RESUMO
The association between choline uptake and androgen receptor (AR) expression is suggested by the upregulation of choline kinase-alpha in prostate cancer. Recently, detection of AR aberration in cell-free DNA as well as early 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) were associated with outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone and enzalutamide. We aimed to make a direct comparison between circulating AR copy number (CN) and choline uptake at FCH-PET/CT. We analysed 80 mCRPC patients progressing after docetaxel treated with abiraterone (n = 47) or enzalutamide (n = 33). We analysed AR CN from plasma samples using digital PCR and Taqman CN assays and total lesion activity (TLA) and metabolic tumor volume (MTV) on FCH-PET/CT at baseline. A meaningful correlation was showed among AR gain and TLA/MTV compared to AR non-gained cases (P = 0.001 and P = 0.004, respectively), independently from type of treatment. Multivariate analysis revealed that AR CN and only TLA were associated with both shorter PFS (P < 0.0009 and P = 0.026, respectively) and OS (P < 0.031 and P = 0.039, respectively). AR gain appeared significantly correlated with choline uptake represented mainly by TLA. Further prospective studies are warranted to better address this pathway of AR-signalling and to identify multiplex biomarker strategies including plasma AR and FCH-PET/CT in mCRPC patients.
Assuntos
Adenocarcinoma/tratamento farmacológico , Cloro/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/sangue , Receptores Androgênicos/genética , Adenocarcinoma/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Biomarcadores Tumorais/metabolismo , Colina/análogos & derivados , Colina/metabolismo , Docetaxel/uso terapêutico , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias de Próstata Resistentes à Castração/sangue , Transdução de SinaisRESUMO
BACKGROUND: This study aimed to investigate copy number variations (CNVs) of CYP17A1 and androgen receptor (AR) genes in serum cell-free DNA collected before starting abiraterone in 53 consecutive patients with castration-resistant prostate cancer (CRPC). METHODS: Serum DNA was isolated and CNVs were analysed for AR and CYP17A1 genes using Taqman copy number assays. The association between CNVs and progression-free/overall survival (PFS/OS) was evaluated by the Kaplan-Meier method and log-rank test. RESULTS: Median PFS of patients with AR gene gain was 2.8 vs 9.5 months of non-gained cases (P < 0.0001). Patients with CYP17A1 gene gain had a median PFS of 2.8 months vs 9.2 months in the non-gained patients (P = 0.0014). A lower OS was reported in both cases (AR: P < 0.0001; CYP17A1: P = 0.0085). Multivariate analysis revealed that PSA decline ⩾ 50%, AR and CYP17A1 CNVs were associated with shorter PFS (P < 0.0001, P = 0.0004 and P = 0.0450, respectively), while performance status, PSA decline ⩾ 50%, AR CNV and DNA concentration were associated with OS (P = 0.0021, P = 0.0014, P = 0.0026 and P = 0.0129, respectively). CONCLUSIONS: CNVs of AR and CYP17A1 genes would appear to be associated with outcome of CRPC patients treated with abiraterone.