Real-world association between the androgen receptor gene polymorphisms (CAG repeats) and aggressiveness of prostate cancer at diagnosis in the Medstar Health Network.

Abstract

e17143 Background: Clinical manifestations of prostate cancer (PC) range from indolent to aggressive disease. Androgen receptor (AR) signaling is central to PC biology, and the AR gene contains a polymorphic CAG trinucleotide repeat in exon 1. Shorter repeat lengths ( < 20) have been associated with increased PC susceptibility; however, their relationship with disease aggressiveness and clinical outcomes remains unclear. Established indicators of aggressiveness include prostate-specific antigen (PSA), clinical stage, and Gleason score (GS), while time to progression and overall survival reflect long-term prognosis. Clarifying the association between AR CAG repeat length and these outcomes may improve understanding of PC biology and risk stratification at diagnosis. Methods: Men with biopsy-proven prostate cancer were included in this retrospective analysis within the MedStar Health Network from 2016–2024. Next-generation sequencing of tissue biopsy samples was used to determine androgen receptor (AR) CAG repeat length in exon 1. Patients were categorized as having short ( < 20 repeats) or long (≥20 repeats) CAG repeat length. PSA level, Gleason score, and clinical stage at diagnosis were obtained from medical records. Ordinal logistic regression was used to assess associations between CAG repeat length ( > 20 vs ≤20) and Gleason risk category or clinical stage at diagnosis, while linear regression was used to assess the association with PSA level. Time-to-event outcomes were evaluated using Cox proportional hazards regression, and Kaplan–Meier survival curves were compared using the log-rank test. Results: A total of 128 men were included in the cohort, of whom 43 (33.6%) had short AR CAG repeats and 85 (66.4%) had long repeats. Using ordinal logistic regression, AR CAG repeat length ( > 20 vs ≤20) was not significantly associated with Gleason score (p = 0.62) or clinical stage at diagnosis (p = 0.17). Linear regression showed no significant association between PSA levels and CAG repeat category (p = 0.47). In Cox proportional hazards analyses, CAG repeat length > 20 was not associated with all-cause mortality compared with ≤20 repeats (HR, 0.91; 95% CI, 0.43-1.95; p = 0.814) or with time to disease progression (HR, 1.13; 95% CI, 0.65-1.98, p = 0.663). Conclusions: In this retrospective cohort, AR CAG repeat length was not significantly associated with established markers of tumor aggressiveness at diagnosis or with clinical outcomes, including progression and overall survival. Despite limited sample size and event rates, this study demonstrates the feasibility of incorporating somatic AR CAG repeat analysis into clinical datasets. Larger, prospective studies are warranted to better define the potential prognostic role of AR CAG repeat length and to explore its utility in risk stratification and personalized management of PC.