Positron emission tomography/computed tomography-based assessments of androgenreceptor expression and glycolytic activity as a prognostic biomarker for metastatic castration-resistant prostate cancer

IMPORTANCE: Androgen receptor-signaling inhibitor (ARSi) drugs prolong life inmetastatic 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 ([¹⁸F]-FDG) for glycolysis (Glyc) and fluorodihydrotestosterone F 18 ([¹⁸F]-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 [¹⁸F]-FDG and [¹⁸F]-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 [¹⁸F]-FDHT and [¹⁸F]-FDG; select individual lesions were biopsied to correlate imaging phenotype with histologic findings. MAIN OUTCOMES AND MEASURES: All metabolically active lesionswere interpreted as [¹⁸F]-FDHT-positive (AR₁) or [¹⁸F]-FDHT-negative (AR₀) and as [¹⁸F]-FDG-positive (Glyc₁) or [¹⁸F]-FDG-negative (Glyc₀). 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%) AR₁Glyc₁, 386 (16.0%) AR₁Glyc₀, and 306 (12.7%) AR₀Glyc₁. On multivariate analysis, each phenotype had an independent negative impact effect on survival, most pronounced for AR₀Glyc₁ lesions (hazard ratio [HR], 1.11; 95%CI, 1.05-1.16; P < .001), followed by AR₁Glyc₁ lesions (HR, 1.05; 95%CI, 1.03-1.06; P < .001) and AR1Glyc0 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 AR₁Glyc₁ (34 patients [25.6%]); (2) AR predominant, with AR₁Glyc₁ and varying numbers of AR₁Glyc₀ (33 [24.8%]); (3) Glyc predominant, with AR₁Glyc₁ and varying numbers of AR₀Glyc₁ (40 [30.1%]); and (4) mixed, with AR₁Glyc₁ plus a mixture of varying numbers of AR₁Glyc₀ and AR₀Glyc₁ (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 AR₀Glyc₁ lesion - the imaging phenotype with the most negative effect on survival, possibly due to ARSi resistance.