Clinicopathological factors vs. molecular model for predicting adjuvant EGFR-TKI benefit in stage I EGFR-mutant non-small cell lung cancer

Introduction

The pathological staging system serves as the gold standard for treatment planning and prognosis prediction for patients with lung cancer. Currently, stage I non-small cell lung cancer (NSCLC) shows significant heterogeneity in clinical outcomes, with approximately 20–40% of patients experiencing local recurrence or distant metastasis within 5 years after surgery (1). This may stem from undetected residual viable tumor cells either locally or systemically (2), making adjuvant therapy for stage I NSCLC a significant clinical challenge.

Currently, the National Comprehensive Cancer Network (NCCN) guidelines for adjuvant therapy in early-stage NSCLC are based on the identification of patients at high risk of recurrence (3). However, the NCCN guidelines lack explicit criteria defining for “high-risk” patients, instead offering clinicopathologic features that may suggest a higher risk of recurrence. There are limitations with these population-level indicators, as a notable proportion of patients classified as low-risk based on these parameters still experience relapse, while some categorized as high-risk remain disease-free for extended periods.

Considerable efforts have been devoted to exploring the potential role of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as adjuvant treatment for early-stage EGFR-mutant NSCLC. For instance, exploratory analyses from the ADAURA and CORIN studies have revealed a decreased risk of recurrence in stage IB patients (4,5). Additionally, our previous retrospective study has provided supporting evidence for the use of adjuvant EGFR-TKIs in stage I patients, including those in stage IA (6). However, according to the current NCCN guidelines, routine adjuvant treatment is not recommended for stage IA patients. For patients with stage IB, the selective recommendation of adjuvant treatment is contingent upon clinicians accurately identifying high-risk factors.

The aforementioned findings indicate that the existing pathological staging system exhibits inadequate prognostic accuracy and fails to effectively identify which patients would experience advantages from adjuvant EGFR-TKIs. Consequently, there is an urgent need for novel stratification approaches that can improve prognosis prediction and identify individuals who would derive the greatest benefits from adjuvant EGFR-TKIs.

A 14-gene molecular assay has been developed to stratify the risk of recurrence in NSCLC patients after surgical resection (7,8). Previous studies have demonstrated that patients classified as molecular high-risk who received adjuvant chemotherapy experienced notably prolonged disease-free survival (DFS) compared to those who did not (9). This assay holds the potential benefits in accurately identifying patients at high risk who could benefit the most from adjuvant therapy. Additionally, it may help identify patients with a low risk of recurrence who are more likely to be cured through surgical resection alone, thus potentially eliminating the need for additional interventions.

In this study, we compared the performance of the 14-gene assay and NCCN clinicopathological factors to assess recurrence events and distinguish patients who may benefit from adjuvant EGFR-TKIs in stage I NSCLC, aiming to provide a more precise approach for guiding treatment decisions and ultimately improving patient outcomes. We present this article in accordance with the STROCSS reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-20/rc) (10).

Methods

Study design and patients

The study design is presented in Figure 1. In this retrospective cohort study, we included patients with resected stage I NSCLC from March 2013 to February 2019. The inclusion criteria were as follows: (I) aged ≥18 years; (II) confirmed pathology of primary non-squamous NSCLC; (III) pathological stage I according to the 8th edition AJCC/UICC classification; (IV) harbored a sensitizing EGFR mutation (19Del or L858R); (V) underwent complete surgical resections via lobectomy or pneumonectomy with systemic intrathoracic lymph node dissection; (VI) available clinicopathological data; and (VII) complete postoperative follow-up of at least 5 years for patients without disease progression. For those experiencing disease progressions, their follow-up duration was determined by the time until progression within the 5-year period.

Figure 1 Study flowchart. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

The exclusion criteria were as follows: (I) incomplete surgical resection, as outlined in the Chinese guidelines on the diagnosis and treatment of primary lung cancer [2019]; (II) initiation of adjuvant EGFR-TKIs more than two months after surgery; (III) combination with other malignant tumors; (IV) received previous preoperative therapy (chemotherapy, radiotherapy, or targeted therapy).

The administration of adjuvant EGFR-TKIs was determined through a collaborative decision-making process involving patients and attending physicians. This process entailed a comprehensive evaluation of the patient’s financial circumstances and treatment preferences, while also considering guidance from the NCCN guidelines, which identify specific high-risk factors. By incorporating these factors, personalized recommendations were formulated regarding the use of adjuvant EGFR-TKIs. The prescribed daily dosages for icotinib, erlotinib, and gefitinib were 125 mg three times, 150 mg once, and 250 mg once, respectively.

