Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors
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 (TSGlow) that was associated with poor out...
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Elsevier
2024-12-01
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| Series: | European Urology Open Science |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666168324010954 |
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| author | Marta Garcia de Herreros Natalia 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 |
| author_facet | Marta Garcia de Herreros Natalia 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 |
| author_sort | Marta Garcia de Herreros |
| collection | DOAJ |
| description | 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 (TSGlow) 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 TSGlow 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. TSGlow (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 TSGlow 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. Patient summary: 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. |
| format | Article |
| id | doaj-art-bbfdf6631a7e44cc9c6c254191b07fed |
| institution | DOAJ |
| issn | 2666-1683 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| series | European Urology Open Science |
| spelling | doaj-art-bbfdf6631a7e44cc9c6c254191b07fed2025-08-20T02:51:46ZengElsevierEuropean Urology Open Science2666-16832024-12-0170869010.1016/j.euros.2024.10.008Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway InhibitorsMarta Garcia de Herreros0Natalia Jiménez1Leonardo Rodríguez-Carunchio2Eva Lillo3Mercedes Marín-Aguilera4Laura Ferrer-Mileo5Caterina Aversa6Samuel García-Esteve7Joan Padrosa8Isabel Trias9Laia Fernández-Mañas10Albert Font11Isabel Chirivella12Mariona Figols13Miguel Ángel Climent14Aleix Prat15Òscar Reig16Begoña Mellado17Translational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Uro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainUro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Pathology, Hospital Clínic, Barcelona, SpainMedical Oncology Department, Hospital Clínic, Barcelona, Spain; Uro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Uro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Uro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, SpainUro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Pathology, Hospital Clínic, Barcelona, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Uro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, SpainMedical Oncology Department, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Badalona, SpainDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria (INCLIVA), University of Valencia, Valencia, SpainMedical Oncology Department, Fundació Althaia, Xarxa Assistencial Universitària de Manresa, Manresa, SpainMedical Oncology Service, Instituto Valenciano de Oncología (IVO), Valencia, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, SpainTranslational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Uro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain; Corresponding authors. Medical Oncology Department, Hospital Clínic of Barcelona Villarroel 170, 08036 Barcelona, Spain. Tel. +34 93 227 5400.Translational Genomics and Targeted Therapeutics in Solid Tumours Lab, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Uro-Oncology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain; Corresponding authors. Medical Oncology Department, Hospital Clínic of Barcelona Villarroel 170, 08036 Barcelona, Spain. Tel. +34 93 227 5400.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 (TSGlow) 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 TSGlow 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. TSGlow (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 TSGlow 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. Patient summary: 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.http://www.sciencedirect.com/science/article/pii/S2666168324010954Hormone-sensitive prostate cancerTumor suppressor genesBiomarkersAndrogen deprivation therapyAndrogen receptor pathway inhibitorsAggressive-variant prostate cancer |
| spellingShingle | Marta Garcia de Herreros Natalia 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 Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors European Urology Open Science Hormone-sensitive prostate cancer Tumor suppressor genes Biomarkers Androgen deprivation therapy Androgen receptor pathway inhibitors Aggressive-variant prostate cancer |
| title | Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors |
| title_full | Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors |
| title_fullStr | Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors |
| title_full_unstemmed | Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors |
| title_short | Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors |
| title_sort | prognostic expression signature of rb1 pten and tp53 genes in patients with metastatic hormone sensitive prostate cancer treated with androgen receptor pathway inhibitors |
| topic | Hormone-sensitive prostate cancer Tumor suppressor genes Biomarkers Androgen deprivation therapy Androgen receptor pathway inhibitors Aggressive-variant prostate cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2666168324010954 |
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