Association between EGFR mutation types and incidence of brain metastases in postoperative patients with stage I

Abstract

Objective:

This retrospective study aims to clarify the association between epidermal growth factor receptor (EGFR) mutation types and brain metastasis incidence in early-stage non-small-cell lung cancer after surgery.

Methods:

Patients pathologically diagnosed with stage I to III non-small-cell lung cancer were consecutively enrolled from January 2010 to January 2017 and reviewed. First-generation TKIs were selected as postoperative therapy for those with EGFR mutations, and platinum-based chemotherapy was used as postoperative therapy for patients with negative wild-type gene mutations. A Kaplan–Meier approach was used to calculate the cumulative incidence of brain metastasis and overall survival. Candidate prognostic factors were checked by log-rank test.

Results:

A total of 669 patients were eligible for the study, comprising 309 who were EGFR(+), and 360 who were EGFR(−). Patients with any type of EGFR mutation have a significantly higher risk of developing brain metastases compared to those with EGFR wild-type (hazard ratio=1.957, P=0.012). The incidence of brain metastasis was 17.1% higher in patients with the 19Del mutation than in those with the L858R mutation (13.6%), other mutations (13.3%), or wild-type EGFR (6.1%). Moreover, those with 19Del mutations showed the greatest increase in incidence of brain metastasis (hazard ratio=3.009, P=0.001); those with L858R mutations showed a smaller increase (hazard ratio=2.750, P=0.003).

Conclusions:

EGFR mutations are predictive factors for the cumulative incidence of brain metastasis. EGFR-mutant non-small-cell lung cancer patients may need more frequent brain magnetic resonance imaging to detect earlier occurrence of brain metastases, allowing for timely and effective treatment to improve patient prognosis.

Keywords

Non-small-cell lung cancer brain metastasis prognosis early stage (I-III)

Introduction

Lung cancer, predominantly non-small-cell lung cancer (NSCLC) (85%), is the most common and deadly cancer globally. Brain metastases (BM) are a major complication of NSCLC.¹ The global incidence of epidermal growth factor receptor (EGFR) mutation in NSCLC was 32.3% (95% CI 30.9-33.7%), which was higher in China than in Europe (38.4% vs. 14.1%).² Advanced NSCLC patients with EGFR mutations have a higher probability of developing BM than those with wild-type EGFR.^3-6 A number of EGFR mutation subtypes have been identified in NSCLC, the most frequently occurring of which are deletions in exon 19 (19Del) and L858R in exon 21 (L858R). NSCLC patients with 19Del mutations have prolonged overall survival (OS) compared with NSCLC patients with other mutation types or wild-type EGFR.^5,6 EGFR TKIs are the preferred treatment for EGFR-mutant NSCLC, providing superior progression-free survival, OS, and tolerability over chemotherapy.^7,8 Many studies have investigated the therapeutic efficacy of TKIs in NSCLC with BM, and these inhibitors have been shown to be able to penetrate the blood–brain barrier and prevent or delay metastatic progression.^9,10 In the phase 3 ADRUA trial, a double-blind, randomized international study of patients with stage IB to IIIA NSCLC, adjuvant osimertinib significantly reduced the incidence of brain metastases (BM). At 24 months, 98% (95% CI, 95–99) of osimertinib-treated patients and 85% (95% CI, 80–89) of placebo-treated patients remained alive and free of CNS-related disease. Osimertinib demonstrated an 82% reduction in the risk of CNS disease recurrence or death (HR, 0.18; 95% CI, 0.10–0.33).¹¹ TKI in combination with radiotherapy is a viable option for patients with BM harboring EGFR mutations In the phase 3, open-label, randomized, controlled trial, iPFS (14.6 vs 12.8 months; P=0.164) of EGFR-mutant patients was not significantly improved in WBRT combined with erlotinib group over WRBT-alone.¹² Despite being statistically negative, a considerable number of patients still demonstrate longer survival periods. Third-generation EGFR-TKIs (osimertinib) have shown better efficacy in crossing the blood-brain barrier.¹³ A combination of osimertinib and radiotherapy can improve overall survival (OS) in patients with brain metastases.¹⁴ Based on these findings, TKIs are used as first-line therapy for advanced NSCLC patients with EGFR mutations to delay the onset of BM.

