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Year : 2018  |  Volume : 14  |  Issue : 4  |  Page : 799-806

The features and prognostic impact of extracranial metastases in patients with epidermal growth factor receptor-mutant lung adenocarcinoma

1 Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, HB, China
2 Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, HB, China
3 Department of Pathology, Hubei Cancer Hospital, Wuhan, HB, China
4 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA

Date of Web Publication27-Jun-2018

Correspondence Address:
Desheng Hu
Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, HB
Weining Zhen
Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_824_17

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 > Abstract 

Aims: We have previously demonstrated that brain metastases were more common among patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. However, the association of EGFR mutation and extracranial metastases (ECM) remains inconclusive. In this study, we explored the potential association between EGFR mutation and the risk of ECM.
Patients and Methods: Between March 2007 and December 2014, 234 patients were analyzed for the potential association between EGFR mutation and ECM.
Statistical Analysis Used: Multivariate Cox regression analysis.
Results: There were no associations between the EGFR mutation and metastases in different organs, except for bone. The frequency of EGFR mutation was statistically higher for patients with bone metastases (BMs) at the initial diagnosis (P = 0.039) and at the last follow-up (P = 0.018) as compared to those with wild-type EGFR. In multivariate logistic regression analysis, EGFR mutation significantly increased the risk of BM at the initial diagnosis (P = 0.036). Among those patients without BM at initial diagnosis, 1- and 2-year accumulative rates of subsequent BM were significantly higher in patients with EGFR-mutant disease (P = 0.026). EGFR mutation was an independent risk factor for subsequent BM (P < 0.05). In addition, patients with finial BM and EGFR-mutant disease had longer median survival as compared to those with wild-type disease (P = 0.020).
Conclusions: Only BM in patients with ECM was significantly correlated with EGFR mutation during their disease course. EGFR mutation was an independent predictive and prognostic factor for developing BM, which was also a positive predictive factor for overall survival of patients who developed BM.

Keywords: Bone metastasis, epidermal growth factor receptor, extracranial metastasis, lung adenocarcinoma, mutation

How to cite this article:
Bi J, Han G, Wei X, Pi G, Zhang Y, Li Y, Wang M, Hu D, Zhen W. The features and prognostic impact of extracranial metastases in patients with epidermal growth factor receptor-mutant lung adenocarcinoma. J Can Res Ther 2018;14:799-806

How to cite this URL:
Bi J, Han G, Wei X, Pi G, Zhang Y, Li Y, Wang M, Hu D, Zhen W. The features and prognostic impact of extracranial metastases in patients with epidermal growth factor receptor-mutant lung adenocarcinoma. J Can Res Ther [serial online] 2018 [cited 2021 Jan 28];14:799-806. Available from: https://www.cancerjournal.net/text.asp?2018/14/4/799/235100

Jianping Bi and Guang Han have contributed equally to this work. Desheng Hu and Weining Zhen Co-corresponding authors.

 > Introduction Top

Lung cancer is the leading cause of cancer-related mortality all over the world in both men and women.[1] Approximately 80% of lung cancers are classified as nonsmall cell lung carcinoma (NSCLC), which can be further subdivided according to specific histologies such as adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma. Among these pathological subtypes, adenocarcinoma is most common and accounts for more than half of all NSCLC patients and highly aggressive with early distant metastasis.[2],[3],[4]

Despite the progresses in various therapeutic modalities, the overall prognosis for patients with NSCLC remains poor with a 5-year survival rate of <20% and much worse at only 4% for patients with distant metastases.[1] The recent progress in medical treatments of advanced lung cancer has been focusing on molecular changes. Epidermal growth factor receptor (EGFR) signaling pathways in lung cancer have been reported to be associated with angiogenesis, activating and regulating cellular proliferation, and the epithelial-mesenchymal transition (EMT), all of which play important roles in oncogenic progression and metastasis.[5],[6],[7] EGFR mutations occur much more commonly in adenocarcinoma than squamous cell carcinoma, being identified in 15%–60% of unselected patients with adenocarcinoma.[8],[9],[10] Some studies have shown that patients with EGFR mutated NSCLC have a predilection to develop brain metastases. The incidence of EGFR mutation positivity among patients with brain metastases is higher, ranging from 44% to 63%, as compared to the usually described 10% incidence of EGFR mutation in all patients diagnosed with NSCLC.[11],[12],[13] However, the features and independent prognostic influence of extracranial metastasis (ECM) have not been elucidated in patients with lung adenocarcinoma harboring EGFR mutations. In this retrospective study, we tried to identify the potential association between ECM and EGFR mutation in lung adenocarcinoma as well as the potential prognostic factors for those patients who developed ECM during their disease course.

