The prognostic effect of the epidermal growth factor receptor gene mutation on recurrence dynamics of lung adenocarcinoma

The prognostic effect of the epidermal growth factor receptor gene mutation on recurrence... Abstract OBJECTIVES The prognostic effects of epidermal growth factor receptor (EGFR) gene mutation on lung adenocarcinoma recurrence have not been well established. The relationship between EGFR gene mutation and recurrence dynamics of lung adenocarcinoma was investigated. METHODS A total of 527 patients with complete resection for adenocarcinoma were reviewed retrospectively. EGFR gene mutation was analysed by polymerase chain reaction followed by bidirectional direct sequencing in recurred patients. Patients were divided into the EGFR gene mutation group (M) or the wild-type EGFR gene group (W). Recurrence types and disease-free intervals (DFIs) of the 2 groups were compared. DFIs were calculated by the Kaplan–Meier method and compared using the log-rank test and Cox proportional hazard model. RESULTS EGFR gene sequencing was performed in 115 recurrent adenocarcinoma patients. Sixty-six patients had EGFR mutations and 49 patients had wild-type EGFR. The median DFI of the 2 groups were significantly different (M: 20.3 months, W: 15.1 months, P = 0.012). EGFR gene mutation was the only prognostic factor for DFI [hazard ratio (HR) = 0.639, 95% confidence interval (CI) = 0.428–0.954, P = 0.029]. The proportion of loco-regional recurrences and distant metastases of both groups were similar (P = 0.50). In subgroup analysis, EGFR gene mutation (HR = 0.534, 95% CI = 0.339–0.839, P = 0.007) was a significant prognostic factor for DFI of distant metastases. CONCLUSIONS Lung adenocarcinoma with EGFR gene mutations had longer DFI than those with wild-type EGFR gene, especially with regard to distant metastasis. EGFR gene mutation was a prognostic factor for lung adenocarcinoma. Epidermal growth factor receptor, Adenocarcinoma, Lung cancer, Prognosis INTRODUCTION Epidermal growth factor receptor (EGFR) gene mutation is detected in 30–40% of lung adenocarcinoma and associated with specific demographic parameters such as never-smoker, Asian and female gender [1–3]. EGFR gene mutation is the most important molecular target, and tyrosine kinase inhibitors (TKIs) targeting EGFR gene mutation have been shown to significantly improve the prognosis of advanced lung adenocarcinoma [4–6]. Post-recurrence survival of lung adenocarcinoma patients with EGFR gene mutation has also been improved by the use of TKIs [7, 8]. It is evident that EGFR gene mutation is a predictive factor in the treatment of lung adenocarcinoma. However, the prognostic effect of EGFR gene mutation on tumour progression, which affects recurrence pattern and dynamics, has not been well established [9]. Several prospective studies have reported that lung adenocarcinoma with EGFR gene mutation had longer progression intervals than those with wild-type EGFR gene in chemotherapy-alone subgroups [2, 10]. As low-dose computed tomography screening becomes more popular [11, 12], the number of detected early adenocarcinomas and the number of surgically treated lung adenocarcinoma will also increase. Therefore, understanding the prognostic characteristics of adenocarcinoma with EGFR gene mutation is important for predicting accurate prognosis and for customizing the surveillance programme for patients with completely resected lung adenocarcinoma. In this study, the relationship between EGFR gene mutations and the recurrence dynamics of completely resected lung adenocarcinoma was investigated. MATERIALS AND METHODS Study population A total of 527 patients who underwent curative surgery for lung adenocarcinoma from January 2006 to December 2009 were reviewed retrospectively. The data for age, sex, histological subtype, presence of EGFR mutation, extent of pulmonary resection, pathological stage (7th edition of Lung cancer stage classification system) [13], adjuvant treatment, recurrence status, first recurrence site, disease-free interval (DFI), survival status and survival duration were obtained by reviewing medical records. DFI was defined as months from the day of operation to the day of clinical or radiological detection of recurrence. The survival duration was counted from the day of surgery to the day of death by any causes or the day of last follow-up in months. Platinum-based cytotoxic chemotherapy was standard adjuvant treatment in patients with pathological stage II disease or more. No adjuvant TKI treatment was performed in the present study. Postoperative surveillance of recurrence was conducted by contrast-enhanced chest computed tomography (CT) every 6 months for 2 years, and then chest low-dose CT was performed annually. Positron emission tomography–CT was performed case by case. Histological confirmation of recurrence was performed in patients with ambiguous image findings on CT or positron emission tomography–CT. Recurrence and second primary lung cancer were classified according to the Martini and Melamed classification [14] and criteria proposal by International Association for the Study of Lung Cancer [15]. Types of recurrences were classified into loco-regional recurrence (recurrences at resection margin or N1/N2 nodes) or distant metastasis (ipsilateral lung, ipsilateral pleural space, contralateral intrathoracic metastasis, extrathoracic metastasis). Histological subtype was determined according to the International Association for the study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma [16]. Tumours were graded according to the dominant subtype: Low grade—adenocarcinoma in situ and minimally invasive adenocarcinoma; Moderate grade—lepidic, acinar and papillary subtypes; High grade—solid and micropapillary subtypes [17]. The last follow-up date was 30 June 2016. Invasive mucinous adenocarcinomas, pathological stage IV and operative mortality cases were excluded. Epidermal growth factor receptor gene mutation test EGFR gene mutation was tested by nested polymerase chain reaction followed by bidirectional direct sequencing in the event of recurrence [7]. EGFR gene expression was also tested in some patients by immunohistochemistry during the early period of this study. The results of immunohistochemistry for EGFR gene mutation were excluded from the analyses. Statistical analyses Adenocarcinoma patients who experienced recurrence and had been tested for EGFR gene mutation by direct sequencing were included in the analyses. Patients were classified according to whether their adenocarcinoma had EGFR gene mutation (M group) or wild-type EGFR genes (W group) (Fig. 1). Recurrence sites and DFIs of the 2 groups were compared. T-test was used for the comparison of continuous variables, and chi-square method was used for the comparison of discrete variables. DFI and overall survival rate were calculated using the Kaplan–Meier method and compared using the log-rank test for univariable analysis. Prognostic effects of age (≤60 vs >60), sex, smoking status (<30 pack-year vs ≥30 pack-year), histological grade, pathological stage (I vs II + III), extent of surgery (lobectomy versus bilobectomy + pneumonectomy), visceral pleural invasion, lymphovascular invasion, adjuvant treatment and EFGR gene mutation on DFI were tested. Parameters showing P-value 0.1 or less in univariable analysis were included in multivariable analysis conducted according to Cox’s proportional hazard model. P-values <0.05 were considered statistically significant. Statistical analyses were performed using the Statistical Package for Social Science (ver. 21.0, IBM Corp., Armonk, NY, USA). This study was approved by the Institutional Review Board of Seoul National University Hospital (approval number: H-1506-018-678), and it complied with the Declaration of Helsinki. Figure 1: View largeDownload slide Diagram of the study population. EGFR: epidermal growth factor receptor. Figure 1: View largeDownload slide Diagram of the study population. EGFR: epidermal growth factor receptor. RESULTS A total of 527 patients with a mean age of 62.5±10 years (range: 23–83 years) had adenocarcinoma, of whom 282 (53.5%) were female. There were 351 (66.6%) patients with stage I, 69 (13.1%) with stage II and 107 (20.3%) with stage III adenocarcinoma. The median follow-up duration was 72 months. The 5-year overall survival rate was 80.1%. Recurrence was detected in 149 patients, and the 5-year disease-free survival (DFS) rate was 60.5%. Initial recurrences of 7 (1.3%) patients were loco-regional recurrences (resection margin—3, N2 node—4), and 142 (26.9%) patients presented with distant metastases (ipsilateral lung—18, ipsilateral pleural seeding—17, others—107). Twenty-four (4.6%) patients underwent additional surgery for second primary lung cancer during the study period. Pathological stage was the only prognostic factor for recurrence (I vs II/III, P = 0.03). EGFR gene mutation test by the direct sequencing method was performed in 115 (77.2%) patients with