Diversity in Androgen Receptor Action Among Treatment-naïve Prostate Cancers Is Reflected in Treatment Response Predictions and Molecular Subtypes
| Autor: | Varadha Balaji Venkadakrishnan, Christopher E. Barbieri, Jean-Noel Billaud, Salma Ben-Salem, Hannelore V. Heemers, Song Liu, Elai Davicioni, Irene Wang, Sangeeta Kumari, Qiang Hu, Felix Y. Feng, Mohammed Alshalalfa, Andrea Sboner, Deli Liu, Yang Liu, Xin Zhao, Dhirodatta Senapati |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Oncology
medicine.medical_specialty Urology medicine.medical_treatment lcsh:RC870-923 Treatment response lcsh:RC254-282 Article Basal (phylogenetics) Prostate cancer Prostate Disease stratification Internal medicine medicine Chemotherapy Castration Radiotherapy business.industry Biomarker medicine.disease lcsh:Diseases of the genitourinary system. Urology lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Androgen receptor Radiation therapy medicine.anatomical_structure Cistrome Biomarker (medicine) Hormonal therapy business |
| Zdroj: | European urology open science European Urology Open Science, Vol 22, Iss, Pp 34-44 (2020) |
| ISSN: | 2666-1683 2666-1691 |
| Popis: | Background Metastatic prostate cancer (CaP) treatments are evolving rapidly but without evidence-based biomarkers to predict responses, and to maximize remissions and survival. Objective To determine the activity of androgen receptor (AR), the target for default first-line systemic treatment, in localized treatment-naive CaP and its association with clinical risk factors, molecular markers, CaP subtypes, and predictors of treatment response. Design, setting, and participants We examined 452 bona fide AR target genes in clinical-grade expression profiles from 6532 such CaPs collected between 2013 and 2017 by US physicians ordering the Decipher RP test. Results were validated in three independent smaller cohorts (n = 73, 90, and 127) and clinical CaP AR ChIP-Seq data. Association with CaP differentiation and progression was analyzed in independent datasets. Outcome measurements and statistical analysis Unsupervised clustering of CaPs based on AR target gene expression was aligned with clinical variables, differentiation scores, molecular subtypes, and predictors of response to hormonal therapy, radiotherapy, and chemotherapy. AR target gene sets were analyzed via Gene Set Enrichment Analysis for differentiation and treatment resistance, Ingenuity Pathway Analysis for associated biology, and Cistrome for genomic AR binding site (ARBS) composition. Results and limitations Expression of eight AR target gene subsignatures gave rise to five CaP clusters, which were preferentially associated with CaP molecular subtypes, differentiation, and predictors of treatment response rather than with clinical variables. Subsignatures differed in contribution to CaP progression, luminal/basal differentiation, CaP biology, and ARBS composition. Validation in prospective trials and optimized quantitation are needed for clinical implementation. Conclusions Measurement of AR activity patterns in treatment-naive CaP may serve as a first branch of an evidence-based decision tree to optimize personalized treatment plans. Patient summary Treatment options for metastatic prostate cancer are increasing without information needed to choose the right treatment for the right patient. We found variation in the behavior of the target for the default first-line therapy before treatment, which may help optimize treatment plans. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|