| Objective:About 12%to 13%of patients with gastric cancer have HER2 overexpression.Targeted anti-HER2 therapy combined with chemotherapy can significantly prolong the overall survival of gastric cancer with HER2 overexpression.Gastroscopy biopsy is the main method to obtain the HER2 status,because the heterogeneity of tumors,it can not represent the HER2 expression in all tumors,because it is invasive,it can not be repeated.PET/CT molecular imaging targeting HER2 is expected to noninvasively show the whole body HER2 expression in patients.Radionuclide-labeled Trastuzumab imaging can directly reflect the distribution of drugs.At present,64Cu-labeled Trastuzumab has been used for HER2-positive breast cancer imaging,but there is no relevant research on gastric cancer.In this study,64Cu-NOTA-Trastuzumab was obtained by improving the 64Cu-labeled Trastuzumab method,and combined with 18F-FDG,PET imaging was used to guide the HER2 positive lesion detection in advanced gastric cancer.Considering the slow clearance in vivo,long imaging time and high cost of complete antibody,this study also carried out 68Ga labeled small molecule HER2 Affibodty imaging in patients with gastric cancer.This study includes two parts,the safety,radiation dose,optimal imaging time and tumor targeting ability of 64Cu-labeled Trastuzumab and 68Ga-labeled HER2 Affibody molecular probes in patients with gastric cancer were studied,and the potential clinical application value was discussed.Methods:This was a single-center prospective stdudy and approved by the Medical Ethics Committee of Peking University Cancer Hospital.Patients with advanced gastric cancer/esophageal junction cancer confirmed by pathology were enrolled.64Cu-NOTA-Trastuzumab PET/CT was scanned at three time points,one hour,24 h and 48 h after injection.18F-FDG PET/CT imaging was performed within one week.In 68Ga-HER2 Affibody PET/CT study,the first 10-15 patients were scanned at three time points,one hour,two hours and three hours after injection,respectively,to determine the optimal imaging time.All patients underwent 18F-FDG PET/CT within one week.The lesions with diameter greater than 1 cm or SUVmax greater than 2.5 identified on 18F-FDG PET/CT were selected for analysis.The lesions with uptke higher than adjacent tissues on targeted PET imaging were considered as positive.Semi-quantitative analysis was performed using SUVmax.The target ability of the probe was determined by observing the lesion uptake in HER2 positive group,and compared with the lesion uptake in HER2 negative group.The sensitivity and specificity of the probe for detection of HER2 positive lesion were observed.The target/liver background ratio of positive group was used to evaluate the image contrast.Result:The 64Cu-NOTA-Trastuzumab clinical transformation study recruited 6 gastric cancer patients with HER2 positive expression in primary lesions from February 2018 to October 2018,including 1 patient without therapy and 5 patients with anti-HER2 therapy.64Cu-NOTA-Trastuzumab PET/CT imaging was performed at 1 h,24 h and 48 h after intravenous drip of the imaging agent.The results showed that the drug was safe and its distribution in vivo was mainly concentrated in the liver and intestine.The total effective dose was 13.5 mSv(0.080 mSv/MBq*169 MBq).The positive lesions(n=32,including primary lesions,lymph nodes,bone and ovarian metastases)were seen clearest in 24 h images.The SUVmax of the lesions was higher than that in 48 h images(8.97±7.60 vs 2.90± 2.78,P=0.000).Further analysis of 24 h 64Cu-NOTA-Trastuzumab PET/CT images showed that the SUVmax of patient without therapy was higher than that with therapy(14.63± 8.89 vs 5.09 ± 2.79;P=0.002).The SUVmax of different lesions ranged from 0.8 to 28.6.The uptake of liver metastases was significantly higher than that of lymph node metastases(21.7 ± 3.2 vs 9.9± 3.7,P=0.001)in patient without therapy.A total of 32 patients with gastric cancer were recruited in the 68Ga-HER2 Affibody