Accepted Manuscript Prognostic factors for survival after recurrence in patients with completely resected lung adenocarcinoma: important roles of epidermal growth factor receptor mutation status and current staging system Yujin Kudo, MD, PhD, Yoshihisa Shimada, MD, PhD, Hisashi Saji, MD, PhD, Yasufumi Kato, MD, PhD, Koichi Yoshida, MD, PhD, Jun Matsubayashi, MD, PhD, Seisuke Nagase, MD, PhD, Masatoshi Kakihana, MD, PhD, Naohiro Kajiwara, MD, PhD, Tatsuo Ohira, MD, PhD, Toshitaka Nagao, MD, PhD, Norihiko Ikeda, MD, PhD PII:

S1525-7304(15)00088-1

DOI:

10.1016/j.cllc.2015.04.005

Reference:

CLLC 374

To appear in:

Clinical Lung Cancer

Received Date: 25 February 2015 Revised Date:

10 April 2015

Accepted Date: 14 April 2015

Please cite this article as: Kudo Y, Shimada Y, Saji H, Kato Y, Yoshida K, Matsubayashi J, Nagase S, Kakihana M, Kajiwara N, Ohira T, Nagao T, Ikeda N, Prognostic factors for survival after recurrence in patients with completely resected lung adenocarcinoma: important roles of epidermal growth factor receptor mutation status and current staging system, Clinical Lung Cancer (2015), doi: 10.1016/ j.cllc.2015.04.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Prognostic factors for survival after recurrence in patients with completely

receptor mutation status and current staging system

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Brief title: Postoperative recurrence in lung adenocarcinoma

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resected lung adenocarcinoma: important roles of epidermal growth factor

Authors: Yujin Kudo, MD, PhD 1), Yoshihisa Shimada, MD, PhD 1), Hisashi Saji, MD, 1,2)

, Yasufumi Kato, MD, PhD 1), Koichi Yoshida, MD, PhD 1), Jun Matsubayashi

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PhD

MD, PhD 3), Seisuke Nagase, MD, PhD

, Masatoshi Kakihana, MD, PhD 1), Naohiro

1)

, Tatsuo Ohira, MD, PhD

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Kajiwara, MD, PhD

1)

1)

, Toshitaka Nagao, MD, PhD

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Norihiko Ikeda, MD, PhD 1)

Institutions and affiliations:

1) Department of Thoracic Surgery, Tokyo Medical University

2) Department of Chest Surgery, St. Marianna University School of Medicine 1

3)

,

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3) Department of Anatomic Pathology, Tokyo Medical University

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Corresponding author: Yujin Kudo, MD, PhD

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Department of Thoracic Surgery, Tokyo Medical University

6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

Tel.: +81-(0)3-3342-6111 (ext. 5070)

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Fax: +81-(0)3-3349-0326

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E-mail: [email protected]

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MicroAbstract

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EGFR status and pathological stage were shown to be essential prognostic factors for estimating postrecurrence survival from lung adenocarcinoma. In patients with mutants, those with early p-staged tumors showed better PRS than those with advanced p-staged

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tumors. Both the EGFR mutation status and p-stage could also prompt the design of

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clinical trials on adjuvant therapy for patients after complete surgical resection.

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Abstract

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Background:

The current staging system and epidermal growth factor receptor (EGFR) mutation

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status are key factors for predicting survival. However, the significance of these factors as predictors of postrecurrence survival (PRS) has not yet been sufficiently elucidated.

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The objective of this study was to investigate the clinicopathological factors, particularly the EGFR mutation status and pathological stage (p-stage), which affect

Methods:

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PRS in completely resected lung adenocarcinoma patients.

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We retrospectively reviewed the data of 198 consecutive lung adenocarcinoma patients

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with recurrence who previously underwent complete surgical resection in our hospital.

Results:

Of the 198 patients, 117 were examined for EGFR mutations. EGFR mutations (mutants) were detected in 57 patients (28.7%). The patients with mutants had a significantly better 3-year PRS (3y-PRS) rate (68.6%) than those with a wild-type (WT) (51.7%) and an unknown (UN) (27.0%) status. The 3y-PRS rates for p-stage I-II (p-I-II) 4

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and p-stage III (p-III) were 52.5% and 29.3%, respectively. Multivariate survival analysis showed that the EGFR mutation status and p-stage had significant associations

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with favorable PRS. The 3y-PRS rate for mutants / p-I-II (81.4%) was significantly better than that for mutants / p-III (48.0%). Conversely, there was no significant

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mutants / p-III and WT/UN / p-III (3y-PRS: 24.4%).

