Molecular and clinical characterization of KLK2 mRNA expression in prostate cancer (PC).

5050 Background: KLK2 is an androgen-regulated gene that plays a critical role in PC biology. Given the development of KLK-2 targeted therapies, we sought to characterize the molecular and clinical features associated with KLK2 mRNA expression in PC. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed on PC specimens (n=6, 978) at Caris Life Sciences. KLK2-High/Low expression was defined as >75^th /<25^th quartile RNA transcripts per million (TPM). Castrate resistant PC (CRPC) and hormone sensitive PC (HSPC) were defined based on androgen deprivation therapy (ADT) duration prior to tissue collection: HSPC < 3 and CRPC ≥ 3 months from ADT start. Overall survival (OS) was defined as the time of collection or first androgen receptor pathway inhibitor (ARPI) to death/last follow-up. Results: Specimens were derived from primary prostate (n=4, 464, 64.0%), lymph nodes (n=828, 11.9%) or other metastatic sites (n=1, 686, 24.2%). Higher KLK2 was observed in tumors from Black vs. White patients (8.88 vs. 8.75 log₂[TPM+1], p<0.001). KLK2 was enriched in adenocarcinoma vs. mixed vs. NEPC (8.79 vs. 7.58 vs. 0.33 log₂[TPM+1], p<0.001). Relative to primary tumors (8.93 log₂[TPM+1]), KLK2 varied by metastatic site, with lowest expression in GI (7.46 Log₂[TPM+1], p<0.001), liver (7.88 log₂[TPM+1], p<0.001), and CNS (8.25 log₂[TPM+1], p<0.001). In primary tumors, high KLK2 associated positively with SPOP and negatively with PI3K/PTEN, TP53, and RB1 alterations. Across primary, lymph node, and distant metastatic tumors, high KLK2 associated positively with AR signaling and negatively with NEPC signaling (all p<0.001). KLK2 strongly correlated with KLK3 (PSA) expression (R=0.87). KLK2 expression was higher in HSPC (n=1504) vs. CRPC (n=4519) tumors (1.78 Log₂[TPM+1], p<0.001). Among HSPC, KLK2-high tumors had decreased TP53, RB1, AKT1, BRCA1 and increased SPOP, CTNNB1, PTEN, BRCA2 mutations. CRPC tumors with high KLK2 had decreased RB1, TP53, PIK3CA and increased RAD54L and ATM mutations compared to low tumors. High KLK2 was associated with improved OS from collection time (median 69.7 vs. 35.9 months, p<0.001) and first ARPI initiation (median 48.9 vs. 39.5 months, p<0.001). KLK2-high HSPC and CRPC tumors had improved OS compared to low tumors (median 82.0 HSPC KLK2-high vs. 54.3 HSPC KLK2-low vs. 23.7 CRPC KLK2-high vs. 16.3 CRPC KLK2-low months, q<0.01). The combination of KLK2-high/AR-high was associated with increased OS compared to KLK2-high/AR-low, KLK2-low/AR-high, and KLK2-low/AR-low tumors (median 70.8 vs. 48.8 vs. 43.5 vs. 20.8 months, respectively, p<0.001). Conclusions: This large-scale clinic-genomic analysis reveals distinct patterns of KLK2 expression in PC. The correlation between high KLK2 expression, favorable genomic features, and improved OS supports its potential utility as a prognostic biomarker and may inform selection for KLK2-directed therapy.