# 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

> **NIH NIH U01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $376,647

## Abstract

Testing for prostate-specific antigen (PSA) in blood has enabled early detection of prostate cancer and
reduced metastasis and death from disease—but also contributed to overdetection of low-risk cancers.
Although no PSA concentration confers zero risk of finding cancer at prostate biopsy, a single PSA
measurement at midlife is a remarkably strong predictor of the risk of developing lethal prostate cancer
decades later. PSA is a proteolytic enzyme that is non-catalytic in blood, and it occurs in multiple forms. A
statistical model based on four kallikrein (4K) markers (free, total, and intact PSA, plus human kallikrein-related
peptidase-2 [hK2]) improves specificity in detecting high-grade prostate cancer among men with elevated PSA
(reducing unnecessary biopsies) and is also a strong predictor of the risk of lethal prostate cancer decades
later. While intra-individual fluctuations in PSA levels are common, an excessive degree of variability is highly
problematic, as temporary “false positive” elevations reduce the specificity of PSA as a cancer marker,
attenuate the diagnostic value of PSA kinetics, and lead to the use of unnecessary antibiotics. Less studied but
similarly abundant in prostatic fluid as PSA, the concentration of microseminoprotein-ß (MSP, MSMB) in blood
is inversely associated with prostate cancer risk, and a single nucleotide polymorphism (SNP, rs10993994) in
the promoter region of the MSMB gene is also associated with prostate cancer risk, but the role of these
markers in clinical decision-making is unclear. Similarly, a SNP in the SERPINA3 gene is significantly
associated with blood levels of PSA, and the encoded protein, alpha-1-antichymotrypsin (ACT), is the
predominant stable complexing ligand to PSA in the blood. However, the clinical value of these makers is
undetermined, and it remains unclear whether ACT levels in blood influence the predictive value of a baseline
PSA value or affect intra-individual variation in PSA. 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 markers 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 value and additional markers. Using blood samples
from the PLCO, Göteborg-1 & -2 trials, and Multiethnic Cohort (MEC), we plan to: 1) quantify the patterns of
variation in the 4K markers + MSP in serial measurements; 2) determine the relationship between a statistical
model based on 4K markers + MSP and subsequent risk of lethal prostate cancer, then independently validate
the clinical utility of the markers in decision-making and risk stratification before treatment decisions in a
randomized trial of prostate cancer treatments (ProtecT); and 3) compare head-t...

## Key facts

- **NIH application ID:** 10898687
- **Project number:** 5U01CA266535-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** JAMES A EASTHAM
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $376,647
- **Award type:** 5
- **Project period:** 2022-09-22 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898687

## Citation

> US National Institutes of Health, RePORTER application 10898687, 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 (5U01CA266535-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10898687. Licensed CC0.

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