Polygenic risk-tailored screening for prostate cancer: A benefit-harm and cost-effectiveness modelling study

Author summaryWhy was this study done? Prostate cancer screening using prostate-specific antigen has been shown to lead to a reduction in prostate-cancer-specific mortality at the expense of overdiagnosis and overtreatment. Genome-wide association studies have identified more than 160 common genetic variants that, when combined together as a polygenic risk score, might be used to develop a tailored screening programme for prostate cancer. The proportion of men overdiagnosed has been shown to vary by polygenic risk; therefore, a risk-tailored screening based on age and polygenic risk profile may improve the balance of benefits and harms of a screening programme for prostate cancer. What did the researchers do and find? We developed a mathematical model that simulated hypothetical cohorts of 4.48 million men aged 55 to 69 in England. Using this model, we analysed the balance of benefits and harms in terms of prostate-cancer-specific mortality reduction against overdiagnosis, as well as the cost-effectiveness, of the introduction of a risk-tailored screening programme for prostate cancer based on age and polygenic risk. We compared risk-tailored screening to age-based screening and no screening. What do these findings mean? Based on this model, we show that a polygenic risk-tailored screening programme might reduce overdiagnosis, maintain the mortality benefits of age-based screening, and improve the cost-effectiveness of a screening programme for prostate cancer. The ideal threshold for risk-tailored screening will depend on societal judgement of the tradeoff between the benefits and harms of screening. Future prospective evaluations are needed to verify these findings. Background The United States Preventive Services Task Force supports individualised decision-making for prostate-specific antigen (PSA)-based screening in men aged 55-69. Knowing how the potential benefits and harms of screening vary by an individual's risk of developing prostate cancer could inform decision-making about screening at both an individual and population level. This modelling study examined the benefit-harm tradeoffs and the cost-effectiveness of a risk-tailored screening programme compared to age-based and no screening. Methods and findings A life-table model, projecting age-specific prostate cancer incidence and mortality, was developed of a hypothetical cohort of 4.48 million men in England aged 55 to 69 years with follow-up to age 90. Risk thresholds were based on age and polygenic profile. We compared no screening, age-based screening (quadrennial PSA testing from 55 to 69), and risk-tailored screening (men aged 55 to 69 years with a 10-year absolute risk greater than a threshold receive quadrennial PSA testing from the age they reach the risk threshold). The analysis was undertaken from the health service perspective, including direct costs borne by the health system for risk assessment, screening, diagnosis, and treatment. We used probabilistic sensitivity analyses to account for parameter uncertainty and discounted future costs and benefits at 3.5% per year. Our analysis should be considered cautiously in light of limitations related to our model's cohort-based structure and the uncertainty of input parameters in mathematical models. Compared to no screening over 35 years follow-up, age-based screening prevented the most deaths from prostate cancer (39,272, 95% uncertainty interval [UI]: 16,792-59,685) at the expense of 94,831 (95% UI: 84,827-105,630) overdiagnosed cancers. Age-based screening was the least cost-effective strategy studied. The greatest number of quality-adjusted life-years (QALYs) was generated by risk-based screening at a 10-year absolute risk threshold of 4%. At this threshold, risk-based screening led to one-third fewer overdiagnosed cancers (64,384, 95% UI: 57,382-72,050) but averted 6.3% fewer (9,695, 95% UI: 2,853-15,851) deaths from prostate cancer by comparison with age-based screening. Relative to no screening, risk-based screening at a 4% 10-year absolute risk threshold was cost-effective in 48.4% and 57.4% of the simulations at willingness-to-pay thresholds of GBP 20,000 pound (US$26,000) and 30,000 pound ($39,386) per QALY, respectively. The cost-effectiveness of risk-tailored screening improved as the threshold rose. Conclusions Based on the results of this modelling study, offering screening to men at higher risk could potentially reduce overdiagnosis and improve the benefit-harm tradeoff and the cost-effectiveness of a prostate cancer screening program. The optimal threshold will depend on societal judgements of the appropriate balance of benefits-harms and cost-effectiveness.