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difference between mutants / p-III and WT/UN / p-I-II (3y-PRS: 40.7%) or between

Conclusion:

EGFR status and p-stage were shown to be essential prognostic factors for estimating

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PRS. In patients with mutants, those with early p-staged tumors showed better PRS than

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those with advanced p-staged tumors.

Keywords: Non-small cell lung cancer, Epidermal growth factor receptor, Postoperative recurrence survival, Pathological stage, Brain metastasis

Abbreviations:

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EGFR, epidermal growth factor receptor; PRS, postrecurrence survival; p-stage, pathological stage; mutant, EGFR mutation; WT, wild-type; UN, unknown; p-I-II,

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pathological stage I-II; p-III, pathological stage III; NSCLC, non-small cell lung cancer; OS, overall survival; RFS, recurrence-free survival; EGFR-TKIs, EGFR tyrosine kinase

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inhibitors; VPI, visceral pleural invasion; CT, computed tomography; RFI,

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recurrence-free interval; HR, hazard ratio; UVA, univariate analysis; MVA, multivariate

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analysis

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Introduction

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Complete surgical resection is the most effective treatment for early-stage (stages I and II) and appropriately selected locally advanced (stage IIIA) non-small cell lung cancer (NSCLC), and provides the best possible cure. The reported recurrence

1-3

. With the advancement of local and

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recurrence is the most common cause of death

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rates after surgical resection in patients with stages I-IIIA range from 35% to 75%, and

systemic therapies for recurrent NSCLC, postrecurrence survival (PRS) has been extensively improved

4, 5

. However, conclusive factors affecting PRS in NSCLC have

not yet been discussed as widely as those affecting overall survival (OS) or

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recurrence-free survival (RFS) from the initial treatment. The risk of relapse is considered to increase exponentially with increased stage.

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Several studies have demonstrated that p-stage at the first operation is strongly

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associated with not only OS and RFS but also PRS 4-10. Yoshino et al. described that the inherent malignant potential of advanced-stage NSCLC may bring a PRS difference 5. In contrast, other reports neglected the association between advanced stage and PRS 12

11,

. Epidermal growth factor receptor (EGFR) mutation, the majority of which have

been detected in lung adenocarcinoma, is a predictor of response to EGFR tyrosine 7

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kinase inhibitors (EGFR-TKIs), with 70% to 80% of NSCLC patients receiving substantial benefits from these targeted therapies

13-15, 16, 17

. EGFR mutation is reported

Testing for these mutations

in all

patients

with

8, 9, 18, 19

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to be both predictive and prognostic factors of EGFR-TKI therapy outcome

.

recurrent/metastatic lung

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adenocarcinoma is therefore recommended for standard practice.

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Although both the current staging system and the EGFR mutation status are considered as determinants for predicting survival, the significance of these factors as predictors of PRS has not yet been sufficiently elucidated. The objectives of this study were 1) to investigate the prognosis of lung adenocarcinoma patients after recurrence

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according to the EGFR mutation status, 2) to clarify whether the pathological status, particularly p-stage, is associated with PRS, and 3) to clarify the postoperative

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recurrence characteristics, including recurrence patterns, of a mutated lung

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adenocarcinoma. This study was performed to provide useful information for more accurately predicting PRS in completely resected lung adenocarcinoma.

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Materials and methods

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Patient selection

A total of 1308 consecutive patients with adenocarcinoma underwent complete

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pulmonary resection between January 2000 and December 2011 at Tokyo Medical University Hospital. We defined complete resection as lobectomy or more extensive

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lung resection with systematic ipsilateral hilar and mediastinal lymph node dissection and with no evidence of residual cancer either macroscopically or microscopically. Of these, 270 patients had postoperative recurrence when EGFR-TKIs were started from

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2002. We excluded 19 patients who had received preoperative chemotherapy, radiotherapy or both, or patients whose tumors had the EGFR mutation exon 20 (9

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patients) (because of resistance for EGFR-TKIs) or EML4-ALK fusion gene (2 patients). We excluded 42 patients who received only the best supportive care including only

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palliative radiotherapy for controlling pain from bone metastasis, and not any treatments such as radiotherapy, chemotherapy, or surgical treatment after recurrence. We enrolled the remaining 198 patients with postoperative recurrent disease in this study.

We reviewed the medical records of the patients regarding their clinicopathological information as follows: age, gender, smoking history, tumor location, 9

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operation procedure, tumor differentiation, histologic type, tumor size, blood vessel invasion, lymphatic permeation, visceral pleural invasion (VPI), EGFR mutation status,

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administration of EGFR-TKI therapy, recurrence pattern, and recurrence-free interval from the date of operation to the date of initial recurrence. The disease stages were

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Union for International Cancer Control (UICC) 20.

