Clinical Value Analyses Of Dual Tracer PET/CT And Next Generation Sequencing In Prostate Cancer

Purpose Prostate cancer seriously affects men’s health,and positron emission tomography/computed tomography(PET/CT)has an important role in identifying early disease spread and monitoring treatment response in patients with aggressive tumors.Prostate specific membrane antigen(PSMA)PET/CT is known to be clinically valuable for the assessment of prostate cancer.However,due to tumor heterogeneity,PET/CT scans using a single tracer often do not provide a comprehensive assessment of tumor heterogeneity and disease burden,and it has been shown that metastatic castration-resistant prostate cancer(mCRPC)patients with low PSMA expression while high fluorodeoxyglucose(FDG)uptake lack effective salvage therapy after resistance to first-line therapy(Novel hormonal agents and Chemotherapy)and have a short overall survival(OS).Therefore,we applied 18F-DCFPyL(target PSMA)PET/CT and 18F-FDG PET/CT,combination with next-generation sequencing to evaluate the enrolled prostate cancer patients and further explore the clinical,genetic,and prognostic characteristics of the population with low PSMA expression while high FDG uptake(PSMA-FDG+).Methods A total of 104 prostate cancer patients underwent 18F-DCFPyL and 18F-FDG dual tracer PET/CT scans,of which 82 cases sent for peripheral blood circulating tumor DNA(ctDNA)and 1 case sent for tumor biopsy to undergo next-generation sequencing to detect commonly genetic alterations such as AR,TP53,RBI,PTEN,and DDR gene.We classified the positive lesions from PET/CT scans according to the tracer uptake values.DCFPyL+FDG-lesions were defined as only with DCFPyL uptake while FDG absent or DCFPyL uptake values were higher than FDG uptake values.DCFPyL-FDG+lesions meant only with FDG uptake while DCFPyL absent or FDG uptake values were higher than DCFPyL.Patients with positive lesions were then grouped.Those only with DCFPyL+FDGlesions were the DCFPyL+FDG-group(Group 1),and those with at least one DCFPyLFDG+lesion was the DCFPyL-FDG+group(Group 2).The correlation between PET imaging parameters and clinical characteristics such as PSA level,Gleason score,CRPC,and treatment response was analyzed using the Mann-Whitney U test.Then we used the chisquare test to compare the distribution of lesion heterogeneity.Next,in the CRPC cohort,clinical,genetic,and treatment response characteristics of Group 1 and Group 2 were analyzed for differences using Mann-Whitney U test and chi-square test.Finally,we included age,PSA level,Gleason score,CRPC,TP53 and/or RB1 gene mutations for univariate analysis and Bonferroni Correction of the detection of DCFPyL-FDG+.All statistical analyses were performed using SPSS 25.0(IBM Corp.)with a two-sided P<0.05 considered statistically significant.Results After double-tracer PET/CT scanning,72 patients had DCFPyL-positive and FDGpositive lesions detected,17 patients only had DCFPyL-positive lesions detected,and 3 patients only had FDG-positive lesions detected,resulting in a total of 1,300 positive lesions detected in 92 enrolled subjects.After classifying the lesions according to their uptake values,our cohort had 1058 DCFPyL+FDG-and 242 DCFPyL-FDG+lesions detected.For comparison of imaging parameters with clinical features,we found that total tumor volume(wbPSMA-TV)and total uptake values(wbTL-PSMA)measured by DCFPyL PET/CT were correlated with PSA levels and ISUP≥4(P<0.05),while tumor volume measured(MTV)by FDG PET/CT were correlated with PSA levels and CRPC(P<0.05).The measured total tumor volume and total uptake values were correlated with poor treatment response for both DCFPyL PET/CT and FDG PET/CT(P<0.05).By comparing lesion distribution with the DCFPyL+FDG-,DCFPyL-FDG+disease had higher proportions of lymph node metastases(30.2%vs.47.9%,P<0.001)and visceral metastases(1.0%vs.4.1%,P=0.002).DCFPyLFDG+lesions were rarely found in the BCR and HSPC cohorts,whereas detection rates were significantly higher in the CRPC cohort(0%vs.12.5%vs.31.3%).There were 68 patients in the DCFPyL+FDG-group(41 with CRPC)and 24 patients in the DCFPyL-FDG+group(20 with CRPC).Patients with CRPC in the DCFPyL-FDG+group had a worse response to treatment compared to the DCFPyL+FDG-group(P=0.036)and had higher rate of TP53 and RBI mutations.Finally,exploratory analysis found that TP53 and/or RB1 mutations was an independent risk factor for DCFPyL+FDG-disease(OR=15.000,95%CI 4.978-45.195,P<0.001).Conclusion Patients with PSMA-FDG+lesions were more likely to have visceral metastases detected,be found in castration-resistant cohorts,have TP53 or RB1 mutations detected,and have poor therapeutic response compared to patients only with high PSMA expression disease.Therefore,18F-DCFPyL and 18F-FDG dual-tracer PET/CT is recommended for patients with low PSMA expression,and those with TP53 or RB1 mutations to better evaluate the disease burden,tumor heterogeneity,and prognosis.