Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients

Abstract

Androgen deprivation therapy; Biomarkers; Prostate cancer

Terapia de privación de andrógenos; Biomarcadores; Cáncer de próstata

Teràpia de privació d'andrògens; Biomarcadors; Càncer de pròstata

Background: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). Objective: To study the clinical implications of TSG mRNA expression in mHSPC patients. Design, setting, and participants: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. Outcome measurements and statistical analysis: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. Results and limitations: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. Conclusions: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. Patient summary: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

This work was supported by Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación (PI18/714) and cofunded by the European Union. Institutional funding from CERCA Programme/Generalitat de Catalunya is gratefully acknowledged. This work was funded by a grant from Janssen-Pharmaceuticals (212082PCR4056) and an Astellas General Research Grant (ID: 71843877). Òscar Reig is awarded with a ‘‘Ayudas SEOM de Intensificación para Investigadores Jovenes’’ from the Spanish Society of Medical Oncology (SEOM). This work was developed at the Centro Esther Koplowitz and CELLEX, Barcelona, Spain.