Breast Cancer 18F-ISO-1 Uptake as a Marker of Proliferation Status

Abstract

The σ₂ receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-¹⁸F-fluoroethoxy)-5-methylbenzamide (¹⁸F-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 ¹⁸F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether ¹⁸F-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 (NCT02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of ¹⁸F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of ¹⁸F-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 = 0.02). SUV_max exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ = 0.46, P = 0.01, n = 29). Partial-volume-corrected SUV_max was positively correlated with Ki-67 for invasive ductal carcinoma (ρ = 0.51, P = 0.02, n = 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 (P > 0.05). Conclusion:¹⁸F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.

Keywords: 18F-ISO-1; TMEM-97, proliferation; breast cancer; σ-2.