Prostate-Specific Antigen Screening Patterns and Metastatic Prostate Cancer in US Veterans

Mehrnaz Siavoshi; Stephen Frochen; Mary Fakunle; Ananta Wadhwa; Ashley-Marie Y Green-Lott; Anissa V Bailey; Lorna Kwan; Candace Haroldsen; Atim Effiong; Brent S Rose; Timothy R Rebbeck; Hari S Iyer; Isla P Garraway

doi:10.1001/jamanetworkopen.2026.21741

. 2026 Jul 6;9(7):e2621741. doi: 10.1001/jamanetworkopen.2026.21741

Prostate-Specific Antigen Screening Patterns and Metastatic Prostate Cancer in US Veterans

Mehrnaz Siavoshi ^1,², Stephen Frochen ^1,², Mary Fakunle ², Ananta Wadhwa ^1,³, Ashley-Marie Y Green-Lott ^1,², Anissa V Bailey ^1,², Lorna Kwan ^1,², Candace Haroldsen ^4,⁵, Atim Effiong ^4,⁵, Brent S Rose ⁶, Timothy R Rebbeck ^7,^8,⁹, Hari S Iyer ^1,¹⁰, Isla P Garraway ^1,^2,^11,^✉

¹Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

²Department of Urology, University of California, Los Angeles

³University of Rochester, School of Medicine and Dentistry, Rochester, New York

⁴Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah

⁵University of Utah, Salt Lake City

⁶Department of Radiation Oncology, University of California, San Diego

⁷Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

⁸Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts

⁹Veterans Affairs Boston Healthcare System, Boston, Massachusetts

¹⁰Section of Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, New Jersey

¹¹Jonsson Comprehensive Cancer Center, University of California, Los Angeles

Accepted for Publication: April 24, 2026.

Published: July 6, 2026. doi:10.1001/jamanetworkopen.2026.21741

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Siavoshi M et al. JAMA Network Open.

^✉

Corresponding Author: Isla P. Garraway, MD, PhD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 10833 Le Conte Ave, PO Box 951738 CHS, Los Angeles, CA 90095 (igarraway@mednet.ucla.edu).

Author Contributions: Drs Iyer and Garraway had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Iyer and Garraway contributed equally.

Concept and design: Siavoshi, Fakunle, Bailey, Rebbeck, Iyer, Garraway.

Acquisition, analysis, or interpretation of data: Siavoshi, Frochen, Wadhwa, Green-Lott, Bailey, Kwan, Haroldsen, Effiong, Rose, Rebbeck, Iyer, Garraway.

Drafting of the manuscript: Siavoshi, Frochen, Wadhwa, Effiong, Rose, Rebbeck, Iyer, Garraway.

Critical review of the manuscript for important intellectual content: Siavoshi, Frochen, Fakunle, Green-Lott, Bailey, Kwan, Haroldsen, Rose, Rebbeck, Iyer, Garraway.

Statistical analysis: Siavoshi, Wadhwa, Bailey, Kwan, Rose, Iyer.

Obtained funding: Rebbeck, Garraway.

Administrative, technical, or material support: Frochen, Green-Lott, Effiong, Rebbeck, Garraway.

Supervision: Fakunle, Rose, Rebbeck, Garraway.

Conflict of Interest Disclosures: Dr Effiong reported grants from US Department of Veterans Affairs (VA) Health Services Research and Development outside the submitted work. No other disclosures were reported.

Funding/Support: Research support for the investigators includes the National Institutes of Health (grant Nos. 5P50CA092131 and R01 PAR-20-077 to Dr Garroway and K01ES035734 to Dr Iyer); US Department of Defense (grant No. W81XWH211075 to Dr Iyer); Prostate Cancer Foundation (grant Nos. PCFCHAL2202 and PCF17CHAL04 to Dr Iyer); Jean Perkins Foundation (grant to Dr Iyer), STOP Cancer Foundation (grant to Dr Iyer); and VA Office of Research and Development Clinical Science and Research Development (grant to Dr Iyer).

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC13338809 PMID: 42406398

This cohort study analyzes associations of prostate-specific antigen testing practices with incidence of metastatic prostate cancer among US veterans.

Key Points

Question

What are the associations of age at prostate-specific antigen (PSA) screening initiation, testing interval, and baseline PSA value with metastatic prostate cancer rates?

Findings

In this cohort study of 103 067 male veterans, older age at screening start (≥60 vs <50 years) and higher baseline PSA value (>4 vs ≤1 ng/mL) were associated with 2.4-fold and 6.7-fold higher rate of metastatic prostate cancer at diagnosis, respectively, with smaller associations with testing interval. Strategies combining younger ages and baseline PSA values were associated with lower rates of metastatic presentation, particularly in Black individuals.

Meaning

These findings suggest that in high-risk populations such as male veterans, optimizing screening based on age at screening start and baseline PSA may reduce metastatic presentation.

Abstract

Importance

Metastatic prostate cancer (PC) incidence has increased in US men, partly due to changes in prostate-specific antigen (PSA) screening recommendations. However, few studies have examined contemporary PSA screening practices in large US health care systems.

Objective

To describe and examine contemporary PSA testing practices associated with metastatic PC incidence.

Design, Setting, and Participants

This cohort study included veterans within the Veterans Health Administration that received a prostate needle biopsy (PNB) between January 2015 and December 2023 with follow-up through 2024, excluding those with a history of PC. Data were analyzed between July 1, 2023, and November 6, 2025.

Exposures

PSA tests were retrieved from the VA Corporate Data Warehouse and categorized by age at first VA PSA (<50, 50-59, and ≥60 years) and by longest interval between consecutive VA PSA tests in the 5 years before PNB (≤24 vs >24 months). Clinical, laboratory, pathological, demographic, and census block group-level socioeconomic status data were obtained from the VA Multi-OMICS Analysis Platform for Prostate Cancer database.

