Loss of ANPEP expression may promote the development of aggressive prostate cancer.

Abstract

e17052 Background: In the era of precision oncology, the development of reliable prognostic biomarkers is essential to facilitate the detection of aggressive prostate cancer (PCa), especially among African Americans (AA), who endure the disproportionate burden of the disease. Our previous work indicated a significantly higher Aminopeptidase N (ANPEP) expression among AA compared to European American men (EA). While ANPEP plays regulatory and/or modulatory functions in many immune and metabolic pathological conditions, its prognostic role in aggressive prostate tumors remains uninvestigated. Methods: We first evaluated ANPEP expression in prostate tumors and adjacent normal tissue. We then measured the association between changes in normalized ANPEP expression and disease progression by examining correlations with certain clinicopathologic features and genomic signature-defined subgroups from the GRID database. Median (M) ANPEP expression values were calculated, and standardized mean differences (SMDs) were used to assess significant changes in expression levels. SMDs were generally interpreted as small (0.2), medium (0.5), or large (0.8). Finally, we explored the prognostic significance of changes in ANPEP expression by analyzing endpoints such as overall survival (OS), distant metastases (DM), and castration-resistant prostate cancer (CRPC). Results: Normal prostate tissue had higher ANPEP expression compared to prostate tumors (M= 5.64 vs. 4.78, p = <0.001). Both physician-reported and genomic-derived race signatures showed high ANPEP expression in AA (M= 1.30 vs. 0.40, SMD = 0.59) compared to other race groups. Aggressive PCa, as indicated by a higher clinical stage [T1 to T4 (M= 1.21 vs. 0.45, SMD = 0.35)], elevated NCCN risk [low to very high (M= 1.35 vs. 0.46, SMD = 0.29)], and higher pathological stage [pT2 to pT4 (M= 0.86 vs. 0.38, SMD = 0.30)] were associated with an overall decrease in ANPEP expression. Additionally, an increase in adverse pathological features [0 to 3 (M= 0.70 vs. 0.11, SMD = 0.38)] showed a continuous decline in ANPEP expression. Genomic markers of aggressive disease, such as high Decipher score [low vs. high (M= 1.53 vs. 0.59, SMD = 0.60)], low AR [high vs. low (M= 1.26 vs. 0.51, SMD = 0.95)], ERG expression [negative vs. positive (M= 1.11 vs. 0.11, SMD = 1.11)], and PTEN loss [no vs. yes (M= 1.26 vs. 0.22, SMD = 1.04)] showed an overall decrease in ANPEP expression. Lastly, genomic information derived from patients on a number of clinical trials showed that a decrease in ANPEP expression of 0.5 was associated with significant detriment in PCa-specific outcomes, including CRPC [aHR=1.17 (95% CI = 1.04 – 1.31, p =0.007)], DM [aHR=2.27 (95% CI = 1.54 – 3.33, p =<0.001)], and OS [aHR=1.21 (95% CI = 1.06 – 1.39, p =0.004)]. Conclusions: Our study is the first to establish ANPEP as a prognostic biomarker for aggressive PCa using both large prospective genomic databases and clinical trial bio-specimen data.