EGFR mutations in patients with lung adenocarcinoma and malignant pleural effusion: a propensity score-matched analysis of a single-center database

Introduction

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death globally, and among the histological subtypes of NSCLC, lung adenocarcinoma (LUAD) is the most prevalent (1). In recent years, significant progress has been made in understanding the signaling pathways involved in the development and progression of LUAD. The abnormal activation of the epidermal growth factor receptor (EGFR) plays a crucial role in LUAD. EGFR is a member of the receptor tyrosine kinase ErbB family. Ligands binding to its extracellular domain induces conformational changes, leading to receptor dimerization, tyrosine phosphorylation, and activation of downstream signaling pathways, including RAS-MAPK, PI3K-AKT, and JAK-STAT, promoting cell growth and survival (2). EGFR tyrosine kinase inhibitors (TKIs) inhibit these pathways, thereby constraining tumor cell proliferation (3-5). The widespread clinical application of various EGFR-TKIs has significantly improved the prognosis of patients with LUAD and EGFR mutations (3,5).

Many studies have shown that EGFR mutations are closely related to various tumor metastases (6,7). In the field of lung cancer, previous research has focused more on the correlation between EGFR mutations and brain metastases (8,9), with the results indicating that patients with NSCLC and brain metastases have a higher frequency of EGFR mutations compared to those without brain metastases (52.0% vs. 22.0%; P<0.001) (10). The pleura is a common site for LUAD metastasis, which mainly manifests as pleural nodules and malignant pleural effusion (MPE). About 50% of patients with advanced NSCLC develop pleural effusion, which is more common in LUAD (11). Despite advances in multidisciplinary treatment improving overall care, the prognosis for patients with MPE remains poor, with a 5-year survival rate of only 6.4% (12,13). Two studies investigated the correlation between EGFR mutations and MPE in LUAD, but these studies were mostly based on nonpaired case-control designs with small sample sizes, resulting in potential bias for which further validation may be necessary (14,15).

Therefore, through a retrospective study, we aimed to determine the correlation between EGFR mutations and MPE in LUAD and evaluate the potential survival impact benefit of therapies based on EGFR mutations for patients with LUAD and MPE. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-757/rc).

Methods

Patients

This retrospective study included patients with LUAD who visited the Thoracic Surgery Department and Oncology Department of the First Hospital of China Medical University between January 2013 and December 2020. The inclusion criteria were as follows: (I) pathologically confirmed LUAD and (II) no history of other malignant tumors. A total of 4,461 patients met these criteria. Patients with incomplete clinical data, loss to follow-up, or death due to non-LUAD-related causes were excluded, resulting in a final sample size of 849 patients. Various clinical data were collected, including baseline information at admission, imaging findings, pathological results, genetic testing results, treatment regimens, and survival times. Tumor diameter and the number of lymph node metastases were restaged according to the ninth edition of the tumor-node-metastasis (TNM) staging system (16). Age was categorized into two groups: <60 and ≥60 years.

MPE was defined as the presence of pleural effusion on computed tomography (CT) imaging, confirmed by cytopathological examination showing tumor cells in the effusion (12). Patients were divided into MPE and non-MPE groups based on the presence of MPE at initial diagnosis. MPE group was categorized as stage IV according to the TNM staging system due to the presence of MPE, while the non-MPE group included patients ranging from stage I to stage IV. To control for confounding factors, propensity score matching (PSM) was performed between the two groups. After matching, the correlation between EGFR mutation and MPE in LUAD was analyzed. Furthermore, univariate and multivariate analyses were conducted to investigate factors associated with overall survival (OS) in patients with LUAD and MPE (Figure 1).

Figure 1 Flowchart of study. PSM, propensity score matching; MPE, malignant pleural effusion; N-MPE, non-malignant pleural effusion; EGFR, epidermal growth factor receptor.

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of the First Hospital of China Medical University (No. 2023-54). The requirement for individual consent was waived due to the retrospective nature of the analysis.

EGFR mutation analysis

This study collected mutation information from patients diagnosed with LUAD who had undergone genetic testing. Testing methods included fluorescence polymerase chain reaction (PCR), amplification refractory mutation system PCR, and next-generation sequencing. All genetic test reports for patients were obtained from accredited genetic testing companies, such as Geneseeq Genetic Testing Company. The mutations in EGFR exons 18 to 21 were detected, including G719X, exon 19 deletion (19 Del), exon 20 insertion (20 Ins), S768I, T790M, L858R, and L681Q, among others.