Main Outcomes and Measures

Multivariable Cox models estimated hazard ratios (HRs) from time of first VA PSA to first PNB, evaluated risk of metastatic (regional or distant) vs localized PC or benign diagnosis, and adjusted for sociodemographic and clinical covariates.

Results

There were 103 067 participants of whom 20 233 (19.6%) were younger than 50 years at first PSA, 31 546 (30.6%) were non-Hispanic Black, 58 264 (56.5%) were non-Hispanic White, and 13 277 (12.9%) had other race or ethnicity. Of all participants, 22 190 (21.5%) had a first PSA value of 1 ng/mL or less, 52 939 (51.4%) had a screening interval of 24 months or less, and 3773 (3.7%) were diagnosed with metastatic PC at time of PNB. Compared with men aged younger than 50 years at first PSA, those aged 50 to 59 years (adjusted HR [aHR], 1.27; 95% CI, 1.24-1.29) and 60 years or older (aHR, 2.37; 95% CI, 2.33-2.42) had higher risk of metastatic PC. Men with longer screening intervals had higher risk of metastatic PC (aHR, 1.14; 95% CI, 1.13-1.16). Men aged younger than 50 years with shorter screening intervals had lower rates of metastatic PC (adjusted risk ratio, 0.10; 95% CI, 0.09-0.12) compared with men aged 60 years or older with longer screening intervals.

Conclusions and Relevance

In this cohort study, few veterans had the most favorable combinations of screening factors in relation to metastatic PC, suggesting potential for further screening optimization.

Introduction

Screening for prostate cancer (PC) using prostate-specific antigen (PSA) testing is controversial due to conflicting evidence of survival benefits from clinical trials and concerns about harm from overdiagnosis.^1,2,3,4,5 In 2012, the US Preventative Services Task Force (USPSTF) advised against routine PSA screening for all men.² By 2018, as longer-term clinical trial results showed benefits in select populations,⁶ guidelines shifted to recommend shared decision-making for PSA screening in men aged 55 to 69 years.⁷ As PSA testing declined from 2012 to 2018, there was an increase in metastatic PC incidence^8,9,10 and plateauing of PC mortality following nearly a decade of decline.¹¹ These reports have prompted renewed debates regarding optimal screening for PC in high-risk populations.^12,13,14

National PSA screening guidelines focus on age to begin screening, time between screening tests (hereafter referred to as a screening interval), and PSA results.^7,13 The National Comprehensive Cancer Institute (NCCN) Prostate Cancer Early Detection Guidelines and American Urological Association and Society of Urologic Oncology Early Detection of Prostate Cancer Guidelines recommend a baseline PSA test starting at age 45 to 50 years in average-risk men and 40 to 45 years in high-risk men.^15,16 PSA screening every 2 to 4 years is recommended in average-risk men, and 1 to 2 years in high-risk men. Lower PSA thresholds can increase overdiagnosis without reducing PC-specific mortality.^17,18 Few studies have evaluated contemporary PSA screening patterns in large health care systems with respect to these 3 screening parameters.^19,20

We studied associations of screening patterns with metastatic PC at diagnosis within the Veterans Administration (VA) health care system. Veterans have higher rates of PC compared with the general population due to military occupational exposures and higher access to care.^21,22 Given the potential for more favorable harm or benefit tradeoffs of screening in veterans, understanding how PSA screening factors influence metastatic PC could inform more optimized screening recommendations.

Methods

Study Design and Population

We conducted a retrospective cohort study using data from the VA Multi-OMICS Analysis Platform for Prostate Cancer (VA-MAPP) database.²³ We captured clinical, laboratory, pathological, demographic, and socioeconomic status data from men with at least 2 VA visits occurring between 2005 to 2020 (11 216 391 individuals).²¹ We identified each participant’s first VA diagnostic prostate needle biopsy (PNB) between 2015 and 2023 (103 419 individuals). We excluded patients with no VA PSA testing in the 5 years before their first PNB or a prior PC diagnosis (eFigure 1 in Supplement 1). VA clinicians generally follow the current USPSTF guidelines, which encourage shared decision making for men between 55 and 69 years and further workup and biopsy following a PSA test value greater than 4 ng/mL.^6,24 However, screening practices and PSA value threshold for further workup vary by patient, clinician, and health facility characteristics that may prevent strict adherence to this guideline. The central VA institutional review board and research and development approved the study. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. We obtained an approved waiver for obtaining informed consent with Health Insurance Portability and Accountability Act of 1996 authorization.

PSA Test Parameters

PSA tests were retrieved from the patient laboratory chemistry data table in the VA Corporate Data Warehouse using Logical Observation Identifiers, Names, and Codes (LOINC), which are standardized coding systems for health informatics. We specified key words to define PSA tests in the EHR (eg, %PSA%, %PROSTAT%, and %PROST%SPEC%). Detailed review by coauthors (C.H. and I.P.G.) confirmed validity of selected terms to identify PSA tests. PSA values were cleaned by excluding erroneous values (eg, extra decimals and characters). Only total PSA tests (LOINC 2857-1, 19195-7, and 35741-8) with numerical values were used for analysis.

We evaluated 3 PSA screening factors: (1) age at first VA PSA test (<50, 50-59, and ≥60 years), (2) first VA PSA test value (≤1.00, 1.01-2.50, 2.51-4.00, and >4.00 ng/mL), and (3) longest PSA test interval in the 5 years prior to biopsy (≤24 and >24 months). Age was categorized to better reflect clinical decision-making thresholds and outcomes for PC care. Screening interval length was dichotomized at 24 months based on commonly reported intervals in major clinical trials.^2,25,26 For consistency with current recommendations,^15,16 we calculated screening intervals starting at age 45 years for Black veterans and 55 years for all others.

