Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish section of the ERSPC.
BACKGROUND
We derived estimates of overdiagnosis by polygenic risk groups and examined whether polygenic risk-stratified screening for prostate cancer reduces overdiagnosis.


METHODS
We calculated the polygenic risk score based on genotypes of 66 known prostate cancer loci for 4967 men from the Finnish section of the European Randomised Study of Screening for Prostate Cancer. We stratified the 72 072 men in the trial into those with polygenic risk below and above the median. Using a maximum likelihood method based on interval cancers, we estimated the mean sojourn time (MST) and episode sensitivity. For each polygenic risk group, we estimated the proportion of screen-detected cancers that are likely to be overdiagnosed from the difference between the observed and expected number of screen-detected cancers.


RESULTS
Of the prostate cancers, 74% occurred among men with polygenic risk above population median. The sensitivity was 0.55 (95% confidence interval (CI) 0.45-0.65) and MST 6.3 (95% CI 4.2-8.3) years. The overall overdiagnosis was 42% (95% CI 37-52) of the screen-detected cancers, with 58% (95% CI 54-65) in men with the lower and 37% (95% CI 31-47) in those with higher polygenic risk.


CONCLUSIONS
Targeting screening to men at higher polygenic risk could reduce the proportion of cancers overdiagnosed.
Department of Applied Health Research, University College London, 1-19 Torrington Place, London WC1E 7HB, UK.
Nora
N
Pashayan
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
Paul Dp
PD
Pharoah
Department of Medical Biochemistry and Genetics, University of Turku, Turku FI20014, Finland.
Johanna
J
Schleutker
Finnish Cancer Registry, Helsinki FI 00130, Finland.
Kirsi
K
Talala
Department of Surgery, Tampere University Hospital and School of Medicine, University of Tampere, Tampere FI 33014, Finland.
Teuvo Lj
TLj
Tammela
Finnish Cancer Registry, Helsinki FI 00130, Finland.
Liisa
L
Määttänen
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
Patricia
P
Harrington
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
Jonathan
J
Tyrer
Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London SM2 5NG, UK.
Rosalind
R
Eeles
Centre for Cancer Prevention, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Stephen W
SW
Duffy
School of Health Sciences, University of Tampere, Tampere FI 33014, Finland.
Anssi
A
Auvinen
D000328:Adult; D000368:Aged; D055088:Early Detection of Cancer / Q000379:methods; D005387:Finland; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008403:Mass Screening / Q000379:methods; D000069342:Medical Overuse / Q000517:prevention & control / Q000706:statistics & numerical data; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000175:diagnosis*; D018570:Risk Assessment / Q000379:methods