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Biologic Correlates of ¹⁸Fluorodeoxyglucose Uptake in Human Breast Cancer Measured by Positron Emission Tomography

From the Departments of Pathology, Medical Oncology, and Nuclear Medicine, Positron Emission Tomography Research Center, Vrije Universiteit Medical Center, Amsterdam; Department of Internal Medicine, Amstelveen Hospital, Amstelveen, the Netherlands; and Department of Pediatrics and Medicine, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Address reprint request to C.F.M. Molthoff, PhD, Vrije Universiteit Medical Center, Positron Emission Tomography Research Center, Department of Nuclear Medicine, PO Box 7057, NL 1007 MB Amsterdam, the Netherlands; email: cfm.molthoff{at}vumc.nl

PURPOSE: Variable uptake of the glucose analog ¹⁸fluorodeoxyglucose (FDG) has been noticed in positron emission tomography (PET) studies of breast cancer patients, with low uptake occurring especially in lobular cancer. At present, no satisfactory biologic explanation exists for this phenomenon. This study compared ¹⁸FDG uptake in vivo with biomarkers expected to be involved in the underlying biologic mechanisms.

PATIENTS AND METHODS: Preoperative ¹⁸FDG-PET scans were performed in 55 patients. ¹⁸FDG activity was assessed visually by three observers using a four-point score. Tumor sections were stained by immunohistochemistry for glucose transporter-1 (Glut-1); Hexokinase (HK) I, II, and III; macrophages; hypoxia-inducible factor-1-alfa (HIF-1); vascular endothelial growth factor (VEGF₁₆₅); and microvessels. Mitotic activity index (MAI), amount of necrosis, number of lymphocytes, and tumor cells/volume were assessed.

RESULTS: There were positive correlations between ¹⁸FDG uptake and Glut-1 expression (P < .001), MAI (P = .001), amount of necrosis (P = .010), number of tumor cells/volume (P = .009), expression of HK I (P = .019), number of lymphocytes (P = .032), and microvessel density (r = .373; P = .005). HIF-1, VEGF₁₆₅, HK II, HK III, and macrophages showed no univariate correlation with ¹⁸FDG. In logistic regression, however, HIF-1 and HK II added value to MAI and Glut-1.

CONCLUSION: ¹⁸FDG uptake in breast cancer is a function of microvasculature for delivering nutrients, Glut-1 for transportation of ¹⁸FDG into the cell, HK for entering ¹⁸FDG into glycolysis, number of tumor cells/volume, proliferation rate (also reflected in necrosis), number of lymphocytes (not macrophages), and HIF-1 for upregulating Glut-1. Together, these features explain why breast cancers vary in ¹⁸FDG uptake and elucidate the low uptake in lobular breast cancer.

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