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: Aysegül Ilhan-Mutlu, Matthias Osswald, Yunxiang Liao, Miriam Gömmel, Martin Reck, David Miles, Paola Mariani, Luca Gianni, Beatrix Lutiger, Viktor Nendel, Stefanie Srock, Pablo Perez-Moreno, Frits Thorsen, Louisa von Baumgarten, Matthias Preusser, Wolfgang Wick, Frank Winkler
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 4 Pg. 702-10 (04 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 26809491 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Bevacizumab

Topics

• Adenocarcinoma (pathology)
• Adenocarcinoma of Lung
• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antineoplastic Agents (therapeutic use)
• Bevacizumab (therapeutic use)
• Brain Neoplasms (diagnosis, drug therapy, mortality, secondary)
• Cell Line, Tumor
• Clinical Trials, Phase III as Topic
• Disease Models, Animal
• Humans
• Incidence
• Lung Neoplasms (pathology)
• Mice
• Multicenter Studies as Topic
• Neoplasm Recurrence, Local
• Neoplasm Staging
• Neovascularization, Pathologic (drug therapy)
• Randomized Controlled Trials as Topic
• Retrospective Studies
• Xenograft Model Antitumor Assays