Positron Emission Tomography/Computed Tomography-Based Assessments of Androgen Receptor Expression and Glycolytic Activity as a Prognostic Biomarker forMetastatic Castration-Resistant Prostate Cancer

IMPORTANCE Androgen receptor-signaling inhibitor (ARSi) drugs prolong life in metastatic castration-resistant prostate cancer (mCRPC), but such tumors eventually become resistant and progress. Comprehensive positron emission tomography/computed tomography (PET/CT) imaging using fluoro-2-D-deoxyglucose F 18 ([F-18]-FDG) for glycolysis (Glyc) and fluorodihydrotestosterone F 18 ([F-18]-FDHT) for androgen receptor (AR) expression determine heterogeneity of imaging phenotypes, which may be useful in distinguishing patients who will benefit from ARSi drugs from those who need alternative treatments. OBJECTIVE To test the hypothesis that PET/CT-based assessments of AR expression and glycolytic activity would reveal heterogeneity affecting prognosis. DESIGN, SETTING, AND PARTICIPANTS Between April 6, 2007, and October 4, 2012, patients with mCRPC underwent imaging with both [F-18]-FDG and [F-18]-FDHT at Memorial Sloan Kettering Cancer Center. The patients were naive to ARSi treatment with enzalutamide or abiraterone acetate and were referred during documented disease progression. Image-directed biopsy determined the presence or absence of prostate cancer at positive imaging sites. INTERVENTIONS PET/CT imaging was performed with [F-18]-FDHT and [F-18]-FDG; select individual lesions were biopsied to correlate imaging phenotype with histologic findings. MAIN OUTCOMES AND MEASURES All metabolically active lesions were interpreted as [F-18]-FDHT-positive (AR(1)) or [(18) F]-FDHT-negative (AR(0)) and as [F-18]-FDG-positive (Glyc(1)) or [F-18]-FDG-negative (Glyc(0)). Correlation was performed with overall survival for both individual lesion imaging phenotype as well as patient-specific imaging phenotype. RESULTS The mean (SD) age of the 133 patients was 68 (8.6) years. Imaging phenotypes of 2405 PET/CT-positive lesions (median, 12.0 per patient) included 1713 (71.2%) AR(1)Glyc(1), 386 (16.0%) AR(1)Glyc(0), and 306 (12.7%) AR(0)Glyc(1). On multivariate analysis, each phenotype had an independent negative impact effect on survival, most pronounced for AR(0)Glyc(1) lesions (hazard ratio [HR], 1.11; 95% CI, 1.05-1.16; P<.001), followed by AR(1)Glyc(1) lesions (HR, 1.05; 95% CI, 1.03-1.06; P<.001) and AR(1)Glyc(0) lesions (HR, 1.03; 95% CI, 1.00-1.05; P=.048). When sorted by lesion type, 4 patient-specific groups emerged: (1) concordant, with all AR(1)Glyc(1) (34 patients [25.6%]); (2) AR predominant, with AR(1)Glyc(1) and varying numbers of AR(1)Glyc(0) (33 [24.8%]); (3) Glyc predominant, with AR(1)Glyc(1) and varying numbers of AR(0)Glyc(1) (40 [30.1%]); and (4) mixed, with AR(1)Glyc(1) plus a mixture of varying numbers of AR(1)Glyc(0) and AR(0)Glyc(1) (26 [19.5%]). CONCLUSIONS AND RELEVANCE Heterogeneity of PET/CT imaging phenotype has clinical relevance on a lesion and individual patient level. With regard to mCRPC lesions, most express ARs, consistent with initial benefit of ARSi drugs. On a patient basis, 49%(groups 3 and 4) had at least 1 AR(0)Glyc(1) lesion-the imaging phenotype with the most negative effect on survival, possibly due to ARSi resistance.