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based on the 7th Edition of the TNM Classification for Lung and Pleural Tumors of the

After resection, the patients were examined at 3-month intervals for 3 years, then at 6-month intervals for the next 2 years, and thereafter at 1-year intervals. The

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evaluations included physical examination, chest roentgenogram, chest computed tomography (CT), and tumor marker measurement. Abdominal CT, brain magnetic resonance imaging, and bone scintigraphy or positron emission tomography/CT were

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performed every year. Patients with cancer recurrence were carefully divided into 2

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groups according to the site of initial relapse: locoregional or distant. The median follow-up period from recurrence was 22.6 (0.7-135.2) months. The Institutional Review Board of our hospital approved the protocols for data collection and analyses, and waived the need to obtain written informed consent from each patient.

EGFR mutation analysis

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All the surgical specimens collected were fixed in 10% formalin and embedded in paraffin. Representative sections were routinely stained with hematoxylin and eosin

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and were reviewed to confirm that the sections included carcinoma cells by experienced pathologists. EGFR mutation analysis of histologic specimens was screened by the

21, 22

. The direct sequencing method is

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November 2009), as previously described

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direct sequencing method (until October 2009) or the cycleave PCR method (after

reported to detect mutation in samples containing ≤ 25% mutant alleles. Conversely, the cycleave PCR method is used to detect mutation in samples containing ≤ 5% mutant alleles

23

. Of the 142 samples that were run using the direct sequencing method, 40

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samples were mutant (28%). Of the 56 samples that were run using the cycleave PCR method, 17 samples were mutant (30%). Deletion mutations in exon 19 and point

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mutations in exon 18 or exon 21 were considered to be EGFR mutations in this study.

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Statistical analysis

Overall survival (OS) and PRS were estimated using the Kaplan-Meier method,

and differences in survival rates were determined by log-rank analysis. OS was defined as the time elapsed from the date of pulmonary resection to the date of death. The length of PRS was defined as the interval between the date of initial recurrence identified and

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the date of either death or the last follow-up. Recurrence-free interval (RFI) was defined as the time elapsed from the date of pulmonary resection to the date of the first

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recurrence. For recurrence patterns, locoregional recurrence was defined as tumor recurrence in a contiguously anatomical site, including the ipsilateral hemithorax and

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mediastinum, after surgical resection. Distant recurrence was defined as tumor

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recurrence in the contralateral lung or outside the hemithorax and mediastinum after surgical resection.

Univariate analysis was conducted among the different groups. Categorical variables were analyzed using the chi-square test. Differences between 2 groups were

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tested using the Mann-Whitney U test. Multivariate analysis was performed by the Cox proportional hazards model using the significant factors identified from the univariate

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analysis to examine the association between survival and potential prognostic factors.

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All p-values were two-sided and p-values of < 0.05 were considered to indicate a statistically significant difference. All statistical calculations were performed using the SPSS statistical software package (version 21.0; SPSS, Inc., Chicago, Ill).

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Results

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The median follow-up time for all the patients was 47.1 months (range: 8.3-160.9 months). The median PRS time for the patients was 22.6 months (range: 0.7-135 months). The characteristics of the patients are listed in Table 1. Of the 198

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patients, 117 patients were examined for EGFR mutations which were detected in 57

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patients (28.7%). The most common EGFR mutation was in frame deletions in exon 19 (34 of 57, 58.6%). The second most common mutation was missense mutation (mostly L858R) in exon 21 of 57 patients (34.5%). For the initial recurrence patterns, 144

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patients (72.7%) had distant or both local and distant recurrence, 54 patients (27.3%) had only local recurrence. Of the 57 patients with EGFR mutations (mutants), 49 patients (85.9%) received EGFR-TKI therapy. Among 141 patients with wild-type (WT)

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and unknown (UN) status, 30 patients (21.2%) received EGFR-TKI therapy.

The 5-year OS rates of patients with mutants, WT status, and UN status were

65.6%, 45.4%, and 34.2%, respectively (Fig. 1a). The 3-year PRS rates of patients with mutants, WT status, and UN status were 68.6%, 51.7%, and 27.0%, respectively (Fig. 1b). There were statistically significant differences in the PRS rates between the patients with mutants and WT status (p = 0.004), and between the patients with mutants and UN

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status (p = 0.036). In the patients who received EGFR-TKI therapy, the 3-year PRS rates of the patients with mutants, WT status, and UN status were 70.0%, 38.5%, and 45.5%,

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respectively . There were statistically significant differences in the PRS rates between the patients with mutants and WT status (p = 0.002). Although the difference in PRS

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was not statistically significant between the patients with mutants and UN status (p =

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0.082), similar relationships were observed among these patients. Therefore, all the patients were classified on the basis of the EGFR status, that is, mutant and WT/UN in the following analysis. When we excluded 11 patients with EGFR UN status who received EGFR-TKI to eliminate the effects of EGFR-TKI on untested mutants, similar

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results were observed among the groups between mutants and WT/UN. The 5-year OS rates for p-stage I-II (p-I-II) and p-stage III (p-III) were 55.6% and 29.6%, respectively

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(p < 0.001) (Fig. 1c). The 3-year PRS rates for p-I-II and p-III were 52.5% and 29.3%,

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respectively (p < 0.001) (Fig. 1d).