This retrospective cohort study was registered at the Research Registry (UIN: researchregistry10105). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of the First Affiliated Hospital of Guangzhou Medical University (No. 2022181) and individual consent for this retrospective analysis was waived due to the retrospective nature.

Data collection

Data for the study were obtained by extracting information from the electronic medical records system, which included baseline clinical data and postoperative follow-up details. Demographic information including age, sex, and smoking status, along with cancer-related details including tumor location, size, tumor-node-metastasis (TNM) classification stage, pathology, histology, tumor differentiation, number of examined lymph nodes, and EGFR mutation status, were collected. EGFR mutations were detected via amplification-refractory mutation system polymerase chain reaction (ARMS-PCR) or next-generation sequencing (NGS) based on institutional availability during the study period. Both are validated and concordant for exon 19/21 mutations. Postoperative information included survival status, disease progression, and any subsequent treatments received.

Patients underwent regular postoperative surveillance with low-dose computed tomography (LDCT) scans every 3 months during treatment and every 6 months thereafter for up to five years. Additional contrast-enhanced CT or positron emission tomography/computed tomography (PET/CT) scans were performed as needed based on clinical symptoms or imaging findings, as determined by the treating oncologist or surgeon. Disease recurrence was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

To minimize selection and recall bias, we included all consecutive patients who satisfied the eligibility criteria during the predefined study period. Data were retrieved from the institution’s standardized electronic medical record system. Two independent researchers abstracted the data following a standardized protocol, and any discrepancies were resolved by consensus. Follow-up data were collected via scheduled outpatient visits and telephone interviews using a uniform questionnaire. While telephone interviews may not provide an equivalent level of comprehensive information as the electronic medical records system, they do offer significant insights into patient-reported outcomes, overall well-being, and disease status. No major clinical or pathological variable had missing data.

Definition of clinicopathological high-risk factors

According to the NCCN guidelines, clinicopathological high-risk factors include: (I) tumor size >4 cm; (II) poorly differentiated histology; (III) vascular invasion; (IV) wedge resection; (V) visceral pleural invasion; and (VI) unknown lymph node status (Nx) (3).

The biological characteristics of lung adenocarcinoma (LUAD) patients at the same stage exhibit significant heterogeneity. In 2011, the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) proposed a new histological classification based on major growth patterns and prognostic relevance, identifying five main subtypes: lepidic, acinar, papillary, micropapillary, and solid (11). This classification was adopted and further refined by the World Health Organization (WHO) in 2015 (12). Numerous studies have confirmed that LUADs dominated by micropapillary or solid patterns is associated with poorer prognosis, and these are considered high-grade patterns (13). Additionally, complex glandular patterns, such as cribriform and fused glands, are also considered high-grade acinar components, exhibiting similar poor survival rates when compared to micropapillary and solid patterns (14).

Therefore, the six clinical high-risk factors defined by the NCCN guidelines and the solid, micropapillary subtypes, as well as complex glandular patterns, were recognized as clinicopathological high-risk factors in this study. High-risk histological subtypes (solid, micropapillary, or complex glandular patterns) were determined by two experienced pulmonary pathologists according to the according to the IASLC/ATS/ERS classification, with any discrepancies resolved by consensus of a third senior pathologist.

14-gene molecular assay

The 14-gene quantitative PCR expression assay (DetermaRx™, Burning Rock Biotech) is a CLIA-certified molecular test developed and validated globally for assessing the recurrence risk of NSCLC after surgical resection. The assay quantifies the expression levels of 14 genes using quantitative reverse transcription PCR (qPCR) on total RNA extracted from formalin-fixed, paraffin-embedded tumor tissues. The RNA extraction, quality control, qPCR procedures, and analytical validation have been comprehensively documented in previous studies. A proprietary algorithm then calculates a risk score based on the gene expression data, classifying patients into low-, intermediate-, or high-risk groups according to validated cutoff values (7,15).

To evaluate the predictive significance of this assay in the context of adjuvant EGFR-TKI treatment, we retrospectively collected formalin-fixed, paraffin-embedded tumor samples submitted for molecular testing. Patients were stratified into low-, intermediate-, or high-risk categories based on the molecular prognostic assay. Since both intermediate- and high-risk patients were considered to have a higher risk of recurrence, they were grouped together and designated as molecular high-risk.

Outcome

The primary endpoint assessed in this study was the 5-year DFS, calculated from the date of surgery to the occurrence of the first recurrence at any site or all-cause death. Patients who did not experience recurrence, were no longer being monitored, or survived without documented recurrence were censored at their last available assessment. Follow-up information was last updated on July 31, 2022 or on the date of death.