Study endpoints

The primary follow-up endpoint of this study was OS, which was defined as the time from the initial diagnosis of LUAD until death or the follow-up cutoff date of September 30, 2023. During the follow-up period, deaths due to LUAD-related causes were recorded as positive outcomes, while data from patients still alive at the end of the follow-up period were considered censored to calculate cumulative survival rates. Follow-up information was primarily obtained through hospital medical records and telephone communications with patients or their relatives.

Statistical methods

PSM analysis was performed using R version 4.2.1 (The R Foundation of Statistical Computing), Factors included in PSM were age, gender, smoking history, T-stage and N-stage, and the matched ratio of MPE group to non-MPE group was 1 to 2 with a caliper value of 0.02. Data processing and statistical analyses were conducted using SPSS 26.0 software (IBM Corp., Armonk, NY, USA). Categorical variables were analyzed using the Chi-squared test or Fisher exact test. Correlation analysis was conducted using binary logistic regression. Univariate analysis was performed using the Cox proportional hazards model, and factors with P values less than 0.05 were included in the multivariate analysis to identify those factors associated with OS. Kaplan-Meier curves were plotted using GraphPad Prism 10 software (GraphPad Software, Inc., La Jolla, CA, USA), and the log-rank test was used to compare survival curves across different subgroups for statistical differences. All statistical tests were two-sided, and P values less than 0.05 were considered statistically significant.

Results

Patient characteristics in the MPE and N-MPE groups

A total of 849 patients were included in the study, with 180 in the MPE group and 669 in the N-MPE group. To control for the influence of confounding factors, PSM analysis was performed between the MPE and N-MPE groups. After PSM, there were 180 patients in the MPE group and 360 in the N-MPE group. The distribution of the aforementioned covariates across the two groups was balanced (P>0.05) (Table 1).

Correlation analysis of EGFR mutation and MPE

The types of EGFR mutations included in this study were exon 18 G719X mutations, 19 Del, 20 Ins, exon 20 S768I mutations, T790M mutations, and exon 21 L858R and L681Q mutations. Among the 540 patients who remained after PSM, 294 had EGFR mutations. The EGFR mutation rate was significantly higher in patients with LUAD and MPE compared to those without MPE, indicating a positive correlation between EGFR mutation and MPE occurrence [62.7% vs. 50.2%; odds ratio (OR) =1.668; P=0.006]. Notably, there was a significant difference in T790M mutation rates between the two groups (8.3% vs. 1.3%; OR =8.015; P<0.001), while no significant differences were observed for other mutation sites (Table 2).

Patient characteristics in the MPE group

Among the 180 patients with LUAD and MPE, 113 (62.8%) patients were EGFR mutant type and 67 (37.2%) patients were EGFR wild type. Therefore, the 180 patients were divided into two groups (EGFR MT group and EGFR WT group), and their characteristics are presented in Table 3. There were 77 male patients (42.7%), and 132 patients (73.3%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. 117 patients (65%) were receiving EGFR-TKI treatment, while 63 patients (35%) were receiving non-EGFR-TKI treatment. A total of 77 patients (42.7%) received systemic antiangiogenic targeted therapy, mainly consisting of bevacizumab. Moreover, 8 patients (4.4%) had mutations other than EGFR and received corresponding targeted drug therapy. These included four patients with ALK mutations treated with crizotinib, two patients treated with the selective MET kinase inhibitor savolitinib, one patient treated with the selective RET inhibitor pralsetinib, and one patient with a BRAF V600 mutation treated with a combination of dabrafenib and trametinib. Due to the small number of cases, these were collectively classified as “other targeted drug treatments”. A total of 141 patients (78.3%) received systemic chemotherapy, mainly platinum-based doublet chemotherapy, 44 patients (24.4%) received immunotherapy with anti-PD-1/PD-L1 drugs, and 51 patients (28.3%) received intrapleural perfusion therapy, which involved indwelling chest catheters and infusion of cisplatin or cisplatin combined with bevacizumab or recombinant human endostatin. Local treatment was administered to 31 patients (17.2%), with 6 patients receiving interventional therapy and 29 patients receiving radiotherapy for primary or metastatic lesions.

