Evaluating the Heterogeneity of Advanced Prostate Cancer by 18F‐DCFPyL and 18F‐FDG PET/CT in a Prospective Cohort

18F-DCFPyL (targeted PSMA) and 18F-FDG dual-tracer PET/CT combination with next-generation sequencing was applied in a prospective cohort of men with prostate cancer to identify the clinical and genetic characteristics with heterogeneous PET/CT imaging features. 104 men with documented prostate cancer underwent 18F-DCFPyL and 18F-FDG PET/CT, of which 83 underwent next-generation sequencing for detecting variation of AR, TP53, RB1, PTEN, etc. Lesions were classified into DCFPyL+FDG± lesions and DCFPyL-FDG+ lesions and analyzed for heterogeneous distribution. We divided the patients with positive lesions into DCFPyL+FDG± group and DCFPyL-FDG+ group, then compared the differences in clinical features and genetic mutations between the two groups with CRPC. Overall, 92 men had positive lesions detected. By comparing lesion distribution with the DCFPyL+FDG ± , DCFPyL-FDG+ disease had higher proportions of visceral metastases (4.1% vs. 1.0%, p = 0.002). DCFPyL-FDG+ was more frequently found in CRPC cohorts, and in the CRPC cohort, patients with DCFPyL-FDG+ lesions often had worse PSA response. Exploratory analysis showed that TP53 and/or RB1 mutations might be a risk factor for DCFPyL-FDG+ disease (OR = 10.625, 95% CI 3.492-32.332, p < 0.001). Patients with DCFPyL-FDG+ lesions were more likely to have visceral metastases detected, be found in castration-resistant cohorts, have TP53 and/or RB1 mutations detected, and have poor therapeutic response compared to patients with DCFPyL+FDG± lesions. Therefore, dual-tracer (18F-DCFPyL and 18F-FDG) PET/CT is recommended for patients with low PSMA expression incompatible with the true burden of the disease and those with TP53 and/or RB1 mutations to better evaluate the disease burden, tumor heterogeneity, and prognosis.