Androgen pathway gene expression and response to hormonal therapy in prostate cancer (SWOG S1216).

Abstract

e17109 Background: With significant advancements in treatments over the past decade, there is a growing need to identify biomarkers that facilitate personalized therapy for prostate cancer. Tumor gene expression profiling provides a detailed understanding of the molecular features of prostate cancer, offering valuable insights into its clinical progression and treatment response. Expression of androgen metabolism genes in primary prostate tumors may predict subsequent response to androgen deprivation therapy. Methods: Participants were men with metastatic castration-sensitive prostate cancer (mCSPC) enrolled in SWOG S1216, a phase III randomized multicenter clinical trial of ADT with a CYP17,20 lyase inhibitor (TAK-700) or an androgen receptor inhibitor (bicalutamide). Tumor blocks from prostatectomies were obtained and sufficient good-quality RNA was obtained from 29 subjects. Gene expression was assayed with the NEBNext Ultra II Directional RNA Library Kit and sequenced on Ilumina NoveSeq with average of 100M paired-end reads. Expression levels normalized as TPM (transcripts per million), generated with the Salmon transcript quantification tool, were obtained for 27 androgen pathway genes. Subjects were classified according to 7-month PSA response (complete response (CR) ≤ 0.2 vs. >0.2 ng/ml) and length of progression free survival (PFS) (≤ 2000 vs. >2000 days). Two subjects with less than 2000 days of follow-up and no progression were excluded from analysis of PFS. Associations of expression levels with 7-month PSA response and PFS were analyzed using negative Binomial regression as implemented in DESeq2. Results: Among those with PSA CR, two androgen pathway genes, HSD17B2 (log 2 fold-change=-2.2; p=0.01) and HSD17B3 (log 2 fold-change=-1.0; p=0.05), were under-expressed. HSD3B2 was overexpressed among those with PSA CR, but did not attain statistical significance (log 2 fold-change=2.6; p=0.07). Among those with short PFS, AKR1C2 (log 2 fold-change=-2.2; p=0.01) was under-expressed and GNRH2 (log 2 fold-change=1.2; p=0.03) was over-expressed compared to those with long PFS. Conclusions: Expression of androgen metabolism genes in primary prostate tumors is associated with response to androgen deprivation therapy and may guide treatment selection in mCSPC. Clinical trial information: NCT01809691 .