The potential risk factors for PRS were analyzed using univariate survival

analysis (Table 2), which showed that sex, smoking habits, p-stage, tumor differentiation, EGFR mutation status, recurrence pattern, recurrence-free interval, and EGFR-TKI therapy were significant risk factors. Multivariate survival analysis (Table 2) showed that patients with p-stage III (hazard ratio (HR) = 2.193, 95% CI, 14

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1.464-3.279, p < 0.001), EGFR WT/UN (HR = 1.984, 95% CI, 1.064-3.378, p = 0.012),

significant association with unfavorable PRS.

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distant recurrence, and a recurrence-free interval of less than 1 year, had a statistically

The relationship between the clinicopathological prognostic factors and the

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EGFR mutation status is shown in Table 3. The rate of mutants was significantly higher

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in women, never-smokers, patients with well or moderate differentiation, patients who had recurrence after postoperative year 1 than in patients with the WT/UN status (p < 0.05). However, there was no significant difference between the EGFR mutation status

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and the p-stage or recurrence patterns (p = 0.512, p = 0.481, respectively).

Figure 2a shows the PRS curves stratified by the EGFR status and p-stage. The

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3-year PRS rates for the patients with mutants with p-I-II, patients with mutants with

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p-III, patients with WT/UN tumors with p-I-II, and patients with WT/UN tumors with p-III were 81.4%, 48.0%, 40.7%, and 24.4%, respectively. There were statistically significant differences in the PRS rates between the patients with mutants with p-I-II and the patients with mutants with p-III (p < 0.001). There were no significant differences between the patients with mutants with p-III and the patients with WT/UN tumors with p-I-II and between the patients with mutants with p-III and the patients

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with WT/UN with p-III (p = 0.872, p = 0.080, respectively). In the patients with mutants who received EGFR-TKI therapy, the 3-year PRS rates for the patients with p-I-II and

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p-III were 81.8% and 43.7%, respectively, with a statistically significant difference (p < 0.001) (Fig. 2b).

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We also examined the relationship between the type of relapse and the EGFR

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mutation status stratified by p-stage (Table 4). There was no significant difference in the initial recurrence pattern in both the patients with mutants and the patients with WT/UN tumors. However, in the initial recurrence site of the patients with mutants, the

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incidence of p-III tumors was significantly higher in brain metastasis but lower in pulmonary metastasis than p-I-II tumors (p < 0.05). The patients with mutants with brain metastasis had statistically significantly worse PRS rates than the patients with

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mutants without brain metastasis (p = 0.017). Conversely, there was no significant

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difference in the PRS rates between the patients with mutants with and without pulmonary metastasis (p = 0.456).

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Discussion

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We set out 1) to identify the prognostic factors after recurrence in patients who underwent complete resection of lung adenocarcinoma, 2) to clarify whether EGFR mutation status and p-stage can be considered as conclusive indicators of OS, and 3) to

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elucidate whether the EGFR mutation status and p-stage affect the prediction of PRS.

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We found that having the EGFR mutation itself was a favorable PRS factor and that the current staging system was useful for predicting PRS.

The concept of PRS of surgically treated patients has been the focus of much 13-15

,

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attention recently because encouraging new treatments such as EGFR-TKIs

anaplastic lymphoma kinase inhibitors 24, vascular endothelial growth factor antibody 25, 26, 27

have afforded long-term PRS and better quality of life to

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or new anticancer agents

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selected patients with recurrent disease 18. Several retrospective studies have reported that RFI, initial recurrence pattern, lymph node metastasis pattern, tumor differentiation, EGFR status, administration of EGFR-TKIs, and p-stage were independent prognostic factors for PRS

4-6, 10-12, 28-31

. Our results demonstrating shorter RFI, distant metastasis,

EGFR mutation of WT/UN, and advanced p-stage as predictors of poor PRS are in agreement with previous studies

4, 19, 32

. In the present study, EGFR status and p-stage

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were shown to be essential factors for estimating PRS. The mutated patients with early p-stage tumors at the time of complete resection showed the best PRS. In contrast, the

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prognosis of the mutated patients with advanced p-stage tumors was not satisfactory.