Outcome

The primary outcome was PC diagnosis at first PNB based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, categorized as metastatic PC, localized PC, or benign (no PC diagnosis following biopsy). Metastatic PC was defined as evidence of metastasis to lymph nodes or distant spread to other organs as described previously.²⁷ Survival time was calculated in years from the first VA PSA test to first VA PNB.

Covariates

Covariates included self-identified race and ethnicity (non-Hispanic Black, non-Hispanic White, and other [includes those who identified as non-Hispanic Asian American and Pacific Islander, non-Hispanic American Indian and Alaska Native, Hispanic, and those who are missing race information]), Agent Orange exposure based on VA-determined probable exposure,²¹ service-connected disability percentage (0-24.9%, 25.0%-49.9%, 50.0%-74.9%, 75.0%-100%), body mass index (calculated as weight in kilograms divided by height in meters squared) at PNB (obese [0 to <30], nonobese [≥30], or missing), and the Census Block Group Area Deprivation Index State Decile at PNB (1-2, 3-4, 5-6, 7-8, or 9-10),²⁸ as a measure of neighborhood socioeconomic disadvantage. We considered Charlson Comorbidity Index but omitted it from main analyses because it had no impact on results.

Statistical Analysis

All statistical analyses were conducted using SAS Enterprise Guide 8.3 (SAS Institute Inc) from July 2023 to November 2025. Statistical significance was set at α = .05.

Primary Analysis

Cohort characteristics were summarized across PC outcomes. Screening patterns and diagnoses were summarized across NCCN and USPSTF adherence indicator variables defined by age at screening initiation, PSA testing interval, and PSA value.^7,29 Kaplan-Meier curves and log-rank tests were calculated to compare the time from first VA PSA test with metastatic PC at first VA PNB, stratified by levels of each screening parameter.

For our primary analysis, we fit covariate-adjusted Cox proportional hazards models to estimate associations of PSA screening parameters with metastatic PC at diagnosis. We first assessed associations of each PSA screening parameter separately and then with mutual adjustment for all PSA screening factors. The proportional hazards assumption was evaluated using Schoenfeld residuals,³⁰ which confirmed no violations.

For our secondary analysis to identify combinations of screening factors associated with lowest metastatic PC rates, we fit Poisson regression models using the same covariates as in the Cox models, with robust variance and an offset term for log person-time to estimate absolute rates of metastatic PC diagnosis.³¹ Poisson models were used to produce rate estimates on the absolute instead of the relative scale. The highest risk group was selected as the reference to facilitate clinical interpretation. Three separate interaction models were fitted: (1) age at first PSA by first PSA value (joint reference: age ≥60 years and PSA >4 ng/mL); (2) PSA testing interval by first PSA value (joint reference: interval >24 months and PSA >4 ng/mL); and (3) age at first PSA by PSA testing interval (joint reference: age ≥60 years and interval >24 months). Relative rates and 95% CIs were estimated for each composite exposure category compared with the joint reference group and were presented as heatmaps to visualize joint effects.

To assess potential differences in associations among non-Hispanic Black men, who experience higher rates of PC, we repeated primary analyses stratified by race using multiplicative interaction terms to test for effect modification. We further repeated interaction analyses restricting to non-Hispanic Black individuals only.

Sensitivity Analyses

Selecting our cohort based on PNB, which occurred after PSA screening started, may have introduced selection bias.³² We performed 2 analyses to assess this bias. First, we calculated inverse probability of censoring weights (IPCW)³³ for all 11 216 391 patients in VA-MAPP, separately for age at first PSA and first PSA value. Stabilized weights were calculated to improve stability, and standardized mean differences showed good balance.³⁴ We then refit separate Cox models for each screening parameter using IPCW to estimate hazard ratios (HRs) adjusted for selection into the biopsy cohort.³⁴ Second, we calculated a bias factor to determine the influence of selection bias arising from unmeasured family history and selection on biopsy on associations of each screening factor.^{35,36,37,38,39,40} We then rescaled the metastatic PC HRs for associations of the age at first PSA test (≥60 vs <50 years), first PA test value (>4 vs ≤1 ng/mL) and screening interval (>24 vs ≤24 months) by this bias factor. Further details about these sensitivity analyses are provided in the eMethods in Supplement 1.

Results

Cohort Characteristics

The analytic cohort included 103 067 veterans who underwent their first VA PNB between 2015 and 2023; of these, 3773 (3.7%) were diagnosed with metastatic PC, 46 132 (44.8%) were diagnosed with localized PC, and 53 162 (51.6%) had benign biopsies (Table 1). Of all participants, 20 233 (19.6%) were younger than 50 years at first PSA, 22 190 (21.5%) had a first PSA value of 1 ng/mL or less, and 52 939 (51.4%) had a screening interval of 24 months or less. Veterans diagnosed with metastatic PC were older at the time of first PSA testing, with 1750 (46.4%) aged 60 years or older at first PSA testing compared with 16 798 localized cases (36.4%) and 17 328 benign cases (32.6%) (P < .001) (Table 1). The cohort was racially diverse (31 546 non-Hispanic Black [30.6%], 58 264 non-Hispanic White, and 13 277 with other race [12.9%]), with non-Hispanic White veterans comprising the majority across all diagnostic groups (metastatic: 2173 cases [57.6%]; localized: 25 368 cases [54.9%]; benign: 30 723 cases [57.8%]). Veterans diagnosed with metastatic (1351 cases [35.8%]) and localized (17 189 cases [37.3%]) PC had higher prevalence of severe service-connected disability (75%-100%) compared with veterans in the benign group (16 559 cases [31.1%]) (P < .001) (Table 1). Median (IQR) follow-up time was 18 (12-23) years.

Table 1. Cohort Characteristics and PSA Testing Factors by Diagnosis at First VA PNB .

