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

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 (US$26,000) and £30,000 ($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

Germline genetic variation in prostate susceptibility does not predict outcomes in the chemoprevention trials PCPT and SELECT

Background The development of prostate cancer can be influenced by genetic and environmental factors. Numerous germline SNPs influence prostate cancer susceptibility. The functional pathways in which these SNPs increase prostate cancer susceptibility are unknown. Finasteride is currently not being used routinely as a chemoprevention agent but the long term outcomes of the PCPT trial are awaited. The outcomes of the SELECT trial have not recommended the use of chemoprevention in preventing prostate cancer. This study investigated whether germline risk SNPs could be used to predict outcomes in the PCPT and SELECT trial. Methods Genotyping was performed in European men entered into the PCPT trial (n = 2434) and SELECT (n = 4885). Next generation genotyping was performed using Affymetrix® Eureka™ Genotyping protocols. Logistic regression models were used to test the association of risk scores and the outcomes in the PCPT and SELECT trials. Results Of the 100 SNPs, 98 designed successfully and genotyping was validated for samples genotyped on other platforms. A number of SNPs predicted for aggressive disease in both trials. Men with a higher polygenic score are more likely to develop prostate cancer in both trials, but the score did not predict for other outcomes in the trial. Conclusion Men with a higher polygenic risk score are more likely to develop prostate cancer. There were no interactions of these germline risk SNPs and the chemoprevention agents in the SELECT and PCPT trials

Genetic predisposition to prostate cancer.

Introduction Prostate cancer (PrCa) is the commonest non-cutaneous cancer in men in the UK. Epidemiological evidence as well as twin studies points towards a genetic component contributing to aetiology.Sources of data Key recently published literature.Areas of agreement A family history of PrCa doubles the risk of disease development in first-degree relatives. Linkage and genetic sequencing studies identified rare moderate-high-risk gene loci, which predispose to PrCa development when altered by mutation. Genome-wide association studies have identified common single-nucleotide polypmorphisms (SNPs), which confer a cumulative risk of PrCa development with increasing number of risk alleles. There are emerging data that castrate-resistant disease is associated with mutations in DNA repair genes.Areas of controversy Linkage studies investigating possible high-risk loci leading to PrCa development identified possible loci on several chromosomes, but most have not been consistently replicated by subsequent studies. Germline SNPs related to prostate specific antigen (PSA) levels and to normal tissue radiosensitivity have also been identified though not all have been validated in subsequent studies.Growing points Utilizing germline SNP profiles as well as identifying high-risk genetic variants could target screening to high-risk groups, avoiding the drawbacks of PSA screening.Areas timely for developing research Incorporating genetics into PrCa screening is being investigated currently using both common SNP profiles and higher risk rare variants. Knowledge of germline genetic defects will allow the development of targeted screening programs, preventive strategies and the personalized treatment of PrCa

Men with a susceptibility to prostate cancer and the role of genetic based screening.

Prostate cancer is the second most common malignancy affecting men worldwide, and the commonest affecting men of African descent. Significant diagnostic and therapeutic advances have been made in the past decade. Improvements in the accuracy of prostate cancer diagnosis include the uptake of multi-parametric MRI and a shift towards targeted biopsy. We also now have more life-prolonging systemic and hormonal therapies for men with advanced disease at our disposal than ever before. However, the development of robust screening tools and targeted screening programs has not followed at the same pace. Evidence to support population-based screening remains unclear, with the use of PSA as a screening test limiting our ability to discriminate between clinically significant and insignificant disease. Prostate cancer has a large heritable component. Given that most men without risk factors have a low lifetime risk of developing lethal prostate cancer, much work is being done to further our knowledge of how we can best screen men in higher risk categories, such as those with a family history (FH) of the disease or those of African ancestry. These men have been reported to carry upwards of a two-fold increased risk of developing the disease at an earlier age, with evidence suggesting poorer survival outcomes. In men with a FH of prostate cancer, this is felt to be due to rare, high-penetrance mutations and the presence of multiple, common low penetrance alleles, with men carrying specific germline mutations in the BRCA and other DNA repair genes at particularly high risk. To date, large scale genome-wide association studies (GWAS) have led to the discovery of approximately 170 single nucleotide polymorphisms (SNPs) associated with prostate cancer risk, allowing over 30% of prostate cancer risk to be explained. Genomic tests, utilising somatic (prostate biopsy) tissue can also predict the risk of unfavourable pathology, biochemical recurrence and the likelihood of metastatic disease using gene expression. Targeted screening studies are currently under way in men with DNA repair mutations, men with a FH and those of Afro-Caribbean ethnicity which will greater inform our understanding of disease incidence and behaviour in these men, treatment outcomes and developing the most appropriate screening regime for such men. Incorporating a patient's genetic mutation status into risk algorithms allows us an opportunity to develop targeted screening programs for men in whom early cancer detection and treatment will positively influence survival, and in the process offer male family members of affected men the chance to be counselled and screened accordingly

CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours

We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele