Circulating androgen receptor combined with 18F-fluorocholine PET/CT metabolic activity and outcome to androgen receptor signalling-directed therapies in castration-resistant prostate cancer

V Conteduca,P Caroli,G Schepisi,S Salvi,F Matteucci,S Testoni,G Gurioli,E Scarpi,C Menna,V Casadio,C Lolli,U De Giorgi,S L Burgio,G Paganelli

doi:10.1038/s41598-017-15928-y

Abstract

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.

Highlights

Prostate cancer (PC) is the most common cancer type for the estimated new cancer cases and the third tumour for the estimated deaths among men in 2015 worldwide[1]
We evaluated the choline uptake in metastatic castration resistant PC (CRPC) (mCRPC) patients measuring the total lesion activity (TLA) and metabolic tumour volume (MTV) which have shown much greater prognostic value than conventional positron emission tomography (PET) measurements such as the maximum standardized uptake value (SUVmax)[25,26]
We aimed to identify an association between circulating androgen receptor (AR) copy number (CN) and choline uptake to better understand the complex AR signalling axis and alternative pathways of the resistance mechanisms, such as choline metabolism, and to improve multiplex biomarker strategy in mCRPC patients

Summary

Introduction

Prostate cancer (PC) is the most common cancer type for the estimated new cancer cases and the third tumour for the estimated deaths among men in 2015 worldwide[1]. Among the indirect mechanisms responsible of increased AR protein expression, there is the up-regulation of choline kinase alpha (CHKA). It binds directly the AR ligand-binding domain (LBD), fulfilling different roles involved in the tumour growth and disease progression[8,9]. Recent genome wide approaches[11] suggested this dual interaction between CHKA and AR in cytoplasm, promoting AR overexpression and increased signalling, which in turn may provide more CHKA production. Some studies have documented the overexpression of CHKA protein in multiple cancer types including breast, colorectal, endometrial, lung, ovarian, and prostate, providing an increased uptake of choline[12,13,14]. Recent studies, investigating the early response assessment on FCH-PET/TC imaging[21,22] in metastatic CRPC (mCRPC) patients treated with novel anti-AR therapies, such as abiraterone[23] and enzalutamide[24], have strengthened the hypothesis of a relationship between choline uptake and AR

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