Statistical analysis

To summarize patient characteristics, continuous variables were summarized using means and standard deviations for normally distributed data, and median with interquartile range (IQR) for non-normally distributed data. Differences between groups were assessed using either Student’s t-test or Mann-Whitney U-test. Categorical variables were presented as frequencies and percentages, and comparisons between groups were conducted using Pearson’s Chi-squared test or Fisher’s exact test. The estimation of DFS was performed utilizing the Kaplan-Meier method and subsequently compared employing the log-rank test. Additionally, Cox proportional hazards regression was employed to calculate hazard ratios (HRs) accompanied by 95% confidence intervals (CIs). Statistical significance was established at a P value below 0.05, and all statistical analyses were executed using IBM SPSS Statistics (version 26.0), R software (version 4.2.2), and GraphPad Prism (version 9.5.1).

Results

Study population

A total of 180 eligible patients were included in the study, with 41 (22.8%) receiving adjuvant EGFR-TKIs therapy and 139 (77.2%) in the observation group. The median follow-up duration was 76.9 (IQR, 67.0–88.6) months. The median age of the study cohort was 61 years. All patients underwent R0 surgical resection by lobectomy with negative margins. Among them, 90 (50.0%) patients were classified as stage IA, while the remaining 90 (50.0%) were classified as stage IB. Leu858Arg and 19Del mutation were identified in 117 (65.0%) and 63 (35.0%) patients, respectively. Cancer cell differentiation was categorized as poor in 67 patients (37.2%), moderate in 82 patients (45.6%), and well in 31 patients (17.2%). A comprehensive summary of the demographic and clinical characteristics of all patients are presented in Table 1.

The clinicopathological high-risk group showed a higher incidence of stage IB disease (75.4%) compared to the low-risk group, where stage IA disease predominated (98.4%). Moreover, high-risk patients were more frequently associated with poorly differentiated tumors (56.8%), while the low-risk group all presented with well/moderately differentiated tumors (100.0%). In terms of adjuvant therapy, a higher proportion of high-risk patients received EGFR-TKIs (27.1%) compared to the low-risk group (14.5%).

Conversely, there were no significant differences observed in TNM stage, vascular invasion, ground glass opacity, or the administration of adjuvant EGFR-TKIs between molecular high-risk and low-risk patients. However, the 14-gene assay revealed significant associations with tumor differentiation grade. The molecular high-risk group exhibited a notably higher prevalence of poorly differentiated tumors (54.7%) compared to the low-risk group (21.3%), which underscores its ability to capture molecular variations influencing tumor aggressiveness.

Predicting postoperative prognosis

In terms of predicting postoperative prognosis, the 14-gene molecular prognostic testing stratified 94 (52.2%) patients as low-risk for 5-year mortality and 86 (47.8%) patients as high-risk. NCCN criteria identified 118 (65.6%) patients as high-risk and 62 (34.4%) patients as low-risk. A total of 82 patients in the cohort had discordant risk results: 57 (31.7%) of 180 patients had high clinical risk and low molecular risk, and 25 (13.9%) of 180 patients had low clinical risk and high molecular risk.

After 5 years of follow-up, the differentiation in 5-year DFS among patients who did not receive adjuvant EGFR-TKIs, as delineated by the 14-gene assay and NCCN-defined clinicopathological high-risk factors, exhibited different performances. The 14-gene assay revealed that patients in molecular high-risk group showed a notably reduced DFS compared to those in the low-risk group [HR =6.49 (95% CI: 2.78–15.2); P<0.001]. The 5-year DFS rates for the molecular low-risk and high-risk group were 94.9% (95% CI: 90.1–99.9%) and 70.5% (95% CI: 59.9–82.9%), indicating a discrimination capacity of 24.4% (P<0.001) (Figure 2A). In comparison, according to NCCN-defined clinicopathological risk factors, clinical high-risk patients experienced a lower DFS compared to low-risk patients (HR =2.18; 95% CI: 0.93–5.14; P=0.12). The 5-year DFS rates for the clinicopathological low- and high-risk group were 90.6% (95% CI: 83.0–98.8%) and 80.2% (95% CI: 72.2–89.1%), reflecting a discrimination capacity of 10.4% (P=0.12) (Figure 2B).

Figure 2 DFS analysis according to (A) 14-gene and (B) clinicopathological factors. The shaded area represents the 95% CI. CI, confidence interval; DFS, disease-free survival.

