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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 318-322

Epidermal growth factor receptor mutations and brain metastasis in patients with nonadenocarcinoma of the lung


1 Department of Internal Medicine, Division of Hematology and Oncology, Cancer Center Hospital, Institute of Radiological and Medical Sciences, Seoul, Korea
2 Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Ulsan, Korea
3 Department of Internal Medicine, Division of Pulmonology, Cancer Center Hospital, Institute of Radiological and Medical Sciences, Seoul, Korea
4 Department of Pathology, Cancer Center Hospital, Institute of Radiological and Medical Sciences, Seoul, Korea
5 Department of Thoracic Surgery, Cancer Center Hospital, Institute of Radiological and Medical Sciences, Seoul, Korea

Date of Web Publication13-Apr-2016

Correspondence Address:
Im Il Na
Department of Internal Medicine, Korea Cancer Center Hospital, 75 Nowon-Gil, Nowon-Gu, Seoul, 139-706
Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.154024

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 > Abstract 

Objective: This study explored the potential association between epidermal growth.factor receptor. (EGFR) mutation status and brain metastasis in patients with nonadenocarcinoma nonsmall cell lung cancer. (NSCLC).
Patients and Methods: We analyzed clinical data from 286 patients with nonadenocarcinoma NSCLC, who were tested for EGFR mutations and underwent brain magnetic resonance imaging at diagnosis. We examined the relationship between EGFR mutation and brain metastasis at initial presentation.
Results: Of the 286 patients, 20 patients (7.0%) had EGFR mutations. EGFR mutations were more frequent in younger patients (11.1% in patients =64 years vs. 3.3% in patients >64 years: P = 0.01), females (21.4% vs. 3.5% in males: P <0.001), never-smokers (25.0% vs. 3.4% in smokers: P < 0.001), and tumors with nonsquamous histology (25.0% vs. 4.1% in squamous histology: P < 0.001). At diagnosis, the frequency of EGFR mutations was significantly different in patients with metastasis to different sites (4.0% [no metastases] vs. 10.4% [extracranial metastases] vs. 40.0% [brain metastases], P < 0.001). The strong association between EGFR mutation and brain metastasis remained significant in multivariate analysis (adjusted odds ratio [OR] = 9.68, 95% confidence interval [CI] =2.32–40.45; P = 0.002). Associations were also found for EGFR mutation status with nonsquamous histology (adjusted OR = 4.46, 95% CI = 1.46–13.56; P = 0.008).
Conclusion: This study indicates that the likelihood of nonadenocarcinoma patients having EGFR mutant tumors may differ according to brain metastasis and squamous cell histology.

Keywords: Brain, epidermal growth factor, metastasis, mutation, nonsmall cell lung carcinoma


How to cite this article:
Shin DY, Lee DH, Kim CH, Koh JS, Lee JC, Baek HJ, Kim SW, Choi CM, Na II. Epidermal growth factor receptor mutations and brain metastasis in patients with nonadenocarcinoma of the lung. J Can Res Ther 2016;12:318-22

How to cite this URL:
Shin DY, Lee DH, Kim CH, Koh JS, Lee JC, Baek HJ, Kim SW, Choi CM, Na II. Epidermal growth factor receptor mutations and brain metastasis in patients with nonadenocarcinoma of the lung. J Can Res Ther [serial online] 2016 [cited 2021 Jan 24];12:318-22. Available from: https://www.cancerjournal.net/text.asp?2016/12/1/318/154024




 > Introduction Top


Epidermal growth factor receptor (EGFR), which is also called ErbB-1, is a member of the ErbB receptor family.[1] Genetic alterations that affect EGFR activity are correlated with cancer.[2] Among nonsmall cell lung cancer (NSCLC) patients, EGFR mutations are predominantly found in patients with adenocarcinomas.[3] Many studies of EGFR mutations have been conducted to identify associated clinical factors that predict the presence of EGFR mutations [4],[5] and to determine the therapeutic potential of EGFR tyrosine kinase inhibitors (TKIs).[6],[7] It is well-known that EGFR mutations are associated with some host factors; these mutations are more common in females, never-smokers, and Asian population.[4],[5] It has been suggested that EGFR mutations are also associated with several disease factors including histology of the adenocarcinoma and several unique metastatic patterns.[8],[9]

Brain metastasis is one of the most common causes of cancer-related mortality in patients with lung adenocarcinoma and nonadenocarcinoma NSCLC. It has been established that the histology of adenocarcinomas is strongly associated with high risk of brain metastasis at the time of initial diagnosis.[10]

A few experimental studies have suggested that EGFR activating mutations in lung tumors can promote invasion and metastasis to the brain.[11] A recent study of patients with pulmonary adenocarcinoma found that EGFR mutations may be associated with a high risk of brain metastasis.[12] However, it is not known whether EGFR mutations are associated with brain metastasis in patients with nonadenocarcinoma of the lung.