 > Patients and Methods Top


Inclusion criteria were as following: (1) patients with pathologically confirmed lung adenocarcinoma who underwent EGFR mutation screening and the treatments in our institution between March 2007 and November 2014; (2) all routine staging workups including chest computed tomography (CT) scan, abdominal ultrasound/CT, bone scan, and magnetic resonance imaging (MRI) of brain were obtained before initial treatment; (3) the clinical stage was classified using tumor, node, metastasis (TNM) system proposed by American Joint Committee on Cancer (7th edition). A total of 234 patients were enrolled into this study. This study protocol was reviewed and approved by the Review Board and Ethics Committee of Our Hospital. All patients gave their informed consent to participate in this study.

Follow-up and data collection

Patients were followed up every 3 months for the first 2 years, then every 6 months for the next 3 years, and annually thereafter. The follow-up evaluations consisted of history and physical examination, and radiologic examinations, which included chest CT, abdominal ultrasound/CT, and other examinations as clinically indicated. Intrapulmonary metastases (IPM) and abdominal metastases were confirmed with contrast enhanced CT or 18 fluorodeoxyglucose positron emission tomography (PET)/CT. Bone metastases (BMs) were documented by more than two imaging modalities including bone scan, X-ray, CT, MRI, or (PET)/CT. Patients with malignant pleural effusion were diagnosed by pleural cytology. Patients with others uncommon sites of metastases were confirmed by biopsies. Disease progression and failure sites were determined by imaging, histologic examination, or both.

Clinical characteristics including patients' age, gender, and smoking history, the treatment they received, the time to disease progression, and survival time, were obtained from medical records. According to different organ metastasis, ECM was divided into the following subgroups: BM, IPM, malignant effusion/pleural (ME/P), liver metastases (LM), adrenal glands metastases (AGM), and other uncommon sites metastases. BMs at the initial diagnosis were called as “initial BM,” and BM found during and after treatment was recorded as “subsequent BM,” and at the end of our follow-up, the total of BM (initial BM + subsequent BM) was named as “finial BM”. The similar classifications were also used for other ECM subgroups according to the different time points of their diagnosis.

Epidermal growth factor receptor mutation testing

Genomic DNA was isolated from paraffin-embedded tissue sections from the primary tumor, and the EGFR mutational status at exons 18–21 was analyzed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, as previously reported.[12]

Statistical analysis

All data were processed with SPSS 19.0 (IBM SPSS Inc., Chicago, IL, USA). The difference in EGFR mutation status and ECM frequency between different groups was compared with the Chi-square test. Clinical factors known to be associated with initial ECM were included in the logistic regression analysis. Univariate and multivariate analyses of risk factors of the subsequent ECM were performed using a log-rank test and Cox regression, respectively. Time to subsequent ECM was calculated by the Kaplan–Meier method. A two-sided P < 0.05 was considered statistically significant.

 > Results Top

Patient characteristics and comparison between patients with mutated and wild-type epidermal growth factor receptor

The clinical characteristics of the 234 patients and the comparison between patients with EGFR mutations and those with wild-type EGFR are summarized in [Table 1]. A total of 234 patients with a median age at initial diagnosis of 57.5 years (range from 27 to 87 years) were consecutively enrolled in this study. Of those patients, 131 (56.0%) were never smokers and 103 (44%) were current or former smokers.
Table 1: Baseline characteristics and epidermal growth factor receptor mutation status (n=234)

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Within the entire cohort, 108 patients (46.2%) had EGFR mutations. The most common EGFR mutation seen was exon 19 deletion, which was seen in 56 patients (51.9%), followed by exon 21 L858R mutation in 44 patients (40.7%). Eight patients (7.4%) had the other sites mutation (3 in the exon 20 mutation, 2 in the exon 18 mutation, and 3 harbored double mutations). EGFR mutations were significantly more frequent in females than in males (64/109 vs. 44/125, P < 0.001) and in never smokers than in current/former smokers (74/131 vs. 34/103, P < 0.001). There were no associations between TNM classifications, clinical stage or age, and EGFR mutation.