However, there is no consensus on whether EGFR genotype has an effect on the incidence of postoperative BM in patients with early-stage NSCLC. Following surgical resection for early-stage NSCLC, both the primary tumor lesions and potentially metastatic lymph nodes are systematically removed. This situation markedly contrasts with the persistent residual tumor cells commonly seen in advanced NSCLC cases. At present, it remains uncertain whether the risk of developing brain metastasis after surgery varies between patients with EGFR mutations and those with wild-type EGFR. Additionally, the impact of post-surgical treatment strategies for early-stage lung cancer on the incidence of brain metastasis in EGFR genotypes versus EGFR-negative patients has not yet been clearly defined. Most previous studies have focused on BM in patients with advanced NSCLC rather than early stages of the disease. Therefore, the two primary aims of this retrospective study were: (1) to investigate whether EGFR mutations have a significant impact on the incidence of BM after surgery in patients with early-stage NSCLC; and (2) to determine the impact of different treatments on the incidence of BM in these patients.

Methods

Cohort selection

Patients pathologically diagnosed with NSCLC in the First Affiliated Hospital of Guangzhou Medical University and Zhujiang Hospital of Southern Medical University and Maoming People’s Hospital from January 2010 to January 2017 were selected and studied. All patients underwent a clinical staging workup, including magnetic resonance imaging (MRI). Patients were clinically staged according to the TNM (tumor size, node, metastasis) system of the American Joint Committee on Cancer (8th edition).¹⁵ NSCLC patients with stage I to III met the inclusion criteria after surgical resection of all lung lesions. First-generation TKIs were selected as postoperative therapy for those with EGFR mutations, and platinum-based chemotherapy was used for patients with negative wild-type gene mutations. In this study, occurrence of BM within three months after the diagnosis of NSCLC was defined as synchronous, and the occurrence after three months was defined as heterosynchronous.¹⁶ Stage IV patients, patients who did not receive surgery, and patients who developed synchronous BM were excluded.

Data collection and follow-up

Baseline data were collected for each patient, including information on gender, age, smoking history, tumor histology, surgical status, treatment modality, use of targeted therapies, date of initial NSCLC diagnosis, date of subsequent BM, time of death, cause of death, extracranial metastases, and EGFR mutation type. If neurological symptoms (persistent headache, neurological focalization, motor deficit, or behavioral abnormality) were present, brain MRI was performed on one or more enhanced lesions. The date of primary diagnosis of NSCLC was determined based on pathology. The date of subsequent BM was defined as the date of MRI diagnosis. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University and Zhujiang Hospital of Southern Medical University and Maoming People’s Hospital. Written informed consent was obtained from all patients included in this study.

Sample analysis

EGFR mutation detection was performed by AmoyDx (Amoy Diagnostics, Xiamen, China). All patient samples were tested for EGFR by amplification refractory mutation system assay using an AmoyDx EGFR 29 mutation detection kit.

Statistical analysis

Descriptive statistical analyses of demographic and clinical characteristics were performed using SPSS statistical software (version 25.0; IBM Corp., Armonk, NY). Categorical variables were compared using chi-square tests. OS after diagnosis of NSCLC and OS after diagnosis of BM was analyzed by Kaplan-Meier approach. Survival curves were compared using the log-rank test. Cox regression analysis was used to estimate hazard ratios (HRs) and it was used to analyze the associations between EGFR status (mutated vs. wild-type) and incidence of BM. In the Cox model, significant covariates (P < 0.05) in the univariate model were subjected to further multivariate analysis. Differences were considered significant at P = 0.05 or less.

Results

A total of 669 eligible patients with histologically or cytologically confirmed NSCLC were included in the study. EGFR mutations were identified in 309 patients (46.2%), including 140 cases (45.3%) with 19Del, 139 cases (45.0%) with L858R, and 30 cases (9.7%) with other mutations. The remaining 360 patients (53.8%) exhibited wild-type EGFR. Comparative analysis revealed significantly higher prevalence of EGFR mutations in patients with the following characteristics: age <60 years (58.8% vs 41.2%; P<0.001), female gender (64.6% vs 35.1%; P<0.001), non-smoking status (60.1% vs 39.9%; P<0.001), and stage I disease (68.1% vs 31.9%; P<0.001) (Table 1).