Several guidelines suggest that testing for EGFR mutations is essential for patients with adenocarcinoma, particularly those with advanced stage disease.[13] Compared to adenocarcinoma, the incidence of EGFR mutations in patients with nonadenocarcinoma has been relatively unstudied. Clinicomolecular factors that predict brain metastasis in patients with nonadenocarcinoma NSCLC have not yet been established. Based on our previous findings,[12] we surmised that there may be a subpopulation of nonadenocarcinoma patients with EGFR mutations that are associated with brain metastasis.

In this study, we retrospectively analyzed the potential relationship between EGFR mutations and brain metastasis in patients with nonadenocarcinoma NSCLC at the time of initial diagnosis.


 > Patients and Methods Top


Patients and data collection

We retrospectively reviewed data from patients with NSCLC with nonadenocarcinoma histology between January 2004 and August 2013 at the Korea Cancer Center Hospital and Asan Medical Center. Informed consent was required for EGFR mutation testing. Patients were evaluated with brain imaging, bone scintigraphy, and chest and upper abdominal computed tomography. Evaluation of brain metastasis was performed using brain magnetic resonance imaging (MRI) at the time of diagnosis. Histologic classification of nonadenocarcinoma was based on the World Health Organization recommendations from 2004.[14] Patients with NSCLC-not otherwise specified as well as carcinoid histology were excluded from the study. We gathered clinicopathological data from medical records. In total, 286 patients with nonadenocarcinoma were included in the study.

Epidermal growth factor receptor genotyping

At the time of initial diagnosis, genomic DNA was extracted from paraffin-embedded tissues or methanol-fixed cytologic specimens, as described previously.[15],[16]EGFR mutation analysis was performed by direct sequencing or pyrosequencing, as described elsewhere.[17],[18]

Statistical analysis and ethics

Distant metastasis was divided into two categories: Metastasis to the brain and metastasis to extracranial sites only. Associations between EGFR mutation status and clinical variables including smoking status and gender were evaluated using Chi-squared tests. Wilcoxon rank-sum tests were used when appropriate. Associations between EGFR mutation status and metastatic patterns were evaluated using logistic regression analysis. P < 0.05 (two-sided) were considered statistically significant.

Statistical analyses were performed using Stata, version 13 (Stata Corp., College Station, TX, USA). The Institutional Review Boards of each institution reviewed and approved this study protocol. We followed the recommendations of the Declaration of Helsinki for biomedical research involving human subjects.


 > Results Top


Patient characteristics

A total of 286 patients (230 males and 56 females) with a median age of 64 years (range, 27–88 years) were reviewed in our study. There were 63 patients (22.0%) with metastatic disease.

Squamous cell carcinoma was the main histologic subtype (246 patients, 86.0%). The other patients included 12 patients (4.2%) with large cell carcinoma, 17 patients (5.9%) with sarcomatoid carcinoma, and 11 patients (3.9%) with adenosquamous carcinoma [Table 1].
Table 1: Baseline characteristics (n=286)

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Epidermal growth factor receptor mutations and baseline characteristics

A total of 20 patients (7.0%) had EGFR mutations. In univariate analysis, EGFR mutations were found more frequently in never-smokers (25.0% vs. 3.4% of smokers; P < 0.001) and females (21.4% vs. 3.5% of males; P < 0.001). When patients were separated into two groups based on the median age of 64 years, EGFR mutations were identified significantly more frequently in younger patients (11.1% of patients ≤ 64 years vs. 3.3% of patients > 64 years; P = 0.01).

EGFR mutations were found less frequently in squamous histology tumors compared to nonsquamous tumors (4.0% vs. 25.0%; P < 0.001). Among tumors with nonsquamous histology, tumors of the adenosquamous subtype had the highest frequency of EGFR mutations (45.5%), and histologies of sarcomatoid (17.7%), and large cell (16.7%) [Figure 1].
Figure 1: Frequency of epidermal growth-factor receptor mutations in different histologic subtypes of nonadenocarcinoma nonsmall cell lung cancer

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Epidermal growth factor receptor mutations and brain metastasis in multivariate analysis

The frequency of EGFR mutations at diagnosis was statistically different according to the site of metastasis (4.0% of patients with no metastasis vs. 10.4% of patients with extracranial metastasis vs. 40.0% of patients with brain metastasis; P < 0.001).

Next, we used a multivariate model to assess the significance of EGFR mutations with respect to brain metastasis. We observed a strong association between EGFR mutation status and brain metastasis (adjusted odds ratio [OR] = 9.68, 95% confidence interval [CI] = 2.42–40.45; P = 0.002), whereas there was no association between EGFR mutation status and extracranial metastasis (adjusted OR = 1.74, 95% CI = 0.47–6.41; P = 0.40) [Table 2].
Table 2: Clinical features related to EGFR mutation status in nonadenocarcinoma NSCLC patients

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In the final model, we identified associations between EGFR mutation status and nonsquamous histology (adjusted OR = 4.46, 95% CI = 1.46–13.56; P = 0.008). However, in the multivariate analysis, the associations of EGFR mutation status with age (adjusted OR = 2.80, 95% CI = 0.86–9.12, P = 0.088), female gender (adjusted OR = 1.30, 95% CI = 0.16–10.82; P = 0.81) and smoking history (adjusted OR = 3.70, 95% CI = 0.44–30.89; P = 0.23) were no longer statistically significant.