In this cohort of patients, the effect of EGFR mutation on tumor metastases is only found in BM subgroup. Compared with patients with wild-type EGFR, patients with EGFR mutations demonstrated a higher rate of BM, regardless of whether it was initial (59.6% vs. 40.4%, P = 0.039) or final BM (57.0% vs. 43.0%, P = 0.018). However, EGFR mutation did not affect the rate of tumor metastases in other ECM subgroups during the disease course. Because only three metastatic lesions were found in other uncommon sites, the lesions in other uncommon sites were not be analyzed in this study.

Risk factors in patients with initial extracranial metastases

At the time of initial diagnosis of pulmonary adenocarcinoma, 87 of 234 patients (37.2%) had developed ECM which included BM (47 patients, 20.1%), IPM (30 patients, 12.8%), ME/P (25 patients, 10.7%), LM (12 patients, 5.1%), and AGM (6 patients, 2.7%). In univariate analysis, N2-3 and EGFR mutation were significantly associated with an increased risk of BM prior to the treatment (P< 0.05). Female, never smoking, and T3-4 were associated with an increased risk of initial ME/P (P< 0.05). Whereas only T3-4 disease was a significant risk factor for initial IPM (P = 0.005). However, no risk factors could be identified in initial LM. The individual risk factors for initial ECM were analyzed using multivariate logistic regression model. The results are shown in [Table 2]. EGFR mutation was strongly associated with the frequency of initial BM (odds ratio [OR] =2.084, 95% confidence interval [CI] = 1.049–4.142, P = 0.036). Female and T3-4 were associated with the initial ME/P (Female gender, OR = 0.352, 95% CI = 0.138–0.896, P = 0.029; T3-4, OR = 2.639, 95% CI = 1.011–6.892, P = 0.048). T3-4 was the only independent risk factor for initial IPM (OR = 3.062, 95% CI = 1.250–7.504, P = 0.014).
Table 2: Multivariate analyses of risk factors of the initial extracranial metastasis and its subgroup

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Risk factors in patients with subsequent extracranial metastases

To evaluate the potential independent prognostic factors for development of subsequent ECM, 147 patients without ECM at initial diagnosis were analyzed. The median follow-up time of the cohort was 16.2 months (range: 1.0–94.4 months). Fifty-four of the 147 patients (36.3%) had developed ECM, which included BM (32 patients, 21.8%), IPM (25 patients, 17.0%), ME/P (16 patients, 10.9%), LM (11 patients, 7.5%), and AGM (1 patients, 0.7%).

EGFR mutation was also found to be associated with subsequent BM. Univariate analysis revealed that female (P = 0.021), age younger than 60 years old (P = 0.031), EGFR mutation (P = 0.046), T3-4(P = 0.037), and N2-3(P = 0.003) significantly increased the risk of subsequent BM. Univariate analysis also showed that T3-4(P = 0.024) and age younger than 60 years old (P = 0.022) significantly increased the risk for subsequent IPM and LM, respectively. When further assessing these results by multivariate Cox regression analysis, only EGFR mutation (hazard ratio [HR] =3.492, P = 0.004) and N2-3(HR = 2.293, P = 0.039) [Table 3] were found to be significant risk prognostic factors for subsequent BM. No association could be found between EGFR mutation and other subsequent ECM subgroups by multivariate Cox regression analysis. Comparing to patients with wild type EGFR, the patients with EGFR mutation had significantly higher 1- and 2-year accumulative rates of BM (20.4% vs. 9.2%, and 28.8% vs. 17.5%, respectively, P = 0.026) [Figure 1]. However, 1- and 2-year accumulative metastasis rates in other organs were not different between patients with the wild-type EGFR and patients with EGFR mutant (P > 0.05).
Table 3: Univariate and multivariate analyses of risk factors of the subsequent bone metastases (n=185)

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Figure 1: Kaplan–Meier curves of accumulative rates of subsequent extracranial metastases metastasis

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Epidermal growth factor receptor-tyrosine kinase inhibitor sensitive mutation status and extracranial metastases

