Sofia Levva1, Vassiliki Kotoula2,3, Ioannis Kostopoulos3, Kyriaki Manousou4, Christos Papadimitriou5, Kyriaki Papadopoulou3, Sotiris Lakis3, Kyriakos Koukoulias3, Vasilios Karavasilis6, George Pentheroudakis7, Eufemia Balassi8, Flora Zagouri5, Ioannis G Kaklamanos9, Dimitrios Pectasides10, Evangelia Razis11, Gerasimos Aravantinos12, Pavlos Papakostas13, Dimitrios Bafaloukos14, Grigorios Rallis6, Helen Gogas15, George Fountzilas3,16. 1. Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece dr.slevva@gmail.com hecogoff@otenet.gr. 2. Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece. 3. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece. 4. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece. 5. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 6. Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece. 7. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece. 8. Department of Pathology, Hatzikosta Hospital, Ioannina, Greece. 9. Department of Surgery, Agii Anargiri Hospital, University of Athens, School of Health Sciences, Athens, Greece. 10. Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece. 11. Third Department of Medical Oncology, Hygeia Hospital, Athens, Greece. 12. Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece. 13. Oncology Unit, Hippokration Hospital, Athens, Greece. 14. First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece. 15. First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 16. Aristotle University of Thessaloniki, Thessaloniki, Greece.
Abstract
BACKGROUND: Epidermal growth factor receptor (EGFR) aberrations have been implicated in the pathogenesis of triple-negative breast cancer (TNBC) but their impact on prognosis and, therefore, druggability, remain controversial. Herein, we studied EGFR aberrations at different molecular levels and assessed their prognostic impact in patients with operable TNBC treated with adjuvant anthracycline-based chemotherapy. MATERIALS AND METHODS: We evaluated the prognostic impact of EGFR gene status by fluorescent in situ hybridization (FISH), EGFR coding mutations by Sanger and next-generation sequencing, relative EGFR messenger RNA (mRNA) levels by qPCR (upper quartile) and EGFR and p53 protein expression by immunohistochemistry (IHC), in 352 centrally-assessed tumors from an equal number of TNBC patients. RESULTS: Approximately 53.5% of the tumors expressed EGFR, 59.3% p53 and 35.9% both EGFR and p53 proteins; 4.1% showed EGFR gene amplification and 4.4% carried EGFR mutations. The latter were located outside the druggable kinase domain region and presented at low frequencies. Amplification and mutations overlapped only in one case of glycogen-rich carcinoma. EGFR and CEN7 copies were higher in tumors from older patients (p=0.002 and p=0.003, respectively). Patients with amplified tumors (n=11) had excellent prognosis (0 relapses and deaths). Upon multivariate analysis, high EGFR copies conferred significantly favorable disease-free survival (HR=0.57, 95% CI 0.36-0.90, Wald's p=0.017) and high CEN7 copies favorable overall survival (HR=0.49, 95% CI=0.29-0.83, Wald's p=0.008). Patients with EGFR-/p53+ and EGFR+/p53- tumors had significantly higher risk for relapse than those with EGFR-/p53- and EGFR+/p53+ tumors (HR=1.73, 95% CI=1.12-2.67, Wald's p=0.013). CONCLUSION: EGFR gene amplification and mutations are rare in TNBC, the latter of no apparent clinical relevance. Surrogate markers of EGFR-related chromosomal aberrations and combined EGFR/p53 IHC phenotypes appear to be associated with favorable prognosis in patients with operable TNBC receiving conventional adjuvant chemotherapy. Copyright
BACKGROUND:Epidermal growth factor receptor (EGFR) aberrations have been implicated in the pathogenesis of triple-negative breast cancer (TNBC) but their impact on prognosis and, therefore, druggability, remain controversial. Herein, we studied EGFR aberrations at different molecular levels and assessed their prognostic impact in patients with operable TNBC treated with adjuvant anthracycline-based chemotherapy. MATERIALS AND METHODS: We evaluated the prognostic impact of EGFR gene status by fluorescent in situ hybridization (FISH), EGFR coding mutations by Sanger and next-generation sequencing, relative EGFR messenger RNA (mRNA) levels by qPCR (upper quartile) and EGFR and p53 protein expression by immunohistochemistry (IHC), in 352 centrally-assessed tumors from an equal number of TNBC patients. RESULTS: Approximately 53.5% of the tumors expressed EGFR, 59.3% p53 and 35.9% both EGFR and p53 proteins; 4.1% showed EGFR gene amplification and 4.4% carried EGFR mutations. The latter were located outside the druggable kinase domain region and presented at low frequencies. Amplification and mutations overlapped only in one case of glycogen-rich carcinoma. EGFR and CEN7 copies were higher in tumors from older patients (p=0.002 and p=0.003, respectively). Patients with amplified tumors (n=11) had excellent prognosis (0 relapses and deaths). Upon multivariate analysis, high EGFR copies conferred significantly favorable disease-free survival (HR=0.57, 95% CI 0.36-0.90, Wald's p=0.017) and high CEN7 copies favorable overall survival (HR=0.49, 95% CI=0.29-0.83, Wald's p=0.008). Patients with EGFR-/p53+ and EGFR+/p53- tumors had significantly higher risk for relapse than those with EGFR-/p53- and EGFR+/p53+ tumors (HR=1.73, 95% CI=1.12-2.67, Wald's p=0.013). CONCLUSION:EGFR gene amplification and mutations are rare in TNBC, the latter of no apparent clinical relevance. Surrogate markers of EGFR-related chromosomal aberrations and combined EGFR/p53 IHC phenotypes appear to be associated with favorable prognosis in patients with operable TNBC receiving conventional adjuvant chemotherapy. Copyright
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