Among 139 patients who did not receive adjuvant EGFR-TKIs, they were divided into four main groups based on their clinicopathological and molecular risk profiles: low clinicopathological risk and low molecular risk, which included 33 patients (23.7%); low clinicopathological risk and high molecular risk, which included 20 patients (14.4%); high clinicopathological risk and low molecular risk, which included 45 patients (32.4%); and high clinicopathological risk and high molecular risk, which included 41 patients (29.5%). For discordant-risk groups, patients with high clinicopathological risk but low molecular risk exhibited a 5-year DFS of 93.3% (95% CI: 86.3–100.0%), while those with low clinicopathological risk but high molecular risk had a 5-year DFS of 80.0% (95% CI: 64.3–99.6%) (P<0.001) (Figure 3). These findings suggested that high molecular risk, regardless of clinicopathological risk, was associated with suboptimal prognosis. Conversely, patients with low molecular risk maintained relatively favorable outcomes even with high clinicopathological risk.

Figure 3 DFS analysis in the four risk groups. The shaded area represents the 95% CI. CI, confidence interval; DFS, disease-free survival.

Predicting adjuvant EGFR-TKIs benefit

Among 86 patients categorized as molecular high-risk, 25 patients underwent adjuvant EGFR-TKIs, resulting in a 5-year DFS rate of 96.0% (95% CI: 88.6–100.0%). Conversely, patients not receiving adjuvant EGFR-TKIs had a 5-year DFS rate of 70.5% (95% CI: 59.9–82.9%), indicating a 25.5% decline compared to the EGFR-TKIs group (P=0.01) (Figure 4A). Similarly, among 118 patients identified as high clinicopathological risk, 32 patients received adjuvant EGFR-TKIs, achieving a 5-year DFS rate of 96.9% (95% CI: 91.0–100.0%). In contrast, those who did not receive adjuvant EGFR-TKIs had a 5-year DFS rate of 80.2% (95% CI: 72.2–89.1%), representing a 16.7% decrease compared to the EGFR-TKIs group (P=0.03) (Figure 4B). These findings underscore the utility of both NCCN high-risk criteria and the 14-gene assay in guiding decisions regarding adjuvant EGFR-TKIs therapy.

Figure 4 Association of adjuvant EGFR-TKIs and DFS in (A) molecular high-risk population and (B) clinicopathological high-risk population. The shaded area represents the 95% CI. CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Among patients in the discordant risk groups, molecular high-risk, rather than clinicopathological high-risk factors, proved more predictive of the benefits of adjuvant EGFR-TKIs. Specifically, for molecular high-risk patients, adjuvant EGFR-TKIs significantly improved 5-year DFS rates from 65.9% (95% CI: 52.8–82.1%) to 95.0% (95% CI: 85.9–100.0%) (P=0.02) in clinically high-risk subgroups and from 80.0% (95% CI: 64.3–99.6%) to 100.0% (95% CI: 100.0–100.0%) (P=0.04) in clinically low-risk subgroups (Figure 5A). However, molecular low-risk patients showed no significant benefit from adjuvant EGFR-TKIs, regardless of clinicopathological high-risk [DFS rate increased from 93.3% (95% CI: 86.3–100.0%) to 100% (95% CI: 100.0–100.0%); P=0.37] or low-risk subgroups [97.0% (95% CI: 91.3–100.0%) to 100.0% (95% CI: 100.0–100.0%); P=0.73] (Figure 5B). In other words, patients categorized as clinically high-risk but molecular low-risk could potentially avoid additional postoperative treatment [93.3% (95% CI: 86.3–100.0%) to 100.0% (95% CI: 100.0–100.0%); P=0.37] (Figure 5C). Conversely, clinically low-risk individuals with molecular high-risk profiles still benefited from adjuvant EGFR-TKIs [80.0% (95% CI: 64.3–99.6%) to 100.0% (95% CI: 100.0–100.0%); P=0.04] (Figure 5D).

Figure 5 Crossover analysis of adjuvant EGFR-TKIs and DFS among (A) molecular high-risk, (B) molecular low-risk, (C) clinical high-risk, and (D) clinical low-risk populations. The shaded area represents the 95% CI. CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Discussion

In our study, we compared NCCN clinicopathological factors and the 14-gene assay in predicting postoperative prognosis and guiding adjuvant EGFR-TKIs decisions for stage I NSCLC. We found that the molecular risk stratification was independent of clinical and pathological factors and outperformed in both prognostic and predictive accuracy. Specifically, the 14-gene assay identified a subset of molecular high-risk patients within the clinically low-risk group who significantly benefited from adjuvant therapy, resulting in a 20% increase in 5-year DFS rates. Also, it identified a molecular low-risk population within the clinically high-risk group that showed limited benefit from adjuvant therapy. This finding holds considerable significance as it figured out the predominant population that could benefit from adjuvant EGFR-TKIs that has previously been overlooked and low-risk recurrence patients, sparing them from unnecessary interventions.

