Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2025 Jun 28;26(13):6244.
doi: 10.3390/ijms26136244.

Clinical and Transcriptomic Characterization of Metastatic Hormone-Sensitive Prostate Cancer Patients with Low PTEN Expression

Marta Garcia de Herreros  1   2   3   4 , Natalia Jiménez  1 , Joan Padrosa  1   2   4   5 , Caterina Aversa  1   2   3 , Laura Ferrer-Mileo  1   2   3   4 , Samuel García-Esteve  1   4 , Leonardo Rodríguez-Carunchio  3   6 , Isabel Trias  3   6 , Laia Fernández-Mañas  1   2   3 , Mercedes Marín-Aguilera  1 , Mariana Altamirano  2 , Manuel Mazariegos  1   2   3 , Albert Font  7 , Alejo Rodriguez-Vida  8 , Miguel Ángel Climent  9 , Sara Cros  10 , Isabel Chirivella  11 , Mariona Figols  12 , Núria Sala-González  13 , Vicenç Ruiz de Porras  14 , Juan Carlos Pardo  7 , Aleix Prat  1   2   4 , Òscar Reig  1   2   3   4 , Begoña Mellado  1   2   3   4
Affiliations
Multicenter Study

Clinical and Transcriptomic Characterization of Metastatic Hormone-Sensitive Prostate Cancer Patients with Low PTEN Expression

Marta Garcia de Herreros et al. Int J Mol Sci. .

Abstract

Alterations in the PTEN tumor suppressor gene are common in prostate cancer. They have been associated with a more aggressive disease and poor outcomes and potential benefit of targeted therapies. The purpose of this work is to study the clinical and transcriptional landscapes associated to low PTEN mRNA expression in metastatic hormone-sensitive prostate cancer (mHSPC) patients. A multicenter biomarker ambispective study was performed in mHSPC patients. PTEN mRNA expression was assessed by nCounter in formalin-fixed paraffin-embedded tumor samples. PTENlow status was defined by a previously validated cut-off and was correlated with castration-resistant prostate cancer (CRPC)-free survival (CRPC-FS) (primary endpoint) and overall survival (OS). RNA-Seq was performed to molecularly characterize PTENlow vs. PTENwt tumors. A total of 380 patients were included, 350 eligible. PTENlow was observed in 28.2% of patients and was independently associated with shorter CRPC-FS (HR 1.6, 95% CI 1.2-2.1, p = 0.002) and OS (HR 1.5, 95% CI 1.1-2, p = 0.014). PTENlow tumors showed overexpression of neuroendocrine, cell cycle, and DNA repair gene signatures, reduced expression of the androgen receptor pathway, and a distinct immune microenvironment. Using microarray data from the CHAARTED trial, we developed a PTEN-low related signature, independently associated with CRPC-FS (HR 1.5, 95% CI 1-2.3, p = 0.036) and OS (HR 1.9, C1 1.2-2.9, p = 0.005), and identified targets for potential therapies in PTEN-altered tumors. We conclude that PTENlow correlates with an aggressive clinical outcome in mHSPC patients and is associated with a unique transcriptional profile. These findings further support the investigation of novel therapeutic strategies for patients with PTEN alterations.

Keywords: CHAARTED trial; PTEN; androgen deprivation therapy; androgen receptor signaling inhibitors; biomarkers; docetaxel; hormone-sensitive prostate cancer.

