title: 68Ga-TRAP-(RGD)3 Hybrid Imaging for the In Vivo Monitoring of αvß3-Integrin Expression as Biomarker of Anti-Angiogenic Therapy Effects in Experimental Breast Cancer.
abstract: OBJECTIVE
  To investigate 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of αvß3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
  
  
  METHODS
  Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq 68Ga-TRAP-(RGD)3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImaxtumor/VOImeanmuscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (αvß3-integrin, microvascular density-CD31, proliferation-Ki-67, apoptosis-TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12).
  
  
  RESULTS
  68Ga-TRAP-(RGD)3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (ΔTBRfollow-up/baseline: therapy -1.07±0.83, control +0.32±1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (Δvolumetherapy 134±77 μL, Δvolumecontrol 132±56 μL, p = 1.000). Immunohistochemistry revealed a significant reduction of αvß3-integrin expression (308±135 vs. 635±325, p = 0.03), microvascular density (CD31, 168±108 vs. 432±70, p = 0.002), proliferation (Ki-67, 5,195±1,002 vs. 7,574±418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432±1,974 vs. 3,776±1,378, p = 0.002) in the therapy compared to the control group.
  
  
  CONCLUSIONS
  68Ga-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of αvß3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
authors.affiliation: Institute for Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Kazmierczak
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Andrei
authors.initials: A
authors.lastname: Todica
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Gildehaus
authors.affiliation: Institute for Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Hirner-Eppeneder
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Brendel
authors.affiliation: Institute for Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Ralf S
authors.initials: RS
authors.lastname: Eschbach
authors.affiliation: Institute for Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Hellmann
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Nikolaou
authors.affiliation: Institute for Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Reiser
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technical University Munich, München, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.affiliation: SCINTOMICS GmbH, Fürstenfeldbruck, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Kropf
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Rominger
authors.affiliation: Institute for Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University Hospital Munich, München, Germany.
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Cyran
mesh_terms: D000818:Animals; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005710:Gallium Radioisotopes / Q000008:administration & dosage*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods; D016896:Treatment Outcome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D005710:Gallium Radioisotopes; D039302:Integrin alphaVbeta3; D000068258:Bevacizumab