The 14-gene assay effectively stratified both clinical high-risk and low-risk patients with greater accuracy than the NCCN criteria alone. The improved predictive accuracy may stem from the inherent limitations of clinical factors, which mainly reflect external manifestations rather than intrinsic molecular characteristics. A large proportion of postoperative deaths in stage I NSCLC were attributed to distant recurrence, suggesting that many patients classified as stage I by traditional standards actually have occult metastases or circulating tumor cells at the time of resection (16). The genes within the 14-gene assay are related to classic lung cancer oncogenic molecular pathways and prognostic gene characteristics (17-21), enabling reliable identification of patient subgroups with different survival outcomes.

The clinical significance of the 14-gene assay lies in its ability to provide more accurate prognostic information and guide personalized treatment strategies. Molecular risk status, independent of clinical risk, effectively stratifies patients into high- and low-risk groups among both clinically high-risk and low-risk patients. Compared to untreated patients, molecularly high-risk patients who received adjuvant EGFR-TKI therapy showed significantly improved 5-year DFS. As reported in previous literature, the 14-gene assay has the ability to identify high-risk patients who benefit from adjuvant chemotherapy (7,9,22,23). In our study, we demonstrated the clinical utility of the 14-gene prognostic assay in guiding adjuvant EGFR-TKIs. These findings highlight the importance of molecular risk assessment in optimizing treatment decisions, ensuring that adjuvant EGFR-TKI is selectively given to patients most likely to derive clinical benefit, thereby minimizing the burden of unnecessary treatment for low molecular risk patients.

While genomic testing, including the 14-gene assay, enhances prognostic accuracy and aids in identifying patients who may benefit from adjuvant EGFR-TKI therapy, molecular residual disease (MRD) monitoring also offers valuable insights into tumor recurrence, metastasis, and treatment efficacy (24-27). However, the challenge with MRD lies in its insufficient sensitivity, potentially yielding false-negative results, particularly in stage I patients on whom the concentration of circulating tumor DNA (ctDNA) may fall below the detection limit (28). In such cases, the 14-gene molecular assay serves as a valuable supplement. Also, the MRD detection methods and assessment standards still need to be standardized. Looking ahead, the combination of molecular markers, clinical risk factors, and MRD assessment may enhance the precision of adjuvant therapy recommendations, potentially leading to improved survival outcomes and reduced cancer-related mortality. Further research and standardization efforts are essential to optimize the integration of these modalities into clinical practice, ultimately improving patient outcomes in early-stage NSCLC management.

Despite the notable findings, this study has several limitations. First, the focus on stage I NSCLC patients receiving off-label adjuvant EGFR-TKI therapy resulted in a small eligible population and limited recurrence events. Consequently, our study could not assess whether the coexistence of multiple high-risk features increases recurrence risk or enhances treatment benefits. Additionally, the retrospective design may have introduced selection bias. Nevertheless, this study demonstrated the prognostic and predictive value of the 14-gene assay with sufficient statistical power. Further validation in larger prospective cohorts is ongoing to address these limitations and confirm the assay’s utility in guiding treatment decisions.

Conclusions

Our study demonstrates that the 14-gene assay offers superior prognostic value and predictive power compared to clinicopathological factors in stage I NSCLC patients. These findings highlight the potential for a more refined and personalized approach to treatment decision-making in this population, ultimately contributing to improved patient outcomes. Further research is needed to validate these results and establish the clinical utility of the 14-gene assay in routine practice.

Acknowledgments

The primary results of the abstract in this study were presented as a meeting poster (P2.07A.01) in the World Conference on Lung Cancer 2024.

Footnote

Reporting Checklist: The authors have completed the STROCSS reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-20/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-20/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-20/prf

Funding: This work was supported by National Key Research and Development Program of China (Nos. 2022YFB4702600 and 2022YFC2505100), Basic and Applied Basic Research Foundation of Guangdong Province (No. 2023B1515120076), and Science and Technology Innovation Committee Joint Funding of Guangzhou (No. 2023A03J0356).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-20/coif). W.L. serves as an associate Editor-in-Chief of Translational Lung Cancer Research from May 2024 to April 2025. S.C. is from Guangzhou Burning Rock Biotech Co., Ltd. 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study received approval from the Institutional Review Board of the First Affiliated Hospital of Guangzhou Medical University (No. 2022181), and individual consent for this retrospective analysis was waived due to the retrospective nature.

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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