Prognostic factors analysis in patients with MPE

We followed up with 180 patients with LUAD and MPE with a median follow-up duration of 61 months and plotted survival curves (Figure 2). As of the follow-up cutoff date, 55 patients (30.5%) were still alive, representing a median OS of 42 months (95% CI: 35.7–44.3) and a 5-year survival rate of 25.5% (Figure 2A). Using the Cox regression model, we conducted univariate and multivariate analyses to identify the factors associated with OS in the 180 patients with LUAD and MPE. In the univariate analysis, an ECOG score ≥2 was associated with shorter OS. Conversely, EGFR mutation, antiangiogenic therapy, and intrapleural perfusion therapy were associated with a longer OS (Figure 3). Multivariate analysis showed that EGFR mutation was an independent prognostic factor for prolonged OS [hazard ratio (HR) 0.662, 95% CI: 0.456–0.962; P=0.03]. Additionally, the factors independently associated with longer OS were antiangiogenic therapy (HR 0.684, 95% CI: 0.474–0.987; P=0.043) and intrapleural perfusion therapy (HR 0.622, 95% CI: 0.441–0.992; P=0.046), Conversely, ECOG scores ≥2 were independently associated with shorter OS (HR 1.911, 95% CI: 1.226–2.886; P=0.002) (Figure 4).

Figure 2 Kaplan-Meier curves for overall survival in different populations. (A) Survival curves for patients with LUAD and MPE. (B) Survival curves for patients with LUAD and MPE stratified by the EGFR mutant type and EGFR wild type. (C) Survival curves for patients with LUAD, MPE, and EGFR mutations stratified by different EGFR-TKI treatment regimens. MPE, malignant pleural effusion; OS, overall survival; CI, confidence interval; EGFR, epidermal growth factor receptor; WT, wild type; MT, mutant type; TKI, tyrosine kinase inhibitor; gen, generation; LUAD, lung adenocarcinoma.

Figure 3 Univariate analyses for OS in patients with LUAD and MPE. HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; WT, wild type; MT, mutant type; OS, overall survival; LUAD, lung adenocarcinoma; MPE, malignant pleural effusion.

Figure 4 Multivariate analyses for OS in patients with LUAD and MPE. HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; WT, wild type; MT, mutant type; OS, overall survival; LUAD, lung adenocarcinoma; MPE, malignant pleural effusion.

To visually present the association of EGFR mutation with OS in patients with LUAD and MPE, we plotted survival curves. The median OS for EGFR-mutant patients was 47 months (95% CI: 41.5–52.5), which was significantly better than the 31 months in those with the EGFR wild type (95% CI: 25.9–36.1; P=0.03) (Figure 2B).

Prognostic factor analysis of patients with EGFR mutations and MPE

To overcome the inevitable resistance to EGFR-TKIs, new EGFR-TKIs drugs continue to be developed, providing various options and strategies for clinical applications. To clarify the impact of different EGFR-TKIs treatment regimens on OS in patients with LUAD, MPE, and EGFR mutations, we further analyzed these patients. Among the 111 patients with EGFR mutations and MPE who received EGFR-TKI treatment, 28 received first-generation EGFR-TKIs alone, 51 received sequential first- and third-generation EGFR-TKIs, and 27 received third-generation EGFR-TKIs alone (5 patients who received second-generation EGFR-TKIs were excluded from the analysis due to the small sample size). The Cox regression model was used for univariate and multivariate analyses. The results showed that the independent prognostic factors for prolonged OS were administration of third-generation EGFR-TKIs alone (HR 0.466, 95% CI: 0.233–0.930; P=0.03) and sequential first- and third-generation EGFR-TKIs (HR 0.385, 95% CI: 0.219–0.676; P=0.001) but not administration of first-generation EGFR-TKIs alone. Additionally, intrapleural perfusion therapy (HR 0.557, 95% CI: 0.327–0.951; P=0.03) was also independently associated with a longer OS (Figures 5,6).

Figure 5 Univariate analyses for OS in patients with LUAD, MPE, and EGFR mutations. HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; gen, generation; OS, overall survival; LUAD, lung adenocarcinoma; MPE, malignant pleural effusion.

Figure 6 Multivariate analyses for OS in patients with LUAD, MPE, and EGFR mutations. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; gen, generation; HR, hazard ratio; CI, confidence interval; OS, overall survival; LUAD, lung adenocarcinoma; MPE, malignant pleural effusion.