The exon 19 deletion and exon 21 L858R point mutation are EGFR tyrosine kinase inhibitor (TKI) sensitive mutation. In order to compare ECM incidences associated with these two mutations, subgroup analyses were performed in patients with exon 19 deletion (56 patients) and exon 21 L858R point mutation (44 patients). As shown in [Table 4], the incidences of ECM subgroup were not significantly different in patients with these two mutations either at initial diagnosis (P > 0.05) or at last follow-up (P > 0.05).
Table 4: Epidermal growth factor receptor-tyrosine kinase inhibitor sensitive mutation status and extracranial metastasis

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Overall survival of patients after diagnosis of finial bone metastases with mutant and wild-type epidermal growth factor receptor

To evaluate prognostic significance of EGFR mutation status with respect to BM, we performed a subgroup analysis in 79 patients with final BM. [Table 5] shows the baseline characteristics of these 79 patients stratified by EGFR mutation status (two groups). There was no statistical difference in the use of either radiotherapy (P = 0.174) or chemotherapy (P = 0.466) in both groups of patients. However, EGFR-TKIs were more commonly administered in EGFR-mutant group than in the wild-type EGFR group (34/44 vs. 2/35, P = 0.000). There was a statistically significant difference in survival between the two groups (P = 0.020). The median survival was 23.0 months for EGFR-mutant group (95% CI = 17.13–30.47) and 15.1 months for wild-type EGFR group (95% CI = 8.55–19.79) [Figure 2].
Table 5: Characteristics of patients with finial bone metastases (n=79) stratified by epidermal growth factor receptor mutation status

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Figure 2: Kaplan–Meier curves of overall survival in patients after diagnosis of final bone metastasis with different epidermal growth factor receptor mutation status (P = 0.020)

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 > Discussion Top

Our previous study [12] showed that patients with tumors harboring an EGFR mutation were more prone to developing brain metastases during the course of their disease. In this study, we retrospectively evaluated different features of ECM according to EGFR mutation status in patients with pulmonary adenocarcinoma. Our data revealed that only BM in patients with ECM was significantly correlated with EGFR mutation status during their disease course. EGFR mutation was also a positive predictive factor for overall survival (OS) in patients with BM. To our knowledge, our research may represent the largest cohort study that analyzed the potential association between EGFR mutation status and ECM in Chinese patients with lung adenocarcinoma.

In this study, there was association between the EGFR mutations and BM. However, another study reported different results. Doebele et al.[14] found that patients with EGFR mutations had no predisposition to BM as compared to the wide-type cohort. Among our patients, the frequency of EGFR mutations was 46.2% which was similar to the results of previous reports in which EGFR mutations were found in approximately 40%–60% of East Asian patients.[15] However, only 18.7% of EGFR mutation was reported in the study report by Doebele et al., which was much lower than that in the Asian population. The low prevalence of EGFR mutations in Caucasian population may be a reason for these differences. Therefore, it may be difficult to draw a conclusion from these data. Future clinical trials with large numbers of patients are needed to provide a definitive conclusion.

Our results showed that EGFR mutation was an independent risk factor for subsequent BM, whereas no such association was found in other subgroups. EGFR mutations raise the speculation that lung adenocarcinomas may have different metastatic patterns according to mutational profiling. Doebele et al.[14] reported that ALK rearrangements were associated with more frequent liver and pleural metastases, whereas the study reported by Fujimoto et al. showed that EGFR mutations tended to be more frequent in case of BM.[16] This is in line with our observations suggesting that EGFR-mutated adenocarcinoma cells may have an increased bone affinity. In addition, Confavreux et al.[17] found that EGFR mutations were more frequent in BM biopsy samples. The potential relationship between bone microenvironment and EGFR-mutant adenocarcinoma cells remains poorly understood. However, the data from several studies may lead to possible hypotheses explaining why patients harboring EGFR mutant may have more frequent BM. One study performed by Du et al.[18],[19] showed versican G3-enhanced breast cancer cell proliferation and migration by upregulating EGFR signaling, and increases in expression of G3, which might lead to the development of BM. Another study suggested that a disintegrin and metalloproteinase with thrombospondin motifs 1 and matrix metalloproteinase-1 release EGF-like ligands from breast cancer cells to repress osteoprotegerin expression in osteoblasts and potentiate osteoclast differentiation leading to BM.[20] Recently, Lue et al.[21] reported LIV-1, a zinc transporter, through heparin binding-epidermal growth factor shedding and EGFR-mediated ERK signaling promotes prostate cancer EMT and BM. Although these studies have provided some insights into the mechanisms underlying the increased BM risk associated with malignant tumor with EGFR mutations, further investigations are needed to elucidate the exact role of EGFR in BM at molecular levels in pulmonary adenocarcinomas.

