Christos Christodoulou1, Georgios Oikonomopoulos2, Georgia Angeliki Koliou3, Ioannis Kostopoulos4, Vassiliki Kotoula4,5, Mattheos Bobos5, George Pentheroudakis6, George Lazaridis7, Maria Skondra8, Sofia Chrisafi5, Angelos Koutras9, Dimitrios Bafaloukos10, Evangelia Razis11, Kyriaki Papadopoulou5, Pavlos Papakostas12, Haralambos P Kalofonos9, Dimitrios Pectasides8, Pantelis Skarlos13, Konstantine T Kalogeras5,14, George Fountzilas5,15. 1. Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece c_christodoulou@yahoo.gr. 2. Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece. 3. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece. 4. Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece. 5. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece. 6. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece. 7. Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece. 8. Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece. 9. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece. 10. First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece. 11. Third Department of Medical Oncology, Hygeia Hospital, Athens, Greece. 12. Oncology Unit, Hippokration Hospital, Athens, Greece. 13. Department of Radiotherapy, Metropolitan Hospital, Piraeus, Greece. 14. Translational Research Section, Hellenic Cooperative Oncology Group, Athens, Greece. 15. Aristotle University of Thessaloniki, Thessaloniki, Greece.
Abstract
BACKGROUND: Trastuzumab is a monoclonal antibody against HER2-positive breast cancer. Despite improving the natural history of the disease, there is a number of patients who are resistant to it, whereas all patients will eventually develop resistance and disease will progress. Inconsistent preclinical data show that the IGF-R pathway may contribute to either de novo or acquired resistance to trastuzumab. MATERIALS AND METHODS: In total, 227 trastuzumab-treated metastatic breast cancer patients were evaluated for IGF-1, IGF-1R, GLP-1R, Akt1, Akt2 Akt3 mRNA expression, and IGF-1Rα, IGF-1Rβ, IGF-2R protein expression. RESULTS: Only 139 patients were truly HER2-positive by central assessment. Among HER2-positive patients, high Akt2 and GLP-1R mRNA expression showed a trend towards higher and lower risk of progression, respectively (HR=1.83, 95%CI=0.90-3.72, p=0.094 and HR=0.62, 95%CI=0.36-1.06, p=0.079), while high Akt1 and GLP-1R mRNA expression presented a trend towards unfavorable survival (HR=1.67, 95%CI=0.93-2.99, p=0.086 and HR=1.67, 95%CI=0.94-2.96, p=0.080). Among HER2-negative patients, high GLP-1R mRNA expression and negative stromal IGF-1Rβ protein expression showed a trend towards worse survival (HR=2.31, 95%CI=0.87-6.13, p=0.094 and HR=2.03, 95%CI=0.94-4.35, p=0.071, respectively). In the multivariate analyses, HER2-positive patients with high Akt1 and GLP-1R mRNA expression had a worse survival (HR=1.86, 95%CI=1.01-3.43, p=0.045 and HR=1.83, 95%CI=0.99-3.41, p=0.055, respectively). CONCLUSION: This study revealed a crosstalk between the IGF-R pathway and HER2. There was evidence that high Akt1 and GLP-1R mRNA expression might affect survival among HER2-positive metastatic breast cancer patients treated with trastuzumab. Copyright
BACKGROUND:Trastuzumab is a monoclonal antibody against HER2-positive breast cancer. Despite improving the natural history of the disease, there is a number of patients who are resistant to it, whereas all patients will eventually develop resistance and disease will progress. Inconsistent preclinical data show that the IGF-R pathway may contribute to either de novo or acquired resistance to trastuzumab. MATERIALS AND METHODS: In total, 227 trastuzumab-treated metastatic breast cancerpatients were evaluated for IGF-1, IGF-1R, GLP-1R, Akt1, Akt2Akt3 mRNA expression, and IGF-1Rα, IGF-1Rβ, IGF-2R protein expression. RESULTS: Only 139 patients were truly HER2-positive by central assessment. Among HER2-positive patients, high Akt2 and GLP-1R mRNA expression showed a trend towards higher and lower risk of progression, respectively (HR=1.83, 95%CI=0.90-3.72, p=0.094 and HR=0.62, 95%CI=0.36-1.06, p=0.079), while high Akt1 and GLP-1R mRNA expression presented a trend towards unfavorable survival (HR=1.67, 95%CI=0.93-2.99, p=0.086 and HR=1.67, 95%CI=0.94-2.96, p=0.080). Among HER2-negative patients, high GLP-1R mRNA expression and negative stromal IGF-1Rβ protein expression showed a trend towards worse survival (HR=2.31, 95%CI=0.87-6.13, p=0.094 and HR=2.03, 95%CI=0.94-4.35, p=0.071, respectively). In the multivariate analyses, HER2-positive patients with high Akt1 and GLP-1R mRNA expression had a worse survival (HR=1.86, 95%CI=1.01-3.43, p=0.045 and HR=1.83, 95%CI=0.99-3.41, p=0.055, respectively). CONCLUSION: This study revealed a crosstalk between the IGF-R pathway and HER2. There was evidence that high Akt1 and GLP-1R mRNA expression might affect survival among HER2-positive metastatic breast cancerpatients treated with trastuzumab. Copyright
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