Characteristic	Participants, No. (%)				P value
	Total (N = 103 067)	Diagnosis at First VA PNB
	Total (N = 103 067)	Metastatic (n = 3773)	Localized (n = 46 132)	Benign (n = 53 162)
Race and ethnicity
Non-Hispanic Black	31 546 (30.6)	1183 (31.4)	15 553 (33.7)	14 810 (27.9)	<.001^a
Non-Hispanic White	58 264 (56.5)	2173 (57.6)	25 368 (54.9)	30 723 (57.8)
Other^b	13 277 (12.9)	417 (11.1)	5204 (11.3)	7629 (14.4)
Agent Orange exposure	18 405 (17.9)	704 (18.7)	9046 (19.6)	8655 (16.3)	<.001^a
Percentage of service-connected disability
0-24.9	49 305 (47.8)	1961 (52.0)	21 084 (45.7)	26 260 (49.4)	<.001^a
25.0-49.9	6059 (5.9)	168 (4.5)	2546 (5.5)	3345 (6.3)
50.0-74.9	12 604 (12.2)	293 (7.8)	5313 (11.5)	6998 (13.2)
75.0-100	35 099 (34.1)	1351 (35.8)	17 189 (37.3)	16 559 (31.1)
Deaths over follow-up	13 344 (12.9)	1660 (44.0)	6805 (14.8)	4879 (9.2)	<.001^a
Body mass index at first PNB^c
Mean (SD)	29.6 (5.64)	29.1 (5.81)	29.8 (5.79)	29.5 (5.50)	<.001^d
Nonobese (<30)	56 114 (54.4)	2243 (59.4)	25 271 (54.8)	28 699 (53.8)	<.001^a
Obese (≥30)	41 970 (40.7)	1475 (39.1)	19 646 (42.6)	20 849 (39.2)
Missing	4983 (4.8)	55 (1.5)	1215 (2.6)	3713 (7.0)
Charlson Comorbidity Index at first PSA
0	96 145 (93.3)	3537 (93.7)	43 014 (93.2)	49 594 (93.3)	.03^a
1-2	5915 (5.7)	200 (5.3)	2621 (5.7)	3094 (5.8)
≥3	1007 (1.0)	36 (1.0)	497 (1.1)	474 (0.9)
State Area Deprivation Index at first PNB
0-2	10 143 (9.8)	401 (10.6)	4778 (10.4)	4964 (9.3)	<.001^a
3-4	15 243 (14.8)	545 (14.4)	7279 (15.8)	7419 (14.0)
5-6	16 851 (16.3)	641 (17.0)	8136 (17.6)	8074 (15.2)
7-8	17 287 (16.8)	704 (18.7)	8430 (18.3)	8153 (15.3)
9-10	17 170 (16.7)	722 (19.1)	8491 (18.4)	7957 (15.0)
Null	26 373 (25.6)	760 (20.1)	9018 (19.5)	16 595 (31.2)
Prostate cancer treatment
Prostatectomy	13 880 (26.2)	858 (22.7)	12 138 (26.3)	884 (28.8)	<.001^a
Radiation	11 267 (21.3)	806 (21.4)	9899 (21.5)	562 (18.3)
Androgen deprivation therapy only	10 153 (19.2)	1926 (51.0)	7739 (16.8)	488 (15.9)
Other or unknown	17 673 (33.4)	183 (4.9)	16 356 (35.5)	1134 (37.0)
Never diagnosed, No.	50 094	0	0	50 094
Follow up, median (IQR), y	18 (12-23)	17 (12-22)	18 (13-23)	17 (12-23)	<.001^d
PSA screening parameters
Age at first PSA, y
<50	20 233 (19.6)	456 (12.1)	7999 (17.3)	11 778 (22.2)	<.001^a
50-59	46 958 (45.6)	1567 (41.5)	21 335 (46.2)	24 056 (45.3)
≥60	35 876 (34.8)	1750 (46.4)	16 798 (36.4)	17 328 (32.6)
First PSA value, ng/mL
≤1.00	22 190 (21.5)	1137 (30.1)	10 651 (23.1)	10 402 (19.6)	<.001^a
1.01-2.50	42 722 (41.5)	1271 (33.7)	19 486 (42.2)	21 965 (41.3)
2.51-4.00	17 713 (17.2)	404 (10.7)	7378 (16.0)	9931 (18.7)
>4.00	20 442 (19.8)	961 (25.5)	8617 (18.7)	10 864 (20.4)
PSA testing interval, mo
≤24	52 939 (51.4)	1210 (32.1)	23 492 (50.9)	28 237 (53.1)	<.001^a
>24	50 128 (48.6)	2563 (67.9)	22 640 (49.1)	24 925 (46.9)	<.001^a

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Abbreviations: PNB, prostate needle biopsy; PSA, prostate-specific antigen; VA, Veterans Health Administration.

^{^a}

χ² P value.

^{^b}

Includes non-Hispanic Asian American and Pacific Islander, non-Hispanic American Indian and Alaska Native, Hispanic, and those who are missing race and ethnicity information.

^{^c}

Calculated as weight in kilograms divided by height in meters squared.

^{^d}

Kruskal-Wallis P value.

Characteristics of the population stratified by USPSTF and NCCN guidelines are presented in eTable 1 in Supplement 1. Of the eligible population, 54 505 (52.9%) were adherent to USPSTF guidelines, 2391 (2.3%) were adherent to NCCN average risk guidelines, and 325 (1.0%) were adherent to NCCN high risk guidelines. Nonadherent men were older than adherent individuals when stratified by NCCN average risk guidelines (mean [SD] age, 56.0 [7.4] vs 48.0 [1.4] years), but younger (mean [SD] age, 50.0 [6.0] years vs 61.1 [3.7] years) when stratified by USPSTF guidelines. The highest frequency of metastatic PC occurred among those screened outside of guidelines (656 of 8603 cases [7.6%]) or who adherent to USPSTF guidelines (2731 cases [4.4%]), while the proportion of patients diagnosed with localized disease were lowest among those adherent to NCCN average risk guidelines (987 cases [41.3%]), which may suggest that overdiagnosis was no worse in this population compared with other screening groups.

