Barbara Klughammer1, Wolfram Brugger2, Federico Cappuzzo3, Tudor Ciuleanu4, Tony Mok5, Martin Reck6, Eng Huat Tan7, Paul Delmar8, Gaëlle Klingelschmitt8, Anny-Yue Yin8, Olivia Spleiss8, Lin Wu8, David S Shames9. 1. F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: Barbara.klughammer@roche.com. 2. Schwarzwald-Baar Klinikum, Academic Teaching Hospital, University of Freiburg, Villingen-Schwenningen, Germany. 3. Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy. 4. Prof. Dr. Ion Chiricuţă Institute of Oncology, Department of Medical Oncology; Universitatea de Medicină şi Farmacie Iuliu Haţieganu, Cluj-Napoca, Romania. 5. State Key Laboratory of Southern China, Hong Kong Cancer Institute, Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China. 6. Department of Thoracic Oncology, LungenClinic Grosshansdorf, Airway Research Center North, Grosshansdorf, Germany; German Research Center for Lung Diseases. 7. Department of Medical Oncology, National Cancer Centre, Singapore. 8. F. Hoffmann-La Roche Ltd, Basel, Switzerland. 9. Oncology Biomarker Development, Genentech Inc., San Francisco, California.
Abstract
INTRODUCTION: Exon 19 deletions and the exon 21 L858R mutation of the epidermal growth factor receptor gene (EGFR) predict activity of EGFR tyrosine kinase inhibitors, including erlotinib; however, the ability of less common EGFR mutations to predict efficacy of erlotinib is unclear. METHODS: The efficacy of erlotinib in individual patients with rare EGFR mutations from the MERIT, SATURN, TITAN, TRUST, ATLAS, BeTa, and FASTACT-2 trials was analyzed and compared with data from the literature. RESULTS: In the patients tested for biomarkers, the frequency of rare mutations identified here ranged from 1.7% (eight of 467) in the SATURN study to 7.4% (27 of 364) in ATLAS. Some rare mutations were associated with greater clinical benefit from EGFR tyrosine kinase inhibitor therapy or improved prognosis independent of treatment, whereas others appeared to have a poorer prognosis. In particular, exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome. Owing to the small number of patients with each mutation, however, it is difficult to confirm whether these rare mutations do indeed confer sensitivity or resistance to erlotinib. CONCLUSIONS: Erlotinib can have different efficacy depending on the specific EGFR mutation. More research is needed to create a central database such as the My Cancer Genome database of rare mutations to definitively confirm whether these mutations are activating, resistant, or neutral.
INTRODUCTION: Exon 19 deletions and the exon 21 L858R mutation of the epidermal growth factor receptor gene (EGFR) predict activity of EGFR tyrosine kinase inhibitors, including erlotinib; however, the ability of less common EGFR mutations to predict efficacy of erlotinib is unclear. METHODS: The efficacy of erlotinib in individual patients with rare EGFR mutations from the MERIT, SATURN, TITAN, TRUST, ATLAS, BeTa, and FASTACT-2 trials was analyzed and compared with data from the literature. RESULTS: In the patients tested for biomarkers, the frequency of rare mutations identified here ranged from 1.7% (eight of 467) in the SATURN study to 7.4% (27 of 364) in ATLAS. Some rare mutations were associated with greater clinical benefit from EGFR tyrosine kinase inhibitor therapy or improved prognosis independent of treatment, whereas others appeared to have a poorer prognosis. In particular, exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome. Owing to the small number of patients with each mutation, however, it is difficult to confirm whether these rare mutations do indeed confer sensitivity or resistance to erlotinib. CONCLUSIONS:Erlotinib can have different efficacy depending on the specific EGFR mutation. More research is needed to create a central database such as the My Cancer Genome database of rare mutations to definitively confirm whether these mutations are activating, resistant, or neutral.
Authors: Pawel Krawczyk; Dariusz M Kowalski; Rodryg Ramlau; Ewa Kalinka-Warzocha; Kinga Winiarczyk; Katarzyna Stencel; Tomasz Powrózek; Katarzyna Reszka; Kamila Wojas-Krawczyk; Maciej Bryl; Magdalena Wójcik-Superczyńska; Maciej Głogowski; Aleksander Barinow-Wojewódzki; Janusz Milanowski; Maciej Krzakowski Journal: Oncol Lett Date: 2017-04-03 Impact factor: 2.967
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