Survival curves were plotted to compare the survival benefits of the three main EGFR-TKI treatment regimens for patients with LUAD and MPE. The results showed that compared to first-generation EGFR-TKIs alone, both third-generation EGFR-TKIs alone and sequential first- and third-generation EGFR-TKIs had better median OS (first-generation EGFR-TKIs: 35 months, 95% CI: 28.4–41.6; third-generation EGFR-TKIs: 50 months, 95% CI: 37.3–62.7; sequential first- and third-generation EGFR-TKIs: 51 months, 95% CI: 45.6–56.4; P<0.001) (Figure 2C).

Discussion

This study demonstrated that EGFR mutations, especially the T790M mutation, are associated with the occurrence of MPE in LUAD. For patients with LUAD and MPE, EGFR mutations independently associated with prolonged OS.

Previous studies have shown that EGFR activation, triggered by ligand binding, activates EGFR intrinsic tyrosine kinase activity and a series of downstream signals, thereby mediating invasion and metastasis in various tumors (7,17,18). In NSCLC, EGFR mutation is most commonly associated with brain metastasis (19-21). Recently, the correlation between EGFR mutation and MPE has also been reported: Zou et al. collected data from 136 East Asian patients with LUAD and found a significant correlation between MPE occurrence and EGFR mutation (P=0.03) (14). Smits et al. analyzed 394 patients with LUAD from 13 hospitals in Western Europe and found that EGFR mutation frequency was significantly higher in patients with MPE (P=0.02) (22). The specific EGFR mutation sites and the precise targeting of metastatic lesions remain a focus of interest for researchers worldwide. Notably, the T790M mutation is particularly relevant due to its association with EGFR-TKI resistance in lung cancer (23-25). A real-world clinical study indicated a positive correlation between T790M mutation and NSCLC brain metastasis (P=0.03) (26). Chen et al. conducted a retrospective study on 365 patients with EGFR-mutant NSCLC and found that the T790M mutation carriers were more prone to metastasis, including brain, bone, liver, and intrapulmonary metastases (P<0.001) (24).

Previous studies on the correlation between EGFR mutation and MPE in NSCLC included relatively small sample sizes, affecting the accuracy of results (14,15). Moreover, limited by gene detection technologies and sample sizes, these studies often only analyzed the presence or absence of EGFR mutations or focused solely on classic mutations such L858R and 19 Dels, neglecting T790M mutation rates in MPE. In our study, the EGFR mutation rate in patients with LUAD and MPE was 62.7% compared to 50.2% in those without MPE (OR =1.668; P=0.006), suggesting a potential association between EGFR mutation and MPE occurrence. Additionally, this study, being the first to examine the correlation between specific EGFR mutation sites and MPE, demonstrated a significant positive correlation between T790M mutation and MPE occurrence (8.3% vs. 1.3%; OR =8.015; P<0.001).

The T790M mutation is a well-established mechanism of secondary resistance to EGFR-TKI therapy. Numerous studies have shown that approximately 50% of NSCLC patients who initially respond to EGFR-TKI eventually develop secondary resistance due to the emergence of the T790M mutation (27,28). Chen et al. have suggested that a significant proportion of untreated NSCLC cases may harbor the T790M mutation from the outset. In this scenario, while first- or second-generation TKIs target and eliminate the initial sensitive mutation sites, T790M-resistant clones can proliferate and become predominant (29). Consequently, the disease progression associated with primary T790M mutation may occur earlier than that driven by acquired T790M mutation, leading to a more rapid disease progression in cases with primary mutations. In our study, we also compared the differences in OS between T790M mutation and common mutations. However, due to the limited sample size, we did not observe significant differences between the two groups.

Reports suggest that the prevalence of primary T790M mutations is quite low, ranging from 1-3%, which is consistent with our study’s finding (overall T790M mutation rate was 3.7%, and 1.3% in the non-MPE group) (30,31). However, we observed a higher rate of 8.3% for T790M mutations in the MPE group, suggesting a potential association between the presence of T790M mutation and MPE. Currently, clinical research has predominantly focused on managing resistance due to secondary T790M mutations after treatment, with limited studies investigating the role of T790M in regulating tumor biology. Our findings suggest that primary T790M mutations may facilitate invasion and metastasis in LUAD. This highlights the need for further research into the underlying signaling pathways and potential therapeutic targets related to T790M mutations. We further sought to identify prognostic factors in patients with LUAD and MPE, particularly the association between EGFR mutation and the OS. ECOG score is a recognized prognostic factor for patients with MPE (32), with higher scores indicating poorer prognosis. We found that an ECOG score ≥2, as compared to lower ECOG scores, was associated with an increase in mortality rate of 91.1% (HR 1.911, 95% CI: 1.226–2.886; P=0.002). Angiogenesis is crucial to tumor growth, proliferation, and metastasis, and numerous preclinical and clinical studies have examined antiangiogenic therapies for inhibiting tumor growth (33,34). In our study, antiangiogenic targeted therapy was associated with better OS. In NSCLC, bevacizumab, U.S. Food and Drug Administration (FDA)-approved antiangiogenic inhibitor, combined with platinum-based chemotherapy is recommended as first-line treatment for patients with advanced LUAD (35). Additionally, intrapleural perfusion therapy is a primary method for treating MPE. Injecting drugs into the pleural cavity can kill metastatic tumor cells, stimulate pleural inflammation, and reduce pleural effusion. A previous study has shown that intravenous cisplatin (100 mg/m²) results in a maximum blood concentration of 6 µg/mL (36), while intrapleural infusion of cisplatin (80 mg/m²) yields a maximum blood concentration of only 0.66±0.31 µg/mL, increasing intrapleural drug concentration and reducing adverse systemic effects (37).