Associations of Screening Parameters With Metastatic PC

Kaplan-Meier curves demonstrated significant differences in the incidence of metastatic PC at PNB across all 3 screening parameters (Figure 1 and Table 2). Veterans aged 60 years or older at first PSA had higher incidence of metastatic PC over follow-up (incidence rate, 766.8 cases per 100 000 person-years) (Table 2 and Figure 1A). The cumulative incidence of metastatic PC in this cohort was highest among those with a first PSA value greater than 4 ng/mL (1420.9 cases per 100 000 person-years) (Figure 1B). Veterans with PSA testing intervals greater than 24 months had higher metastatic PC over follow-up compared with those with testing intervals of 24 months or less (582.3 v 199.4 cases per 100 000 person-years) (Figure 1C).

Three-panel Kaplan-Meier plots of survival probability versus time from first PSA. Three stacked Kaplan-Meier panels labeled A, B, and C at the upper left of each plot. All panels share a vertical axis labeled Survival probability ranging from zero to one point zero, and a horizontal axis labeled Time from first PSA to first PNB, y, ranging from zero to twenty five, with tick marks at approximately zero, five, ten, fifteen, twenty, and twenty five. Panel A title text at upper left: Age at first PSA. Legend box in the lower left maps orange to Age less than fifty y at first PSA, dark teal to Age fifty to fifty nine y at first PSA, and light blue to Age greater than or equal to sixty y at first PSA. Curves start near one point zero at time zero; the light blue curve declines most, reaching about zero point four by about twenty three to twenty five years, while the orange curve remains highest near about zero point nine to zero point nine five at twenty five years and the dark teal curve ends near about zero point eight. Small plus symbols appear near the right ends of curves. A No. at risk table beneath lists, at time zero, five, ten, fifteen, twenty, and twenty five: Age less than fifty: 20233, 18664, 15502, 9213, 2421, 0; Age fifty to fifty nine: 46957, 39094, 29465, 14789, 2579, 0; Age greater than or equal to sixty: 35875, 19749, 8194, 2174, 251, 0. Panel B title: First PSA value. Legend maps light green to First PSA value less than or equal to one, dark teal to one to two point five, orange to two point five to four, and gray to greater than four. The gray curve is lowest, reaching about zero point six by about twenty two to twenty five years; the other three curves cluster between about zero point eight and zero point eight five at twenty five years. Plus symbols appear near right ends. No. at risk values at zero, five, ten, fifteen, twenty, twenty five: less than or equal to one: 22190, 21592, 18937, 11516, 2717, 0; one to two point five: 42722, 39353, 27657, 12613, 2202, 0; two point five to four: 17713, 11658, 4922, 1568, 208, 0; greater than four: 20440, 4929, 1646, 507, 49, 0. Panel C title: PSA testing interval. Legend maps dark teal to PSA testing interval less than or equal to twenty four mo gap and orange to PSA testing interval greater than twenty four mo gap. Both curves start near one point zero; by about twenty five years the dark teal curve is near about zero point eight eight and the orange curve near about zero point seven five, with plus symbols near the right ends. No. at risk at zero, five, ten, fifteen, twenty, twenty five: less than or equal to twenty four mo gap: 52939, 45686, 31117, 15155, 2933, 0; greater than twenty four mo gap: 50126, 31806, 22045, 11013, 2292, 0. — All comparisons were significant, with a log-rank P < .001. PSA values were measured in nanograms per milliliter. PNB indicates prostate needle biopsy.

Table 2. Cumulative Incidence of Metastatic Prostate Cancer and Median Time to Prostate Needle Biopsy by Screening Factors.

PSA screening factor	Cases of metastatic prostate cancer, No.	Population at risk, No.	Cumulative incidence of metastatic prostate cancer, %^a	Person-years, No.	Incidence rate per 100 000 person-years
Age at first PSA, y
<50	456	20 233	2.3	277 821	164.1
50-59	1567	46 958	3.3	540 808	289.8
≥60	1750	35 876	4.9	228 208	766.8
First PSA value, ng/mL
≤1.00	1137	22 190	5.1	328 514	346.1
1.01-2.50	1271	42 722	3	515 418	246.6
2.51-4.00	404	17 713	2.3	135 273	298.7
>4.00	961	20 442	4.7	67 632	1420.9
PSA testing interval, mo
≤24	1210	52 939	2.3	606 706	199.4
>24	2563	50 128	5.1	440 131	582.3

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Abbreviation: PSA, prostate-specific antigen.

^{^a}

All χ² tests for cumulative incidence were significant at P < .001.

In Cox models separately analyzing each screening parameter (eTable 2 in Supplement 1), a first PSA value greater than 4 ng/mL (vs ≤1 ng/mL) had the largest magnitude of association with PC (adjusted HR [aHR], 8.62; 95% CI, 8.45-8.81), followed by age of 60 years or older (vs <50 years) at first PSA (aHR, 3.56; 95% CI, 3.49-3.63), while testing interval of more than 24 (vs ≤24) months showed a more modest association (aHR, 1.25; 95% CI, 1.24-1.27).

