Breast Cancer¹⁸F-ISO-1 Uptake as a Marker of Proliferation Status

Abstract

The σ 2 receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using N-(4-(6,7-dimethoxy-3,4dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-18 F-fluoroethoxy)-5-methylbenzamide (18 F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of 18 F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether 18 F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression. Methods: Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT 02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of 18 F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of 18 F-ISO-1 was quantitated by SUV max and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67. Results: Tumor SUV max (median, 2.0 g/mL; range, 1.3-3.3 g/mL), partial-volume-corrected SUV max , and SUV ratios were tested against Ki-67. Tumors stratified into the high-Ki-67 ($20%) group had SUV max greater than the low-Ki-67 (,20%) group (P 5 0.02). SUV max exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ 5 0.46, P 5 0.01, n 5 29). Partial-volume-corrected SUV max was positively correlated with Ki-67 for invasive ductal carcinoma (ρ 5 0.51, P 5 0.02, n 5 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 (P. 0.05). Conclusion: 18 F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.

The Biological Function of Sigma-2 Receptor/TMEM97 and Its Utility in PET Imaging Studies in Cancer

“…McDonald et al conducted the clinical trial of [ 18 F]ISO-1 in women with primary breast cancer to determine the correlation of [ 18 F]ISO-1 PET uptake and Ki-67 expression [ 20 ]. Twenty-eight women with 29 primary invasive breast cancers were evaluated.…”

“…The graph shows the significant difference in [18F]ISO-1 uptake in patients above and below the Ki-67 score of 20 (* p < 0.05). Data from reference [ 20 ].…”

Differential gene expression by RNA-Seq in Sigma-2 Receptor/TMEM97 knockout cells reveals its role in complement activation and SARS-CoV-2 viral uptake

“…HeLa sigma-2R/TMEM97 KO cells were plated and RNA-Seq was performed to analyze differentially expressed genes compared to scramble/cas9 control cells (Fig 1). The top 25 upregulated and downregulated genes showed several genes that play a role in molecular pathways involving cancer development, which was no surprise as sigma-2R/TMEM97 has been shown to be a proliferation marker and has been studied extensively in the context of cancer [19][20][21][22][23] . Interestingly, Complement Component 4 Binding Protein (C4BP) Beta (C4BPB) and Complement Component 4 Binding Protein Alpha (C4BPA) were amongst the top upregulated genes upon loss of sigma-2R/TMEM97.…”

Sigma-2 Receptor—A Potential Target for Cancer/Alzheimer’s Disease Treatment via Its Regulation of Cholesterol Homeostasis

“…Up to now, both 11 C- and 18 F-radiolabeled sigma-2 receptor ligands have been developed and validated in a variety of tumor models [ 80 , 81 ]. [ 18 F]ISO-1 has been tested in humans for tumor positron emission tomography (PET) imaging [ 80 , 82 ] and used as a predictor of the cancer therapy response [ 83 ]. In 28 breast cancer patients, the uptake of [ 18 F] ISO-1 was significantly correlated with expression of tumor proliferation marker Ki-67 [ 82 ].…”