PubMed Disclaimer

Conflict of interest statement

The authors have provided the following conflicts to disclose (which may not be related to the subject matter of this manuscript): M.G.d.H.: speaker honoraria from Ipsen and travel and accommodation expenses from Novartis, Pfizer, and Bayer. C.A.: speaker honoraria from AstraZeneca, Pfizer, BMS, and Ipsen; travel accommodation from Pfizer, Ipsen, and Janssen. L.F.-M. (Laura Ferrer-Mileo): speaker honoraria from Pfizer, BMS, Ipsen, and Janssen; travel accommodation expenses from Pfizer and Janssen; research funding from Roche; advisory role from Pfizer. L.F.-M. (Laia Fernández-Mañas): speaker’s Bureau from Ipsen; financial relationships with commercial interests from Janssen, Ipsen, MSD, and Merck. A.F.: research funding from AstraZeneca; consulting or advisory role for Janssen, Astellas, and Bayer; travel and accommodation expenses from Janssen. A.R.-V.: research funding from Takeda, MSD, and Pfizer; consulting or advisory role for Astellas, Bayer, BMS, MSD, Janssen, Roche, Pfizer, and Clovis; honoraria or travel expenses from Pfizer, MSD, Astellas, BMS, Janssen, AstraZeneca, Roche, Bayer, and Sanofi Aventis. M.Á.C.: consulting or advisory role for BMS, MSD, Bayer, EUNSA, Pfizer, Roche, Janssen, Pierre Fabre, and Ipsen; travel and accommodation expenses from Janssen, Astellas, Roche, Ipsen, and MSD. S.C.: research funding from Pfizer and Janssen; consulting or advisory role for GSK; and speaker’s bureau for GSK, BMS, and Merck. I.C.: advisory boards for Pfizer, EISAI, and BMS. MF: speaker’s bureau for Pfizer, Ipsen, and Astellas; travel and accommodation expenses from Merck. NSG: advisory board for Pfizer, Bristol Myers Squibb, and Roche; speaker’s bureau for Ipsen and Astellas Pharma. A.P.: advisory and consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc, and Lilly; lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, Daiichi Sankyo, and Nanostring technologies; institutional financial interests from Boehringer, Novartis, Roche, Nanostring technologies, Sysmex Europe GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas, and Pfizer; leadership role in Reveal Genomics, SL; a patent PCT/EP2016/080056. Ò.R.: consulting or advisory role for BMS, EISAI, and Ipsen; travel and accommodation expenses from Ipsen and Pfizer. B.M.: research funding from Janssen, Roche, Bayer, and Pfizer; speaker’s bureau for Roche, Sanofi, Janssen, Astellas, Pfizer, Novartis, and Bristol-Myers Squibb; and travel and accommodation expenses from Janssen and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Clinical outcomes according to PTEN expression status. Kaplan–Meier curves representing CRPC-free survival (CRPC-FS) (A) and overall survival (OS) (B) according to PTEN expression (nCounter) in all patients; forest plots representing the univariate (C,D) and multivariate (E,F) analysis for CRPC-FS and OS in all patients. ADT: androgen deprivation therapy; ARSI: androgen receptor signaling inhibitors; CI: confidence interval; D: docetaxel; m: median months. Significant p values (p < 0.05) are indicated in bold.
Figure 2
Figure 2
Clinical outcomes according to PTEN expression status in the CHAARTED trial patients. Kaplan–Meier curves representing CRPC-free survival (CRPC-FS) (A) and overall survival (OS) (B) according to PTEN expression of microarray data from the CHAARTED trial; forest plots representing the multivariate analysis for CRPC-FS (C) and OS (D) in the CHAARTED trial patients; Kaplan–Meier curves representing CRPC-FS (E,G) and OS (F,H) for patients from the CHAARTED trial according to PTEN expression segregated by treatment arm. ADT: androgen deprivation therapy; CI: confidence interval; D: docetaxel; ECOG: Eastern Cooperative Oncology Group; m: median months; significant p values (p < 0.05) are indicated in bold.
Figure 3
Figure 3