Genetic alteration of EGFR is a representative marker in determining the 13-15

. Treatment with EGFR-TKIs has

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appropriate treatment for advanced NSCLC

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resulted in prolonged progression-free survival for patients with unresectable stage IIIB, IV or recurrent NSCLC in several randomized phase III studies. Within the mutated patients, however, some clinicopathological characteristics may be associated with poor survival. Patients with EGFR mutation and brain metastasis were reported to have

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worse outcomes than those without brain metastasis

33

. Recently, the effectiveness of

EGFR-TKIs on central nerve system metastases from NSCLC has also been 34-37

. However, no significant difference in survival after brain metastasis

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demonstrated

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was reported between the tumors with mutations and wild type, although the mutated patients had better survival than the patients with EGFR wild type tumors

38

. In a

separate study, brain metastases from NSCLC were present in 20%-30% of the patients and were associated with a poor prognosis, with a median survival period of less than 6 months after conventional therapy 39. In our series, all 35 patients with brain metastasis received radiotherapy with or without surgery at the initial recurrence, and there was no 18

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significant difference in the PRS between mutants and non-mutants in the patients with brain metastasis (data not shown). The results showed that in the initial recurrence site

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of the patients with mutations, the incidence rates of p-III tumors were significantly higher in brain metastasis than earlier stage tumors, which might be one reason for the

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poor PRS. Therefore, information on the EGFR mutation status and the presence of

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brain metastases would greatly contribute to upfront treatment decisions for recurrent disease.

Recent randomized controlled trials have demonstrated the survival benefit varying with stage and the usefulness of platinum-based adjuvant chemotherapy in 1, 3, 40

. For some cases of stage I adenocarcinoma,

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p-stage II to IIIA NSCLC patients

based on a large adjuvant trial on oral uracil-tegafur (UFT), UFT adjuvant 41, 42

. Most of the

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chemotherapy is recommended as the standard treatment in Japan

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primary endpoint for adjuvant chemotherapy was to compare ‘overall survival’ in the 2 groups, not recurrence-free survival. In our series, the WT/UN tumors with p-I-II have a similar PRS to tumors with p-III, which is much worse than the mutants with p-I-II. Hence, our results suggest that both the EGFR mutation status and p-stage could also prompt the design of clinical trials on adjuvant therapy for patients after complete surgical resection. 19

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There are several limitations and biases of this study that should be taken into account when interpreting the results. As a retrospective single-institute study, patient

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selection bias and time trend bias regarding the treatment for recurrent disease were inevitable. The definition of an ipsilateral recurrence as a local recurrence (2 cases) also

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generated inherent bias while differentiating a new primary lung cancer from a recurrent

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adenocarcinoma. This study included approximately 40% of patients with an unknown EGFR status, although most of these patients did not receive EGFR-TKI therapy, as well as patients with the EGFR WT status. There was a difference in sensitivity between the direct sequencing method and the cycleave PCR method in terms of detecting EGFR

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mutation. However, since follow-up examination of the patients after the initial resection was comparatively uniform, systematic follow-up might be suggested to

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treatment.

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increase the early detection of recurrent lesions to which we could apply intensive

In conclusion, there were distinct survival differences in patients with recurrent

adenocarcinoma based on the EGFR mutation status. Furthermore, p-stage was also found to be associated with PRS. In patients with mutants, those with early p-staged tumors showed better PRS than those with advanced p-staged tumors. This study indicated that it is essential to identify the EGFR status and p-stage to more accurately 20

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estimate the prognosis after recurrence. The EGFR mutation status and the presence of brain metastases would greatly contribute to upfront treatment decisions for recurrent

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disease. Both the EGFR mutation status and p-stage could also prompt the design of

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clinical trials on adjuvant therapy for patients after complete surgical resection.

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Funding:

This study was supported by a Grant-in-Aid for Young Scientists (B) from the

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Japan Society for the Promotion of Science (KAKENHI 26861129) to Y.K.

Acknowledgements:

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The authors are indebted to Dr. Edward Barroga, Associate Professor and Senior Medical Editor from the Department of International Medical Communications of Tokyo Medical University for editing and reviewing the English manuscript. The

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authors thank Mr. Tatsuya Isomura, Adjunct Assistant Professor from the Institute of

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Medical Science of Tokyo Medical University, for his advice on the statistical analysis.

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Conflict of interest: none declared.

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Figure legends

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Figure 1

a. Overall survival stratified by EGFR status (mutant, wild type, or unknown)

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Significant differences in the OS rates were observed between the patients with mutants

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and wild type status (p = 0.041), and between the patients with mutants and unknown status (p = 0.033).

b. Postoperative recurrence survival stratified by EGFR status

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Significant differences in the PRS rates were observed between the patients with mutants and wild type status (p = 0.004), and between the patients with mutants and

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unknown status (p = 0.036).

c. Overall survival stratified by pathological stage (I-II or III) Significant differences in the OS rates were observed between the patients with p-stage I-II and p-stage III (p < 0.001).

d. Postoperative recurrence survival stratified by pathological stage (I-II or III) 23

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Significant differences in the PRS rates were observed between the patients with p-stage

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I-II and p-stage III (p < 0.001).