recurrent adenocarcinoma. Reasons for excluding 34 (22.8%) patients were (i) EGFR gene mutation test was done only by immunohistochemistry and (ii) no EGFR gene mutation test was performed due to omission of subsequent TKI treatment because of impaired performance status or refusal of treatment. Recurrent adenocarcinoma with epidermal growth factor receptor gene sequencing Table 1 lists the demographics and pathological characteristics of the study population. The mean age was 64 ± 10 (range: 34–83), and 59 (50%) patients were female. The median DFI was 19.0 [95% confidence interval (CI) = 16.6–21.3] months. There were 6 (5.2%) loco-regional recurrences (resection margin—2, N2 nodes—4) and 109 (94.8%) distant metastases (ipsilateral lung—17, ipsilateral pleural seeding—13, others—79). EGFR gene mutations were detected in 66 (57.4%) patients, and 49 (42.6%) patients had wild-type EGFR genes. EGFR gene mutations were found at exon 18 in 2 (3%) patients, exon 19 in 37 (56.1%) patients, exon 20 in 5 (7.6%) patients, exon 21 in 21 (31.8%) patients and exon 22 in 1 (1.5%) patient. No recurrence occurred in patients with low-grade histology. The proportion of females was higher in the M group, and the proportion of heavy smokers was higher in the W group. There was no difference in age, pathological stage, extent of resection and adjuvant treatment between M and W groups (Table 2). Types of recurrence in the M group were loco-regional in 4 (6.1%) patients and distant metastasis in 62 (93.9%) patients. The types of recurrence in the W group were loco-regional in 2 (4.1%) patients and distant metastasis in 47 (95.9%) patients. The types of recurrence were not significantly different between the 2 groups (P = 0.50). However, the median DFI of the 2 groups were significantly different (M group: 20.3 months, W group: 15.1 month, P = 0.012) (Fig. 2). Univariable analyses showed that EGFR gene mutation was the only prognostic factor for DFI. Sex, age, smoking history, histological grade, pathological stage, visceral pleural invasion, lymphovascular invasion, extent of resection and adjuvant treatment were not prognostic factors for DFI (Table 3). Multivariable analysis showed that EGFR gene mutation [hazard ratio (HR) = 0.639, 95% CI = 0.428–0.954, P = 0.029] was the only prognostic factor for DFI (Table 4). Table 1: Characteristics of the patients Variables n = 115 Age (years), mean ± SD 62.7 ± 10.3 Sex, n (%)  Male 56 (48.7)  Female 59 (51.3) Smoking history, n (%)  <30 PY 91 (79.1)  ≥30 PY 24 (20.9) Histological grade, n (%)  Moderate 94 (81.7)  High 21 (18.3) Visceral pleural invasion, n (%) 64 (55.7) Lymphovascular invasion, n (%) 39 (33.9) Pathological stage, n (%)  I 57 (49.6)  II/III 58 (50.4) Extent of lung resection, n (%)  Lobectomy 108 (93.9)  >Lobectomy 7 (6.1) Adjuvant chemotherapy, n (%) 54 (47.0) Adjuvant radiotherapy, n (%) 5 (4.3) Type of recurrence, n (%)  Loco-regional 6 (5.2)  Distant 109 (94.8) Variables n = 115 Age (years), mean ± SD 62.7 ± 10.3 Sex, n (%)  Male 56 (48.7)  Female 59 (51.3) Smoking history, n (%)  <30 PY 91 (79.1)  ≥30 PY 24 (20.9) Histological grade, n (%)  Moderate 94 (81.7)  High 21 (18.3) Visceral pleural invasion, n (%) 64 (55.7) Lymphovascular invasion, n (%) 39 (33.9) Pathological stage, n (%)  I 57 (49.6)  II/III 58 (50.4) Extent of lung resection, n (%)  Lobectomy 108 (93.9)  >Lobectomy 7 (6.1) Adjuvant chemotherapy, n (%) 54 (47.0) Adjuvant radiotherapy, n (%) 5 (4.3) Type of recurrence, n (%)  Loco-regional 6 (5.2)  Distant 109 (94.8) SD: standard deviation. Table 1: Characteristics of the patients Variables n = 115 Age (years), mean ± SD 62.7 ± 10.3 Sex, n (%)  Male 56 (48.7)  Female 59 (51.3) Smoking history, n (%)  <30 PY 91 (79.1)  ≥30 PY 24 (20.9) Histological grade, n (%)  Moderate 94 (81.7)  High 21 (18.3) Visceral pleural invasion, n (%) 64 (55.7) Lymphovascular invasion, n (%) 39 (33.9) Pathological stage, n (%)  I 57 (49.6)  II/III 58 (50.4) Extent of lung resection, n (%)  Lobectomy 108 (93.9)  >Lobectomy 7 (6.1) Adjuvant chemotherapy, n (%) 54 (47.0) Adjuvant radiotherapy, n (%) 5 (4.3) Type of recurrence, n (%)  Loco-regional 6 (5.2)  Distant 109 (94.8) Variables n = 115 Age (years), mean ± SD 62.7 ± 10.3 Sex, n (%)  Male 56 (48.7)  Female 59 (51.3) Smoking history, n (%)  <30 PY 91 (79.1)  ≥30 PY 24 (20.9) Histological grade, n (%)  Moderate 94 (81.7)  High 21 (18.3) Visceral pleural invasion, n (%) 64 (55.7) Lymphovascular invasion, n (%) 39 (33.9) Pathological stage, n (%)  I 57 (49.6)  II/III 58 (50.4) Extent of lung resection, n (%)  Lobectomy 108 (93.9)  >Lobectomy 7 (6.1) Adjuvant chemotherapy, n (%) 54 (47.0) Adjuvant radiotherapy, n (%) 5 (4.3) Type of recurrence, n (%)  Loco-regional 6 (5.2)  Distant 109 (94.8) SD: standard deviation. Table 2: Comparison of patient characteristics according to the presence of EGFR gene mutation Variables Mutation Wild-type P-value (n = 66) (n= 49) Age (years), mean ± SD 62.8 ± 9.7 62.5 ± 11.2 0.91 Sex, n (%)  Male 25 (37.9) 31 (63.3) 0.007  Female 41 (62.1) 18 (36.7) Smoking history, n (%)  <30 PY 59 (89.4) 31 (63.3) 0.001  ≥30 PY 7 (10.6) 18 (36.7) Histological grade, n (%)  Moderate 54 (81.8) 41 (83.7) 0.80  High 12 (18.2) 8 (16.3) Visceral pleural invasion, n (%) 33 (50) 31 (63.3) 0.16 Lymphovascular invasion, n (%) 19 (28.8) 20 (40.8) 0.18 Pathological stage, n (%)  I 30 (45.5) 27 (55.1) 0.31  II/III 36 (54.5) 22 (44.9) Extent of lung resection, n (%)  Lobectomy 64 (97) 44 (89.8) 0.11  >Lobectomy 2 (3) 5 (10.2) Adjuvant chemotherapy, n (%) 34 (51.5) 20 (40.8) 0.26 Adjuvant radiotherapy, n (%) 3 (4.5) 2 (4.1) 0.90 Type of recurrence  Loco-regional, n (%) 4 (6.1) 2 (4.1) 0.50  Distant, n (%) 62 (93.9) 47 (95.9) Variables Mutation Wild-type P-value (n = 66) (n= 49) Age (years), mean ± SD 62.8 ± 9.7 62.5 ± 11.2 0.91 Sex, n (%)  Male 25 (37.9) 31 (63.3) 0.007  Female 41 (62.1) 18 (36.7) Smoking history, n (%)  <30 PY 59 (89.4) 31 (63.3) 0.001  ≥30 PY 7 (10.6) 18 (36.7) Histological grade, n (%)  Moderate 54 (81.8) 41 (83.7) 0.80  High 12 (18.2) 8 (16.3) Visceral pleural invasion, n (%) 33 (50) 31 (63.3) 0.16 Lymphovascular invasion, n (%) 19 (28.8) 20 (40.8) 0.18 Pathological stage, n (%)  I 30 (45.5) 27 (55.1) 0.31  II/III 36 (54.5) 22 (44.9) Extent of lung resection, n (%)  Lobectomy 64 (97) 44 (89.8) 0.11  >Lobectomy 2 (3) 5 (10.2) Adjuvant chemotherapy, n (%) 34 (51.5) 20 (40.8) 0.26 Adjuvant radiotherapy, n (%) 3 (4.5) 2 (4.1) 0.90 Type of recurrence  Loco-regional, n (%) 4 (6.1) 2 (4.1) 0.50  Distant, n (%) 62 (93.9) 47 (95.9) EGFR: epidermal growth factor receptor; SD: standard deviation. Table 2: Comparison of patient characteristics according to the presence of EGFR gene mutation Variables Mutation Wild-type P-value (n = 66) (n= 49) Age (years), mean ± SD 62.8 ± 9.7 62.5 ± 11.2 0.91 Sex, n (%)  Male 25 (37.9) 31 (63.3) 0.007  Female 41 (62.1) 18 (36.7) Smoking history, n (%)  <30 PY 59 (89.4) 31 (63.3) 0.001  ≥30 PY 7 (10.6) 18 (36.7) Histological grade, n (%)  Moderate 54 (81.8) 41 (83.7) 0.80  High 12 (18.2) 8 (16.3) Visceral pleural invasion, n (%) 33 (50) 31 (63.3) 0.16 Lymphovascular invasion, n (%) 19 (28.8) 20 (40.8) 0.18 Pathological stage, n (%)  I 30 (45.5) 27 (55.1) 0.31  II/III 36 (54.5) 22 (44.9) Extent of lung resection, n (%)  Lobectomy 64 (97) 44 (89.8) 0.11  >Lobectomy 2 (3) 5 (10.2) Adjuvant chemotherapy, n (%) 34 (51.5) 20 (40.8) 0.26 Adjuvant radiotherapy, n (%) 3 (4.5) 2 (4.1) 0.90 Type of recurrence  Loco-regional, n (%) 4 (6.1) 2 (4.1) 0.50  Distant, n (%) 62 (93.9) 47 (95.9) Variables Mutation Wild-type P-value (n = 66) (n= 49) Age (years), mean ± SD 62.8 ± 9.7 62.5 ± 11.2 0.91 Sex, n (%)  Male 25 (37.9) 31 (63.3) 0.007  Female 41 (62.1) 18 (36.7) Smoking history, n (%)  <30 PY 59 (89.4) 31 (63.3) 0.001  ≥30 PY 7 (10.6) 18 (36.7) Histological grade, n (%)  Moderate 54 (81.8) 41 (83.7) 0.80  High 12 (18.2) 8 (16.3) Visceral pleural invasion, n (%) 33 (50) 31 (63.3) 0.16 Lymphovascular invasion, n (%) 19 (28.8) 20 (40.8) 0.18 Pathological stage, n (%)  I 30 (45.5) 27 (55.1) 0.31  II/III 36 (54.5) 22 (44.9) Extent of lung resection, n (%)  Lobectomy 64 (97) 44 (89.8) 0.11  >Lobectomy 2 (3) 5 (10.2) Adjuvant chemotherapy, n (%) 34 (51.5) 20 (40.8) 0.26 Adjuvant radiotherapy, n (%) 3 (4.5) 2 (4.1) 0.90 Type of recurrence  Loco-regional, n (%) 4 (6.1) 2 (4.1) 0.50  Distant, n (%) 62 (93.9) 47 (95.9) EGFR: epidermal growth factor receptor; SD: standard deviation. Table 3: Univariable analyses for the risk factors of DFI Variables DFI (95% CI) P-value Age (years)  ≤60 19.6 (15.3–23.7) 0.38  >60 18.5 (14.1–22.9) Sex  Male 16.0 (10.0–21.8) 0.28  Female 19.3 (17.6–21.0) Smoking history  <30 PY 19.4 (17.8–20.9) 0.14  ≥30 PY 13.8 (9.9–17.7) Histological grade  Moderate 19.0 (17.3–20.7) 0.095  High 14.6 (11.2–18.1) EGFR gene  Wild type 15.1 (9.5–20.8) 0.012  Mutation 20.3 (14.9–25.6) Visceral pleural invasion  No 20.2 (16.1–24.3) 0.093  Yes 16.9 (12.2–21.7) Lymphovascular invasion  No 20.2 (16.3–24.0) 0.075  Yes 15.0 (10.9–19.1) Pathological stage  I 20.3 (16.0–24.6) 