clinical transformation study from 2018.06 to 2019.02.Among them,22 were HER2 positive in primary lesions and 10 were HER2 negative.68Ga-HER2 Affibody PET/CT imaging was performed at 1,2 and 3 h after intravenous injection of imaging agent.The results showed that the drug was safe.No obvious adverse reactions were found in all patients.The effective absorbed dose was 3.7 mSv(0.0215 mSv/MBq*170 MBq),the probe mainly through kidney metabolism.The best imaging time was 2 h.The positive lesions detected included primary lesions and metastases on lymph nodes,brain,lung,liver,adrenal gland,bone,pleura and muscle.The SUVmax of different lesions varied greatly,ranging from 1.6 to 72.7,suggesting heterogeneity of HER2 expression among the lesions.One patient in the negative group with positive PET imaging was confirmed to be HER2 positive by second-generation gene sequencing.The uptake of HER2 positive group was significantly higher than that of negative group(10.7 ± 12.5 vs 3.8 ± 1.7,P=0.005).The threshold value of SUVmax 6.6 was determined by ROC curve.The diagnostic sensitivity and specificity of 68Ga-HER2 Affibody PET/CT imaging for HER2 positive lesions were 55.4%and 100%respectively.Compared with 64Cu-NOTA-Trastuzumab,68Ga-HER2 Affibody PET/CT imaging not only has the advantages of short imaging time and low radiation dose,but also has better image contrast.Compared with 64Cu-NOTA-Trastuzuma(24 h image),68Ga-HER2 Affibody(2 h image)had a lower liver background(SUVmax:7.5 ± 3.2 vs 11.4 ± 3.2,P = 0.003),and a higher ratio of tumor to liver(1.88 ± 0.8 vs 0.94 ± 0.6,P=0.033).Thirty-two patients with gastric cancer(22 patients with HER2 positive and 10 patients with HER2 negative)underwent dual imaging of 68Ga-HER2 Affibody PET/CT and 18F-FDG PET/CT.The results showed that,in the negative group,1 case of positive uptake of metastases was detected.128 primary and metastatic lesions were detected by the two imaging methods.There was no correlation of uptake between the two imaging agents in the same lesion(r2=0.00026,P=0.86).The uptake of 68Ga-HER2 Affibody had organ-based different in 23 patients with HER2 positive expression,bone metastasis was the highest(SUVmax 40.5 ± 24.9),followed by liver metastasis(SUVmax 11.9 ± 3.9),lymph node metastasis(SUVmax 5.6± 3.7)and other lesions including primary lesions were relatively low(SUVmax 7.3 ± 3.7),but there was no difference in 18F-FDG uptake among different organ lesions(P>0.05).Of 23 HER2-positive patients,10 received anti-HER2 treatment within 60 days and 13 did not receive anti-HER2 treatment.The positive lesions in the treatment group showed that SUVmax was lower than that in the untreated group(8.8±4.9 vs 11.8 ± 15.2),but there was no significant difference between the two groups(P=0.253).The baseline SUVmax was different in patients with different progression free survival(PFS)(4.3 ± 0.7 vs.8.8 ± 0.7,P= 0.002)Conclusion:In this study,we successfully completed the clinical transformation study of 64Cu-NOTA-Trastuzumab and 68Ga-HER2 Affibody molecular probes in HER2 positive gastric cancer patients.The results showed that both probes were safe and effective,and had good targeting ability for HER2 positive lesions.Compared with 64Cu-NOTA-Trastuzumab,68Ga-HER2 Affibody has the advantages of early imaging time,good image contrast and low radiation dose.PET/CT imaging targeting HER2 shows good potential clinical application value,including HER2 positive metastases detection in patients with HER2 negative primary lesions,HER2 heterogeneity monitoring,HER2 evaluation of lesions at unsuitable biopsy sites,monitoring initial efficacy of targeted therapy,and reassessment of HER2 status in patients undergoing treatment.The preliminary results indicate that PET/CT targeting HER2 can provide a noninvasive and valuable method for monitoring HER2 expression in gastric cancer,but it still needs to be verified by larger sample data in the future. |
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