EGFR, epidermal growth factor receptor; OS, overall survival; PRS, postoperative

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recurrence survival; EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase

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inhibitors; p-stage, pathological stage.

Figure 2

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a. Postoperative recurrence survival stratified by EGFR status (mutant or WT / UN and pathological stage (I-II or III)

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Significant differences in the PRS rates were observed between the patients with

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mutants with p-I-II and the patients with mutants with p-III (p < 0.001). No significant differences in the PRS rates were observed between the patients with mutants with p-III and the patients with WT/UN tumors with p-I-II and between the patients with mutants with p-III and the patients with WT/UN with p-III (p = 0.872, p = 0.080, respectively).

b. Postoperative recurrence survival stratified by p-stage (I-II or III) in mutated 24

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patients with EGFR-TKIs Significant differences in the PRS rates were observed between the patients with p-I-II

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and the patients with p-III (p < 0.001).

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EGFR, epidermal growth factor receptor; EGFR-TKIs, epidermal growth factor

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receptor-tyrosine kinase inhibitors; WT, wild type; UN, unknown; PRS, postoperative

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recurrence survival; p-I-II, pathological stage I or II; p-III, pathological stage III.

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Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388.

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Youlden DR, Cramb SM, Baade PD. The International Epidemiology of Lung Cancer: geographical distribution and secular trends. J Thorac Oncol. 2008;3:819-831.

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Sasaki H, Endo K, Konishi A, et al. EGFR Mutation status in Japanese lung cancer patients: genotyping analysis using LightCycler. Clin Cancer Res. 2005;11:2924-2929.

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Socinski MA, Evans T, Gettinger S, et al. Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e341S-368S.

19.

Hung JJ, Jeng WJ, Hsu WH, et al. Prognostic factors of postrecurrence survival in completely resected stage I non-small cell lung cancer with distant metastasis. Thorax. 2010;65:241-245.

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20.

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12.

Sobin LH, Gospodarowicz MK, Wittekind C, International Union against Cancer. TNM classification of malignant tumours. 7th ed. Chichester, West Sussex, UK ; Hoboken, NJ: Wiley-Blackwell; 2010.

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Yatabe Y, Hida T, Horio Y, Kosaka T, Takahashi T, Mitsudomi T. A rapid, sensitive assay to detect EGFR mutation in small biopsy specimens from lung cancer. J Mol Diagn. 2006;8:335-341.

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Yoshida K, Yatabe Y, Park JY, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in 27

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patients with non-small cell lung cancer. J Thorac Oncol. 2007;2:22-28. Pao W, Ladanyi M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin Cancer Res. 2007;13:4954-4955.

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Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703.

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Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.

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Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol. 2007;18:317-323.

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Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551.

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Okami J, Taniguchi K, Higashiyama M, et al. Prognostic factors for gefitinib-treated postoperative recurrence in non-small cell lung cancer. Oncology. 2007;72:234-242.

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Sonobe M, Yamada T, Sato M, et al. Identification of subsets of patients with favorable prognosis after recurrence in completely resected non-small cell lung cancer. Ann Surg Oncol. 2014;21:2546-2554.

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Zhang J, Yu J, Sun X, Meng X. Epidermal growth factor receptor tyrosine 28

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kinase inhibitors in the treatment of central nerve system metastases from non-small cell lung cancer. Cancer Lett. 2014;351:6-12. Porta R, Sanchez-Torres JM, Paz-Ares L, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J. 2011;37:624-631.

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Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer. 2012;77:556-560.

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Eichler AF, Kahle KT, Wang DL, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol. 2010;12:1193-1199.

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Hendriks LE, Smit EF, Vosse BA, et al. EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases? Lung Cancer. 2014;84:86-91.

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Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004;350:1713-1721.

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Hamada C, Tsuboi M, Ohta M, et al. Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a meta-analysis of six randomized controlled trials. J Thorac Oncol. 2009;4:1511-1516.

AC C

EP

TE D

M AN U

SC

RI PT

35.