0.46  II/III 16.8 (13.7–19.9) Extent of lung resection  Lobectomy 19.0 (16.4–21.5) 0.34  >Lobectomy 17.3 (6.8–27.8) Adjuvant treatment  No 19.0 (17.2–20.7) 0.41  Yes 17.2 (11.4–22.9) Variables DFI (95% CI) P-value Age (years)  ≤60 19.6 (15.3–23.7) 0.38  >60 18.5 (14.1–22.9) Sex  Male 16.0 (10.0–21.8) 0.28  Female 19.3 (17.6–21.0) Smoking history  <30 PY 19.4 (17.8–20.9) 0.14  ≥30 PY 13.8 (9.9–17.7) Histological grade  Moderate 19.0 (17.3–20.7) 0.095  High 14.6 (11.2–18.1) EGFR gene  Wild type 15.1 (9.5–20.8) 0.012  Mutation 20.3 (14.9–25.6) Visceral pleural invasion  No 20.2 (16.1–24.3) 0.093  Yes 16.9 (12.2–21.7) Lymphovascular invasion  No 20.2 (16.3–24.0) 0.075  Yes 15.0 (10.9–19.1) Pathological stage  I 20.3 (16.0–24.6) 0.46  II/III 16.8 (13.7–19.9) Extent of lung resection  Lobectomy 19.0 (16.4–21.5) 0.34  >Lobectomy 17.3 (6.8–27.8) Adjuvant treatment  No 19.0 (17.2–20.7) 0.41  Yes 17.2 (11.4–22.9) CI: confidence interval; DFI: disease-free interval (median, months); EGFR: epidermal growth factor receptor. Table 3: Univariable analyses for the risk factors of DFI Variables DFI (95% CI) P-value Age (years)  ≤60 19.6 (15.3–23.7) 0.38  >60 18.5 (14.1–22.9) Sex  Male 16.0 (10.0–21.8) 0.28  Female 19.3 (17.6–21.0) Smoking history  <30 PY 19.4 (17.8–20.9) 0.14  ≥30 PY 13.8 (9.9–17.7) Histological grade  Moderate 19.0 (17.3–20.7) 0.095  High 14.6 (11.2–18.1) EGFR gene  Wild type 15.1 (9.5–20.8) 0.012  Mutation 20.3 (14.9–25.6) Visceral pleural invasion  No 20.2 (16.1–24.3) 0.093  Yes 16.9 (12.2–21.7) Lymphovascular invasion  No 20.2 (16.3–24.0) 0.075  Yes 15.0 (10.9–19.1) Pathological stage  I 20.3 (16.0–24.6) 0.46  II/III 16.8 (13.7–19.9) Extent of lung resection  Lobectomy 19.0 (16.4–21.5) 0.34  >Lobectomy 17.3 (6.8–27.8) Adjuvant treatment  No 19.0 (17.2–20.7) 0.41  Yes 17.2 (11.4–22.9) Variables DFI (95% CI) P-value Age (years)  ≤60 19.6 (15.3–23.7) 0.38  >60 18.5 (14.1–22.9) Sex  Male 16.0 (10.0–21.8) 0.28  Female 19.3 (17.6–21.0) Smoking history  <30 PY 19.4 (17.8–20.9) 0.14  ≥30 PY 13.8 (9.9–17.7) Histological grade  Moderate 19.0 (17.3–20.7) 0.095  High 14.6 (11.2–18.1) EGFR gene  Wild type 15.1 (9.5–20.8) 0.012  Mutation 20.3 (14.9–25.6) Visceral pleural invasion  No 20.2 (16.1–24.3) 0.093  Yes 16.9 (12.2–21.7) Lymphovascular invasion  No 20.2 (16.3–24.0) 0.075  Yes 15.0 (10.9–19.1) Pathological stage  I 20.3 (16.0–24.6) 0.46  II/III 16.8 (13.7–19.9) Extent of lung resection  Lobectomy 19.0 (16.4–21.5) 0.34  >Lobectomy 17.3 (6.8–27.8) Adjuvant treatment  No 19.0 (17.2–20.7) 0.41  Yes 17.2 (11.4–22.9) CI: confidence interval; DFI: disease-free interval (median, months); EGFR: epidermal growth factor receptor. Table 4: Multivariable analysis for the risk factors of disease-free interval Variables HR (95% CI) P-value Histological grade  Moderate 1 0.08  High 1.567 (0.946–2.593) EGFR gene  Wild-type 1 0.029  Mutation 0.639 (0.428–0.954) Visceral pleural invasion  No 1 0.23  Yes 1.263 (0.860–1.857) Lymphovascular invasion  No 1 0.37  Yes 1.207 (0.797–1.828) Variables HR (95% CI) P-value Histological grade  Moderate 1 0.08  High 1.567 (0.946–2.593) EGFR gene  Wild-type 1 0.029  Mutation 0.639 (0.428–0.954) Visceral pleural invasion  No 1 0.23  Yes 1.263 (0.860–1.857) Lymphovascular invasion  No 1 0.37  Yes 1.207 (0.797–1.828) CI: confidence interval; EGFR: epidermal growth factor receptor; HR: hazard ratio. Table 4: Multivariable analysis for the risk factors of disease-free interval Variables HR (95% CI) P-value Histological grade  Moderate 1 0.08  High 1.567 (0.946–2.593) EGFR gene  Wild-type 1 0.029  Mutation 0.639 (0.428–0.954) Visceral pleural invasion  No 1 0.23  Yes 1.263 (0.860–1.857) Lymphovascular invasion  No 1 0.37  Yes 1.207 (0.797–1.828) Variables HR (95% CI) P-value Histological grade  Moderate 1 0.08  High 1.567 (0.946–2.593) EGFR gene  Wild-type 1 0.029  Mutation 0.639 (0.428–0.954) Visceral pleural invasion  No 1 0.23  Yes 1.263 (0.860–1.857) Lymphovascular invasion  No 1 0.37  Yes 1.207 (0.797–1.828) CI: confidence interval; EGFR: epidermal growth factor receptor; HR: hazard ratio. Figure 2: View largeDownload slide Kaplan–Meier curves for disease-free intervals according to the presence of epidermal growth factor receptor gene mutation. Figure 2: View largeDownload slide Kaplan–Meier curves for disease-free intervals according to the presence of epidermal growth factor receptor gene mutation. Subgroup analyses of patients with distant metastasis showed similar results. The median DFI of the M group was significantly longer than that of the W group (M group: 20.3 months, W group: 14.6 months, P = 0.002). EGFR gene mutation (HR = 0.534, 95% CI = 0.339–0.839, P = 0.007) was the only significant prognostic factor for DFI of distant metastasis in univariable and multivariable analyses. DISCUSSION This study found that lung adenocarcinomas with an EGFR gene mutation progress more slowly than those with a wild-type EGFR gene. The difference was more pronounced in distant metastasis. DFI was significantly longer in the EGFR gene mutation group than in the wild-type EGFR gene group by about 5 months in all recurrence and about 6 months in distant metastasis. This finding suggests that the recurrence dynamics of adenocarcinoma differ according to whether EGFR gene mutation had occurred and that the prognosis of adenocarcinoma with EGFR gene mutation is better than that with wild-type EGFR gene. The predictive effect of EGFR gene mutation has been investigated extensively in lung adenocarcinoma because it is a promising target for TKI treatment [4–8]. In contrast, the prognostic effect of EGFR gene mutation has received less attention, and the findings regarding the prognostic effect of EGFR gene mutation have been controversial. Several prospective studies revealed a favourable prognostic effect of EGFR gene mutation in advanced lung adenocarcinomas. Secondary analysis of the IDEAL/INTACT trial showed that adenocarcinomas with EGFR gene mutation had a better prognosis than those with a wild-type EGFR gene in patients treated by cytotoxic chemotherapy only [10]. The TRIBUTE trial also showed that the time-to-progression of non-small-cell carcinoma with EGFR gene mutation was longer than that with wild-type EGFR gene in the cytotoxic chemotherapy alone group [2]. These findings suggest that adenocarcinomas with EGFR gene mutation are less aggressive and that the presence of EFGR gene mutation is a prognostic factor in lung adenocarcinoma. Retrospective studies about the prognostic effect of EGFR mutation in early lung adenocarcinoma were performed on a small number of patients because EGFR gene mutation test was not routinely performed on the completely resected early lung adenocarcinoma patients in clinical settings. Several of these retrospective studies showed similar results to those shown in the present study. Lee et al. [18] reported that the presence of wild-type EGFR gene was a risk factor for recurrence with an adjusted HR of 1.42. Marks et al. [19] reported that adenocarcinoma patients with EGFR gene mutation showed longer overall survival times compared with those with wild-type EGFR gene after adjusting for the stage (HR = 0.4) in a study that included only patients who had not received TKI treatment. Izar et al. reported that EGFR mutation was associated with a significantly lower recurrence rate than wild-type EGFR gene (mutation group: 9.7%, wild-type group: 21.6%, P = 0.03) and longer median DFS (mutation group: 8.8 years, wild-type group: 7.0 years, P = 0.0085). The presence of an EGFR mutation was an independent prognostic factor for DFS in completely resected stage I non-small-cell carcinoma patients in that study [20]. However, other studies have reported opposite results. Lin et al. reported that EGFR gene mutation had no prognostic effect in resected stage I lung adenocarcinoma after analysing adenocarcinoma patients (87 with EGFR gene mutation and 33 with wild-type EGFR gene). However, considering that approximately 60% of their patients had low-grade histology, the sample size was too small to draw meaningful conclusions [21]. Ohba et al. [22] analysed 256 patients with resected pathological stage I adenocarcinoma and could not find the prognostic effect of EGFR gene mutation on DFS. The types of recurrence were similar for adenocarcinoma with EGFR gene mutation and wild-type EGFR gene, which suggested that mode of recurrence did not differ according to EGFR gene mutation status. Most of the recurrences in the present study were distant metastasis, and a subgroup analysis with distant metastases also showed longer DFI in adenocarcinoma with EGFR gene mutation. This finding suggests that sub-clinical micrometastases of adenocarcinoma with EGFR gene mutation progress to clinically detectable metastases more slowly. EGFR gene mutation has been shown to be associated with histological subtypes of adenocarcinoma. No EGFR gene mutation is expected in mucinous adenocarcinoma. An EGFR gene mutation is more frequent in adenocarcinoma in situ, non-mucinous