Transcriptional characterization of PTENlow tumors. (A) Volcano plot of differential expressed genes (DEGs) in PTENlow tumors vs. PTENwt (FDR < 0.1); gene names in blue indicate DEGs with a significant FDR < 0.05; (B) flowchart diagram of DEGs in PTENlow tumors, according to cellular localization and available inhibitors; (C) gene set enrichment analysis (GSEA) of hallmark MSigDB pathways in the PTENlow tumors vs. PTENwt (RNA-Seq, n = 60); (D) Venn diagram of the overexpressed pathways found in this study and the CHAARTED trial microarrays (p-adj < 0.1) from GSEA of hallmark MSigDB pathways in the PTENlow tumors vs. PTENwt.
Figure 4
Figure 4
PTEN-low related signature. (A) Expression heatmap of the PTEN-low related signature genes in microarray data from the CHAARTED trial; Kaplan–Meier representing CRPC-free survival (CRPC-FS) (B) and overall survival (OS) (C) and forest plots representing the multivariate analysis according to classification by the PTEN-low signature in the training cohort of CHAARTED trial patients. ADT: androgen deprivation therapy; CI: confidence interval; D: docetaxel; m: median months; significant p values (p < 0.05) are indicated in bold.
Figure 5
Figure 5
Immune microenvironment characterization of tumors according to PTEN expression status. (A) Gene set enrichment analysis (GSEA) of immune microenvironment populations and signatures in the PTENlow tumors vs. PTENwt (RNA-Seq); (B) boxplots of the most relevant immune cell signatures expression (ssGSEA score) in PTENlow tumors vs. PTENwt (Wilcoxon-test p-value); EMT: epithelial–mesenchymal transition; GEP: T-cell inflamed gene expression profile; IGG: 14-gene immunoglobuline signature; M2 Macrophages: macrophages with M2 differentiation over M1; PRAD: prostate adenocarcinoma.
Figure 6
Figure 6
Neuroendocrine genes and clinical outcomes according to PTEN and EZH2 expression status. (A) Correlation matrix between PTEN and neuroendocrine genes from RNA-Seq expression values (correlation coefficient (r) and colored dots if p < 0.05); (B) boxplot of EZH2 expression according to PTEN status (nCounter) (Wilcoxon test p-value); (C) spine plot representing the proportion of patients according to PTEN and EZH2 expression status (nCounter) (Fisher’s exact test p-value); Kaplan–Meier curves representing CRPC-free survival (CRPC-FS) (D) and overall survival (OS) (E) of all patients according to PTENlow-EZH2high expression (nCounter); (F) forest plots representing the multivariate analysis for CRPC-FS and OS in all patients. ADT: androgen deprivation therapy; ARSI: androgen receptor signaling inhibitors; CI: confidence interval; m: median months; pts: patients. Significant p values (p < 0.05) are indicated in bold.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Sweeney C.J., Chen Y.-H., Carducci M., Liu G., Jarrard D.F., Eisenberger M., Wong Y.-N., Hahn N., Kohli M., Cooney M.M., et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N. Engl. J. Med. 2015;373:737–746. doi: 10.1056/NEJMoa1503747. - DOI - PMC - PubMed
    1. James N.D., Sydes M.R., Clarke N.W., Mason M.D., Dearnaley D.P., Spears M.R., Ritchie A.W.S., Parker C.C., Russell J.M., Attard G., et al. Addition of Docetaxel, Zoledronic Acid, or Both to First-Line Long-Term Hormone Therapy in Prostate Cancer (STAMPEDE): Survival Results from an Adaptive, Multiarm, Multistage, Platform Randomised Controlled Trial. Lancet. 2016;387:1163–1177. doi: 10.1016/S0140-6736(15)01037-5. - DOI - PMC - PubMed
    1. Fizazi K., Tran N., Fein L., Matsubara N., Rodriguez-Antolin A., Alekseev B.Y., Özgüroğlu M., Ye D., Feyerabend S., Protheroe A., et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N. Engl. J. Med. 2017;377:352–360. doi: 10.1056/NEJMoa1704174. - DOI - PubMed
    1. James N.D., De Bono J.S., Spears M.R., Clarke N.W., Mason M.D., Dearnaley D.P., Ritchie A.W.S., Amos C.L., Gilson C., Jones R.J., et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N. Engl. J. Med. 2017;377:338–351. doi: 10.1056/NEJMoa1702900. - DOI - PMC - PubMed
    1. Davis I.D., Martin A.J., Stockler M.R., Begbie S., Chi K.N., Chowdhury S., Coskinas X., Frydenberg M., Hague W.E., Horvath L.G., et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N. Engl. J. Med. 2019;381:121–131. doi: 10.1056/NEJMoa1903835. - DOI - PubMed

Publication types

LinkOut - more resources