Table 1.

Basic characteristics of patients with NSCLC with and without EGFR mutations.

Cumulative incidence of BM after surgery in NSCLC patients with different EGFR types and treatments

BM finally occurred in 69 patients (47 of 309 patients [15.2%] in the EGFR mutation group and 22 of 360 patients [6.1%] in the wild-type EGFR group). Individual factors including TNM stage (P=0.026), tumor size (P=0.023), lymph node involvement (P=0.014), and EGFR status (P=0.011) were related to the incidence of subsequent BM in the univariate analysis (Table 2). Cox proportional hazards models were conducted to adjust the confounding factors of subsequent BM, including T, N, TNM stage, and EGFR status (Table 2). The cumulative incidence of BM was higher in EGFR-mutant patients than in those with wild-type EGFR (HR=1.957, 95% CI=1.158-3.307, P=0.012). 19Del mutation was associated with the greatest increase in BM incidence (HR=3.009, 95% CI=1.606-5.639, P=0.001) and L858R mutation also showed a higher incidence of BM (HR=2.750, 95% CI=1.411-5.357, P=0.003). However, there was no statistical significance in other mutation types (HR=2.369, 95% CI=0.798-7.044, P=0.121). And we found no significant difference in the incidence of BM between the 19Del group and the L858R group (P=0.565) (Figure 1). The multivariate analysis also indicated that stage distribution affected the incidence of BM (P=0.001). Patients in both stage II and stage III had a higher incidence of BM (HR=2.7318, 95% CI=1.391-5.360, P=0.004; HR=2.628, 95% CI=1.492-4.361, P=0.001). EGFR(+) patients who received TKIs did not show advantage in prolonging occurrence of BM, compared with patients who received chemotherapy (P=0.526).

Table 2.

Incidence of BM after surgery in NSCLC patients with different EGFR genotypes.

OS of patients in different EGFR mutations and after BM

Patients with EGFR mutations had longer OS than those with wild-type EGFR (median overall survival: 85 vs 62 months, P < 0.001). Compared with wild-type EGFR, all subgroups of EGFR mutations, including 19Del (P < 0.001), L858R (P < 0.001), and other EGFR mutation types (P = 0.036), showed a significant difference in OS (Figure 3). However, there was no significant difference in overall survival between the 19Del group and the L858R group (P=0.512). Comparison of different treatment strategies showed that 333 patients who received systematic chemotherapy had an OS of 72.4 months; only 35 patients who received TKIs had an OS of 61.5 months and the OS of the non-treatment group (patients who did not receive systematic therapy) was 62.5 months (P=0.652).

The median OS after BM was longer in the EGFR(+) group than in the EGFR(–) group (42.0 vs. 25.1 months), but there was no significant difference between them (P=0.577) (Figure 3). BM as the first recurrence occurred in 50 patients, with 34 patients in the EGFR mutation group and 16 patients in the wild- type EGFR group, respectively. Nineteen patients developed BM as the second relapse (10 patients had their first relapse in the lung, three in the liver, five in bone and one in the adrenal gland) (Figure 4). However, the first relapse did not affect the OS of patients with BM (P=0.912). After the development of BM, systemic therapy (including chemotherapy and TKI therapy) plus local therapy (including radiotherapy and surgery) appeared to produce a better OS compared with other groups (systemic or local only), but this did not reach significance (P = 0.709).