Previous studies have shown that EGFR-mutant patients treated with EGFR-TKIs have better survival than do those with the EGFR wild type (38-40). Similarly, we found that the median OS of EGFR-mutant patients was longer than that of those with the EGFR wild type (EGFR mutant: 47 months, 95% CI: 41.5–52.5; EGFR wild-type: 31 months, 95% CI: 25.9–36.1; P=0.03). Another finding of our study was that among patients with LUAD, EGFR mutations, and MPE, sequential first- and third-generation EGFR-TKIs or third-generation EGFR-TKIs alone were associated with longer OS compared to first-generation EGFR-TKIs alone. First-generation EGFR-TKIs lead to good initial treatment response in patients with classic EGFR mutations; however, most patients develop resistance after 9–14 months, with the T790M mutation being the most common mechanism of resistance(40,41). After resistance, a switch to third-generation EGFR-TKIs, which inhibit the T790M mutation, can significantly improve prognosis as compared to continuation on first-generation EGFR-TKIs or a switch to chemotherapy (40). Therefore, patients receiving sequential first- and third-generation EGFR-TKIs or third-generation EGFR-TKIs alone have a longer median OS, likely due to prolonged inhibition of the EGFR pathway, whereas patients receiving first-generation EGFR-TKIs alone do not benefit from new EGFR inhibitors after the emergence of resistance, resulting in a shorter median OS. This suggests that continuous inhibition of the EGFR pathway is beneficial for OS in patients with LUAD, MPE, and EGFR mutations.

This study involved certain limitations which should be acknowledged. First, although we attempted to reduce bias through PSM analysis and multivariable regression models, there were confounding factors not included in the models, and selection bias could not be completely excluded. Second, grouping certain variables might have simplified certain types of information, such as age, tumor diameter, and the number of lymph node metastases. Finally, as we employed a single-center, retrospective design, this study may be limited by a small sample size and a lack of regional differences and thus may not be more broadly generalizable.

Conclusions

Patients with LUAD with MPE exhibiteda higher incidence of EGFR mutations, including T790M mutations, compared to those without MPE. Specifically, EGFR mutations, especially the T790M mutations, were positively associated with the development of MPE in LUAD. Among patients with LUAD and MPE, EGFR mutations were linked to improved survival. For those with LUAD, MPE, and EGFR mutations, the use of sequential first-generation and third-generation EGFR-TKIs, or third-generation EGFR-TKIs alone, may lead to an improved OS benefit.

Acknowledgments

Funding: This study was supported by the Natural Science Foundation of Liaoning Provincial Science and Technology Department (No. 2023-MS-159 to W.L.), Liaoning “Xingliao Yingcai Program” Medical Masters Foundation of Liaoning Provincial Health Commission (No. YXMJ-QN-08 to W.L.), and Post-doctor Research Initiation Project of 2023 Joint Fund Project (No. 2023-BSBA-362 to D.L.).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-757/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-757/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-757/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-757/coif). W.L. has received support from the Natural Science Foundation of Liaoning Provincial Science and Technology Department (No. 2023-MS-159) and Liaoning “Xingliao Yingcai Program” Medical Masters Foundation of Liaoning Provincial Health Commission (No. YXMJ-QN-08). D.L. has received support from Post-doctor Research Initiation Project of 2023 Joint Fund Project (No. 2023-BSBA-362). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of the First Hospital of China Medical University (No. 2023-54). The requirement for individual consent was waived due to the retrospective nature of the analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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