ORIGINAL ARTICLE – THORACIC
Interactive CardioVascular and Thoracic Surgery 23 (2016) 216–222 doi:10.1093/icvts/ivw116 Advance Access publication 12 May 2016
Cite this article as: 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.
Epidermal growth factor receptor gene mutation as risk factor for recurrence in patients with surgically resected lung adenocarcinoma: a matched-pair analysis Yuki Matsumuraa,*, Yuki Owadaa, Takumi Yamauraa, Satoshi Mutoa, Jun Osugia, Mika Hoshinoa, Mitsunori Higuchia, Tetsuya Ohirab, Hiroyuki Suzukia and Mitsukazu Gotoha a b
Department of Regenerative Surgery, School of Medicine, Fukushima Medical University, Fukushima, Japan Department of Epidemiology, School of Medicine, Fukushima Medical University, Fukushima, Japan
* Corresponding author. Department of Regenerative Surgery, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan. Tel: +81-24-5471111; fax: +81-24-5482735; e-mail:
[email protected] (Y. Matsumura). Received 30 October 2015; received in revised form 28 January 2016; accepted 17 February 2016
Abstract OBJECTIVES: Epidermal growth factor receptor (EGFR) mutation is a robust prognostic factor in patients with lung adenocarcinoma (ADC). However, the role of EGFR mutation status as a recurrence-risk factor remains unknown because the presence of such mutations is associated with other background characteristics. We therefore conducted a matched-pair analysis to compare recurrence-free survival (RFS) in matched cohorts of patients with lung ADC. METHODS: We enrolled 379 patients who underwent surgical resection for lung ADC between 2005 and 2012. We determined the EGFR mutation status of each tumour. Matching their age, gender, smoking history and pathological stage ( pStage), we compared RFS between matched cohorts with and without EGFR mutation (n = 86 each). RESULTS: The median age was 67 years, there were 39 (45%) men, 39 (45%) ex- or current smokers and pStage I: 71 (83%), II: 5 (6%), III: 8 (9%), IV: 2 (2%) in each group. The 3- and 5-year RFS rates in patients with mutant and wild-type EGFR were 85 and 78%, and 74 and 60%, respectively, with significant differences between the groups (P = 0.040). Multivariate analysis identified vascular invasion and lymphatic permeation, but not EGFR mutation status, as independent risk factors for recurrence. CONCLUSIONS: EGFR-gene mutation might be a favourable recurrence-risk factor in patients with surgically resected lung ADC, but further studies in larger cohorts are needed to verify this hypothesis. Keywords: Lung adenocarcinoma • Epidermal growth factor receptor • Recurrence factor • Matched-pair analysis
INTRODUCTION The identification of epidermal growth factor receptor (EGFR) gene mutations and introduction of EGFR tyrosine kinase inhibitors (EGFR–TKI) have dramatically changed the treatment of advanced or recurrent lung adenocarcinoma (ADC) over the last decade [1, 2]. The value of EGFR–TKIs has been demonstrated in Phase III randomized trials [3, 4], and they are currently the first-choice treatment for patients with advanced or recurrent lung ADCs harbouring EGFR mutations [2, 5]. Regarding surgically resected ADCs, some retrospective studies also reported that mutant EGFR was a favourable prognostic factor for postoperative overall survival (OS) [6, 7], but were unable to demonstrate whether EGFR mutation itself makes effects on the postoperative survival of ADCs, partly because of well-known biases in clinical backgrounds between lung ADC
patients with mutant and wild-type EGFR. EGFR mutations are more common in women and in non-smokers, and many reports have shown better survival in these patients, irrespective of their EGFR status [8, 9]. Furthermore, EGFR–TKIs appear to prolong post-recurrence survival in surgically resected lung ADC in patients harbouring EGFR mutations [6, 10], making it impossible to determine if the prolonged survival of EGFRmutated ADC patients was the result of EGFR–TKIs or EGFR mutation itself. We reduced these biases in patient backgrounds by carrying out a matched-pair analysis to compare recurrence-free survival (RFS) between lung ADC patients with and without EGFR mutations, free from the effects of EGFR–TKIs. The primary aim of the study was thus to clarify the value of EGFR mutation status as a recurrence-risk factor in patients with surgically resected lung ADCs, using matched-pair analysis.
© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
Y. Matsumura et al. / Interactive CardioVascular and Thoracic Surgery
PATIENTS AND METHODS
Histopathological examination
Patient selection
Resected specimens were immediately examined macroscopically, and lobar and sublobar lymph nodes were removed in the operating room. Whole specimens were then fixed in 10% formalin and sectioned horizontally at 5–10-mm intervals. We routinely created paraffin-embedded sections of several surfaces of the main tumour. Other nodules off the main tumour were examined macroscopically and pathologically. Serial 4-µm sections were stained with haematoxylin and eosin for routine histopathological work-up. Elastica–Masson staining was routinely used to visualize elastic fibres in all sections containing tumour cells for evaluating vascular invasion, lymphatic permeation and pleural invasion. We re-evaluated the invasiveness of the enrolled lung ADCs in terms of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA), and classified their pathological stage ( pStage) according to the TNM classification of malignant tumours of the Union for International Cancer Control (UICC, 7th edition) [11] and the newly published World Health Organization (WHO) classification [12].
A total of 601 consecutive patients underwent surgical resection for primary lung cancer in Fukushima Medical University between January 2005 and December 2012, of which 546 (91%) had lobectomies. Among them, 406 (68%) had ADCs that were examined for EGFR mutation status. Patients were excluded if they had undergone incomplete resection, or had anaplastic lymphoma kinase fusion genes. We excluded also the patients who took EGFR–TKIs before recurrence because EGFR–TKIs were reported to make effects on RFS. The patients in whom EGFR mutation status could not be determined because of insufficient specimens were also excluded. A total of 379 patients (93%) were finally enrolled in this study (Supplementary Fig. 1). The study was approved by the institutional review board of Fukushima Medical University in July 2015. Most patients underwent preoperative evaluations including physical examination, chest X-ray, chest and upper abdomen computed tomography (CT), brain magnetic resonance imaging (MRI) and positron emission tomography (PET).
Table 1: Clinicopathological characteristics of all enrolled patients (n = 379) Characteristic
Median age (years) Sex Smoking history Serum CEA Median FEV1.0 Procedure
Pathological stage
WHO classification
Pleural invasion Vascular invasion Lymphatic permeation Adjuvant therapy
EGFR mutation
EGFR–TKI
Range Male Ex- or current Never >5 mg/dl l (range) Lobectomy Segmentectomy Wedge resection IA IB II III IV AIS MIA IA Present Present Present Not performed Platinum double Oral drugs Others Exon21 L858R Exon19 del Exon20 T790M Others Administered
EGFR Mutant n = 192 (%)
EGFR Wild-type n = 187 (%)
P-value
69 (26–88) 67 (35) 55 (29) 137 (71) 33 (17) 2.1 (0.8–3.9) 175 (91) 12 (6) 5 (3) 115 (60) 34 (18) 16 (8) 23 (12) 4 (2) 8 (4) 18 (9) 166 (87) 34 (18) 44 (23) 57 (30) 141 (73) 23 (12) 26 (14) 2 (1) 102 (53) 68 (35) 11 (6)a 16 (8) 39 (20)
67 (37–87) 118 (63) 125 (67) 62 (33) 45 (24) 2.2 (1.0–5.0) 170 (91) 8 (4) 9 (5) 91(49) 42 (22) 27 (14) 20 (11) 7 (4) 17 (9) 9 (5) 161 (86) 50 (27) 51 (27) 63 (34) 132 (71) 24 (13) 27 (14) 4 (2) NA NA NA NA 10 (5)
0.103