lepidic predominant, papillary and micropapillary subtypes [16]. Yoshizawa et al. [17] reported that EGFR gene mutation was found more frequently in the adenocarcinomas with non-mucinous lepidic and micropapillary patterns and less frequently in those with a solid component. Similarly, Yanagawa et al. [23] found EGRF gene mutations in more than 40% of adenocarcinomas with a lepidic, acinar, papillary and micropapillary subtype and only in 28% of those with a solid subtype. A French study also reported that EGFR gene mutation was more frequent in intermediate-grade histologies than in high-grade histologies [24]. In the present study, EGFR gene mutation rates did not differ according to histological grades in recurrent lung adenocarcinoma. This result suggests that the likelihood of the presence of EGFR gene mutation is similar between histological subtypes of recurrent adenocarcinoma and that the effect of TKI treatment on recurrent adenocarcinoma would be similar for different histological subtypes. Limitations Limitations of this study are the small number of patients and the fact that only patients with recurrence were included. During the study period, direct sequencing of EGFR gene was usually performed in recurrent adenocarcinomas only. Therefore, the present study had to be focused on patients with recurrence. Although it could not show the whole picture of the recurrence dynamics of completely resected lung adenocarcinoma, the present study did reflect the recurrence dynamics of lung adenocarcinoma with micrometastases at the time of surgery because the follow-up duration was long enough to detect any possible recurrences and the presence of EGFR gene mutation was tested with a reliable method. Further study with a prospective cohort of resected lung adenocarcinoma with EGFR gene mutation test is required to verify the results of this small study. We have begun collecting such data for a study in the future. CONCLUSION In conclusion, lung adenocarcinoma with EGFR gene mutation was shown to have longer progression intervals and less aggressive recurrence dynamics than that with wild-type EGFR gene, especially with regard to distant metastasis. This finding should be considered in the conduct of postoperative surveillance of completely resected lung adenocarcinomas. The mechanism controlling the slow progression of distant metastasis in the lung adenocarcinoma with EGFR gene mutation should be investigated. Funding This work was supported by the grant from the Seoul National University College of Medicine Research Fund (800–20130175). Conflict of interest: none declared. REFERENCES 1 Shigematsu H , Lin L , Takahashi T , Nomura M , Suzuki M , Wistuba II et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers . J Natl Cancer Inst 2005 ; 97 : 339 – 46 . Google Scholar CrossRef Search ADS PubMed 2 Eberhard DA , Johnson BE , Amler LC , Goddard AD , Heldens SL , Herbst RS et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib . J Clin Oncol 2005 ; 23 : 5900 – 9 . Google Scholar CrossRef Search ADS PubMed 3 Tsuta K , Kawago M , Inoue E , Yoshida A , Takahashi F , Sakurai H et al. The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations . Lung Cancer 2013 ; 81 : 371 – 6 . Google Scholar CrossRef Search ADS PubMed 4 Kris MG , Natale RB , Herbst RS , Lynch TJ Jr , Prager D , Belani CP et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial . JAMA 2003 ; 290 : 2149 – 58 . Google Scholar CrossRef Search ADS PubMed 5 Shepherd FA , Rodrigues Pereira J , Ciuleanu T , Tan EH , Hirsh V , Thongprasert S et al. Erlotinib in previously treated non-small-cell lung cancer . N Engl J Med 2005 ; 353 : 123 – 32 . Google Scholar CrossRef Search ADS PubMed 6 Lynch TJ , Bell DW , Sordella R , Gurubhagavatula S , Okimoto RA , Brannigan BW et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib . N Engl J Med 2004 ; 350 : 2129 – 39 . Google Scholar CrossRef Search ADS PubMed 7 Kim YT , Seong YW , Jung YJ , Jeon YK , Park IK , Kang CH et al. The presence of mutations in epidermal growth factor receptor gene is not a prognostic factor for long-term outcome after surgical resection of non-small-cell lung cancer . J Thorac Oncol 2013 ; 8 : 171 – 8 . Google Scholar CrossRef Search ADS PubMed 8 Takenaka T , Takenoyama M , Yamaguchi M , Toyozawa R , Inamasu E , Kojo M et al. Impact of the epidermal growth factor receptor mutation status on the post-recurrence survival of patients with surgically resected non-small-cell lung cancer . Eur J Cardiothorac Surg 2015 ; 47 : 550 – 5 . Google Scholar CrossRef Search ADS PubMed 9 Zhang Z , Wang T , Zhang J , Cai X , Pan C , Long Y et al. Prognostic value of epidermal growth factor receptor mutations in resected non-small cell lung cancer: a systematic review with meta-analysis . PLoS One 2014 ; 9 : e106053. Google Scholar CrossRef Search ADS PubMed 10 Bell DW , Lynch TJ , Haserlat SM , Harris PL , Okimoto RA , Brannigan BW et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials . J Clin Oncol 2005 ; 23 : 8081 – 92 . Google Scholar CrossRef Search ADS PubMed 11 Wood DE , Kazerooni E , Baum SL , Dransfield MT , Eapen GA , Ettinger DS et al. Lung cancer screening, version 1.2015: featured updates to the NCCN guidelines . J Natl Compr Canc Netw 2015 ; 13 : 23 – 34 . Google Scholar CrossRef Search ADS PubMed 12 Ten Haaf K , Tammemagi MC , Bondy SJ , van der Aalst CM , Gu S , McGregor SE et al. Performance and cost-effectiveness of computed tomography lung cancer screening scenarios in a population-based setting: a microsimulation modeling analysis in Ontario, Canada . PLoS Med 2017 ; 14 : e1002225. Google Scholar CrossRef Search ADS PubMed 13 Goldstraw P , Crowley J , Chansky K , Giroux DJ , Groome PA , Rami-Porta R et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours . J Thorac Oncol 2007 ; 2 : 706 – 14 . Google Scholar CrossRef Search ADS PubMed 14 Martini N , Melamed MR. Multiple primary lung cancers . J Thorac Cardiovasc Surg 1975 ; 70 : 606 – 12 . Google Scholar PubMed 15 Detterbeck FC , Franklin WA , Nicholson AG , Girard N , Arenberg DA , Travis WD et al. The IASLC lung cancer staging project: background data and proposed criteria to distinguish separate primary lung cancers form metatstic foci in patients with two lung tumors in the forthcoming eight edition of the TNM classification for lung cancer . J Thorac Oncol 2016 ; 11 : 651 – 65 . Google Scholar CrossRef Search ADS PubMed 16 Travis WD , Brambilla E , Noguchi M , Nicholson AG , Geisinger KR , Yatabe Y et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma . J Thorac Oncol 2011 ; 6 : 244 – 85 . Google Scholar CrossRef Search ADS PubMed 17 Yoshizawa A , Sumiyoshi S , Sonobe M , Kobayashi M , Fujimoto M , Kawakami F et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients . J Thorac Oncol 2013 ; 8 : 52 – 61 . Google Scholar CrossRef Search ADS PubMed 18 Lee YJ , Park IK , Park MS , Choi HJ , Cho BC , Chung KY et al. Activating mutations within the EGFR kinase domain: a molecular predictor of disease-free survival in resected pulmonary adenocarcinoma . J Cancer Res Clin Oncol 2009 ; 135 : 1647 – 54 . Google Scholar CrossRef Search ADS PubMed 19 Marks JL , Broderick S , Zhou Q , Chitale D , Li AR , Zakowski MF et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma . J Thorac Oncol 2008 ; 3 : 111 – 16 . Google Scholar CrossRef Search ADS PubMed 20 Izar B , Sequist L , Lee M , Muzikansky A , Heist R , Iafrate J et al. The impact of EGFR mutation status on outcomes in patients with resected stage I non-small cell lung cancers . Ann Thorac Surg 2013 ; 96 : 962 – 8 . Google Scholar CrossRef Search ADS PubMed 21 Lin CY , Wu YM , Hsieh MH , Wang CW , Wu CY , Chen YJ et al. Prognostic implication of EGFR gene mutations and histological classification in patients with resected stage I lung adenocarcinoma . PLoS One 2017 ; 12 : e0186567. Google Scholar CrossRef Search ADS PubMed 22 Ohba T , Toyokawa G , Kometani T , Nosaki K , Hirai F , Yamaguchi M et al. Mutations of the EGFR and K-ras genes in resected stage I lung adenocarcinoma and their clinical significance . Surg Today 2014 ; 44 : 478 – 86 . Google Scholar CrossRef Search ADS PubMed 23 Yanagawa N , Shiono S , Abiko M , Ogata SY , Sato T , Tamura G. The correlation of the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification with prognosis and EGFR mutation in lung adenocarcinoma . Ann Thorac Surg 2014 ; 98 : 453 – 8 . Google Scholar CrossRef Search ADS PubMed 24 Mansuet-Lupo A , Bobbio A , Blons H , Becht E , Ouakrim H , Didelot A et al. The new histologic classification of lung primary adenocarcinoma subtypes is a reliable prognostic marker and identifies tumors with different mutation status: the experience of a French cohort . Chest 2014 ; 146 : 633 – 43 . 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. 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The prognostic effect of the epidermal growth factor receptor gene mutation on recurrence dynamics of lung adenocarcinoma

