| Objective To investigate the experimental basis of polypeptied receptor imaging agent 99mTc-AF7 P in animal models and the primary clinical application of 99mTc-3PRGD2 in patients with breast cancer.Methods The 6-hydrazinonicotinic acid?HYNIC?-modified biofunctional carrier molecue AF7 p were chemically linked with ligand molecules Tricine and TPPTS before labeled with 99 mTc to form the membrane type I matrix metalloproteinase?MT1-MMP?-targeted imaging agent [99mTc]-?HYNIC-AF7p??tricine??TPPTS?.The pharmopeutical features including stablity,biological distribution and tumor specificity were evaluated through the tumor-bearing mouse models.Next,we evaluated the correlations between 99mTc-3PRGD2/ADC and the subtype classification of breast cancer by investigating the data of 99mTc-3PRGD2 uptake,ADC calculations and prognositc biomarkers in tissues of breast cancer.Then,through a single centric modest-scaled clinical trial involving patients with HER2 positive breast cancer for neoadjuvant chemotherapy?NCT?,we estimated the diagnostic and prognostic values of T/N ratio and SUVmax in patients with such pathological types.Results 1.In tis research,we successfully developed a 99mTc-labeled MT1-MMP specific binding peptide,[99mTc]-?HYNIC-AF7p??tricine??TPPTS?,for in vivo detection of MDA-MB-435 s breast tumor by single photon emission computed tomography?SPECT?.2.[99mTc]-?HYNIC-AF7p??tricine??TPPTS?demonstrated nice biostability and high MT1-MMP binding affinity in vitro and in vivo.Tumor-to-muscle ratio was found to reach to the highest?4.17±0.49?at 2 hour after intravenously administration of [99mTc]-?HYNICAF7P??tricine??TPPTS?into MDA-MB-435 s tumor bearing mice.3.The Mean±standard deviation age of the 68 patients was 48.19±11.5 years?range 19-73 years?.The Mean±standard deviation size of the invasive tumor was 2.29±1.03cm?range 0.8-5.2cm?.The histological classifications of the cancers were: invasive ductal carcinoma?54 patients,79.4%?,invasive lobular carcinoma?9 patients,13.2%?and other types?5 patients,7.4%?.The subtype of the 68 tumors were luminal A in 21 patients?30.9%?,luminal B in 32 patients?47.1%?,HER2-positive in 9 patients?13.2%?and triple-negative in 6 patients?8.8%?.Larger lesion diameter,HER2 positivity and positive LN status were found significantly associated with a higher T/N ratio.Positive LN status,HER2 positivity and larger lesion diameter were found significantly associated with higher SUVmax.PR positivity and ER positivity were found significantly associated with higher ADC.In the ROC analysis,a cut-off T/N ratio of 3.52 yielded a sensitivity of 84.2% and a specificity of 83.7% for differentiation of HER2 positive tumor from non-HER2 positive subtypes.A cut-off SUVmax of 3.94 yielded a sensitivity of 89.5% and a specificity of 87.8% for differentiation of HER2 positive tumor from non-HER2 positive subtypes.The optimal area under the ROC curve?AUC?was 0.851 and 0.866 for T/N ratio and SUVmax,respectively.However,there was no significant difference between them?P=0.5627?.4.One week after initiation of NCT treatment,the coefficient of variation for SUVmax between the two reproducibility scans were 8.1±3.2%.The corresponding difference between scans were-0.05±0.44.Surgery was performed after four cycles of NCT and pathological analysis revealed 20 responders and 16 non-responders.For primary lesion,the sensitivity and specificity of ?T/N as 26.6% in identifying responders were 84.6% and 80%,respectively.However,the sensitivity and specificity of ?SUVmax as 16.8% in identifying responders were 84.6% and 85%,respectively The corresponding ROC-areas under the curve?ROC-AUC?were 0.869 and 0.904,compariable to the response results evaluated with FDG PET for HER-2 postitive.For ALN metastases,the sensitivity and specificity of ?T/N as 20.5% in identifying responders were 100% and 69.2%,respectively.The sensitivity and specificity of ?SUVmax as 18.3% in identifying responders were 100% and 84.6%,respectively.The corresponding ROC-AUCs were 0.915 and 0.957.Both T/N ratio and ?SUVmax were favorable markers for prognosis of primary and metastatic breast caner.The prognositc value of ?SUVmax was prior to the change of T/N ratios.Conclusions 1.The methodology of developing [99mTc]-?HYNIC-AF7p?was well established.The high affinity and specificity of [99mTc]-?HYNIC-AF7p?to breast cancer tissues with overexpressed MT1-MMP potentiated a bright perspective in clinical applications.2.The correlations between 99mTc-3PRGD2/ADC and the subtype classification of breast cancer provided a theoretical basis for further clinical application.3.In patients with HER2 positive breast cancer,serial 99mTc-3PRGD2 SPECT-CT studies are reproducible with relatively low variability.99mTc-3PRGD2 SPECT-CT could predict tumor response as early as 1 week after initiation of neoadjuvant chemotherapy. |
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