Discussions

In this retrospective study, which investigated the impact of EGFR mutations on the cumulative incidence of subsequent BM in patients with resected stage I-III NSCLC, the results suggested that the probability of BM appeared to be higher in the EGFR(+) group than in the EGFR(−) group (P=0.004). EGFR mutation was considered as a predictive risk factor for BM in the univariate analysis (P=0.011). After adjustment for various factors, including stage of NSCLC, we noted that EGFR mutation was an independently positive predictor of BM development, indicating that patients with EGFR mutations had a tendency to develop BM (Figure 1). In advanced NSCLC, EGFR mutant patients have been verified to be more vulnerable to BM than those with wild-type EGFR. Tao et al17. found that the percentage of patients who were diagnosed as BM at 12 months was 29.3% in the EGFR mutation group and 21.7% in the wild-type EGFR group (hazard ratio = 1.476, P=0.039), which was equal to a 47% increase in the risk of BM occurrence. A Canadian study has showed that the cumulative incidence of BM was 39.2% for EGFR mutant patients compared to 28.2% for EGFR WT (P=0.038; HR=1.4).¹⁸ However, the relationship between EGFR mutations and the incidence of BM in stage I-III NSCLC patients remains inconclusive. Stanic et al.¹⁹ investigated the correlation between EGFR mutation status and subsequent BM in stages I-III NSCLC patients, and showed that EGFR status had no influence upon the cumulative incidence of BM. Chang et al.²⁰ investigated the impact on the incidence of subsequent BM according to EGFR mutation status in patients with stages I-III NSCLC, and found that EGFR mutations is one of the predictive factors for the development of BM, though it did not reach statistical significance. Our study is a retrospective analysis with the largest number of patients in comparison with other works. We found that the cumulative incidence of BM was higher in EGFR-mutant patients than in those with wild-type EGFR (HR=1.957, 95% CI=1.158-3.307, P=0.012), which was equal to a 95% increase in the risk of the development for BM. In EGFR mutant patients, not only exon 19 deletions (HR=3.009, 95% CI=1.606-5.639, P=0.001) but also L858R (HR=2.750, 95% CI=1.411-5.357, P=0.003) was relevant to a higher cumulative incidence of BM, nevertheless there was no significant difference between them (P=0.565). Though patients with other mutation types (HR=2.369, 95% CI=0.798-7.044, P=0.121) seemed to have a higher cumulative incidence of BM than patients with wild-type EGFR, it was not statistically significant. These outcomes revealed that EGFR mutant cancer cells tended to invade the brain. The underlying mechanisms by which EGFR mutations cause BM in NSCLC is poorly understood. Li et al.²¹ found that the protein WNT5A, which inhibited the growth, migration, and invasion of EGFR-mutant cells, significantly downregulated in BM tissues and EGFR-mutant samples, and proved that E2F1-mediated repression of WNT5A was dependent on the ERK1/2 pathway, offering a probably effective strategy for targeting BM in EGFR-mutant NSCLC. Recently, a major study carried out by Biswas and his team²² from Columbia University has demonstrated that S100A9 highly expressed in EGFR-mutant lung cancer cells could upregulate ALDH1D1 expression and activate the retinoic acid (RA) signaling pathway in osimertinib-refractory cancer cells. Target treatment with a pan-RAR antagonist or the genetic repression of S100A9, ALDH1D1, or RA receptions (RAR) significantly reduced BM, identifying a novel, therapeutically targetable S100A9- ALDH1D1-RA axis that drives fatal brain relapse. However, more studies are needed to elucidate the exact role of EGFR mutation in BM at the molecular level. In our study, patients in stage II (HR=2.7318, 95% CI=1.391-5.360, P=0.004) and stage III (HR=2.628, 95% CI=1.492-4.361, P=0.001) tended to develop BM than those in stage I, which meant that the risk of the development for BM in patients with stages II-III was around 2.6 times higher than that in patients with stage I. This factor is severely detrimental to survival, serving as a reminder that clinicians should pay more attention to the risk evaluation of BM in patients with worse stages. We noted that there was no distinction on the incidence of BM under different treatment between TKIs and chemotherapy (P=0.526). But the number in the chemotherapy group (n=333) was much larger than that in the TKIs group (n=35). This bias was too large to accurately assess the effect of TKIs on delaying the occurrence of BM. Osimertinib, the third-generation TKI, has shown superior blood-brain barrier permeability and impressive clinical response in NSCLC patients with BM.^23,24 In the ADAURA trial involving patients with IB to IIIA disease, 98% of the patients in the osimertinib group and 85% of the patients in the placebo group were alive without CNS-related disease at 24 months (overall hazard ratio for CNS disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33), indicating an 82% reduction in the risk of CNS disease recurrence or death with osimertinib.²⁵ Therefore, osimer6tinib is a better option for EGFR-mutant patients with BM and to prevent the occurrence of BM.

