Utility of polygenic risk scores in UK cancer screening: a modelling analysis.

Background: 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).
Methods: 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.
Findings: 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.
Interpretation: 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.
Funding: The Wellcome Trust.
Competing Interests: Declaration of interests ADH acknowledges funding from the British Heart Foundation (AA/18/6/34223) and UKRI-NIHR (MR/V033867/1), is a member of the Advisory Group for the Industrial Strategy Challenge Fund Accelerating Detection of Disease Challenge, and a co-opted member of the National Institute for Health and Care Excellence Guideline update group for Cardiovascular disease: risk assessment and reduction, including lipid modification, CG181. CS acknowledges grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx—collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical, and Personalis; is chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the Steering Committee chair; is co-chief investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL's Scientific Advisory Board; receives consultant fees from Achilles Therapeutics (and is also a Scientific Advisory Board member), Bicycle Therapeutics (and is also a Scientific Advisory Board member), Genentech, Medicxi, China Innovation Centre of Roche (formerly Roche Innovation Centre–Shanghai), Metabomed (until July, 2022), and the Sarah Cannon Research Institute; has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer, and Roche-Ventana; has previously held stock options in Apogen Biotechnologies and GRAIL, and currently has stock options in Epic Bioscience and Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics; has a patents issued for an immune checkpoint intervention in cancer (PCT/EP2016/071471), in treating cancer based on identification of clonal neo-antigens (PCT/EP2016/059401), in lung cancer detection (PCT/US2017/028013), in detecting tumour recurrence (PCT/GB2017/053289), in treating cancer (PCT/EP2016/059401), in treating cancer by targeting insertion–deletion mutations (PCT/GB2018/051893), in identifying insertion–deletion mutation targets (PCT/GB2018/051892), in determining whether an HLA allele is lost in a tumour (PCT/GB2018/052004), in identifying responders to cancer treatment (PCT/GB2018/051912), and in predicting survival rates for cancer patients (PCT/GB2020/050221). CT has received personal fees from AstraZeneca and Roche. HH has received personal fees from AstraZeneca. KS has received personal fees from BUPA, AstraZeneca, Pfizer, Merck, and AXA. MM receives royalties from authorship of books and book chapters, in addition to freelance journalism; consulting fees from her work as an NHS general practitioner; and fees for acting as an expert witness to the Infected Blood Inquiry and for lectures at Oxford and Glasgow Universities. All other authors declare no competing interests.
(Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)