Re-biopsy by endobronchial ultrasound procedures for mutation analysis of non-small cell lung cancer after EGFR tyrosine kinase inhibitor treatment

Izumo et al. BMC Pulmonary Medicine (2016) 16:106 DOI 10.1186/s12890-016-0268-3 RESEARCH ARTICLE Open Access Re-biopsy by endobronchial ultrasound procedures for mutation analysis of non-small cell lung cancer after EGFR tyrosine kinase inhibitor treatment Takehiro Izumo*, Yuji Matsumoto, Christine Chavez and Takaaki Tsuchida Abstract Background: Re-biopsy for resistant non-small cell lung cancer (NSCLC) after treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is important for selection of better therapy, but there have been no reports about the utility of endobronchial ultrasound (EBUS)-guided procedures for such purpose. The aim of this study was to evaluate the utility of EBUS-guided re-biopsy for resistant NSCLC after treatment with EGFR-TKIs. Methods: From January 2013 to December 2015, 53 consecutive patients who underwent EBUS-guided re-biopsy for mutation analysis of NSCLC after EGFR-TKI treatment were assessed. Results: Nine patients underwent EBUS-guided transbronchial needle aspiration (EBUS-TBNA) and 44 patients underwent EBUS with a guide sheath (EBUS-GS) transbronchial biopsy. The technical success rates were 100 %. As for mutation analysis, all 9 specimens (100 %) from EBUS-TBNA and 33 specimens (75.0 %) from EBUS-GS were adequate for gene profiling. The remaining 11 specimens from EBUS-GS procedures were inadequate for mutation analysis owing to the absence of tumor component in the sample (n = 6) or insufficient specimen (n = 5). There were no related severe complications. Conclusions: Re-biopsy by both EBUS-TBNA and EBUS-GS were useful and safe sampling procedures for mutation analysis of EGFR-TKI resistant NSCLC. Keywords: EGFR-TKI, EBUS-TBNA, EBUS-GS, T790M, Lung cancer, Re-biopsy Background Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been demonstrated to be effective in treating non-small cell lung cancer (NSCLC) patients with EGFR mutations [1–3]. EGFR-TKIs offer both good clinical response and survival benefit in NSCLC patients who have EGFR mutation [4]. However, a majority of the responders eventually develop acquired resistance to EGFR-TKIs [5]. Until now, several studies have uncovered several mechanisms of acquired resistance, such as secondary EGFR mutations (T790M mutation), mesenchymal-to* Correspondence: Department of Endoscopy, Respiratory Endoscopy Division, National Cancer Center Hospital, 5-1-1, Tsukiji Chou-ku, Tokyo 104-0045, Japan epithelial transition factor receptor (MET) amplification, and human epidermal growth factor receptor 2 (HER2) gene amplification [6]. Among these, a secondary missense T790M mutation was observed in nearly half of all cases that were resistant to EGFR-TKIs [7]. In November 2015, a third generation EGFR-TKI (Osimertinib; Astra Zeneca, London) has been approved by the US Food and Drug Administration (FDA) to treat patients with a type of advanced NSCLC that has a specific EGFR mutation, called T790M, and which has become worse after treatment with other EGFR-TKIs. Osimertinib has shown clinical effectiveness and tolerability in NSCLC patients with T790M mutation of EGFR [8]. © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Izumo et al. BMC Pulmonary Medicine (2016) 16:106 Examining T790M is very important in treatment selection. Because EGFR-TKI treatment is indicated for advanced and unresectable NSCLC, examination for T790M mutation is usually performed on small biopsy specimens. So far, most reports on re-biopsy procedures after EGFRTKI resistance have been on computed tomographyguided transthoracic needle biopsy (CTNB), which is also the common first method of choice for the initial diagnosis of lung cancer [9]. However, complications, such as pneumothorax and bleeding, after CTNB have been reported [9]. Another biopsy approach is by bronchoscopy, but its use has been limited by a lower diagnostic accuracy compared with CTNB. Recently, endobronchial ultrasound (EBUS) guidance during bronchoscopy procedures, such as EBUS guided-transbronchial needle aspiration (EBUS-TBNA) and EBUS with a guide sheath (EBUS-GS) transbronchial biopsy, have been introduced and improved the diagnostic accuracy of bronchoscopy [10, 11]. However, there have been no reports about the utility of EBUS procedures for re-biopsy. In this study, we evaluated the efficacy and safety of EBUS procedures for re-biopsy and mutation analysis of EGFR-TKI resistant NSCLC. Methods Subjects This study was approved by the National Cancer Center Institutional Review Board. Written informed consent for the procedure was obtained from all patients. Consecutive patients who underwent re-biopsy by EBUS procedures for mutation analysis of NSCLC after EGFRTKI treatment at the hospital between January 2013 and December 2015 were enrolled. There were 2907 patients in whom EBUS-guided bronchoscopy procedures were performed during the study period. Among these, 89 patients were for re-biopsy purposes. Among these rebiopsy patients, we selected NSCLC patients who were treated with at least one EGFR-TKI regimen. Disease progression during chemotherapy, based on the RECIST ver1.1 definition, was a criterion for inclusion; 36 patients were ineligible because of the absence of prior EGFR-TKI treatment. Methods and equipment All bronchoscopies were performed via the oral route under local anesthesia with mild sedation by intravenous administration of midazolam. EBUS-GS was performed for patients with peripheral pulmonary lesions (PPLs) without mediastinal and hilar lymphadenopathy; a GS kit (K-201 or K-203; Olympus Ltd, Tokyo, Japan) and a radial EBUS (R-EBUS) probe (UM-S20-20R or UM-S20-17S; Olympus Ltd, Tokyo, Page 2 of 6 Japan) were used. The bronchial route was planned by reviewing the chest CT images before EBUS-GS. Virtual bronchoscopic navigation/simulation systems (Ziostation2, Ziosoft Ltd, Tokyo, Japan; LungPoint, Bronchus Ltd, Mountain View, CA, USA; or Bf-Navi, Olympus Ltd, Tokyo, Japan) were used to detect the bronchial route to the target PPLs. A PPL was defined as an abnormal growth surrounded by normal lung parenchyma and was bronchoscopically invisible. Upon reaching the target bronchus, the GS together with the R-EBUS probe was inserted through the working channel of the bronchovideoscope and was advanced towards the PPL under fluoroscopic guidance (VersiFlex VISTAVR; Hitachi Ltd, Tokyo, Japan). Ultrasound sc (...truncated)