title: Bevacizumab Prevents Brain Metastases Formation in Lung Adenocarcinoma.
abstract: Patients with nonsquamous non-small cell lung cancer (nsNSCLC; largely lung adenocarcinoma) are at high risk of developing brain metastases. Preclinical data suggested that anti-VEGF-A therapy may prevent the formation of nsNSCLC brain metastases. Whether non-brain metastases are also prevented, and whether bevacizumab shows a brain metastases-preventive activity in cancer patients is unknown. Data of one nsNSCLC (stage IIIB/IV, AVAiL) and two breast cancer bevacizumab trials (HER2 negative, AVADO; HER2 positive, AVEREL) were retrospectively analyzed regarding the frequency of the brain versus other organs being the site of first relapse. For animal studies, the outgrowth of PC14-PE6 lung adenocarcinoma cells to brain macrometastases in mice was measured by intravital imaging: under control IgG (25 mg/kg) treatment, or varying doses of bevacizumab (25 mg/kg, 2.5 mg/kg, 0.25 mg/kg). Brain metastases as site of first relapse were significantly less frequent in the bevacizumab arm of the AVAiL trial (HR = 0.36, P < 0.001). In AVADO and AVEREL, no significant difference was seen. In mice, bevacizumab treatment led to secondary regressions of non-brain macrometastases, but did not reduce their total incidence, and did not improve survival. In a brain-seeking nsNSCLC metastasis model, treatment with bevacizumab inhibited brain metastases formation, which resulted in improved overall survival. In summary, bevacizumab has the potential to prevent brain metastases in nsNSCLC, but no preventive activity could be detected outside the brain. These data indicate that anti-VEGF-A agents might be particularly relevant for those stage III nsNSCLC patients who are at high risk to develop future brain metastases. Mol Cancer Ther; 15(4); 702-10. ©2016 AACR.
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Medicine 1, Medical University of Vienna, Vienna, Austria. Comprehensive Cancer Center Vienna, Central Nervous System Tumors Unit, Vienna, Austria.
authors.forename: Aysegül
authors.initials: A
authors.lastname: Ilhan-Mutlu
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Neurology Clinic & National Center for Tumor Diseases, Ruprecht-Karls University, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Osswald
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gömmel
authors.affiliation: Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of German Center for Lung Research (DZL), Grosshansdorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Mount Vernon Cancer Centre, Rickmansworth Road, Northwood Middlesex, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Miles
authors.affiliation: Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Mariani
authors.affiliation: Department of Oncology, San Raffaele Hospital, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Lutiger
authors.affiliation: DASTA GmbH, Heddesheim, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Nendel
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Srock
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Pablo
authors.initials: P
authors.lastname: Perez-Moreno
authors.affiliation: The Kristian Gerhard Jebsen Brain Tumour Research Center and The Molecular Imaging Center, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Frits
authors.initials: F
authors.lastname: Thorsen
authors.affiliation: Department of Neurology, Ludwig-Maximilians University Hospital, Munich, Germany.
authors.forename: Louisa
authors.initials: L
authors.lastname: von Baumgarten
authors.affiliation: Department of Medicine 1, Medical University of Vienna, Vienna, Austria. Comprehensive Cancer Center Vienna, Central Nervous System Tumors Unit, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Neurology Clinic & National Center for Tumor Diseases, Ruprecht-Karls University, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Neurology Clinic & National Center for Tumor Diseases, Ruprecht-Karls University, Heidelberg, Germany. frank.winkler@med.uni-heidelberg.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D045744:Cell Line, Tumor; D017326:Clinical Trials, Phase III as Topic; D004195:Disease Models, Animal; D006801:Humans; D015994:Incidence; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D015337:Multicenter Studies as Topic; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000068258:Bevacizumab