title: Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography.
abstract: OBJECTIVE
  Variable uptake of the glucose analog (18)fluorodeoxyglucose (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 (18)FDG uptake in vivo with biomarkers expected to be involved in the underlying biologic mechanisms.
  
  
  METHODS
  Preoperative (18)FDG-PET scans were performed in 55 patients. (18)FDG 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-1alpha); vascular endothelial growth factor (VEGF(165)); and microvessels. Mitotic activity index (MAI), amount of necrosis, number of lymphocytes, and tumor cells/volume were assessed.
  
  
  RESULTS
  There were positive correlations between (18)FDG 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-1alpha, VEGF(165), HK II, HK III, and macrophages showed no univariate correlation with (18)FDG. In logistic regression, however, HIF-1alpha and HK II added value to MAI and Glut-1.
  
  
  CONCLUSIONS
  (18)FDG uptake in breast cancer is a function of microvasculature for delivering nutrients, Glut-1 for transportation of (18)FDG into the cell, HK for entering (18)FDG into glycolysis, number of tumor cells/volume, proliferation rate (also reflected in necrosis), number of lymphocytes (not macrophages), and HIF-1alpha for upregulating Glut-1. Together, these features explain why breast cancers vary in (18)FDG uptake and elucidate the low uptake in lobular breast cancer.
authors.affiliation: Department of Pathology, Positron Emission Tomography Research Center, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bos
authors.forename: Jacobus J M
authors.initials: JJ
authors.lastname: van Der Hoeven
authors.forename: Elsken
authors.initials: E
authors.lastname: van Der Wall
authors.forename: Petra
authors.initials: P
authors.lastname: van Der Groep
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Emile F I
authors.initials: EF
authors.lastname: Comans
authors.forename: Urvi
authors.initials: U
authors.lastname: Joshi
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Otto S
authors.initials: OS
authors.lastname: Hoekstra
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: Carla F M
authors.initials: CF
authors.lastname: Molthoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000494:pharmacology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008214:Lymphocytes; D008833:Microcirculation; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000494:pharmacology; D009336:Necrosis; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D012039:Regional Blood Flow; D014055:Tomography, Emission-Computed / Q000379:methods*; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D019275:Radiopharmaceuticals; D014157:Transcription Factors; D019788:Fluorodeoxyglucose F18