Our study demonstrated that there was no difference in ECM rates in Chinese pulmonary adenocarcinoma patients either with EGFR mutations in exon 19 or in exon 21. To our knowledge, this result has never been reported before. However, because the conclusion was based on a retrospective study, further clinical trials with larger patient population should be warranted to validate our study findings.

As reported, BM was associated with significantly worse prognosis and reduced OS.[16],[22] Our previous study [12] showed that in patients with brain metastases, EGFR mutation was associated with a longer OS when compared with those patients with wild-type EGFR. In this study, we also showed the similar finding that EGFR mutation was a favorable prognostic factor for OS in Chinese pulmonary adenocarcinoma patients with BM. The major contributing factor for improved survival might be due to the use of EGFR-TKIs. Furthermore, Pluquet et al.'s study [23] suggested that the presence of an osteoblastic reaction during the treatment with EGFR-TKIs for patients with BM could be detected, and the osteoblastic reaction seems to be related to the better survival. Our finding suggested that EGFR mutation may be a useful predictor for clinicians to monitor BM. Active use of EGFR-TKIs may be able to improve OS for EGFR-mutant patients with BM.

Skeletal-related events (SREs) are a term used to describe a collection of adverse events associated with BM which include pathologic fractures, spinal cord compression, and malignant hypercalcemia. Patients who developed a SRE have a prognosis worse than patients without SREs, this occurrence increases the risk of death by 20%–40%.[24] Therefore, it is important to prevent BM and reduce the incidence of SREs in clinical practice. Previous study has suggested that EGFR-TKIs treatment may be effective in delaying and/or preventing BM in NSCLC patients with EGFR mutations.[25] However, in our study, EGFR-TKIs treatment did not significantly decrease the risk of subsequent BM. This may be attributed to the relatively small number of patients with EGFR mutations (30/83, 36.1%), who were treated with EGFR-TKIs before the development of subsequent BM. Further studies are awaited. Preclinical and clinical evidences support that bisphosphonates may be useful agents for prophylactic treatment of patients with cancers that are known to preferentially metastasize to bone.[26],[27],[28] Based on our results, we hypothesize that bisphosphonates may also provide benefits in reducing the development of BM in pulmonary adenocarcinoma patients with EGFR mutations (especially in exon 19 or 21), who cannot receive EGFR-TKIs for any reason. Well-designed prospective randomized clinical trials are warranted to validate our presupposition.

There were some limitations in this study. First, it is a retrospective study, which cannot exclude a potential bias during the disease course under the complexity of treatment modalities and orders. Second, EGFR mutation status was evaluated by using samples from the original lung tumors rather than the ECM lesions, and the potential heterogeneity of tumor tissue might be omitted in this study. Third, we cannot exclude the possibility that a lead-time bias might have contributed to the differences in metastasis, and the incidence of ECM may be inaccurate for asymptomatic patients. Finally, this study did not evaluate the relationship between ECM and other clinically relevant genetic changes such as KRAS mutation, ALK rearrangement, and MET amplification.

 > Conclusions Top

We demonstrated that only BM in patients with ECM was significantly correlated with EGFR mutation status during the disease course. Patients with EGFR-mutant disease had a higher incidence of BM, which may represent one of the distinct clinical features for EGFR-mutant tumors. EGFR mutation was also a positive predictive factor for OS of patients with BM. We speculate that it might be due to important roles of EGFR signaling and adenocarcinoma cells–bone interactions in disease progression. Further molecular studies are needed to elucidate the mechanisms underlying this finding.

Financial support and sponsorship

This work was supported by grants from General Program from Hubei Provincial Health Department (Grant NO. WJ2017M012) and Natural Science Foundation of Hubei (Grant NO.2016CFC737).

Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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