Research Papers:

Detection of the T790M mutation of EGFR in plasma of advanced non–small cell lung cancer patients with acquired resistance to tyrosine kinase inhibitors (West Japan oncology group 8014LTR study)

Takayuki Takahama, Kazuko Sakai, Masayuki Takeda, Koichi Azuma, Toyoaki Hida, Masataka Hirabayashi, Tetsuya Oguri, Hiroshi Tanaka, Noriyuki Ebi, Toshiyuki Sawa, Akihiro Bessho, Motoko Tachihara, Hiroaki Akamatsu, Shuji Bandoh, Daisuke Himeji, Tatsuo Ohira, Mototsugu Shimokawa, Yoichi Nakanishi, Kazuhiko Nakagawa and Kazuto Nishio _

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Oncotarget. 2016; 7:58492-58499. https://doi.org/10.18632/oncotarget.11303

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Takayuki Takahama1,*, Kazuko Sakai2,*, Masayuki Takeda1,*, Koichi Azuma3, Toyoaki Hida4, Masataka Hirabayashi5, Tetsuya Oguri6, Hiroshi Tanaka7, Noriyuki Ebi8, Toshiyuki Sawa9, Akihiro Bessho10, Motoko Tachihara11, Hiroaki Akamatsu12, Shuji Bandoh13, Daisuke Himeji14, Tatsuo Ohira15, Mototsugu Shimokawa16, Yoichi Nakanishi17, Kazuhiko Nakagawa1, Kazuto Nishio2

1Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan

2Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan

3Department of Internal Medicine, Division of Respirology, Neurology, and Rheumatology, Kurume University School of Medicine, Kurume, Fukuoka, Japan

4Department of Thoracic Oncology, Aichi Cancer Center, Nagoya, Japan

5Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan

6Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

7Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan

8Department of Respiratory Oncology, Iizuka Hospital, Fukuoka, Japan

9Department of Respiratory Medicine and Oncology, Gifu Municipal Hospital, Gifu, Japan

10Department of Pulmonary Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan

11Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan

12Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

13Division of Hematology, Rheumatology, and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan

14Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan

15Department of Surgery, Tokyo Medical University, Tokyo, Japan

16Department of Cancer Information Research, National Kyushu Cancer Center, Fukuoka, Japan

17Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

*These authors have contributed equally to this work

Correspondence to:

Kazuto Nishio, email: [email protected]

Keywords: non–small cell lung cancer, epidermal growth factor receptor (EGFR), mutation, T790M, cell-free DNA

Received: April 14, 2016    Accepted: July 27, 2016    Published: August 16, 2016


Introduction: Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic.

Methods: We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation–positive non–small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance.

Results: A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M.

Conclusions: Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.

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