As shown in our study, patients with EGFR mutations were associated with longer OS than those with wild-type EGFR (P<0.001), probably because the proportion of patients with stage I in the EGFR-mutant group (211 of 309; 68.3%) was much higher than that in the wild-type group (99 of 360; 27.5%). In a large retrospective analysis involving 5214 patients that underwent R0 resection,²⁶ the difference in overall survival between patients with EGFR mutations and those with wild-type EGFR was distinct in the univariate analysis (P<0.001) and multivariate analysis (HR=0.729; 95% CI: 0.642 to 0.829; P<0.001). Kosaka et al.27 analyzed 397 patients with surgically resected stage I to IV lung adenocarcinomas and without any treatment of EGFR-TKIs. They found that patients with EGFR mutations had better OS than those without mutations in the univariate analysis (P=0.005), but the survival difference did not approach significance in the multivariate analysis. Although EGFR mutations seemed to be a positive prognostic factor of patients with resected lung cancer, some previous studies revealed conflicting results. Deng et al.²⁸ showed that EGFR mutation was a strong poor prognostic factor in patients with radiologic solid (P<0.001), histologic acinar pattern-predominant adenocarcinoma/papillary pattern-predominant adenocarcinoma/invasive mucinous adenocarcinoma (P<0.001), and pathologic stage II and III lung adenocarcinomas (P=0.004) in the Cox multivariate analysis. We noted that patients receiving systematic chemotherapy had longer OS than those receiving TKIs or without any treatment after surgery, but with no statistical significance. The effect of treatment with EGFR-TKIs on the incidence of BM would be minimal due to most of these patients not receiving EGFR-TKIs. Platinum-based adjuvant chemotherapy for NSCLC patients with stages I to III, such as paclitaxel plus carboplatin, has been the standard treatment included in CSCO and NCCN guidelines.^29
-31 In the randomized, placebo-controlled RADIANT trial involving patients with stage IB to IIIA disease, adjuvant erlotinib was associated with longer disease-free survival.³² The randomized ADJUVANT/CTONG1104 trial involving patients with EGFR mutation-positive stage II to IIIA disease showed longer disease-free survival among patients who received adjuvant gefitinib than among those who received chemotherapy (hazard ratio for disease recurrence or death, 0.60; 95% CI, 0.14 to 0.30; p=0.005).³³ At 24 months, 89% of the patients with stage IB to III disease in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.20; 95% CI, 0.14 to 0.30; p<0.001), indicating an 80% reduction in the risk of disease recurrence or death with osimertinib.²⁶ With the dramatic effectiveness of EGFR-TKIs on EGFR-mutant NSCLC, osimertinib has been recommended as the standard adjuvant therapy for EGFR-mutated patients with resected NSCLC.

The median OS after BM was 42.0 months in the EGFR(+) group versus 25.1 months in the EGFR(−) group, but with no statistical significance (P=0.577). Chang et al.³⁴ found that the EGFR mutation status seemed to influence the median survival time after BM (17.8 vs 12.2 months) and noted that patients with 19Del had a longer median survival after BM than that for patients harboring other EGFR mutations (29.4 vs 14.3 months) and wild-type EGFR (29.4 vs 12.2 months). All the outcomes did not reach statistical difference. On the contrary, Han et al.⁴ demonstrated that EGFR mutation was a negative predictive factor for OS in patients with BM (median overall survival: 23.8 months in the EGFR(+) group; 25.1 months in the EGFR(−) group; P=0.028). Based on these controversial results, large cohorts are needed to illuminate the impact of EGFR mutations on the survival after BM in patients with stages I-III.

The mode of systematic therapy (including chemotherapy and TKIs) plus local therapy (including radiotherapy and surgery) appeared to produce a better OS compared with other groups (systemic or local only), although with no statistical significance (P = 0.709). Patients with EGFR mutations tended to develop BM, especially when diagnosed at stage II to III. Unfortunately, outcome for both brain metastases and leptomeningeal metastases under the main treatment options of surgical resection, SRS and/or WBRT remains poor with median survival between three and six months.³⁵ Blood-brain barrier (BBB) only allows passage of small molecules and substances with high lipid solubility.³⁶ Most of chemotherapeutic drugs are too large to cross the BBB. There is limited penetration of EGFR-TKIs blocked by completely functional BBB. CNS metastasis and radiotherapy can destroy the integrity of BBB and increase the permeability of BBB, leading to a higher concentration of TKIs into the brain. In addition, EGFR-mutant NSCLC cells are more sensitive to radiotherapy.^9,37 EGFR-TKIs combined with radiotherapy has become one of the alternative strategies for EGFR-mutant NSCLC patients with BM. In analyzing the relationship between OS and the incidence of BM, we found that EGFR(+) patients had a higher probability of developing BM in the first three years. Hsiao et al.³⁸ showed that favorable OS is an essential factor associated with BM. And the rise in cumulative incidence of BM was more pronounced three years after lung cancer diagnosis, which is similar to our findings (Figure 2). According to these, NSCLC patients with EGFR mutations may require frequent brain MRI examinations to detect the occurrence of BM when accompanied by neurological symptoms during early follow-up.