When all 3 screening parameters were included simultaneously (Figure 2 and eTable 2 in Supplement 1), compared with those aged younger than 50 years at first PSA, veterans aged 50 to 59 years (aHR, 1.27; 95% CI, 1.24-1.29) and 60 years or older (aHR, 2.37; 95% CI, 2.33-2.42) had higher rate of metastatic PC at PNB. Compared with men with PSA values of 1 ng/mL or less, those with values of 1.01 to 2.50 ng/mL (aHR, 1.48; 95% CI, 1.46-1.51), 2.51 to 4.00 ng/mL (aHR, 2.83; 95% CI, 2.77-2.90), and greater than 4.00 ng/mL (aHR, 6.67; 95% CI, 6.53-6.82) had higher rates of metastatic PC risk. Compared with men with a PSA testing interval 24 months or less, those with intervals greater than 24 months had higher rate of metastatic PC diagnosis (aHR 1.14; 95% CI, 1.13-1.16). In models stratified by race and ethnicity (eTable 3 in Supplement 1), the association of age at first PSA (age ≥60 vs <50 years) and rate of metastatic PC was higher in the non-Hispanic Black subgroup (aHR, 2.62; 95% CI, 2.53-2.72) compared with the non-Hispanic White subgroup (aHR, 2.23; 95% CI, 2.17-2.29) and other race or ethnicity subgroup (aHR, 2.15; 95% CI, 2.03-2.27) (P for heterogeneity<.001). Similarly, the association of first PSA value with metastatic PC was largest in the non-Hispanic Black subgroup (aHR, 7.53; 95% CI, 7.24-7.84) compared with other groups (P for heterogeneity<.001).

Forest plot of adjusted hazard ratios by age, first P S A, and testing interval. Two-column layout with a table on the left and a forest plot on the right. Table headers at top: Characteristic and a H R with 95 percent C I. Group heading Age at first P S A, y, followed by three rows: less than 50 with value 1 and label Reference; 50 to 59 with 1.27 and 95 percent C I 1.24 to 1.29; greater than or equal to 60 with 2.37 and 95 percent C I 2.33 to 2.42. Next group heading First P S A value, ng per m L, with four rows: less than or equal to 1.0 with 1 Reference; 1.0 to 2.5 with 1.48 and 95 percent C I 1.46 to 1.51; 2.5 to 4.0 with 2.83 and 95 percent C I 2.77 to 2.90; greater than 4.0 with 6.67 and 95 percent C I 6.53 to 6.82. Next group heading P S A testing interval with two rows: less than or equal to 24 mo with 1 Reference; greater than 24 mo with 1.14 and 95 percent C I 1.13 to 1.16. On the right, a horizontal axis labeled a H R with 95 percent C I, with tick labels 1 at the left and 10 at the right. A vertical dotted reference line at 1 aligns with the Reference rows. For each non-reference row, a dark square marker appears to the right of 1, aligned with its row; thin horizontal lines extend left and right from each square indicating the 95 percent C I. The square for 50 to 59 lies slightly right of 1; the square for greater than or equal to 60 lies farther right near 2 to 3. For first P S A value, squares progress rightward with increasing category, with the greater than 4.0 square farthest right near 6 to 7. The P S A testing interval greater than 24 mo square lies just right of 1 with a short confidence interval line. — Points represent the point estimate, and lines represent 95% CIs. Results from multivariable Cox models were adjusted for age at first PSA, first PSA value, PSA testing interval, Agent Orange exposure, service-connected disability percentage, state Area Deprivation Index at first prostate needle biopsy, race and ethnicity (non-Hispanic Black compared with other race or ethnicity [American and Pacific Islander, non-Hispanic American Indian and Alaska Native, Hispanic, and those who are missing race information]), and body mass index (obese vs not obese vs missing) at first prostate needle biopsy. aHR indicates adjusted hazard ratio.

Interactions Between Screening Parameters and Metastatic PC

Multivariable Poisson regression models with interaction terms revealed complex risk stratification patterns (Figure 3 and eTables 3-5 in Supplement 1). For the interaction between age at first PSA and first PSA value, first PSA value was the primary factor underlying risk variation as demonstrated by the gradient differences across PSA categories within each age group (Figure 3A and eTable 4 in Supplement 1). All combinations of age of 59 years or younger and PSA values of 4 ng/mL or less had lower metastatic PC risk than the joint reference group (age ≥60 years and PSA >4 ng/mL). The lowest risk occurred in veterans aged younger than 50 years with PSA values between 1.01 and 2.50 ng/mL (adjusted risk ratio [aRR], 0.07, 95% CI, 0.06-0.08).

