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 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 8  |  Issue : 3  |  Page : 373-378

Epidermal growth factor receptor mutations in female patients with postoperative recurrent non-small-cell lung cancer


1 Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
2 Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
3 Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
4 Department of Thoracic Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
5 Department of Radiology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

Date of Web Publication17-Nov-2012

Correspondence Address:
Im Il Na
Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-dong, Nowon-gu, Seoul, 139-706
Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.103515

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 > Abstract 

Purpose: We did this retrospective study to explore the association between epidermal growth factor receptor (EGFR) mutation and clinical features in postoperative recurrent female non-small-cell lung cancer (NSCLC).
Materials and Methods: We reviewed clinical data on 86 female patients who had postoperative recurrent disease between December 1992 and July 2007. The start of tyrosine kinase inhibitor therapy was treated as a censoring event. Corresponding surgical specimens of primary tumors were used to test for EGFR mutations.
Results: Thirty patients presented with local recurrence and distant recurrence was identified in 56. Thirty-four of the 86 patients (40%) harbored EGFR mutations. Patients with distant recurrence were more likely to have EGFR mutations than patients with local recurrence (48% versus 23%; P = 0.024). On multivariate analysis, distant recurrence was associated with a high frequency of EGFR mutations (OR, 3.3; P = 0.028). Survival analysis showed poor survival of patients with mutated EGFR (HR, 2.3; P = 0.017) or with non-adenocarcinoma histology (HR, 3.3; P = 0.001).
Conclusion: The association between recurrence pattern and EGFR mutation status was suggested in recurrent female NSCLC patients. In addition, our data indicate unfavorable disease process of EGFR mutated tumors. Further studies need to be conducted to validate these findings.

Keywords: Epidermal growth factor receptor female, mutation, non-small-cell lung cancer, recurrence


How to cite this article:
Na II, Kim HR, Lee JK, Park SH, Kim CH, Koh JS, Baek HJ, Choe DH. Epidermal growth factor receptor mutations in female patients with postoperative recurrent non-small-cell lung cancer. J Can Res Ther 2012;8:373-8

How to cite this URL:
Na II, Kim HR, Lee JK, Park SH, Kim CH, Koh JS, Baek HJ, Choe DH. Epidermal growth factor receptor mutations in female patients with postoperative recurrent non-small-cell lung cancer. J Can Res Ther [serial online] 2012 [cited 2017 Dec 11];8:373-8. Available from: http://www.cancerjournal.net/text.asp?2012/8/3/373/103515


 > Introduction Top


Non-small-cell lung cancer (NSCLC) accounts for the majority of deaths from lung cancer, the leading cause of cancer mortality. [1],[2] Although surgery is the initial preferred modality to achieve long-term survival, there is a high risk of postoperative recurrence. [3],[4] Due to the poor prognosis of recurrent disease, [5],[6] postoperative recurrence still remains an obstacle to improved outcomes. Thus, understanding the clinical course of postoperative recurrent disease is essential to guide effective treatment.

Recent studies have shown that the incidence of female lung cancer has risen over recent decades. [7],[8] Studies also suggest that a female patient with NSCLC is a unique entity compared with the male counterpart. [7],[9] Never-smokers and adenocarcinoma histology are predominant in female patients. [10],[11] In particular, molecular data have shown that female patients are associated with a high incidence of epidermal growth factor receptor (EGFR) mutation. [12]

According to Eastern studies, [13],[14],[15],[16],[17] Asian female NSCLC patients are predominantly never-smokers and are likely to have adenocarcinoma histology. Molecular studies have also reported that Eastern ethnicity is associated with a high incidence of EGFR mutation, [18] a factor that strongly predicts outcomes after treatment with tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib. [19],[20]

Until now, p[atients with postoperative recurrence have generally been treated with systemic chemotherapy. However, investigators have reported different processes in postoperative recurrence compared with Stage IV disease. [6],[21] In addition, previous studies have suggested different recurrence patterns depending on mutational status or immunohistochemical subtypes in other solid tumors in females. [22],[23] However, in lung cancer patients, the significance of EGFR mutations with respect to recurrence patterns is uncertain.

In the current era of targeted therapy, EGFR mutations, which are predominant in female NSCLC patients, are suggested to have a role in the treatment with TKI at postoperative recurrence. [21],[24] However, the role of EGFR mutation when the effect of TKI therapy is excluded has not been fully evaluated. Despite recent data on TKI-naοve patients with advanced disease, [25] the disease process of mutated EGFR tumors in postoperative recurrent disease is uncertain. Thus, we did this retrospective study to explore the association between EGFR mutation and clinical features of postoperative female patients with recurrent NSCLC.


 > Materials and Methods Top


Patients

Female patients with NSCLC who had recurrent disease after surgery between December 1992 and July 2007 were identified consecutively in the database of the Korea Cancer Center Hospital. Recurrence was diagnosed through physical examinations and diagnostic imaging of lesions, including computed tomography of the thorax with histological confirmation when clinically feasible. Recurrence was differentiated from primary lung cancer using criteria from Martini and Melamed. [26] We included resected female patients with available tissues for tests for mutations. Patients who were diagnosed as disseminated disease at the time of exploration were excluded. The institutional review board of the Korea Cancer Center Hospital approved this study.

