Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel

SIMPLE SUMMARY: The combination of androgen deprivation therapy (ADT) with docetaxel (DX) or/and with novel anti-androgen receptor therapies have become standards for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, metastatic PC remains incurable, and biomarkers for individual treatment selection are needed. We propose here that molecular alterations associated with castration resistance may predict the clinical evolution of mHSPC patients. To test this hypothesis, we designed a custom expression panel of 184 genes and tested it in tumor biopsies from patients with mHSPC treated with ADT+DX. We found that AR and ESR signatures and ESR2 gene expression correlate with a good prognosis. The lower expression of TSG (PTEN, TP53 and RB1) signature, as well as high ARV7 and low RB1 gene expression, were associated with adverse clinical outcomes. The usefulness of transcriptomic analysis of such signatures as a strategy for personalized treatment selection should be further explored. ABSTRACT: (1) Background: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3–0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4–0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2–0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1–3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1–2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2–2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2–1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1–3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX.