Abstract After pulmonary resection for non-small-cell lung cancer, some patients with postoperative recurrence and mutated epidermal growth factor receptor (EGFR) subsequently receive EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib may be efficacious if those patients become resistant to the 1st-line EGFR-TKI because of the T790M mutation. We recently performed thoracoscopic rebiopsy to detect the T790M mutation in 4 patients who became resistant to the 1st-line EGFR-TKI treatment for postoperative recurrence. Our limited experience suggests that thoracoscopic biopsy is associated with limited morbidity, can help detect the T790M mutation and may improve the management of select patients with acquired resistance to the 1st-line EGFR-TKIs. Lung cancer, Epidermal growth factor receptor, Thoracoscopy, Rebiopsy INTRODUCTION Epidermal growth factor receptor (EGFR) mutations are robust prognostic factors in patients with lung adenocarcinoma . EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are efficacious in patients with lung adenocarcinoma who harbour EGFR mutations. However, almost all patients with EGFR-mutant adenocarcinoma will develop resistance to the 1st-line EGFR-TKI. This tendency also applies to patients who are receiving EGFR-TKIs for postoperative recurrence after pulmonary resection of lung adenocarcinoma. The major mechanism of this acquired resistance is a secondary T790M mutation in exon 20 of the EGFR gene. Osimertinib is an oral, 3rd generation, irreversible and selective drug that is administered to patients with EGFR-TKI-sensitizing mutation or the T790M resistance mutation. A relatively less invasive rebiopsy is preferred to detect the T790M mutation, although a more invasive biopsy may be required if a rebiopsy provides negative results. To the best of our knowledge, no report has described thoracoscopic rebiopsy for detecting the T790M mutation. Therefore, we report our early experience on using thoracoscopic lung biopsy to detect the T790M mutation in patients with acquired resistance to EGFR-TKIs after pulmonary resection of non-small-cell lung cancer (NSCLC). CASE SERIES Four patients underwent thoracoscopic rebiopsy of peripheral pulmonary lesions under general anaesthesia at the Kyoto University Hospital between 2016 and 2017. All patients had maintained a satisfactory performance status (the Eastern Cooperative Oncology Group score of 0 or 1). Preoperative pulmonary function testing revealed a median expected vital capacity of 86.2% and a median expected forced expiratory volume in 1 s of 78.3%. The operating time ranged from 40 to 55 min. All rebiopsy specimens were tested for the T790M mutation using the Cobas EGFR Mutation Test kit. Acquired resistance to EGFR-TKIs was defined according to Jackman’s criteria . The treatment sequences of patient are summarized in Fig. 1. Figure 1: View largeDownload slide The treatment sequences for each patient. (A) Patient A; (B) patient B; (C) patient C; (D) patient D. Figure 1: View largeDownload slide The treatment sequences for each patient. (A) Patient A; (B) patient B; (C) patient C; (D) patient D. Patient A A 65-year-old woman with no smoking history and no significant comorbidities underwent thoracoscopic right upper lobectomy for lung adenocarcinoma (pT1N2M0). Her initial EGFR status was positive for exon 19 deletion. Multiple recurrent pulmonary lesions developed during adjuvant cytotoxic chemotherapy, which was switched to gefitinib. On the basis of the disease progression, the patient was switched to erlotinib treatment and then to treatment using carboplatin plus pemetrexed. There was no candidate site for rebiopsy other than multiple peripheral pulmonary lesions (Fig. 2), and the patient underwent thoracoscopic left lower lobe wedge resection as rebiopsy. The specimen had a diameter of 2.4 cm and testing revealed the T790M mutation. The patient subsequently underwent osimertinib treatment and has survived with stable disease. Figure 2: View largeDownload slide Computed tomography for the pulmonary lesions at each patient’s rebiopsy. (A) Patient A; (B) patient B; (C) patient C; (D) patient D. Figure 2: View largeDownload slide Computed tomography for the pulmonary lesions at each patient’s rebiopsy. (A) Patient A; (B) patient B; (C) patient C; (D) patient