡人数的减少都有适度的潜在获益。将筛查限制在高风险五分位数意味着，许多或大多数新发癌症将出现在被认为是低风险的人群中。为了量化实际的临床影响、成本和危害，需要在英国进行特定的集群随机试验。
英国惠康基金会。