The recurrence pattern was determined at the first site of disease recurrence using clinical assessment, imaging studies and additional data from procedures such as biopsy and bronchoscopy. Disease recurrence at the ipsilateral lung, bronchial stump, or regional lymph nodes, including the supraclavicular node, was considered a local recurrence. Presence of metastases at all other sites, including pleural seeding, chest wall, adrenal gland, bone, brain, contralateral lung, or distant nodes, was considered a distant recurrence.

EGFR genotyping

DNA extraction using paraffin-embedded tissues of resected primary tumors was performed as described elsewhere. [27] To detect the presence of EGFR mutations, pyrosequencing was performed using a previously described method. [28] Mutations in Exons 18, 19 and 21 were considered indicators of a mutated EGFR.

Statistical analysis

Univariate analysis of categorical variables was performed using Pearson's χ2 test. Stepwise backward logistic regression was used to analyze the clinical factors in terms of the presence of EGFR mutations. Overall survival (OS) was calculated from the time of disease recurrence to the time of death from any cause. Survival curves were plotted using the Kaplan-Meier method. Log-rank tests were performed for univariate analysis. Multivariate analysis was performed using stepwise Cox regression. [29] Odds ratios (ORs), hazard ratios (HRs) and their 95% confidence intervals (CIs) were determined. Stata version 9.0 (Stata Corp., College Station, TX) was used for statistical analyses. All P values were derived from two-sided tests, and P < 0.05 was considered significant.


 > Results Top


Descriptive data and EGFR mutations

[Table 1] shows the characteristics of female patients with postoperative recurrence. Mean time from surgery to recurrence was 22 months (95% CI, 2.8-57.9 months). The median age of those patients was 60 years (range, 34-75 years). Most individuals were never-smokers (89%), and 83% of the patients had adenocarcinomas. Thirty patients presented with local recurrence. The distribution of local failures was as follows: ipsilateral lung (13 patients); regional lymph nodes (17 patients). Distant recurrences were identified in 56 patients. The majority of patients presented with multiple metastases. Common metastatic sites included contralateral lung (44 patients), brain (15 patients), pleura (7 patients), lymph node (5 patients), and bone (6 patients). Sixty-eight patients received therapy including radiation, metastasectomy, or chemotherapy. Fifty-seven patients had no history of TKI therapy for postoperative recurrence, and 18 patients received supportive care only.
Table 1: Patient Characteristics (n = 86)

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Thirty four patients (40%) harbored EGFR mutations (in-frame deletions within Exon 19 [n = 28], and L858R substitutions in Exon 21 [n = 6]). The frequency of EGFR mutations was not significantly different between patients with adenocarcinomas and those with non-adenocarcinomas (39% versus 40%; P = 0.968) and between never- and ever-smokers (37% versus 56%; P = 0.272). However, the incidence of EGFR mutations was positively associated with age (51% [>60 years] versus 28% [ͳ60 years]; P = 0.027). A significant difference in the incidence of EGFR mutation according to stage (P = 0.897) and postoperative treatment (P = 0.147) was not observed.

Recurrence pattern and prognosis according to EGFR mutations

When we analyzed the association between EGFR mutations and recurrence pattern, patients with distant recurrence were more likely to have EGFR mutations than those with local recurrence [48% versus 23%; P = 0.024; [Table 2]]. Importantly, on multivariate analysis, distant recurrence was associated with a higher frequency of EGFR mutations than local recurrence [OR, 3.3; 95% CI, 1.1-9.4; P = 0.028; [Table 2]]. In addition, EGFR mutations were more common in old females than in young females [OR, 2.7; 95% CI, 1.0-7.2; P = 0.044; [Table 2]].
Table 2: Relationship Between Clinical Factors and EGFR mutations

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To exclude therapeutic effects, we treated the start of TKI therapy as a censoring event. Of 86 patients, 45 patients had died by July 2011. The median OS of all patients was 28.2 months (95% CI, 15.0-45.4 months). [Table 3] lists the results of univariate and multivariate analyses of OS. On univariate analysis of OS, patients with mutated EGFR had poor survival [P = 0.027; [Table 3]; [Figure 1]], as did patients with non-adenocarcinoma histology (P < 0.001). However, recurrence patterns, in addition to smoking history (P = 0.440), did not affect outcomes (P = 0.175). Outcomes of patients who received treatments, compared with those with supportive care only, were not statistically significant (data not shown). Multivariate analysis showed that mutated EGFR (HR, 2.3; 95% CI, 1.2-4.4; P = 0.017) and non-adenocarcinoma histology (HR, 3.3; 95% CI, 1.6-6.8; P = 0.001) were associated with poor survival. When clinical outcomes were analyzed without consideration of TKI therapy, the same trends were observed for OS with respect to mutational status (HR adjusted for histology, 2.3; 95% CI, 1.1-9.4; P < 0.001).
Figure 1: Kaplan– Meier plots of overall survival according to EGFR mutational status

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Table 3: Results of Survival Analysis

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 > Discussion Top


The aim of this study was to explore clinical features of female NSCLC at recurrence and their relationship to EGFR mutation. We found that mutated EGFR was more prevalent in distant recurrence than in local recurrence. Of interest, multivariate analysis revealed that mutated EGFR, and non-adenocarcinoma histology, were independent predictors of poor survival, when the impact of TKI therapy was excluded.