D. Patient B A 55-year-old man with a 4-pack-year smoking history and no significant comorbidities underwent thoracoscopic left lower lobectomy for lung adenocarcinoma (pT1aN0M0). His initial EGFR status was positive for the L858R mutation in exon 21. At 2 years after surgery, the patient experienced recurrence as vertebral and multiple pulmonary lesions, and treatment was initiated using erlotinib. The patient subsequently experienced disease progression (Fig. 2), and the erlotinib treatment was discontinued 2 weeks before he underwent thoracoscopic right middle lobe wedge resection. The postoperative course was complicated by a prolonged air leak that required pleurodesis. The specimen had a diameter of 0.7 cm, and testing revealed the T790M mutation. The patient subsequently underwent treatment using osimertinib and has survived with stable disease. Patient C A 60-year-old woman with no smoking history and no significant comorbidity underwent thoracoscopic right upper lobectomy for lung adenocarcinoma (pT3N2M1). Her initial EGFR status was positive for the L858R mutation in exon 21. Two years after surgery, the patient experienced recurrence at the mediastinal and supraclavicular lymph nodes, with multiple lung lesions, and treatment was initiated using gefitinib. The gefitinib treatment was continued until the patient underwent a liquid biopsy, which revealed negative results for the T790M mutation. Thus, the patient underwent thoracoscopic left lower lobe wedge resection (Fig. 2). The specimen had a diameter of 0.9 cm, and testing revealed negative results for the T790M mutation. The patient has been switched to erlotinib treatment from gefitinib treatment. One year after the thoracoscopic rebiopsy, liquid biopsy was repeated, and the T790M mutation was not detected. The patient has been switched to cytotoxic chemotherapy with bevacizumab for slowly growing pulmonary metastases. Patient D A 67-year-old man with a 9-pack-year smoking history and bronchial asthma, but no other comorbidities, underwent thoracoscopic left upper lobectomy for lung adenocarcinoma (pT2N0M0). His initial EGFR status was positive for exon 19 deletion. The patient experienced recurrence 1 year after surgery and began platinum-based chemotherapy. After he experienced disease progression, erlotinib treatment was initiated (with bevacizumab for 1 year) and achieved stable disease for 7 years. However, growth in peripheral lung lesions was detected (Fig. 2), and a liquid biopsy revealed negative results for the T790M mutation. Thus, the patient underwent thoracoscopic right lower lobe wedge resection, and the erlotinib treatment was continued during the perioperative period. The specimen had a diameter of 1.7 cm and was positive for the T790M mutation. The patient initiated osimertinib treatment and remains alive with stable disease. DISCUSSION Approximately 40% of patients with NSCLC experience recurrence after pulmonary resection . In that setting, patients with EGFR-mutant NSCLC experience initially a high response to EGFR-TKIs, although their progression-free survival is relatively short (∼16 months) . Two patients had exon 19 deletions as their initial EGFR status, and both patients were detected with the T790M mutation on thoracoscopic rebiopsy. The other 2 patients harboured the L858R mutation in exon 21 as their initial EGFR status, and 1 patient was detected with the T790M mutation on thoracoscopic rebiopsy. Two patients did not undergo liquid biopsy before thoracoscopic rebiopsy, and the 2 patients who underwent liquid biopsy tested negative for the T790M mutation. Most of the patients continued erlotinib treatment during the perioperative periods, although this has not been described in previous reports of rebiopsy to detect the T790M mutation [5, 6]. For example, Ko et al. reported that all the rebiopsies were performed after the EGFR-TKI treatment was discontinued. However, our experience indicates that thoracoscopic rebiopsy with perioperative erlotinib treatment was associated with a low morbidity rate (25%) and no mortality. Thus, erlotinib may be safe for patients who are undergoing thoracoscopic rebiopsy. An alternative for these patients could be trans-bronchial lung biopsy, although this approach is unlikely to be successful for peripheral