| Objective: 1. Determine the utility of 99mTc-3PRGD2 SPECT/CT imaging in lung cancer, breast cancer bearing mouse model for curative effect detection. Clarify the feasibility of its use in the evaluation of early therapeutic efficacy of tumor targeted therapy, and provide basis for clinical application. 2. Discuss the application of 99mTc-3PRGD2 SPECT/CT in the evaluation of the therapeutic effect of breast cancer targeted therapy. 3. Assess the value of 99mTc-3PRGD2 SPECT/CT for the early identification of response and prognosis to targeted therapy in patients with advanced non-small cell lung cancer.Methods: 1. Establishment of the nude mouse model of human lung adenocarcinoma（A549） and human breast cancer（MDA-MB-435）. The average tumor volume was 180 ± 90 mm3 the day prior to baseline SPECT/CT. The nude mice were divided into targeted drug therapy group and saline control group. 99mTc-3PRGD2 SPECT/CT imaging was performed at baseline（-1 day） and day 5, and 15, at the same time, quantitative analysis of tumor volume and radioactivity uptake（T/N ratio, %ID and %ID/g）. Compare the index before and after the treatment. Tumor were harvested at all imaging time points for histopathological analysis with H&E and immunofluorescence. The results were compared with the value tumor uptake 99mTc-3PRGD2. 2. Thirty-three patients with stage II and III breast cancer were scheduled to undergo 99mTc-3PRGD2 SPECT at baseline, after the first and second cycle of NCT. Changes in tumor to nontumor（T/N） ratio were compared with pathological tumor responses classified using the residual cancer burden system. Receiver operator characteristic（ROC） analysis was used to compare the power to identify responders between the end of the first and the end of the second cycle of NCT. The impact of breast cancer subtype on 99mTc-3PRGD2 uptake was evaluated. The correlation between 99mTc-3PRGD2 uptake and pathological tumor response was also evaluated in each breast cancer subtype. 3. Patients with advanced NSCLC were prospectively studied with 99mTc-3PRGD2 SPECT/CT before and after 2 weeks from start of treatment. The tumor response was evaluated with RECIST criteria and related to observed change in the T/N ratio for the largest known lesion. ROC curve analysis was used to determine T/N ratio changes with regard to predicting response to bevacizumab therapy. Change in T/N ratio was also related to progression-free survival（PFS） and overall survival（OS）.Results: 1. The tumor volume was slightly increased in the fifth days after treatment in treatment group of A549 model, and there was no significant difference before and after treatment. After fifteenth days of treatment, the tumor size was reduced. The treatment group of MDA-MB-435 model showed a slight increase in tumor volume duration, but there is no significant difference before and after treatment. After 5 and 15 days of treatment, the tumor volume was significantly reduced in treatment group of A549 and MDA-MB-435 model. Compared with the corresponding saline control group, the difference was statistically significant. In A549 and MDA-MB-435 model, %ID/g, %ID and T/N ratio tumor uptake of 99mTc-3PRGD2 was significantly decreased in treated group fifth days after treatment, which were significantly lower than saline control group. 2. Surgery was performed after four cycles of NCT and pathological analysis revealed 18 responders and 15 non-responders. In patients with clearly visible 99mTc-3PRGD2 uptake at baseline, the sensitivity, specificity, and negative predictive value of 99mTc-3PRGD2 SPECT were 86.7 %, 85.7 % and 86.7 % after the first cycle of NCT, and 92.9 %, 93.3 % and 93.3 % after the second cycle, respectively. Among these patients, the HER-2-positive group demonstrated both higher T/N ratios and a greater change in T/N ratio than patients with other breast cancer subtypes（P<0.05）. A strong correlation was found between changes in T/N ratio and pathological tumor response in the HER-2-positive group（P<0.03）. 3. Twenty-six patients were included, and 23 were finally assessable for metabolic response evaluation with 99mTc-3PRGD2 SPECT/CT. The cut-off value of T/N ratio change defined by ROC analysis was 24.4%. The sensitivity, specificity, and negative predictive value of 99mTc-3PRGD2 SPECT/CT for predicting tumor response were 81.8%, 91.7%, and 84.6%, respectively. Using the cut-off value defined by ROC analysis on 99mTc-3PRGD2 SPECT/CT, metabolic non-progressive disease patients（m NP） showed prolonged PFS（5.6 months versus 3.4 months; P < 0.001） and OS（17.1 months versus 8.6 months; P < 0.001） than metabolic progressive disease patients（m P）.Conclusion: 99mTc-3PRGD2 SPECT/CT can effectively reflect tumor integrin αv β 3 expression level. It can be used for monitoring effective treatment of tumor early and detecting reduction of 99mTc-3PRGD2 uptake in tumor as early as 5 days after targeted therapy. 99mTc-3PRGD2 SPECT is useful for determining the pathological tumor response in patients with stage II or III breast cancer undergoing NCT, especially those with the HER-2-positive subtype. 99mTc-3PRGD2 SPECT/CT is a promising modality to predict tumor response in patients with advanced non-small cell lung cancer early in the course of targeted therapy. |
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