Abstract 1441: Genetic determinants of PSA levels improve prostate cancer screening
Authors: Kachuri Linda , Graff Rebecca E. , Berndt Sonja I. , Machiela Mitchell , Freedman Neal D. , Chanock Stephen J. , Shelley John P. , Schaffer Kerry , Mosley Jonathan D. , Goodman Phyllis J. , Till Cathee , Thompson Ian , Klein Robert J. , Van Den Eeden Stephen K. , Hoffmann Thomas J. , Witte John S. 
Published: June 2022

Abstract
Prostate-specific antigen (PSA) screening for prostate cancer (PCa) remains controversial due to poor sensitivity and specificity that lead to overdiagnosis and overtreatment. The aim of our study is to characterize genetic determinants of PSA levels in cancer-free men in order to personalize PCa screening. We hypothesize that test accuracy may be improved by accounting for PSA variation that is due to genetic factors and does not reflect PCa.
We conducted the largest ever genome-wide association study (GWAS) of PSA in men without PCa (N=95,768; 85,924 predominantly European ancestry) using data from the UK Biobank, BioVU, PLCO, and Kaiser Permanente cohorts. Our GWAS discovered 129 PSA-associated variants (P&lt;5×10-8), 82 of which were novel. A polygenic score (PGSPSA) comprised of these 129 variants was successfully validated in two cancer prevention trials: PCPT (n=5737) and SELECT (n=22,247). PGSPSA explained 7.3% (p=7.0×10-98) of variation in baseline PSA in PCPT and 8.7% (p=7.0×10-476) in SELECT. Importantly, PGSPSA was not associated with PCa status in PCPT (OR=0.98, p=0.71) or SELECT (OR=1.04, p=0.98), which confirms that it reflects benign PSA variation.
Potential clinical utility of PSA genetic adjustment was explored by examining reclassification at thresholds used for biopsy referrals in a real-world setting at Kaiser Permanente. We estimated that correction using PGSPSA would have avoided 21.2% of negative biopsies in non-cases. Reclassification below the biopsy referral threshold was also more common in cases, particularly with low-grade disease with Gleason score &lt;7 (7.3% below vs. 2.6% above). Overall, genetic correction of PSA appeared to improve the accuracy of referral decisions, with a Net Reclassification Index of 0.148.
Next, we evaluated genetically adjusted PSA in the context of detection of aggressive PCa, defined as Gleason score ≥7, PSA ≥10 ng/mL, T3-T4 stage, and/or distant or nodal metastases. Genetically adjusted baseline PSA was more robustly associated with aggressive PCa than observed PSA and yielded a higher area under the curve (AUC) in PCPT (OR=3.03, p=3.5×10-7; AUC: 0.72 vs. 0.68) and SELECT (OR=3.37, p=3.5×10-11; AUC: 0.78 vs. 0.74) when added to a baseline model with age and trial arm. Furthermore, genetically adjusted PSA provides complementary information to PCa risk variants. In PCPT, a logistic regression model that included genetically corrected PSA and the 269-variant PGSPCa achieved a significantly higher AUC than PGSPCa-269 alone for aggressive PCa (AUC: 0.73 vs. 0.65, p=3.3×10-4) and overall PCa (AUC=0.69 vs. 0.66, p=3.3×10-6).
Our work provides evidence that accounting for genetic determinants of PSA has the potential to reduce unnecessary testing and overdiagnosis of low-risk PCa, as well as increase detection of aggressive disease. Larger and more diverse study populations are required to fully characterize the genetic basis of PSA variation and optimize its clinical utility.
Citation Format: Linda Kachuri, Rebecca E. Graff, Sonja I. Berndt, Mitchell Machiela, Neal D. Freedman, Stephen J. Chanock, John P. Shelley, Kerry Schaffer, Jonathan D. Mosley, Phyllis J. Goodman, Cathee Till, Ian Thompson, Robert J. Klein, Stephen K. Van Den Eeden, Thomas J. Hoffmann, John S. Witte. Genetic determinants of PSA levels improve prostate cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1441.