Although an association of metastatic presentation with mutational status was reported for Stage IV disease, [28] this is the first study to suggest that mutated EGFR is predominantly found in female patients with distant recurrence. This finding is in part consistent with a previous study of other solid tumors, [22] suggesting that mutational status may affect metastatic patterns in the disease process. Considering no association between EGFR mutation and stage at presentation, which was observed in a prior study, [30] a genetic abnormality might contribute to presentation at recurrence rather than to disease status at diagnosis, which was observed in a prior study on other solid tumors. [22] Theoretically, control of distant failure in EGFR-mutant patients may be a practical strategy with which to improve outcomes in resected female NSCLC patients. Thus, we believe that the results of our study are worth validation through further studies.

In our data, EGFR mutational status was not significantly associated with smoking history and adenocarcinoma histology, whereas EGFR mutation was predominant in older females, which is consistent with previous studies. [17],[19] Although statistical difference could not be reached with a limited sample size of non-adenocarcinoma and smokers, it appears that a relationship between smoking history and mutational status is not prominent in Asian female patients, [17],[31],[32] indicating their unique characteristics compared with Western patients.

Recurrence time from surgery in this cohort is within the range reported previously [32],[33] and survival outcome is consistent with other studies. [6],[32] Of interest, in this female cohort, mutated EGFR was associated with poor survival after recurrence. There are relatively few reports focusing on postoperative recurrent disease in female patients. In fact, the role of EGFR mutation could be defined differently according to clinical settings such as disease extent (early versus advanced) or delivery of TKI. [12],[19],[24],[25],[30] In addition, it should be considered that the disease process in postoperative recurrent disease may be different, as suggested in previous studies. [6],[32] Until now, the natural process of recurrence in patients with mutated EGFR has been unknown. Excluding a potential effect of TKI therapy using the method described previously, [34] we observed poorer survival in EGFR-mutated patients with recurrence. To our knowledge, there are no reports that observed different outcomes for postoperative recurrent disease according to EGFR mutation status (with the impact of TKI therapy excluded). Even when data on TKI-treated patients were excluded, a survival difference according to a mutational difference remained (adjusted HR, 2.4; 95% CI, 1.3-4.5; P = 0.007). Considering the effect of TKI therapy in advanced disease, it might change outcomes of patients with mutated EGFR in recurrent disease. [19],[20],[34],[35]

Several limitations, in addition to the retrospective nature of this study, need cautious interpretation. First, postoperative adjuvant treatments affect the incidence of recurrence. [36] Although a part of the population was treated using a prospective protocol, [37],[38] our results of the metastatic pattern in recurrent disease may be affected by postoperative treatments. However, postoperative treatments, including radiation and chemotherapy, were not significantly different in our cohort. Particularly, it should be considered that adjuvant chemotherapy may decrease the incidence of local recurrence as well as distant recurrence. [36] In fact, when data were confined to recurrent disease without adjuvant chemotherapy, there was a trend towards a high prevalence of EGFR mutation in those with distant recurrence, compared with wild type (58% versus 29%; P = 0.069). However, heterogeneous postoperative treatments, and a limitation due to the small number of patients in our study, means that we cannot draw a firm conclusion regarding a survival difference according to mutational status. Second, across studies, the definition of local recurrence is different. [39],[40] In our study, we regarded disease without distant metastases as local recurrence, as suggested by the Lung Cancer Study Group. [39] Third, we cannot exclude the possibility that the results of this study would be biased by the effect of histology. However, when the data on adenocarcinoma were analyzed separately, EGFR mutation remained associated with distant recurrence (79% versus 53% [wild type]; P = 0.032) as well as poor survival (adjusted HR, 2.4; 95% CI, 1.0-5.5; P = 0.044). Last, the prognostic role of EGFR mutation should be defined prospectively because we collected long-term survival data retrospectively. However, considering the rarity of studies on Asian female patients with postoperative recurrence, we believe that survival difference according EGFR mutations is worthy of further studies.


 > Conclusion Top


The results of our study suggest an association between recurrence pattern and EGFR mutational status in recurrent female NSCLC patients. In addition, our data indicate unfavorable disease process in patients with mutated EGFR. However, we collected the data retrospectively, and only from one institution, and large-scale studies should be undertaken to validate these findings.

 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


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