 > Discussion Top


To our knowledge, this is the first study to show that nonadenocarcinoma patients with brain metastasis have a high probability of EGFR mutations, which is similar to a previous finding in pulmonary adenocarcinoma.[12] In addition, our multivariate model indicated that the incidence of EGFR mutations was positively associated with nonsquamous cell carcinoma, but not with age, gender or smoking history, suggesting that predictive factors for EGFR mutation status are different in patients with adenocarcinoma.

Compared with pulmonary adenocarcinoma, predictive factors for EGFR mutation status have not been established for nonadenocarcinoma. A previous study by our group showed a clinical association between EGFR mutation status and brain metastasis in pulmonary adenocarcinoma patients.[12] This study indicates that the metastatic pattern may predict the molecular profile in nonadenocarcinoma NSCLC patients, which is a subpopulation with a relatively low frequency of brain metastasis. Several in vitro studies have supported our findings by demonstrating that Lung tumors with EGFR activating mutations tend to metastasize to the brain through MET activation and subsequent intracellular signaling pathways.[11],[19] Another indicator of the link between EGFR mutations and brain metastasis comes from another type of malignancy, glioblastoma multiforme, which is known to be associated with EGFR mutations. EGFRvIII is a specific mutated variant of EGFR that is known to be associated with more aggressive invasion of brain tumors into brain parenchymal tissue.[20]

We studied a population with a low probability of EGFR mutations compared to patients with adenocarcinoma [12] and found that the incidence of EGFR mutations differed according to whether or not the tumors had squamous cell histology. This suggests that verification of nonsquamous cell histology is important for selecting the patients who will benefit most from TKI treatment. Interestingly, a high incidence of EGFR mutations was observed in patients with adenosquamous cell histology (45.5%), which is in agreement with previous studies in Asian population that have reported a high frequency of EGFR mutations in tumors with this histology (28.6% to 38.2%).[21],[22] Nonsquamous cell carcinomas, including large cell carcinomas and tumors with sarcomatoid histology, also had relatively high frequencies of EGFR mutations compared to squamous cell carcinomas. Our results emphasize the potential usefulness of testing for EGFR mutations in patients with nonsquamous cell carcinoma, which is in contrast to a current guideline [13] that recommends testing for EGFR mutations only in adenocarcinomas.

In this study, we observed a significant association between EGFR mutations and young age (≤64 years) in univariate analysis. However, it did not reach the statistical significance in multivariate analysis (P = 0.088). Our result is partly consistent with a recent study,[23] which negative associations between age and EGFR mutations were observed in a predominantly male population.[23] In contrast, a high frequency of EGFR mutations was reported in older patients in other populations [24] that were enriched for adenocarcinoma or female gender.[17] The relationship between EGFR mutations and age appears to be complex. It is possible to consider populations across different studies to increase our understanding of the interactions between age and gender in terms of the incidence of EGFR mutations.

Though this study was limited by its retrospective nature, we were able to obtain data from patients who underwent routine brain MRI scans to minimize the potential bias introduced by heterogeneous methods of brain imaging. Importantly, our population consisted of a distinct group of patients with nonadenocarcinoma, the population with questionable usefulness of mutational tests. The finding that there was a high prevalence of brain metastasis in patients with mutant EGFR tumors sheds light on the way distinct metastatic preferences may be based on molecular profiles. In the era of targeted therapy,[25] testing for EGFR mutations might be justified in clinical setting with nonsquamous cell carcinoma, young age, or brain metastasis even in patients with nonadenocarcinoma.


 > Conclusion Top


Our study explored the potential association between EGFR mutation status and brain metastasis in patients with nonadenocarcinoma NSCLC. Notwithstanding several limitations, our study indicates that brain metastasis in nonadenocarcinoma patients is not associated only with nonsquamous cell histology, but also with a high probability of EGFR mutations, which is useful knowledge for EGFR TKI therapy. Further extensive molecular studies need to be performed.

 
 > References Top

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Onozato R, Kosaka T, Kuwano H, Sekido Y, Yatabe Y, Mitsudomi T. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 2009;4:5-11.  Back to cited text no. 19
    
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Micallef J, Taccone M, Mukherjee J, Croul S, Busby J, Moran MF, et al. Epidermal growth factor receptor variant III-induced glioma invasion is mediated through myristoylated alanine-rich protein kinase C substrate overexpression. Cancer Res 2009;69:7548-56.  Back to cited text no. 20
    
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