Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors
Marta García de Herreros, Natàlia Jiménez, Leonardo Rodríguez‐Carunchio, Eva Lillo, Mercedes Marín‐Aguilera, Laura Ferrer‐Mileo, Caterina Aversa, Samuel García-Esteve, Joan Padrosa, Isabel Trias, Laia Fernández-Mañas, Albert Font, Isabel Chirivella, Mariona Figols, Miguel Ángel Climent, Aleix Prat, Òscar Reig, Begoña Mellado
Abstract
Alterations in the tumor suppressor genes (TSGs) RB1 , PTEN , and TP53 are associated with treatment resistance, worse survival, and aggressive variants of prostate cancer (AVPC). We previously developed and validated a signature reflecting low TSG expression (TSG low ) that was associated with poor outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) ± docetaxel. The aim of this multicenter retrospective study was to validate the TSG low signature in patients with mHSPC treated with ADT and an androgen receptor pathway inhibitor (ARPI) and to explore clinical characteristics at progression according to TSG status. TSG mRNA expression in formalin-fixed, paraffin-embedded samples was assessed via nCounter. Correlation of expression levels with castration-resistant prostate cancer–free survival (CRPC-FS; primary endpoint) and overall survival (OS) was investigated via Kaplan-Meier and multivariate Cox analyses. Of the 137 patients included, 77.4% had de novo stage IV cancer and 44.5% had high-risk disease. TSG low (16.8%) was correlated with visceral metastases ( p = 0.013), high-risk disease ( p = 0.038), higher Gleason score ( p = 0.026), shorter CRPC-FS (hazard ratio 1.9; p = 0.046) and higher AVPC frequency ( p = 0.01). Our results confirm that a TSG low signature is an adverse prognostic factor and is associated with AVPC development in patients with mHSPC treated with ADT + ARPI. Further prospective validation is needed to define specific therapeutic strategies for these patients. We looked at outcomes for patients with metastatic hormone-sensitive prostate cancer treated with hormone therapies. We found that patients with low expression of two out of three tumor suppressor genes ( TP53 , RB1 , PTEN ) had worse clinical outcomes and had aggressive variants of prostate cancer. Measuring the expression of these genes in early-stage prostate cancer could help in finding better treatments for these patients.