29

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Category

Sex

Men

Smoking habits

TE D

Ever-smoker / unknown

AC C

Median age (years) (range)

EP

Women

M AN U

Variable

SC

RI PT

Table 1. Patient characteristics (n = 198)

Never-smoker

Number (%)

115 (58.1)

83 (41.9)

63.0 (26-85)

120 (60.6)

78 (39.4)

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123 (62.1)

RI PT

Right

Left

Lobectomy/Bilobectomy

Pneumonectomy

pN category

N0

EP

N1

TE D

Median tumor size (cm) (range)

196 (99.0)

2 (1.0)

3.2 (0.8 – 15.0)

102 (51.5)

32 (16.2)

N2

64 (32.3)

IA / IB

82 (41.4)

AC C

p-Stage

M AN U

Operation procedure

75 (37.9)

SC

Tumor location

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47 (23.7)

RI PT

IIA / IIB

69 (34.8)

Lymphatic permeation

Positive

Visceral pleural invasion

Positive

Tumor differentiation

poor

M AN U

Positive

TE D

Vascular invasion

SC

IIIA

mutant

AC C

EGFR mutation status

EP

well / moderate

(Exon 18/ 19 / 21)

133 (67.2)

150 (75.8)

91 (46.0)

66 (33.3)

132 (66.7)

57 (28.7)

(3 / 34 / 20)

Unknown

81 (40.9)

M AN U

SC

Chemotherapy

116 (58.6)

43 (21.7)

Radiotherapy

24 (12.1)

TE D

Chemotherapy with radiotherapy

Surgical resection

14 (7.1)

Other

1 (0.5)

EP

EGFR-TKI therapy

60 (30.3)

With

AC C

Treatment for initial recurrence

Wild type

RI PT

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(Gefitinib / Erlotinib / both)

79 (39.9)

(53 / 11 / 15 )

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Without

119 (60.1)

Initial recurrence site

Brain

(including duplication)

Bone

TE D

Locoregional

SC

Distant / both

M AN U

Initial recurrence pattern

Pleural dissemination/ malignant effusion

EP

(27 / 35 / 17)

RI PT

(1st line / 2nd line / 3rd line or more)

144 (72.7)

54 (27.3)

36 (18.2)

34 (17.2)

20 (10.1)

67 (33.8)

Lymph nodes

55 (27.8)

AC C

Lung

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9 (4.5)

RI PT

Liver

Adrenal grand

11 (5.6)

M AN U

SC

Chest wall

6 (3.0)

AC C

EP

TE D

EGFR, epidermal growth factor receptor; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor

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SC

RI PT

Table 2. Univariate and multivariate analyses for postrecurrence survival (n = 198)

UVA

M AN U

Variable

NS (0.055)

Sex: men (vs women)

0.003

Smoking history: others (vs

EP

Age: < 75 (vs ≥ 75)

Hazard ratio

TE D

p-value

never-smoker )

AC C

0.004

Operation procedure:

NS (0.252)

MVA

95% CI

p-value

Not included in MVA

1.457

0.899-2.361

NS (0.127)

1.017

0.628-1.645

NS (0.946)

Not included in MVA

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p-Stage: III (vs I-II)

< 0.001

2.193

NS (0.063)

M AN U

Lymphatic permeation: present NS (0.143)

AC C

Tumor differentiation: poor (vs

0.012

well or moderate)

Not included in MVA

Not included in MVA

EP

NS (0.964)

TE D

(vs absent)

present (vs absent)

*< 0.001

Not included in MVA

absent)

Visceral pleural invasion:

1.464-3.279

SC

Vascular invasion: present (vs.

RI PT

pneumonectomy (vs others)

1.198

0.820-1.751

NS (0.351)

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< 0.001

1.984

< 0.001

1.664

1.064-3.378

*0.012

1.126-2.457

*0.011

1.173

0.759-1.813

NS (0.437)

1.761

1.122-2.762

*0.014

SC

(vs mutant)

M AN U

Recurrence-free interval: < 1 year (vs ≥ 1 year)

EGFR-TKI therapy: without (vs

TE D

0.034

locoregional)

0.025

AC C

distant or both (vs

EP

with)

Initial recurrence pattern:

RI PT

EGFR mutation status: WT/UN

RI PT

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UVA, univariate analysis; MVA, multivariate analysis; EGFR, epidermal growth factor receptor; EGFR-TKI, epidermal growth factor

SC

receptor-tyrosine kinase inhibitor; WT/UN, EGFR mutation wild-type and unknown status

AC C

EP

TE D

M AN U

*p < 0.05

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SC

RI PT

Table 3. Patient characteristics in the 2 groups according to EGFR mutation status (n = 198)

EGFR mutation status; number (%)

Mutant (n = 57)

Women

36 (63.6)

Age

< 75

50 (87.7)

WT/UN (n = 141)

* < 0.001

94 (66.7)

EP

21 (36.8)

AC C

Men

p-value

TE D

Sex

M AN U

Variable

47 (33.3)

NS (0.083)

108 (76.6)

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7 (12.2)

