Inter-heterogeneity and intra-heterogeneity of α_vβ₃ in non-small cell lung cancer and small cell lung cancer patients as revealed by ⁶⁸Ga-RGD₂ PET imaging.

Abstract

Integrin α_vβ₃ is the therapeutic target of the anti-angiogenic drug cilengitide. The objective of this study was to compare α_vβ₃ levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer ⁶⁸Ga-labeled dimerized-RGD (⁶⁸Ga-RGD₂). Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/CT images were acquired using ⁶⁸Ga-RGD₂.¹⁸F-FDG PET/CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/nontarget (T/NT) values were quantitatively compared. Expression of the angiogenesis marker α_vβ₃ in NSCLC and SCLC lesions was analyzed by immunohistochemistry. The ¹⁸F-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The ⁶⁸Ga-RGD₂ uptake of SCLC patients was at background levels in both SUV and T/NT measurements and was significantly lower than that of NSCLC patients. The range value of ⁶⁸Ga-RGD₂ SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that α_vβ₃ integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression. The uptake of ⁶⁸Ga-RGD₂ in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower α_vβ₃ target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of α_vβ₃ also exist in both NSCLC and SCLC. Such inter- and intra-heterogeneity of α_vβ₃ may potentially improve current applications of α_vβ₃-targeted therapy and diagnostic imaging in lung cancer.