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1010-7940
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1873-734X
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10.1093/ejcts/ezy220
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Abstract

Abstract OBJECTIVES The prognostic effects of epidermal growth factor receptor (EGFR) gene mutation on lung adenocarcinoma recurrence have not been well established. The relationship between EGFR gene mutation and recurrence dynamics of lung adenocarcinoma was investigated. METHODS A total of 527 patients with complete resection for adenocarcinoma were reviewed retrospectively. EGFR gene mutation was analysed by polymerase chain reaction followed by bidirectional direct sequencing in recurred patients. Patients were divided into the EGFR gene mutation group (M) or the wild-type EGFR gene group (W). Recurrence types and disease-free intervals (DFIs) of the 2 groups were compared. DFIs were calculated by the Kaplan–Meier method and compared using the log-rank test and Cox proportional hazard model. RESULTS EGFR gene sequencing was performed in 115 recurrent adenocarcinoma patients. Sixty-six patients had EGFR mutations and 49 patients had wild-type EGFR. The median DFI of the 2 groups were significantly different (M: 20.3 months, W: 15.1 months, P = 0.012). EGFR gene mutation was the only prognostic factor for DFI [hazard ratio (HR) = 0.639, 95% confidence interval (CI) = 0.428–0.954, P = 0.029]. The proportion of loco-regional recurrences and distant metastases of both groups were similar (P = 0.50). In subgroup analysis, EGFR gene mutation (HR = 0.534, 95% CI = 0.339–0.839, P = 0.007) was a significant prognostic factor for DFI of distant metastases. CONCLUSIONS Lung adenocarcinoma with EGFR gene mutations had longer DFI than those with wild-type EGFR gene, especially with regard to distant metastasis. EGFR gene mutation was a prognostic factor for lung adenocarcinoma. Epidermal growth factor receptor, Adenocarcinoma, Lung cancer, Prognosis INTRODUCTION Epidermal growth factor receptor (EGFR) gene mutation is detected in 30–40% of lung adenocarcinoma and associated with specific demographic parameters such as never-smoker, Asian and female gender [1–3]. EGFR gene mutation is the most important molecular target, and tyrosine kinase inhibitors (TKIs) targeting EGFR gene mutation have been shown to significantly improve the prognosis of advanced lung adenocarcinoma [4–6]. Post-recurrence survival of lung adenocarcinoma patients with EGFR gene mutation has also been improved by the use of TKIs [7, 8]. It is evident that EGFR gene mutation is a predictive factor in the treatment of lung adenocarcinoma. However, the prognostic effect of EGFR gene mutation on tumour progression, which affects recurrence pattern and dynamics, has not been well established [9]. Several prospective studies have reported that lung adenocarcinoma with EGFR gene mutation had longer progression intervals than those with wild-type EGFR gene in chemotherapy-alone subgroups [2, 10]. As low-dose computed tomography screening becomes more popular [11, 12], the number of detected early adenocarcinomas and the number of surgically treated lung adenocarcinoma will also increase. Therefore, understanding the prognostic characteristics of adenocarcinoma with EGFR gene mutation is important for predicting accurate prognosis and for customizing the surveillance programme for patients with completely resected lung adenocarcinoma. In this study, the relationship between EGFR gene mutations and the recurrence dynamics of completely resected lung adenocarcinoma was investigated. MATERIALS AND METHODS Study population A total of 527 patients who underwent curative surgery for lung adenocarcinoma from January 2006 to December 2009 were reviewed retrospectively. The data for age, sex, histological subtype, presence of EGFR mutation, extent of pulmonary resection, pathological stage (7th edition of Lung cancer stage classification system) [13], adjuvant treatment, recurrence status, first recurrence site, disease-free interval (DFI), survival status and survival duration were obtained by reviewing medical records. DFI was defined as months from the day of operation to the day of clinical or radiological detection of recurrence. The survival duration was counted from the day of surgery to the day of death by any causes or the day of last follow-up in months. Platinum-based cytotoxic chemotherapy was standard adjuvant treatment in patients with pathological stage II disease or more. No adjuvant TKI treatment was performed in the present study. Postoperative surveillance of recurrence was conducted by contrast-enhanced chest computed tomography (CT) every 6 months for 2 years, and then chest low-dose CT was performed annually. Positron emission tomography–CT was performed case by case. Histological confirmation of recurrence was performed in patients with ambiguous image findings on CT or positron emission tomography–CT. Recurrence and second primary lung cancer were classified according to the Martini and Melamed classification [14] and criteria proposal by International Association for the Study of Lung Cancer [15]. Types of recurrences were classified into loco-regional recurrence (recurrences at resection margin or N1/N2 nodes) or distant metastasis (ipsilateral lung, ipsilateral pleural space, contralateral intrathoracic metastasis, extrathoracic metastasis). Histological subtype was determined according to the International Association for the study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma [16]. Tumours were graded according to the dominant subtype: Low grade—adenocarcinoma in situ and minimally invasive adenocarcinoma; Moderate grade—lepidic, acinar and papillary subtypes; High grade—solid and micropapillary subtypes [17]. The last follow-up date was 30 June 2016. Invasive mucinous adenocarcinomas, pathological stage IV and operative mortality cases were excluded. Epidermal growth factor receptor gene mutation test EGFR gene mutation was tested by nested polymerase chain reaction followed by bidirectional direct sequencing in the event of recurrence [7]. EGFR gene expression was also tested in some patients by immunohistochemistry during the early period of this study. The results of immunohistochemistry for EGFR gene mutation were excluded from the analyses. Statistical analyses Adenocarcinoma patients who experienced recurrence and had been tested for EGFR gene mutation by direct sequencing were included in the analyses. Patients were classified according to whether their adenocarcinoma had EGFR gene mutation (M group) or wild-type EGFR genes (W group) (Fig. 1). Recurrence sites and DFIs of the 2 groups were compared. T-test was used for the comparison of continuous variables, and chi-square method was used for the comparison of discrete variables. DFI and overall survival rate were calculated using the Kaplan–Meier method and compared using the log-rank test for univariable analysis. Prognostic effects of age (≤60 vs >60), sex, smoking status (<30 pack-year vs ≥30 pack-year), histological grade, pathological stage (I vs II + III), extent of surgery (lobectomy versus bilobectomy + pneumonectomy), visceral pleural invasion, lymphovascular invasion, adjuvant treatment and EFGR gene mutation on DFI were tested. Parameters showing P-value 0.1 or less in univariable analysis were included in multivariable analysis conducted according to Cox’s proportional hazard model. P-values <0.05 were considered statistically significant. Statistical analyses were performed using the Statistical Package for Social Science (ver. 21.0, IBM Corp., Armonk, NY, USA). This study was approved by the Institutional Review Board of Seoul National University Hospital (approval number: H-1506-018-678), and it complied with the Declaration of Helsinki. Figure 1: View largeDownload slide Diagram of the study population. EGFR: epidermal growth factor receptor. Figure 1: View largeDownload slide Diagram of the study population. EGFR: epidermal growth factor receptor. RESULTS A total of 527 patients with a mean age of 62.5±10 years (range: 23–83 years) had adenocarcinoma, of whom 282 (53.5%) were female. There were 351 (66.6%) patients with stage I, 69 (13.1%) with stage II and 107 (20.3%) with stage III adenocarcinoma. The median follow-up duration was 72 months. The 5-year overall survival rate was 80.1%. Recurrence was detected in 149 patients, and the 5-year disease-free survival (DFS) rate was 60.5%. Initial recurrences of 7 (1.3%) patients were loco-regional recurrences (resection margin—3, N2 node—4), and 142 (26.9%) patients presented with distant metastases (ipsilateral lung—18, ipsilateral pleural seeding—17, others—107). Twenty-four (4.6%) patients underwent additional surgery for second primary lung cancer during the study period. Pathological stage was the only prognostic factor for recurrence (I vs II/III, P = 0.03). EGFR gene mutation test by the direct sequencing method was performed in 115 (77.2%) patients with recurrent adenocarcinoma. Reasons for excluding 34 (22.8%) patients were (i) EGFR gene mutation test was done only by immunohistochemistry and (ii) no EGFR gene mutation test was performed due to omission of subsequent TKI treatment because of impaired performance status or refusal of treatment. Recurrent adenocarcinoma with epidermal growth factor receptor gene sequencing Table 1 lists the demographics and pathological characteristics of the study population. The mean age was 64 ± 10 (range: 34–83), and 59 (50%) patients were female. The median DFI was 19.0 [95% confidence interval (CI) = 16.6–21.3] months. There were 6 (5.2%) loco-regional recurrences (resection margin—2, N2 nodes—4) and 109 (94.8%) distant metastases (ipsilateral lung—17, ipsilateral pleural seeding—13, others—79). EGFR gene mutations were detected in 66 (57.4%) patients, and 49 (42.6%) patients had wild-type EGFR genes. EGFR gene mutations were found at exon 18 in 2 (3%) patients, exon 19 in 37 (56.1%) patients, exon 20 in 5 (7.6%) patients, exon 21 in 21 (31.8%) patients and exon 22 in 1 (1.5%) patient. No recurrence occurred in patients with low-grade histology. The proportion of females was higher in the M group, and the proportion of heavy smokers was higher in the W group. There was no difference in age, pathological stage, extent of resection and adjuvant treatment between M and W groups (Table 2). Types of recurrence in the M group were loco-regional in 4 (6.1%) patients and distant metastasis in 62 (93.9%) patients. The types of recurrence in the W group were loco-regional in 2 (4.1%) patients and distant metastasis in 47 (95.9%) patients. The types of recurrence were not significantly different between the 2 groups (P = 0.50). However, the median DFI of the 2 groups were significantly different (M group: 20.3 months, W group: 15.1 month, P = 0.012) (Fig. 2). Univariable analyses showed that EGFR gene mutation was the only prognostic factor for DFI. Sex, age, smoking history, histological grade, pathological stage, visceral pleural invasion, lymphovascular invasion, extent of resection and adjuvant treatment were not prognostic factors for DFI (Table 3). Multivariable analysis showed that EGFR gene mutation [hazard ratio (HR) = 0.639, 95% CI = 0.428–0.954, P = 0.029] was the only prognostic factor for DFI (Table 4). Table 1: Characteristics of the patients Variables n = 115 Age (years), mean ± SD 62.7 ± 10.3 Sex, n (%)  Male 56 (48.7)  Female 59 (51.3) Smoking history, n (%)  <30 PY 91 (79.1)  ≥30 PY 24 (20.9) Histological grade, n (%)  Moderate 94 (81.7)  High 21 (18.3) Visceral pleural invasion, n (%) 64 (55.7) Lymphovascular invasion, n (%) 39 (33.9) Pathological stage, n (%)  I 57 (49.6)  II/III 58 (50.4) Extent of lung resection, n (%)  Lobectomy 108 (93.9)  >Lobectomy 7 (6.1) Adjuvant chemotherapy, n (%) 54 (47.0) Adjuvant radiotherapy, n (%) 5 (4.3) Type of recurrence, n (%)  Loco-regional 6 (5.2)  Distant 109 (94.8) Variables n = 115 Age (years), mean ± SD 62.7 ± 10.3 Sex, n (%)  Male 56 (48.7)  Female 59 (51.3) Smoking history, n (%)  <30 PY 91 (79.1)  ≥30 PY 24 (20.9) Histological grade, n (%)  Moderate 94 (81.7)  High 21 (18.3) Visceral pleural invasion, n (%) 64 (55.7) Lymphovascular invasion, n (%) 39 (33.9) Pathological stage, n (%)  I 57 (49.6)  II/III 58 (50.4) Extent of lung resection, n (%)  Lobectomy 108 (93.9)  >Lobectomy 7 (6.1) Adjuvant chemotherapy, n (%) 54 (47.0) Adjuvant radiotherapy, n (%) 5 (4.3) Type of recurrence, n (%)  Loco-regional 6 (5.2)  Distant 109 (94.8) SD: standard deviation. Table 1: Characteristics of the patients Variables n = 115 Age (years), mean ± SD 62.7 ± 10.3 Sex, n (%)  Male 56 (48.7)  Female 59 (51.3) Smoking history, n (%)  <30 PY 91 (79.1)  ≥30 PY 24 (20.9) Histological grade, n (%)  Moderate 94 (81.7)  High 21 (18.3) Visceral pleural invasion, n (%) 64 (55.7) Lymphovascular invasion, n (%) 39 (33.9) Pathological stage, n (%)  I 57 (49.6)  II/III 58 (50.4) Extent of lung resection, n (%)  Lobectomy 108 (93.9)  >Lobectomy 7 (6.1) Adjuvant chemotherapy, n (%) 54 (47.0) Adjuvant radiotherapy, n (%) 5 (4.3) Type of recurrence, n (%)  Loco-regional 6 (5.2)  Distant 109 (94.8) Variables n = 115 Age (years), mean ± SD 62.7 ± 10.3 Sex, n (%)  Male 56 (48.7)  Female 59 (51.3) Smoking history, n (%)  <30 PY 91 (79.1)  ≥30 PY 24 (20.9) Histological grade, n (%)  Moderate 94 (81.7)  High 21 (18.3) Visceral pleural invasion, n (%) 64 (55.7) Lymphovascular invasion, n (%) 39 (33.9) Pathological stage, n (%)  I 57 (49.6)  II/III 58 (50.4) Extent of lung resection, n (%)  Lobectomy 108 (93.9)  >Lobectomy 7 (6.1) Adjuvant chemotherapy, n (%) 54 (47.0) Adjuvant radiotherapy, n (%) 5 (4.3) Type of recurrence, n (%)  Loco-regional 6 (5.2)  Distant 109 (94.8) SD: standard deviation. Table 2: Comparison of patient characteristics according to the presence of EGFR gene mutation Variables Mutation Wild-type P-value (n = 66) (n= 49) Age (years), mean ± SD 62.8 ± 9.7 62.5 ± 11.2 0.91 Sex, n (%)  Male 25 (37.9) 31 (63.3) 0.007  Female 41 (62.1) 18 (36.7) Smoking history, n (%)  <30 PY 59 (89.4) 31 (63.3) 0.001  ≥30 PY 7 (10.6) 18 (36.7) Histological grade, n (%)  Moderate 54 (81.8) 41 (83.7) 0.80  High 12 (18.2) 8 (16.3) Visceral pleural invasion, n (%) 33 (50) 31 (63.3) 0.16 Lymphovascular invasion, n (%) 19 (28.8) 20 (40.8) 0.18 Pathological stage, n (%)  I 30 (45.5) 27 (55.1) 0.31  II/III 36 (54.5) 22 (44.9) Extent of lung resection, n (%)  Lobectomy 64 (97) 44 (89.8) 0.11  >Lobectomy 2 (3) 5 (10.2) Adjuvant chemotherapy, n (%) 34 (51.5) 20 (40.8) 0.26 Adjuvant radiotherapy, n (%) 3 (4.5) 2 (4.1) 0.90 Type of recurrence  Loco-regional, n (%) 4 (6.1) 2 (4.1) 0.50  Distant, n (%) 62 (93.9) 47 (95.9) Variables Mutation Wild-type P-value (n = 66) (n= 49) Age (years), mean ± SD 62.8 ± 9.7 62.5 ± 11.2 0.91 Sex, n (%)  Male 25 (37.9) 31 (63.3) 0.007  Female 41 (62.1) 18 (36.7) Smoking history, n (%)  <30 PY 59 (89.4) 31 (63.3) 0.001  ≥30 PY 7 (10.6) 18 (36.7) Histological grade, n (%)  Moderate 54 (81.8) 41 (83.7) 0.80  High 12 (18.2) 8 (16.3) Visceral pleural invasion, n (%) 33 (50) 31 (63.3) 0.16 Lymphovascular invasion, n (%) 19 (28.8) 20 (40.8) 0.18 Pathological stage, n (%)  I 30 (45.5) 27 (55.1) 0.31  II/III 36 (54.5) 22 (44.9) Extent of lung resection, n (%)  Lobectomy 64 (97) 44 (89.8) 0.11  >Lobectomy 2 (3) 5 (10.2) Adjuvant chemotherapy, n (%) 34 (51.5) 20 (40.8) 0.26 Adjuvant radiotherapy, n (%) 3 (4.5) 2 (4.1) 0.90 Type of recurrence  Loco-regional, n (%) 4 (6.1) 2 (4.1) 0.50  Distant, n (%) 62 (93.9) 47 (95.9) EGFR: epidermal growth factor receptor; SD: standard deviation. Table 2: Comparison of patient characteristics according to the presence of EGFR gene mutation Variables Mutation Wild-type P-value (n = 66) (n= 49) Age (years), mean ± SD 62.8 ± 9.7 62.5 ± 11.2 0.91 Sex, n (%)  Male 25 (37.9) 31 (63.3) 0.007  Female 41 (62.1) 18 (36.7) Smoking history, n (%)  <30 PY 59 (89.4) 31 (63.3) 0.001  ≥30 PY 7 (10.6) 18 (36.7) Histological grade, n (%)  Moderate 54 (81.8) 41 (83.7) 0.80  High 12 (18.2) 8 (16.3) Visceral pleural invasion, n (%) 33 (50) 31 (63.3) 0.16 Lymphovascular invasion, n (%) 19 (28.8) 20 (40.8) 0.18 Pathological stage, n (%)  I 30 (45.5) 27 (55.1) 0.31  II/III 36 (54.5) 22 (44.9) Extent of lung resection, n (%)  Lobectomy 64 (97) 44 (89.8) 0.11  >Lobectomy 2 (3) 5 (10.2) Adjuvant chemotherapy, n (%) 34 (51.5) 20 (40.8) 0.26 Adjuvant radiotherapy, n (%) 3 (4.5) 2 (4.1) 0.90 Type of recurrence  Loco-regional, n (%) 4 (6.1) 2 (4.1) 0.50  Distant, n (%) 62 (93.9) 47 (95.9) Variables Mutation Wild-type P-value (n = 66) (n= 49) Age (years), mean ± SD 62.8 ± 9.7 62.5 ± 11.2 0.91 Sex, n (%)  Male 25 (37.9) 31 (63.3) 0.007  Female 41 (62.1) 18 (36.7) Smoking history, n (%)  <30 PY 59 (89.4) 31 (63.3) 0.001  ≥30 PY 7 (10.6) 18 (36.7) Histological grade, n (%)  Moderate 54 (81.8) 41 (83.7) 0.80  High 12 (18.2) 8 (16.3) Visceral pleural invasion, n (%) 33 (50) 31 (63.3) 0.16 Lymphovascular invasion, n (%) 19 (28.8) 20 (40.8) 0.18 Pathological stage, n (%)  I 30 (45.5) 27 (55.1) 0.31  II/III 36 (54.5) 22 (44.9) Extent of lung resection, n (%)  Lobectomy 64 (97) 44 (89.8) 0.11  >Lobectomy 2 (3) 5 (10.2) Adjuvant chemotherapy, n (%) 34 (51.5) 20 (40.8) 0.26 Adjuvant radiotherapy, n (%) 3 (4.5) 2 (4.1) 0.90 Type of recurrence  Loco-regional, n (%) 4 (6.1) 2 (4.1) 0.50  Distant, n (%) 62 (93.9) 47 (95.9) EGFR: epidermal growth factor receptor; SD: standard deviation. Table 3: Univariable analyses for the risk factors of DFI Variables DFI (95% CI) P-value Age (years)  ≤60 19.6 (15.3–23.7) 0.38  >60 18.5 (14.1–22.9) Sex  Male 16.0 (10.0–21.8) 0.28  Female 19.3 (17.6–21.0) Smoking history  <30 PY 19.4 (17.8–20.9) 0.14  ≥30 PY 13.8 (9.9–17.7) Histological grade  Moderate 19.0 (17.3–20.7) 0.095  High 14.6 (11.2–18.1) EGFR gene  Wild type 15.1 (9.5–20.8) 0.012  Mutation 20.3 (14.9–25.6) Visceral pleural invasion  No 20.2 (16.1–24.3) 0.093  Yes 16.9 (12.2–21.7) Lymphovascular invasion  No 20.2 (16.3–24.0) 0.075  Yes 15.0 (10.9–19.1) Pathological