High Incidence of C797S Mutation in Patients With Long Treatment History of EGFR Tyrosine Kinase Inhibitors Including Osimertinib

Atsushi Osoegawa, MD, PhD; Masafumi Yamaguchi, MD, PhD; Tomomi Nakamura, MD, PhD; Ryotaro Morinaga, MD; Kentaro Tanaka, MD, PhD; Kosuke Kashiwabara, MD, PhD; Takashi Miura, MD, PhD; Takayuki Suetsugu, MD, PhD; Taishi Harada, MD, PhD; Tatsuma Asoh, MD, PhD; Kenichi Taguchi, MD, PhD; Kazuki Nabeshima, MD, PhD; Junji Kishimoto, MA; Kazuko Sakai, PhD; Kazuto Nishio, MD, PhD; Kenji Sugio, MD, PhD

JTO Clinical and Research Reports (Jul 2021)

High Incidence of C797S Mutation in Patients With Long Treatment History of EGFR Tyrosine Kinase Inhibitors Including Osimertinib

Atsushi Osoegawa, MD, PhD,
Masafumi Yamaguchi, MD, PhD,
Tomomi Nakamura, MD, PhD,
Ryotaro Morinaga, MD,
Kentaro Tanaka, MD, PhD,
Kosuke Kashiwabara, MD, PhD,
Takashi Miura, MD, PhD,
Takayuki Suetsugu, MD, PhD,
Taishi Harada, MD, PhD,
Tatsuma Asoh, MD, PhD,
Kenichi Taguchi, MD, PhD,
Kazuki Nabeshima, MD, PhD,
Junji Kishimoto, MA,
Kazuko Sakai, PhD,
Kazuto Nishio, MD, PhD,
Kenji Sugio, MD, PhD

Affiliations

Atsushi Osoegawa, MD, PhD: Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Yufu, Japan
Masafumi Yamaguchi, MD, PhD: Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan
Tomomi Nakamura, MD, PhD: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
Ryotaro Morinaga, MD: Department of Thoracic Medical Oncology, Oita Prefectural Hospital, Oita, Japan
Kentaro Tanaka, MD, PhD: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Kosuke Kashiwabara, MD, PhD: Division of Respiratory Disease, Kumamoto Regional Medical Center, Kumamoto, Japan
Takashi Miura, MD, PhD: Department of Thoracic Surgery, Shinbeppu Hospital, Beppu, Japan
Takayuki Suetsugu, MD, PhD: Department of Respiratory Medicine, Sendai Medical Association Hospital, Satsumasendai, Japan
Taishi Harada, MD, PhD: Department of Respiratory Medicine, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan
Tatsuma Asoh, MD, PhD: Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, Japan
Kenichi Taguchi, MD, PhD: Department of Pathology, National Kyushu Cancer Center, Fukuoka, Japan
Kazuki Nabeshima, MD, PhD: Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
Junji Kishimoto, MA: Center for Clinical and Translational Research, Kyushu University Hospital, Japan
Kazuko Sakai, PhD: Department of Genome Biology, Faculty of Medicine, Kindai University, Higashiosaka, Japan
Kazuto Nishio, MD, PhD: Department of Genome Biology, Faculty of Medicine, Kindai University, Higashiosaka, Japan
Kenji Sugio, MD, PhD: Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Yufu, Japan; Corresponding author. Address for correspondence: Kenji Sugio, MD, PhD, Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan.

Journal volume & issue: Vol. 2, no. 7
p. 100191

Abstract

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Introduction: Although treatment with osimertinib confers survival benefits in patients with lung cancer with the EGFR T790M mutation, the mechanism of acquired resistance to osimertinib remains poorly understood. We conducted a prospective observational study to identify the mechanism on the basis of repeated tissue biopsies. Methods: Patients with EGFR-mutated advanced lung cancer with a T790M mutation detected on a tissue biopsy underwent a rebiopsy after developing acquired resistance to osimertinib. Nucleic acids extracted from the biopsy samples were subjected to targeted resequencing (Oncomine Comprehensive Assay), and circulating cell-free DNA (ccfDNA) was analyzed by CAncer Personalized Profiling by deep Sequencing (AVENIO ctDNA Surveillance Kit). Results: Between November 2016 and March 2020, a total of 87 patients were screened. Among them, 44 developed acquired resistance. Of these, 19 samples from rebiopsies and 12 from preosimertinib biopsies were able to be analyzed by an Oncomine Comprehensive Assay. A ccfDNA analysis was performed in 16 patients. Regarding the mechanisms of acquired resistance, structural change in EGFR, namely, C797S, G796S, or L792V, was the most frequent alteration, being observed in 57.9% of the cases. MET gain was observed in 31.6% of the cases, and gains in cell cycle genes were observed in 26.3% of the cases. In addition, we identified GAS6 gain and an ATM mutation in a patient with small-cell transformation and a BRAF V600E mutation in a patient with oligoprogressive disease. Conclusions: A repeated tissue biopsy and a ccfDNA analysis were useful in analyzing the mechanisms underlying acquired resistance. A long treatment history of EGFR TKIs may result in a high percentage of EGFR structural change.

Published in JTO Clinical and Research Reports

ISSN: 2666-3643 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/jto-clinical-and-research-reports/

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