Three-panel heat maps of relative rates by first P S A, age, and testing interval. Three heat-map panels labeled A, B, and C arranged left to right, each using a light blue to dark blue color gradient, with some cells in beige labeled as reference. Panel A title: First P S A value vs age at first P S A. Horizontal axis labeled Age at first P S A, y, with categories less than 50, 50 to 59, and greater than or equal to 60. Vertical axis labeled First P S A value, ng per mL, with categories greater than or equal to 4 point 0, 2 point 5 to 4 point 0, 1 point 0 to 2 point 5, and less than or equal to 1 point 0. Cell values listed as relative rate with 95 percent C I in parentheses: for greater than or equal to 4 point 0, less than 50 equals 0 point 43 (0 point 31 to 0 point 61), 50 to 59 equals 0 point 58 (0 point 50 to 0 point 67), greater than or equal to 60 equals 1 Reference. For 2 point 5 to 4 point 0, less than 50 equals 0 point 09 (0 point 06 to 0 point 13), 50 to 59 equals 0 point 14 (0 point 12 to 0 point 17), greater than or equal to 60 equals 0 point 27 (0 point 23 to 0 point 31). For 1 point 0 to 2 point 5, less than 50 equals 0 point 07 (0 point 06 to 0 point 08), 50 to 59 equals 0 point 13 (0 point 11 to 0 point 14), greater than or equal to 60 equals 0 point 34 (0 point 31 to 0 point 38). For less than or equal to 1 point 0, less than 50 equals 0 point 12 (0 point 10 to 0 point 14), 50 to 59 equals 0 point 22 (0 point 20 to 0 point 24), greater than or equal to 60 equals 0 point 52 (0 point 45 to 0 point 59). Panel B title: P S A testing interval vs age at first P S A. Horizontal axis labeled Age at first P S A, y, with the same three categories. Vertical axis labeled P S A testing interval, mo, with categories greater than 24 and less than or equal to 24. For greater than 24, less than 50 equals 0 point 23 (0 point 20 to 0 point 26), 50 to 59 equals 0 point 43 (0 point 40 to 0 point 47), greater than or equal to 60 equals 1 Reference. For less than or equal to 24, less than 50 equals 0 point 10 (0 point 09 to 0 point 12), 50 to 59 equals 0 point 17 (0 point 15 to 0 point 19), greater than or equal to 60 equals 0 point 35 (0 point 31 to 0 point 38). Panel C title: First P S A value vs P S A testing interval. Horizontal axis labeled P S A testing interval, mo, with categories less than or equal to 24 and greater than 24. Vertical axis labeled First P S A value, ng per mL, with the same four categories as panel A. For greater than or equal to 4 point 0, less than or equal to 24 equals 0 point 18 (0 point 15 to 0 point 22), greater than 24 equals 1 Reference. For 2 point 5 to 4 point 0, less than or equal to 24 equals 0 point 09 (0 point 08 to 0 point 11), greater than 24 equals 0 point 23 (0 point 20 to 0 point 26). For 1 point 0 to 2 point 5, less than or equal to 24 equals 0 point 10 (0 point 09 to 0 point 11), greater than 24 equals 0 point 23 (0 point 21 to 0 point 26). For less than or equal to 1 point 0, less than or equal to 24 equals 0 point 17 — Relative rates and 95% CIs were calculated from multivariable Poisson regression models with an interaction between first PSA value, age at first PSA, and PSA testing interval, adjusting for the third variable. Relative rates are shown as a color gradient ranging from light blue (lowest relative rate) to dark blue (highest relative rate). All Poisson models were adjusted for Agent Orange exposure, service-connected disability percentage, State Area Deprivation Index at first prostate needle biopsy, race and ethnicity (Non-Hispanic Black compared with other race or ethnicity [American and Pacific Islander, non-Hispanic American Indian and Alaska Native, Hispanic, and those who are missing race information]), and body mass index (obese vs not obese vs missing) at first prostate needle biopsy.

For the interaction between age at first VA PSA and testing interval, risk increased progressively with both older age and longer testing gaps (Figure 3B and eTable 5 in Supplement 1). The lowest risk occurred among veterans aged younger than 50 years with an interval of 24 months or less (aRR, 0.10; 95% CI, 0.09-0.12) relative to the joint reference group (age ≥60 years and gap >24 months).

For the interaction between first VA PSA value and testing interval (eTable 6 in Supplement 1 and Figure 3C), the lowest risk occurred among veterans with a testing interval of 24 months or less and PSA values between 2.50 and 4.00 ng/mL (aRR, 0.09; 95% CI, 0.08-0.11) as compared with the joint reference group (gap >24 months and PSA >4 ng/mL). Among those with baseline PSA values between 2.50 and 4.00 ng/mL, those with gaps of 24 months or less (aRR, 0.36; 95% CI, 0.32-0.40) had higher risks of metastatic PC compared with those with gaps greater than 24 months (aRR, 0.23; 95% CI, 0.21-0.26), possibly reflecting delayed diagnosis in men with initially low PSA who were screened infrequently.

In general, these interactions were consistent when performed within the non-Hispanic Black population alone (eTables 4-6 and eFigure 2 in Supplement 1). However, we found that the age and PSA value interactions revealed larger-magnitude inverse associations in the non-Hispanic Black population compared with the overall population. For example, among men aged 50 to 59 years at screening initiation with PSA values between 1.01 and 2.50 ng/mL, compared with those with age 60 years or older at screening start and PSA values greater than 4.00 ng/mL, the inverse association was larger in magnitude in the non-Hispanic Black population (aRR, 0.09; 95% CI, 0.07-0.11) compared with the total population (aRR, 0.13; 95% CI, 0.11-0.14) (eTable 4 in Supplement 1).

Sensitivity Analyses

In IPCW analyses to assess robustness of results to potential selection bias, the effective sample sizes were 47.7% of the original cohort (11.2 million individuals) for age at first PSA and 72.2% (11.2 million individuals) for first PSA value. The weighted analysis yielded results consistent with the primary findings, with slight attenuation of the effect estimates for age at first PSA and slight elevation for first PSA value (eTable 7 in Supplement 1).

In bias analyses evaluating the magnitude of unmeasured family history of PC associations required to attenuate selected screening factor effect size estimates, age at first PSA test and value at first PSA test associations were robust to plausible levels of family history of PC as an unmeasured confounder (eFigure 3 in Supplement 1). Based on this analysis, even with the prevalence ratio for family history and biopsy or risk of metastatic PC associated with a family history prevalence ratio of 2.5 (strong selection bias), the age at first PSA of 60 years or older vs younger than 50 years remained significantly associated with higher metastatic PC. For the association of first PSA value of greater than 4 ng/mL vs 1 ng/mL or less, none of the bias-corrected estimates across the range of plausible bias factor components had a 95% CI crossing the null. For the association of screening interval greater than 24 months vs 24 months or less, we found that selection bias across moderate levels of association between family history, biopsy, and metastatic PC would reverse the association of screening interval with risk of metastatic PC.

Discussion

In this cohort study of men undergoing PNB within the VA health care system, older age at first VA PSA test and higher initial PSA values were independently associated with metastatic disease at PC diagnosis, with less reliable associations with testing interval. The lowest metastatic PC risk was observed in veterans aged younger than 50 years at first VA PSA test and initial PSA value of 1.01 to 2.50 ng/mL. Veterans aged younger than 50 years with a testing interval of 24 months or less also demonstrated very low risk, as did those with PSA values between 2.51 and 4.00 ng/mL and a testing interval of 24 months or less.