stage  I 20.3 (16.0–24.6) 0.46  II/III 16.8 (13.7–19.9) Extent of lung resection  Lobectomy 19.0 (16.4–21.5) 0.34  >Lobectomy 17.3 (6.8–27.8) Adjuvant treatment  No 19.0 (17.2–20.7) 0.41  Yes 17.2 (11.4–22.9) Variables DFI (95% CI) P-value Age (years)  ≤60 19.6 (15.3–23.7) 0.38  >60 18.5 (14.1–22.9) Sex  Male 16.0 (10.0–21.8) 0.28  Female 19.3 (17.6–21.0) Smoking history  <30 PY 19.4 (17.8–20.9) 0.14  ≥30 PY 13.8 (9.9–17.7) Histological grade  Moderate 19.0 (17.3–20.7) 0.095  High 14.6 (11.2–18.1) EGFR gene  Wild type 15.1 (9.5–20.8) 0.012  Mutation 20.3 (14.9–25.6) Visceral pleural invasion  No 20.2 (16.1–24.3) 0.093  Yes 16.9 (12.2–21.7) Lymphovascular invasion  No 20.2 (16.3–24.0) 0.075  Yes 15.0 (10.9–19.1) Pathological stage  I 20.3 (16.0–24.6) 0.46  II/III 16.8 (13.7–19.9) Extent of lung resection  Lobectomy 19.0 (16.4–21.5) 0.34  >Lobectomy 17.3 (6.8–27.8) Adjuvant treatment  No 19.0 (17.2–20.7) 0.41  Yes 17.2 (11.4–22.9) CI: confidence interval; DFI: disease-free interval (median, months); EGFR: epidermal growth factor receptor. Table 3: Univariable analyses for the risk factors of DFI Variables DFI (95% CI) P-value Age (years)  ≤60 19.6 (15.3–23.7) 0.38  >60 18.5 (14.1–22.9) Sex  Male 16.0 (10.0–21.8) 0.28  Female 19.3 (17.6–21.0) Smoking history  <30 PY 19.4 (17.8–20.9) 0.14  ≥30 PY 13.8 (9.9–17.7) Histological grade  Moderate 19.0 (17.3–20.7) 0.095  High 14.6 (11.2–18.1) EGFR gene  Wild type 15.1 (9.5–20.8) 0.012  Mutation 20.3 (14.9–25.6) Visceral pleural invasion  No 20.2 (16.1–24.3) 0.093  Yes 16.9 (12.2–21.7) Lymphovascular invasion  No 20.2 (16.3–24.0) 0.075  Yes 15.0 (10.9–19.1) Pathological stage  I 20.3 (16.0–24.6) 0.46  II/III 16.8 (13.7–19.9) Extent of lung resection  Lobectomy 19.0 (16.4–21.5) 0.34  >Lobectomy 17.3 (6.8–27.8) Adjuvant treatment  No 19.0 (17.2–20.7) 0.41  Yes 17.2 (11.4–22.9) Variables DFI (95% CI) P-value Age (years)  ≤60 19.6 (15.3–23.7) 0.38  >60 18.5 (14.1–22.9) Sex  Male 16.0 (10.0–21.8) 0.28  Female 19.3 (17.6–21.0) Smoking history  <30 PY 19.4 (17.8–20.9) 0.14  ≥30 PY 13.8 (9.9–17.7) Histological grade  Moderate 19.0 (17.3–20.7) 0.095  High 14.6 (11.2–18.1) EGFR gene  Wild type 15.1 (9.5–20.8) 0.012  Mutation 20.3 (14.9–25.6) Visceral pleural invasion  No 20.2 (16.1–24.3) 0.093  Yes 16.9 (12.2–21.7) Lymphovascular invasion  No 20.2 (16.3–24.0) 0.075  Yes 15.0 (10.9–19.1) Pathological stage  I 20.3 (16.0–24.6) 0.46  II/III 16.8 (13.7–19.9) Extent of lung resection  Lobectomy 19.0 (16.4–21.5) 0.34  >Lobectomy 17.3 (6.8–27.8) Adjuvant treatment  No 19.0 (17.2–20.7) 0.41  Yes 17.2 (11.4–22.9) CI: confidence interval; DFI: disease-free interval (median, months); EGFR: epidermal growth factor receptor. Table 4: Multivariable analysis for the risk factors of disease-free interval Variables HR (95% CI) P-value Histological grade  Moderate 1 0.08  High 1.567 (0.946–2.593) EGFR gene  Wild-type 1 0.029  Mutation 0.639 (0.428–0.954) Visceral pleural invasion  No 1 0.23  Yes 1.263 (0.860–1.857) Lymphovascular invasion  No 1 0.37  Yes 1.207 (0.797–1.828) Variables HR (95% CI) P-value Histological grade  Moderate 1 0.08  High 1.567 (0.946–2.593) EGFR gene  Wild-type 1 0.029  Mutation 0.639 (0.428–0.954) Visceral pleural invasion  No 1 0.23  Yes 1.263 (0.860–1.857) Lymphovascular invasion  No 1 0.37  Yes 1.207 (0.797–1.828) CI: confidence interval; EGFR: epidermal growth factor receptor; HR: hazard ratio. Table 4: Multivariable analysis for the risk factors of disease-free interval Variables HR (95% CI) P-value Histological grade  Moderate 1 0.08  High 1.567 (0.946–2.593) EGFR gene  Wild-type 1 0.029  Mutation 0.639 (0.428–0.954) Visceral pleural invasion  No 1 0.23  Yes 1.263 (0.860–1.857) Lymphovascular invasion  No 1 0.37  Yes 1.207 (0.797–1.828) Variables HR (95% CI) P-value Histological grade  Moderate 1 0.08  High 1.567 (0.946–2.593) EGFR gene  Wild-type 1 0.029  Mutation 0.639 (0.428–0.954) Visceral pleural invasion  No 1 0.23  Yes 1.263 (0.860–1.857) Lymphovascular invasion  No 1 0.37  Yes 1.207 (0.797–1.828) CI: confidence interval; EGFR: epidermal growth factor receptor; HR: hazard ratio. Figure 2: View largeDownload slide Kaplan–Meier curves for disease-free intervals according to the presence of epidermal growth factor receptor gene mutation. Figure 2: View largeDownload slide Kaplan–Meier curves for disease-free intervals according to the presence of epidermal growth factor receptor gene mutation. Subgroup analyses of patients with distant metastasis showed similar results. The median DFI of the M group was significantly longer than that of the W group (M group: 20.3 months, W group: 14.6 months, P = 0.002). EGFR gene mutation (HR = 0.534, 95% CI = 0.339–0.839, P = 0.007) was the only significant prognostic factor for DFI of distant metastasis in univariable and multivariable analyses. DISCUSSION This study found that lung adenocarcinomas with an EGFR gene mutation progress more slowly than those with a wild-type EGFR gene. The difference was more pronounced in distant metastasis. DFI was significantly longer in the EGFR gene mutation group than in the wild-type EGFR gene group by about 5 months in all recurrence and about 6 months in distant metastasis. This finding suggests that the recurrence dynamics of adenocarcinoma differ according to whether EGFR gene mutation had occurred and that the prognosis of adenocarcinoma with EGFR gene mutation is better than that with wild-type EGFR gene. The predictive effect of EGFR gene mutation has been investigated extensively in lung adenocarcinoma because it is a promising target for TKI treatment [4–8]. In contrast, the prognostic effect of EGFR gene mutation has received less attention, and the findings regarding the prognostic effect of EGFR gene mutation have been controversial. Several prospective studies revealed a favourable prognostic effect of EGFR gene mutation in advanced lung adenocarcinomas. Secondary analysis of the IDEAL/INTACT trial showed that adenocarcinomas with EGFR gene mutation had a better prognosis than those with a wild-type EGFR gene in patients treated by cytotoxic chemotherapy only [10]. The TRIBUTE trial also showed that the time-to-progression of non-small-cell carcinoma with EGFR gene mutation was longer than that with wild-type EGFR gene in the cytotoxic chemotherapy alone group [2]. These findings suggest that adenocarcinomas with EGFR gene mutation are less aggressive and that the presence of EFGR gene mutation is a prognostic factor in lung adenocarcinoma. Retrospective studies about the prognostic effect of EGFR mutation in early lung adenocarcinoma were performed on a small number of patients because EGFR gene mutation test was not routinely performed on the completely resected early lung adenocarcinoma patients in clinical settings. Several of these retrospective studies showed similar results to those shown in the present study. Lee et al. [18] reported that the presence of wild-type EGFR gene was a risk factor for recurrence with an adjusted HR of 1.42. Marks et al. [19] reported that adenocarcinoma patients with EGFR gene mutation showed longer overall survival times compared with those with wild-type EGFR gene after adjusting for the stage (HR = 0.4) in a study that included only patients who had not received TKI treatment. Izar et al. reported that EGFR mutation was associated with a significantly lower recurrence rate than wild-type EGFR gene (mutation group: 9.7%, wild-type group: 21.6%, P = 0.03) and longer median DFS (mutation group: 8.8 years, wild-type group: 7.0 years, P = 0.0085). The presence of an EGFR mutation was an independent prognostic factor for DFS in completely resected stage I non-small-cell carcinoma patients in that study [20]. However, other studies have reported opposite results. Lin et al. reported that EGFR gene mutation had no prognostic effect in resected stage I lung adenocarcinoma after analysing adenocarcinoma patients (87 with EGFR gene mutation and 33 with wild-type EGFR gene). However, considering that approximately 60% of their patients had low-grade histology, the sample size was too small to draw meaningful conclusions [21]. Ohba et al. [22] analysed 256 patients with resected pathological stage I adenocarcinoma and could not find the prognostic effect of EGFR gene mutation on DFS. The types of recurrence were similar for adenocarcinoma with EGFR gene mutation and wild-type EGFR gene, which suggested that mode of recurrence did not differ according to EGFR gene mutation status. Most of the recurrences in the present study were distant metastasis, and a subgroup analysis with distant metastases also showed longer DFI in adenocarcinoma with EGFR gene mutation. This finding suggests that sub-clinical micrometastases of adenocarcinoma with EGFR gene mutation progress to clinically detectable metastases more slowly. EGFR gene mutation has been shown to be associated with histological subtypes of adenocarcinoma. No EGFR gene mutation is expected in mucinous adenocarcinoma. An EGFR gene mutation is more frequent in adenocarcinoma