33 (23.4)

RI PT

≥ 75

32 (56.1)

Ever-smoker / unknown

25 (43.9)

46 (32.6)

M AN U

Never-smoker

95 (67.4)

Lobectomy / bilobectomy

56 (98.2)

I / II

140 (99.3)

AC C

p-Stage

1 (0.7)

EP

1 (1.8)

35 (61.4)

NS (0.494)

TE D

Operation procedure

Pneumonectomy

*0.004

SC

Smoking history

NS (0.512)

94 (66.7)

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22 (38.6)

47 (33.3)

RI PT

III

35 (61.4)

Absent

22 (38.6)

98 (69.5)

M AN U

Present

43 (30.5)

Absent

9 (15.8)

Present

39 (27.7)

AC C

Visceral pleural invasion

102 (72.3)

EP

48 (84.2)

27 (47.4)

NS (0.063)

TE D

Lymphatic permeation

Present

NS (0.315)

SC

Vascular invasion

NS (0.753)

64 (45.4)

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30 (52.6)

77 (54.6)

RI PT

Absent

13 (22.8)

Well / moderate

44 (77.2)

53 (37.6)

M AN U

Poor

88 (62.4)

≥ 1 year

49 (86.0)

Distant / both

85 (60.3)

AC C

Initial recurrence pattern

56 (39.7)

EP

8 (14.0)

44 (77.2)

* < 0.0001

TE D

Recurrence-free interval

< 1 year

*0.048

SC

Tumor differentiation

NS (0.481)

100 (70.9)

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41 (29.1)

Brain

13 (22.8)

22 (15.6)

Bone

12 (21.1)

Lung

20 (35.1)

Lymph node

15 (26.3)

Others

9 (15.8)

RI PT

13 (22.8)

M AN U

Initial recurrence site

SC

Locoregional

0.303

0.406

47 (33.3)

0.869

TE D

22 (15.6)

0.862

33 (23.4)

0.257

AC C

EP

40 (28.4)

EGFR, epidermal growth factor receptor; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; WT/UN, EGFR mutation wild-type and unknown status

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AC C

EP

TE D

M AN U

SC

RI PT

*p < 0.05

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p-stage III

(n = 35)

(n = 22)

(p-I-II vs p-III)

TE D

p-stage I-II

Initial recurrence pattern

EGFR WT/UN

p-stage I-II

p-stage III

(n = 94)

(n = 39)

0.060

24 (68.6)

Locoregional

11 (31.4)

p-value

(p-I-II vs p-III)

0.432

20 (90.1)

69 (73.4)

31 (66.0)

2 (9.1)

25 (26.6)

16 (34.0)

AC C

Distant / both

Initial recurrence site

p-value

M AN U

EGFR mutant

EP

Variable

SC

RI PT

Table 4. Relationship between type of relapse and EGFR mutation status stratified by pathological stage (n = 198)

4 (11.4)

9 (40.9)

*0.021

14 (14.9)

Bone

7 (20.0)

5 (22.7)

0.100

9 (9.6)

13 (27.7)

*0.012

Lung

16 (45.7)

4 (18.2)

*0.047

35 (37.2)

12 (25.5)

0.188

Lymph node

9 (25.7)

6 (27.3)

Others

6 (17.1)

3 (13.6)

M AN U

SC

Brain

RI PT

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23 (24.5)

17 (36.2)

0.168

1.000

25 (26.6)

8 (20.5)

0.291

TE D

EP AC C

0.807

1.000

p-stage, pathological stage; WT/UN, EGFR mutation wild-type and unknown status

*p < 0.05

8 (17.0)

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

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Clinical Practice Points

RI PT

• What is already known about this subject? The current staging system and epidermal growth factor receptor (EGFR) mutation status, which particularly affects the actions of EGFR tyrosine-kinase inhibitors, are key

M AN U

• What are the new findings?

SC

factors for predicting survival.

In patients with EGFR mutants, those with advanced pathological staged tumors

TE D

showed worse postrecurrence survival (PRS) than those with early pathological staged

EP

tumors. p-stage was also found to be associated with PRS.

• How might it impact on clinical practice in the foreseeable future?

AC C

It is essential to identify EGFR mutation status and p-stage to more accurately estimate prognosis after recurrence. Both EGFR mutation status and p-stage could also prompt the design of clinical trials on adjuvant therapy for patients after complete surgical resection.

Prognostic Factors for Survival After Recurrence in Patients With Completely Resected Lung Adenocarcinoma: Important Roles of Epidermal Growth Factor Receptor Mutation Status and the Current Staging System.

Epidermal growth factor receptor (EGFR) status and pathological stage (p-stage) were shown to be essential prognostic factors for estimating survival ...
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