Although this study yielded some key clinical results, there are several limitations to be thrown out. First, in a retrospective study with a small sample size, the number of samples with wild-type EGFR and mutant EGFR was not equal, patient enrollment limitations may introduce selection bias, particularly as loss to follow-up could lead to underrepresentation of critical cases. In our cohort, the EGFR-negative group demonstrated a low incidence of brain metastasis (6.1%, n=22). This limited sample size raises potential concerns regarding selection bias, particularly if any lost-to-follow-up cases developed undetected brain metastases. Notably, this patient population typically receives conventional chemotherapy regimens, where premature treatment discontinuation - often attributable to either suboptimal therapeutic response or intolerable adverse effects - may disproportionately contribute to follow-up attrition. There are many significant differences between EGFR(+) and EGFR(−) in clinical characteristics, including gender, stage, tumor size, lymph nodes, and pathology, these factors may also significantly affect the study outcomes. Second, not all patients were evaluated for brain MRI, which could lead to delayed diagnosis of subsequent BM or missing information for some patients. Third, analysis did not include mutations in other driver oncogenes, such as KRAS and ALK mutations. We hope that future prospective studies on this topic will clarify the factors associated with BM. In addition, the precise detailed treatment is unclear, which may lead to different OS and further influence BM incidence.

Conclusion

We found that patients with EGFR mutations were more likely to develop subsequent BM after surgery for early-stage NSCLC than patients with wild-type EGFR. EGFR mutations are predictors associated with cumulative incidence of BM. When accompanied by neurological symptoms, NSCLC patients with EGFR mutations may require more frequent brain MRI to detect the early onset of BM, allowing for timely and effective treatment to improve patient prognosis.

Footnotes

Acknowledgements

We thank the hospital staff for their efforts in recruiting patients. We are indebted to Drs. Meifeng Ye, Yuxuan Pan, Jianhao Liang, Lifeng Xu, Zixian Liang, Zhouling Chen, Yitian Tan, Lijun Chen, and Liangyan Ouyang (Guangzhou Medical University) for their contributions.

Author contributions

J.X.Z. and J.Q.Z. participated in study design. H.P., L.X.C., Z.L.X. and J.H. performed data analysis; H.M.L., L.M.W., C.H.W., Y.H.Z., and J.Q.Z. recruited patients; Z.Q.L, Z.L.X. and J.H. drafted the manuscript; J.X.Z. and J.Q.Z. were responsible for study conception; and all authors provided critical review of the manuscript and approved the final draft for publication. J.X.Z. and Z.Q.L. contributed equally to this work.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by the Guangzhou Science and Technology Plan Project of 2018 – LncRNA (LAST1) as a prognostic factor of non-small cell lung cancer and its mechanism on the development of lung cancer – and the Open Project of State Key Laboratory of Respiratory Disease (SKLRD2016OP020).

Data availability statement

Data cannot be shared publicly because of containing sensitive patient information but are available from the corresponding author on reasonable request.

ORCID iD

Jiaqing Zhang

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Association between EGFR mutation types and incidence of brain metastases in postoperative patients with stage I–III NSCLC

Abstract

Objective:

Methods:

Results:

Conclusions:

Keywords

Introduction

Methods

Cohort selection

Data collection and follow-up

Sample analysis

Statistical analysis

Results

Cumulative incidence of BM after surgery in NSCLC patients with different EGFR types and treatments

OS of patients in different EGFR mutations and after BM

Discussions

Conclusion

Footnotes

Acknowledgements

Author contributions

Declaration of conflicting interests

Funding

Data availability statement

ORCID iD

References