in situ, non-mucinous lepidic predominant, papillary and micropapillary subtypes [16]. Yoshizawa et al. [17] reported that EGFR gene mutation was found more frequently in the adenocarcinomas with non-mucinous lepidic and micropapillary patterns and less frequently in those with a solid component. Similarly, Yanagawa et al. [23] found EGRF gene mutations in more than 40% of adenocarcinomas with a lepidic, acinar, papillary and micropapillary subtype and only in 28% of those with a solid subtype. A French study also reported that EGFR gene mutation was more frequent in intermediate-grade histologies than in high-grade histologies [24]. In the present study, EGFR gene mutation rates did not differ according to histological grades in recurrent lung adenocarcinoma. This result suggests that the likelihood of the presence of EGFR gene mutation is similar between histological subtypes of recurrent adenocarcinoma and that the effect of TKI treatment on recurrent adenocarcinoma would be similar for different histological subtypes. Limitations Limitations of this study are the small number of patients and the fact that only patients with recurrence were included. During the study period, direct sequencing of EGFR gene was usually performed in recurrent adenocarcinomas only. Therefore, the present study had to be focused on patients with recurrence. Although it could not show the whole picture of the recurrence dynamics of completely resected lung adenocarcinoma, the present study did reflect the recurrence dynamics of lung adenocarcinoma with micrometastases at the time of surgery because the follow-up duration was long enough to detect any possible recurrences and the presence of EGFR gene mutation was tested with a reliable method. Further study with a prospective cohort of resected lung adenocarcinoma with EGFR gene mutation test is required to verify the results of this small study. We have begun collecting such data for a study in the future. CONCLUSION In conclusion, lung adenocarcinoma with EGFR gene mutation was shown to have longer progression intervals and less aggressive recurrence dynamics than that with wild-type EGFR gene, especially with regard to distant metastasis. This finding should be considered in the conduct of postoperative surveillance of completely resected lung adenocarcinomas. The mechanism controlling the slow progression of distant metastasis in the lung adenocarcinoma with EGFR gene mutation should be investigated. Funding This work was supported by the grant from the Seoul National University College of Medicine Research Fund (800–20130175). Conflict of interest: none declared. REFERENCES 1 Shigematsu H , Lin L , Takahashi T , Nomura M , Suzuki M , Wistuba II et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers . J Natl Cancer Inst 2005 ; 97 : 339 – 46 . Google Scholar CrossRef Search ADS PubMed 2 Eberhard DA , Johnson BE , Amler LC , Goddard AD , Heldens SL , Herbst RS et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib . J Clin Oncol 2005 ; 23 : 5900 – 9 . Google Scholar CrossRef Search ADS PubMed 3 Tsuta K , Kawago M , Inoue E , Yoshida A , Takahashi F , Sakurai H et al. The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations . Lung Cancer 2013 ; 81 : 371 – 6 . Google Scholar CrossRef Search ADS PubMed 4 Kris MG , Natale RB , Herbst RS , Lynch TJ Jr , Prager D , Belani CP et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial . JAMA 2003 ; 290 : 2149 – 58 . Google Scholar CrossRef Search ADS PubMed 5 Shepherd FA , Rodrigues Pereira J , Ciuleanu T , Tan EH , Hirsh V , Thongprasert S et al. Erlotinib in previously treated non-small-cell lung cancer . N Engl J Med 2005 ; 353 : 123 – 32 . Google Scholar CrossRef Search ADS PubMed 6 Lynch TJ , Bell DW , Sordella R , Gurubhagavatula S , Okimoto RA , Brannigan BW et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib . N Engl J Med 2004 ; 350 : 2129 – 39 . Google Scholar CrossRef Search ADS PubMed 7 Kim YT , Seong YW , Jung YJ , Jeon YK , Park IK , Kang CH et al. The presence of mutations in epidermal growth factor receptor gene is not a prognostic factor for long-term outcome after surgical resection of non-small-cell lung cancer . J Thorac Oncol 2013 ; 8 : 171 – 8 . Google Scholar CrossRef Search ADS PubMed 8 Takenaka T , Takenoyama M , Yamaguchi M , Toyozawa R , Inamasu E , Kojo M et al. Impact of the epidermal growth factor receptor mutation status on the post-recurrence survival of patients with surgically resected non-small-cell lung cancer . Eur J Cardiothorac Surg 2015 ; 47 : 550 – 5 . Google Scholar CrossRef Search ADS PubMed 9 Zhang Z , Wang T , Zhang J , Cai X , Pan C , Long Y et al. Prognostic value of epidermal growth factor receptor mutations in resected non-small cell lung cancer: a systematic review with meta-analysis . PLoS One 2014 ; 9 : e106053. Google Scholar CrossRef Search ADS PubMed 10 Bell DW , Lynch TJ , Haserlat SM , Harris PL , Okimoto RA , Brannigan BW et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials . J Clin Oncol 2005 ; 23 : 8081 – 92 . Google Scholar CrossRef Search ADS PubMed 11 Wood DE , Kazerooni E , Baum SL , Dransfield MT , Eapen GA , Ettinger DS et al. Lung cancer screening, version 1.2015: featured updates to the NCCN guidelines . J Natl Compr Canc Netw 2015 ; 13 : 23 – 34 . Google Scholar CrossRef Search ADS PubMed 12 Ten Haaf K , Tammemagi MC , Bondy SJ , van der Aalst CM , Gu S , McGregor SE et al. Performance and cost-effectiveness of computed tomography lung cancer screening scenarios in a population-based setting: a microsimulation modeling analysis in Ontario, Canada . PLoS Med 2017 ; 14 : e1002225. Google Scholar CrossRef Search ADS PubMed 13 Goldstraw P , Crowley J , Chansky K , Giroux DJ , Groome PA , Rami-Porta R et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours . J Thorac Oncol 2007 ; 2 : 706 – 14 . Google Scholar CrossRef Search ADS PubMed 14 Martini N , Melamed MR. Multiple primary lung cancers . J Thorac Cardiovasc Surg 1975 ; 70 : 606 – 12 . Google Scholar PubMed 15 Detterbeck FC , Franklin WA , Nicholson AG , Girard N , Arenberg DA , Travis WD et al. The IASLC lung cancer staging project: background data and proposed criteria to distinguish separate primary lung cancers form metatstic foci in patients with two lung tumors in the forthcoming eight edition of the TNM classification for lung cancer . J Thorac Oncol 2016 ; 11 : 651 – 65 . Google Scholar CrossRef Search ADS PubMed 16 Travis WD , Brambilla E , Noguchi M , Nicholson AG , Geisinger KR , Yatabe Y et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma . J Thorac Oncol 2011 ; 6 : 244 – 85 . Google Scholar CrossRef Search ADS PubMed 17 Yoshizawa A , Sumiyoshi S , Sonobe M , Kobayashi M , Fujimoto M , Kawakami F et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients . J Thorac Oncol 2013 ; 8 : 52 – 61 . Google Scholar CrossRef Search ADS PubMed 18 Lee YJ , Park IK , Park MS , Choi HJ , Cho BC , Chung KY et al. Activating mutations within the EGFR kinase domain: a molecular predictor of disease-free survival in resected pulmonary adenocarcinoma . J Cancer Res Clin Oncol 2009 ; 135 : 1647 – 54 . Google Scholar CrossRef Search ADS PubMed 19 Marks JL , Broderick S , Zhou Q , Chitale D , Li AR , Zakowski MF et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma . J Thorac Oncol 2008 ; 3 : 111 – 16 . Google Scholar CrossRef Search ADS PubMed 20 Izar B , Sequist L , Lee M , Muzikansky A , Heist R , Iafrate J et al. The impact of EGFR mutation status on outcomes in patients with resected stage I non-small cell lung cancers . Ann Thorac Surg 2013 ; 96 : 962 – 8 . Google Scholar CrossRef Search ADS PubMed 21 Lin CY , Wu YM , Hsieh MH , Wang CW , Wu CY , Chen YJ et al. Prognostic implication of EGFR gene mutations and histological classification in patients with resected stage I lung adenocarcinoma . PLoS One 2017 ; 12 : e0186567. Google Scholar CrossRef Search ADS PubMed 22 Ohba T , Toyokawa G , Kometani T , Nosaki K , Hirai F , Yamaguchi M et al. Mutations of the EGFR and K-ras genes in resected stage I lung adenocarcinoma and their clinical significance . Surg Today 2014 ; 44 : 478 – 86 . Google Scholar CrossRef Search ADS PubMed 23 Yanagawa N , Shiono S , Abiko M , Ogata SY , Sato T , Tamura G. The correlation of the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification with prognosis and EGFR mutation in lung adenocarcinoma . Ann Thorac Surg 2014 ; 98 : 453 – 8 . Google Scholar CrossRef Search ADS PubMed 24 Mansuet-Lupo A , Bobbio A , Blons H , Becht E , Ouakrim H , Didelot A et al. The new histologic classification of lung primary adenocarcinoma subtypes is a reliable prognostic marker and identifies tumors with different mutation status: the experience of a French cohort . Chest 2014 ; 146 : 633 – 43 . 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. 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European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Jun 5, 2018

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