Relapsed and De Novo Metastatic HER2-positive Breast Cancer Treated With Trastuzumab: Tumor Genotypes and Clinical Measures Associated With Patient Outcome |
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| Authors: | Vassiliki Kotoula Kalliopi Tsakiri Georgia-Angeliki Koliou Georgios Lazaridis Kyriaki Papadopoulou Eleni Giannoulatou Ioannis Tikas Christos Christodoulou Kyriakos Chatzopoulos Mattheos Bobos George Pentheroudakis Eleftheria Tsolaki Anna Batistatou Athanassios Kotsakis Angelos Koutras Helena Linardou Evangelia Razis Eleni Res George Fountzilas |
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| Institution: | 1. Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece;2. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece;3. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece;4. Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece;5. Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia;6. The University of New South Wales, Kensington, NSW, Australia;7. Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece;8. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece;9. Department of Pathology, Ioannina University Hospital, Ioannina, Greece;10. University Hospital of Heraklion, University of Crete, School of Medicine, Heraklion, Crete, Greece;11. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece;12. First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece;13. Third Department of Medical Oncology, Hygeia Hospital, Athens, Greece;14. Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece;15. Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece;16. Aristotle University of Thessaloniki, Thessaloniki, Greece |
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| Abstract: | BackgroundWe examined tumor genotype characteristics of human epidermal growth factor receptor 2 (HER2)-positive relapsed (R-) and de novo (dn-) metastatic breast cancer (MBC) in trastuzumab-treated patients who were previously not exposed to this agent.Materials and MethodsWe analyzed genotypes obtained upon deep sequencing from 113 HER2-positive primary tumors from 69 patients with R-MBC and 44 patients with dn-MBC.ResultsMutations were observed in 90 (79.6%) tumors, 56 R-MBC and 34 dn-MBC (median number per tumor: 2; mean: 11.2; range: 0-150). The top mutated gene was TP53 (63.7%) followed by PIK3CA (24.8%) and others that were mostly co-mutated with TP53 (eg, 22 of 28 PIK3CA mutated tumors were co-mutated in TP53, 17 of these were R-MBC P = .041]). dn-MBC had higher CEN17 average copies (P = .048). Tumor mutational burden inversely correlated with average HER2 copies (rho ?0.32; P < .001). In all patients, PIK3CA mutations and higher proliferation rate were independent unfavorable prognosticators. In R-MBC, longer disease-free interval between initial diagnosis and relapse conferred lower risk for time-to-progression (P < .001) and death (P = .009); PIK3CA mutations conferred higher risk for death (P = .035). In dn-MBC, surgical removal of the primary tumor before any other therapy was favorable for time-to-progression (P = .002); higher tumor mutational burden was unfavorable for survival (P = .026).ConclusionsExcept for the overall unfavorable prognostic effect of PIK3CA mutations in trastuzumab-treated MBC, our exploratory findings indicate that the outcome of patients with R-MBC is related to patient benefit from the preceding adjuvant chemotherapy and provide initial evidence that tumor mutational burden may be related to prognosis in dn-MBC, which is of potential clinical relevance and merits further investigation. |
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| Keywords: | Disease-free interval Locoregional surgery Tumor mutational burden |
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