Understanding how combinations of PSA screening parameters (age, testing interval, and PSA value) interact in association with risks of metastatic PC is essential for balancing harm-benefit tradeoffs.^{13,41,42,43,44,45} In response to lower PSA screening rates in the years following the USPSTF guideline changes in 2012,⁴⁶ VA studies have reported increased metastatic PC risk.²⁴ Previous studies have also found that more frequent PSA screening (shorter intervals between tests) was associated with lower risk of metastatic PC, consistent with our findings,⁴¹ but at the cost of unnecessary biopsies and overtreatment.⁴⁷ We found that successive PSA tests more than24 months apart was associated with moderately increased risk of metastatic PC, which was exacerbated with delayed age at initial screening. Veterans with longer screening intervals who also started screening at older age were at highest risk of metastatic presentation, emphasizing the importance of earlier testing in detecting and reducing metastatic PC at diagnosis. Further, the risk of metastatic PC increased with baseline PSA level in veterans with consecutive tests, with the greatest risk of metastatic PC occurring in patients with longer intervals between VA tests and initial PSA values greater than 4.00 ng/mL. However, because of the modest magnitude of the association of PSA screening interval with metastasis, and sensitivity analyses showing potential impact of selection bias on this result, this association should be interpreted with caution.

Disparities in metastatic PC associated with screening factors are often magnified among veterans, particularly among non-Hispanic Black veterans and veterans with service-related exposures, such as Agent Orange, which predicts higher PC risk in this population.^21,48,49 Polygenic risk scores could facilitate tailoring of screening to genetic risk, inform shared decision-making conversations, and inform appropriately delivered magnetic resonance imaging–based triage and biopsy alongside PSA testing.^49,50,51,52 Black men and individuals residing in more deprived neighborhoods are at greater risk of metastatic PC in non-VA health care settings.^27,53,54 Because VA guidelines are adopted centrally and applied throughout the health system, changes in screening practice may be more consistently applied and therefore lead to greater impacts. For example, there are ongoing efforts to assess the effectiveness of polygenic risk score–based screening for PC based on a model derived in the Million Veterans program.⁵⁵

Population-based screening may introduce harms from overdiagnosis of indolent tumors, leading to unnecessary treatment. Overdiagnosis in epidemiologic studies has been assessed by comparing rates of cancer before and after screening became widespread, or by assessing the incidence of low-grade disease.⁵⁶ Adverse effects of resulting radiation treatment or surgery include urinary incontinence, erectile dysfunction, and bowel toxic effects.⁵⁷ There may be opportunities to reduce overdiagnosis from repeated PSA tests through use of complementary diagnostics, such as multiparametric magnetic resonance imaging, PSA derivatives, and other clinical composite variables or biomarkers.^52,58,59 However, with longer follow-up of 20 years or more, PSA screening may offer more favorable benefit-harm tradeoffs.⁵ Our findings can therefore inform efforts to model impacts of different screening strategies using more detailed tumor characteristics and assess harm-benefit tradeoffs of these newer technologies optimized based on age and PSA value in relation to treatment adverse effects and survival.^60,61

Limitations

This study has limitations. Restricting to men with PNB could have also introduced selection bias if more aggressive testing by clinicians and medical practitioners, as well as access to different forms of health care, was correlated with biopsy and subsequent metastatic PC. The present study design was chosen to balance the tradeoff between selection bias and misclassification of screening and metastatic PC in the full VA-MAPP population, who may have received care and staging outside of the VA. Sensitivity analyses using IPCW and bias factor–corrected results for age at initiation and baseline PSA value suggested that selection bias was insufficient to explain our main findings. Our sample may have overrepresented veterans who were more engaged in VA care, such as those with higher service-connected disability ratings and urban or Black patients, who may undergo biopsy with greater frequency at VA,⁶² which could limit the generalizability of our findings to the broader US population. We did not assess prostate cancer–specific mortality as an end point, which is important for informing ongoing debates to balance harms of overdiagnosis against benefits of PSA screening. Study strengths included a large and diverse cohort of veterans over an extended follow-up period, utilizing administrative data from a nationally integrated US health care system.

Conclusions

In this cohort study of male veterans, we provided a contemporary assessment of associations between age at first PSA, PSA screening interval, and PSA value at first test in a large US population of men at risk of PC. Combinations of earlier age at screening initiation and lower baseline PSA values may reduce risks of metastatic PC in high-risk men, with less robust evidence for changing PSA testing intervals. Our findings support continued efforts to focus screening in high-risk men, and to tailor strategies based on age and PSA value when starting screening.

Supplement 1.

eFigure 1. Selection of prostate needle biopsy cohort analytic sample from VA-MAPP database

eMethods. Sensitivity analysis for selection bias

eTable 1. Prostate-specific antigen screening patterns and outcomes by NCCN and USPSTF screening guidelines (among PNB cohort, N = 103,067)

eTable 2. Adjusted hazard ratios for associations of age at first PSA, first PSA value, and PSA testing interval with metastatic prostate cancer

eTable 3. Adjusted hazard ratios for race-stratified associations of age at first PSA, first PSA value, and PSA testing interval with metastatic prostate cancer

eTable 4. Relative rates for interaction between first PSA value and age at first PSA

eTable 5. Relative rates for interaction between age at first PSA and PSA testing interval

eTable 6. Relative rates for interaction between first PSA value and PSA testing interval

eFigure 2. Relative rates for interactions between first PSA value, age at first PSA, and PSA testing interval in Non-Hispanic Black men receiving care in the Veterans Health Administration

eTable 7. Sensitivity analysis comparison of unweighted and inverse probability of censoring weighted Cox model to adjust for selection bias

eFigure 3. Sensitivity analysis for selection bias arising from unmeasured family history and conditioning on biopsy using bias factors

jamanetwopen-e2621741-s001.pdf^{(562.7KB, pdf)}

Supplement 2.

Data sharing statement

jamanetwopen-e2621741-s002.pdf^{(14.7KB, pdf)}

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