Association of androgen receptor gene expression signature and ARV7with clinical outcome in metastatic hormone-sensitive prostate cancer.
Authors: Garcia de Herreros Marta , Jiménez Natalia , Reig Oscar , Aversa Caterina , Ferrer-Mileo Laura , Bueno Mireia , García-Esteve Samuel , Fernandez-Mañas Laia , Rodriguez-Carunchio Leonardo , Trias Isabel , Font Pous Albert , Rodriguez-Vida Alejo , Cros Sara , Figols Mariona , Climent Duran Miguel A. , Marin Mercedes , Chirivella Isabel , Mellado-Gonzalez Begoña 
Published: June 2024

5090

Background: The androgen receptor (AR) plays a predominant role in prostate cancer (PC) biology and it represents a cornerstone of PC treatment strategies, including androgen deprivation therapy (ADT) and androgen receptor selective inhibitors (ARSI). However, the androgen receptor splice variant 7 ( ARV7) has emerged as a biomarker for resistance to AR target therapies. In this study we aim to investigate a signature of AR-regulated genes and the ARV7 in a cohort of metastatic hormone-sensitive prostate cancer (mHSPC) patients (pts). Methods: This is a multicenter retrospective biomarker study performed in mHSPC pts treated with ADT, ADT+Docetaxel (D) and ADT+ARSI (abiraterone/enzalutamide). A customized panel of 184 genes was tested in from FFPE tumor samples by nCounter platform (Nanostring Technologies). AR signature was comprised of 31 AR-related genes. Single-sample GSEA (ssGSEA) was used to calculate a gene-set enrichment score per patient. RNA expression levels were correlated with castration resistance-free survival (CRPC-FS) (primary endpoint) and overall survival (OS) by Kaplan Meier and multivariate Cox modeling. Analyses were performed with R software (v.4.3.2). Results: A total of 326 pts were included: 93 treated with ADT, 125 with ADT+D, and 108 with ADT+ARSI. Baseline PSA was 44 ng/ml (range 0.2–7448), Gleason score was ≥ 8 in 72.7% of pts, 15.3% had visceral metastasis, 64.6% had high volume disease and 77.9% were de novo stage IV disease. Median follow-up was 39.5 months (m) (95%CI 4.4–223.5). Median time to CRPC was 21.7 m (95%CI 19.4–25.9) and median OS 49.1 m (95%CI 43.9–57.1). Among the 326 pts, 108 (33.1%) were classified as high AR signature, while 81 of them (24.8%) were considered high ARV7. High AR signature expression levels were associated with less frequency of visceral metastasis ( p=0.01) and high ARV7expression correlated with higher Gleason scores ( p=0.009). High AR signature expression independently correlated with longer CRPC-FS (33 vs 19.3 m; HR 0.7, p=0.011). Considering AR signature individual genes as continuous variables in the multivariate analysis, the high expression of four genes was independently associated with longer CPRC-FS: KLK3 (HR 0.9, p=0.024), KLK2 (HR 0.9, p=0.027), CD200 (HR 0.8, p=0.028), and GNMT (HR 0.9, p=0.013). Besides, the high expression of these genes was independently associated with longer OS: KLK3 (HR 0.8, p<0.001), KLK2(HR 0.9, p=0.014), CD200(HR 0.8, p=0.014), ACSL3(HR 0.8, p=0.015), and PTGER4 (HR 0.8, p=0.04). Focusing in the ARV7gene, a high expression of ARV7 was independently associated with shorter OS (43.2 vs 52.2 m; HR 1.4, p=0.028). Conclusions: High expression of the AR signature correlates with a better prognosis in mHSPC pts, while high expression of ARV7is associated with adverse clinical outcomes. This may be useful as a potential biomarker to personalize treatment strategies.