pulmonary lesions. Nevertheless, Ko et al. and Kawamura et al. have reported that most rebiopsies for peripheral pulmonary lesions have been trans-bronchial, although the success rate was not available in that report. Another option may be computed tomography (CT)-guided transthoracic needle biopsy. Advantages of CT-guided transthoracic biopsy over thoracoscopic rebiopsy include no requirement for general anaesthesia and an outpatient procedure, whereas disadvantages include a presumably higher rate of false negatives than obtained with thoracoscopic rebiopsy. There have been no studies to compare CT-guided rebiopsy and thoracoscopic rebiopsy in tissue volume to detect the T790M mutation [7, 8]. We suspect that one of our patients (Patient A) may benefit from a CT-guided rebiopsy. On the other hand, acquired resistance to EGFR-TKIs varies. In addition to target gene modification (such as the T790M mutation), alternative pathway activation (such as MET amplification) and histological or phenotypic transformation (such as transformation to small cell lung cancer or epithelial-mesenchymal transformations) should also be considered when analysing acquired resistance to EGFR-TKIs . In the future perspective, thoracoscopic rebiopsy would be advantageous in terms of sufficient tissue volume to perform the additional analyses simultaneously and in the same specimen. Rebiopsy for detecting the T790M mutation has become an important technique for managing patients with EGFR-mutant NSCLC, and a less invasive rebiopsy (such as liquid rebiopsy) is preferred. However, Kawamura et al. demonstrated that tissue samples, rather than fluid samples, are more likely to be positive for the T790M mutation. If liquid biopsy fails, selected patients who can tolerate general anaesthesia may undergo thoracoscopic rebiopsy for peripheral pulmonary lesions. The contralateral side should be selected for patients who have previously undergone pulmonary resection. Conflict of interest: none declared. REFERENCES 1 Matsumura Y , Owada Y , Yamaura T , Muto S , Osugi J , Hoshino M et al. Epidermal growth factor receptor gene mutation as risk factor for recurrence in patients with surgically resected lung adenocarcinoma: a matched-pair analysis . Interact CardioVasc Thorac Surg 2016 ; 23 : 216 – 22 . Google Scholar CrossRef Search ADS PubMed 2 Jackman D , Pao W , Riely GJ , Engelman JA , Kris MG , Jänne PA et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer . J Clin Oncol 2010 ; 28 : 357 – 60 . Google Scholar CrossRef Search ADS PubMed 3 Sugimura H , Nichols FC , Yang P , Allen MS , Cassivi SD , Deschamps C et al. Survival after recurrent nonsmall-cell lung cancer after complete pulmonary resection . Ann Thorac Surg 2007 ; 83 : 409 – 17 . Google Scholar CrossRef Search ADS PubMed 4 Yokoyama Y , Sonobe M , Yamada T , Sato M , Menju T , Aoyama A et al. Gefitinib treatment in patients with postoperative recurrent non-small-cell lung cancer harboring epidermal growth factor receptor gene mutations . Int J Clin Oncol 2015 ; 20 : 1122 – 9 . Google Scholar CrossRef Search ADS PubMed 5 Ko R , Kenmotsu H , Serizawa M , Koh Y , Wakuda K , Ono A et al. Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients . BMC Cancer 2016 ; 16 : 864. Google Scholar CrossRef Search ADS PubMed 6 Kawamura T , Kenmotsu H , Omori S , Nakashima K , Wakuda K , Ono A et al. Clinical factors predicting detection of T790M mutation in rebiopsy for EGFR-mutant non-small-cell lung cancer . Clin Lung Cancer 2018 ; 19 : e247 – 52 . Google Scholar CrossRef Search ADS PubMed 7 Li X , Zhou C. Comparison of cross-platform technologies for EGFR T790M testing in patients with non-small cell lung cancer . Oncotarget 2017 ; 8 : 100801 – 18 . Google Scholar PubMed 8 Wu YL , Tong RZ , Zhang Y , Hu BB , Zheng K , Ding ZY et al. Conventional real-time PCR-based detection of T790M using tumor tissue or blood in patients with EGFR TKI-resistant NSCLC . Onco Targets Ther 2017 ; 10 : 3307 – 12 . Google Scholar CrossRef Search ADS PubMed 9 Wu SG , Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer . Mol Cancer 2018 ; 17 : 38. Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Interactive CardioVascular and Thoracic Surgery – Oxford University Press
Published: Apr 2, 2018
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