Loic Verlingue1, Antoine Hollebecque2, Ludovic Lacroix3, Sophie Postel-Vinay1, Andrea Varga2, Yolla El Dakdouki1, Capucine Baldini1, Rastilav Balheda1, Anas Gazzah1, Jean-Marie Michot1, Aurélien Marabelle1, Olivier Mir4, Monica Arnedos4, Etienne Rouleau3, Eric Solary5, Thierry De Baere6, Eric Angevin1, Jean-Pierre Armand1, Stefan Michiels7, Fabrice André8, Eric Deutsch9, Jean-Yves Scoazec3, Jean-Charles Soria10, Christophe Massard11. 1. Drug Development Department, Gustave Roussy, Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France. 2. Drug Development Department, Gustave Roussy, Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France; Gustave Roussy Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France. 3. Genomic Platform Molecular Biopathology Unit and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655, University Paris XI, Gustave Roussy, Villejuif, France; Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France. 4. Gustave Roussy Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France. 5. Inserm Unit UMR 1170, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France. 6. Department of Interventional Radiology, Gustave Roussy, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France. 7. Service de Biostatistique et D'épidémiologie, Gustave Roussy, Villejuif, France; CESP, INSERM, Fac. de Médecine, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France. 8. Gustave Roussy Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France; Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France. 9. Radiotherapy Unit, Gustave Roussy, Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France. 10. Drug Development Department, Gustave Roussy, Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France; Gustave Roussy Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France; Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France. 11. Drug Development Department, Gustave Roussy, Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France; Gustave Roussy Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Kremlin-Bicêtre, France. Electronic address: Christophe.MASSARD@gustaveroussy.fr.
Abstract
INTRODUCTION: Therapeutic inhibition of the human epidermal receptor 3 (ERBB3, HER3) has been challenged by the low frequency of ERBB3 somatic alterations across cancer types. We have evaluated the clinical utility to use available inhibitors of the HER family in the context of ERBB3 mutations. PATIENTS AND METHODS: In this study, we have selected patients with somatic ERBB3 alterations detected in their tumours from the molecular screening programs running at our institution. Techniques used for molecular screening were targeted next generation sequencing, comparative genomic hybridisation and/or whole exome sequencing on fresh frozen tumour biopsies. RESULTS: On the 844 patients with a molecular portrait of their tumours, 31 (3.7%) had a somatic mutation of ERBB3. Overall, 9 patients received available inhibitors of HER family, including trastuzumab and/or lapatinib or afatinib. Sixteen patients received other molecularly targeted agents, including the Mammalian Target Of Rapamycin (mTOR), the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K) or NOTCH inhibitors or chemotherapy, and 4 patients failed being treated. Thirteen different histological subtypes were affected by ERBB3 mutations; top ones were colorectal carcinomas (6 patients), non-small cell lung cancers (4 patients, including a squamous cell carcinoma), head and neck squamous cell carcinomas (3 patients) and breast carcinomas (3 patients). The presence of a mutation in the tyrosine kinase domain of the ERBB3/HER3 protein detected in four patients' tumours was significantly related to good progression-free survival (hazard ratio [HR] = 0.18, p value = 0.022) and overall survival (HR = 0.19, p value = 0.03) in univariate analysis. Treatment of these four patients included at least a tyrosine kinase inhibitor lapatinib or afatinib. CONCLUSION: Our exploratory analysis suggests that mutations in the tyrosine kinase domain of the HER3 protein are related to a favourable outcome under HER family inhibitors.
INTRODUCTION: Therapeutic inhibition of the human epidermal receptor 3 (ERBB3, HER3) has been challenged by the low frequency of ERBB3 somatic alterations across cancer types. We have evaluated the clinical utility to use available inhibitors of the HER family in the context of ERBB3 mutations. PATIENTS AND METHODS: In this study, we have selected patients with somatic ERBB3 alterations detected in their tumours from the molecular screening programs running at our institution. Techniques used for molecular screening were targeted next generation sequencing, comparative genomic hybridisation and/or whole exome sequencing on fresh frozen tumour biopsies. RESULTS: On the 844 patients with a molecular portrait of their tumours, 31 (3.7%) had a somatic mutation of ERBB3. Overall, 9 patients received available inhibitors of HER family, including trastuzumab and/or lapatinib or afatinib. Sixteen patients received other molecularly targeted agents, including the Mammalian Target Of Rapamycin (mTOR), the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K) or NOTCH inhibitors or chemotherapy, and 4 patients failed being treated. Thirteen different histological subtypes were affected by ERBB3 mutations; top ones were colorectal carcinomas (6 patients), non-small cell lung cancers (4 patients, including a squamous cell carcinoma), head and neck squamous cell carcinomas (3 patients) and breast carcinomas (3 patients). The presence of a mutation in the tyrosine kinase domain of the ERBB3/HER3 protein detected in four patients' tumours was significantly related to good progression-free survival (hazard ratio [HR] = 0.18, p value = 0.022) and overall survival (HR = 0.19, p value = 0.03) in univariate analysis. Treatment of these four patients included at least a tyrosine kinase inhibitor lapatinib or afatinib. CONCLUSION: Our exploratory analysis suggests that mutations in the tyrosine kinase domain of the HER3 protein are related to a favourable outcome under HER family inhibitors.
Authors: Swapnil Parmar; Jamie M Keck; Ben Kong; Regan Look; Brett Johnson; Janice Patterson; Marilyne Labrie; Alexander R Guimaraes; Christopher L Corless; Carol Beadling; Annette Kolodzie; Raymond Bergan; Joe W Gray; Gordon B Mills; Zahi I Mitri Journal: JCO Precis Oncol Date: 2021-01-08
Authors: Marzia Del Re; Federico Cucchiara; Iacopo Petrini; Stefano Fogli; Antonio Passaro; Stefania Crucitta; Ilaria Attili; Filippo De Marinis; Antonio Chella; Romano Danesi Journal: ESMO Open Date: 2020-08
Authors: Aideen M McInerney-Leo; Hui Yi Chew; Po-Ling Inglis; Paul J Leo; Shannon R Joseph; Caroline L Cooper; Satomi Okano; Tim Hassall; Lisa K Anderson; Rayleen V Bowman; Michael Gattas; Jessica E Harris; Mhairi S Marshall; Janet G Shaw; Lawrie Wheeler; Ian A Yang; Matthew A Brown; Kwun M Fong; Fiona Simpson; Emma L Duncan Journal: Hum Mol Genet Date: 2021-11-30 Impact factor: 6.150