Sigrid Carlsson

M.D., Ph.D., M.P.H.

Memorial Sloan Kettering Cancer Center

Assistant Attending Epidemiologist

PLCO (Learn more about this study)

2021-1016

Oct 6, 2022

Influence of intra-individual variability in serial screening samples on clinical decision-making for risk stratification and biopsy by a single PSA and additional markers

Blood biomarkers based on prostate-specific antigen (PSA) and its isoforms are central in contemporary screening and early detection of prostate cancer. A man’s baseline PSA concentration in midlife is a strong prognostic marker of his risk of developing lethal prostate cancer later in life. A statistical model combining clinical information with 4 kallikrein (4K) markers (free, total, and intact PSA, plus human kallikrein-related peptidase-2 [hK2]) among men with elevated PSA can improve the detection of high-grade prostate cancer and reduce the number of unnecessary biopsies. While spontaneous year-to-year fluctuations in PSA levels are common, a high degree of variability is problematic because temporary, “false positive” elevations reduce the specificity of PSA as a marker of cancer, dilute the value of PSA kinetics, and may provoke unnecessary antibiotic use. Furthermore, microseminoprotein-ß (MSMB) is the second most abundantly secreted prostatic protein after PSA, yet it is less studied. A single nucleotide polymorphism (SNP) in the promoter region of the MSMB-gene (available from genome-wide association studies [GWAS] data in PLCO) as well as blood levels of the encoded protein (MSP) are both associated with prostate cancer risk, but their role in clinical decision-making for screening and biopsy remains unclear. Moreover, a SNP in the SERPINA3 gene (available from GWAS data in PLCO) is significantly associated with blood levels of PSA (Hoffman et al. Nature Comm. 2017), but the clinical value of determining this SNP or the encoded protein alpha-1-antichymotrypsin (ACT)—which is the predominant stable complexing ligand to PSA in the blood—has not previously been thoroughly investigated. It remains unclear whether the blood levels of ACT may influence the predictive value of a baseline PSA or may affect intra-individual variation of PSA, which could be determined using serial blood samples in PLCO. Additionally, the intra-individual variation of the 4K-panel is currently unknown but could be determined using high-quality serial samples. As the role of these different molecular forms in combined risk prediction models of aggressive prostate cancer is not well understood, we plan to delineate the influence of intra-individual variability in serial screening samples on clinical decision-making for risk stratification and biopsy by a single PSA and additional markers. Using serial samples from PLCO and the Göteborg-1 trial, we plan to: 1) describe and quantify the patterns of variation in total PSA in serial measurements from the same individuals over time; 2) measure and characterize the patterns of variation in the levels of 4K markers + MSP in serial measurements; and 3) validate the association between a statistical model based on 4K markers + MSP and subsequent risk of lethal prostate cancer. We will then independently validate the clinical utility of the 4K markers in decision-making and risk stratification before treatment decisions in a randomized trial of active monitoring, radical prostatectomy, and radiation therapy, using blood samples from the ProtecT trial. These insights will shed light on how to improve the specificity of prostate cancer screening and early detection.