The IASLC grading system as a predictor for EGFR-TKI therapy in patients with EGFR-mutant lung adenocarcinoma

Introduction

Lung adenocarcinoma (LADC) reveals marked heterogeneous histologic features in growth patterns (1), and it has taken decades to establish a consensus classification system for routine practice. Not until 2020 did the International Association for the Study of Lung Cancer (IASLC) Pathology Committee propose a novel grading system for invasive nonmucinous LADC, which recognized the importance of predominant patterns plus high-grade components (2). Since its publication, Rokutan-Kurata et al. and our previous study have validated the reproducibility and prognostic relevance of this new grading system in Asian patients (3,4).

Identifying predictive factors beyond stage is crucial to decide who need adjuvant therapies, and what regimens they need. Several retrospective studies have suggested a predictive value of high-grade patterns for adjuvant chemotherapy (ACT) benefit (5,6), and our previous study further confirmed an improved prognosis with ACT in patients with stages Ib to III IASLC grade 3 adenocarcinomas (4). However, the potential role of tumor grade data in adjuvant therapy selection has not been well demonstrated, including ACT and EGFR tyrosine kinase inhibitors (TKIs) treatment. EGFR-TKIs have been the recommended first-line (1L) standard of care for advanced non-small cell lung cancer (NSCLC) harboring sensitive EGFR mutations. The ADJUVANT and EVAN trial indicated a significant disease-free survival (DFS) benefit from first-generation TKIs (gefitinib and erlotinib) compared to ACT only in stage II–IIIa and stage IIIa EGFR-mutant NSCLC, respectively (7,8). Recently, based on the results from the ADAURA trial (9,10), osimertinib was approved as adjuvant treatment in patients with surgically resected stage Ib–III EGFR-mutant NSCLC (11,12). We previously reported the correlation between tumor grades and the incidence of EGFR mutations (4), but there is still a clinical knowledge gap for the effect of this IASLC grading system on EGFR-TKIs efficacy. In this study, therefore, we retrospectively collected 2,160 patients with EGFR-mutant surgically resected LADCs, analyzing the frequency of EGFR mutations and co-occurring mutations. Specifically, we aimed to investigate whether the IASLC grading system could identify a subgroup of patients who derive superior survival benefit from EGFR-TKI treatment. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1419/rc).

Methods

Study design and participants

From January 2008 to April 2021, we consecutively collected LADC patients who underwent complete resection at the Department of Thoracic Surgery, Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. The 8^th tumor-node-metastasis (TNM) staging was used in this study. Inclusion criteria were invasive LADC with positive EGFR mutations in exons 18–21. We excluded adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), invasive mucinous adenocarcinoma and other variants of adenocarcinoma. Patients with pathologic slides unavailable for re-evaluation were also excluded. The study included three main subgroups: (I) patients with p-TNM stage Ib–III LADCs who received adjuvant EGFR-TKI (adjuvant EGFR-TKI therapy was generally recommended for 1 to 2 years or until disease recurrence or unacceptable toxicity, in accordance with clinical guidelines at the time) or chemotherapy (ADJUVANT subgroup, N=620); (II) patients developed post-operative recurrence and treated with either EGFR-TKI, chemo- or immune checkpoint inhibitor (ICI) therapy (RECURRENCE subgroup, N=321); and (III) next-generation sequencing (NGS) was carried out which provided co-occurring mutation information (NGS subgroup, N=1158). The flowchart of patients enrolled are presented in Figure S1.

Data on clinicopathologic variables were obtained by reviewing patient medical records specifically for this study purpose. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review board (Fudan University Shanghai Cancer Center IRB 2008223-9, date: July 14, 2020). Informed consent was waived in this retrospective study.

Histologic evaluation

Histologic evaluation was performed as previously described (4) and according to the proposed IASLC grading system (2): grade 1, lepidic predominant tumor with no or less than 20% of high-grade patterns; grade 2, acinar or papillary predominant tumor, both with no or less than 20% of high-grade patterns; and grade 3, any tumor with 20% or more of high-grade patterns (solid, micropapillary, or complex gland).

Mutational analysis

In this study, EGFR-targeted monogene assay was used to detect hot-spot regions (exon 18–21) in 46.4% patients and customized NGS panels were used in 53.6% of the cases (NGS subgroup). Monogene assay procedure was described as previous studies (13,14). We used two NGS-based panel assays including the Lung Core target sequencing (Burning Rock Biotech, Shanghai, China) and OncoScreen Plus sequencing (Burning Rock Biotech). The Lung Core target sequencing is a hot-spot panel test that analyze lung cancer related mutations and fusions in 68 genes. The OncoScreen Plus sequencing is a comprehensive genome profile test that interrogates point mutations, insertions/deletions, fusions/rearrangements, and amplifications in 520 genes; and tumor mutation burden (TMB) and microsatellite instability (MSI). In addition to classical EGFR mutations L858R and exon 19 deletions, other atypical EGFR mutations were categorized into several major subgroups based on previous analyses (15,16): (I) exon 20 insertions; (II) uncommon mutations including E709X, G719X, S768I and L861Q and combinations of those with classical EGFR mutations; (III) de-novo T790M mutations; and (IV) other very rare and complex mutations including exon 18 deletions, exon 19 insertion and exon 20 point mutations.

Statistical analysis

DFS was defined as time from initiation of surgery to date of first event (recurrence or death). Progression-free survival (PFS) was defined as time from initiation of systemic palliative treatment to date of disease progression or death for 1L treatment of each patient and the initiation time was re-assigned additionally for each drug applied during the treatment history of the patients regardless of line of therapy (all lines). Overall survival (OS) was defined as time from surgery to date of death resulting from any cause in ADJUVANT subgroup and from 1L systemic palliative treatment assignment to date of death resulting from any cause in RECURRENCE subgroup. Survival was investigated by Kaplan-Meier method and log-rank test was employed to compare differences between groups. Hazard ratios (HRs) were calculated by Cox regressions models. Since objective response rates were available for a minority of patients, we only analyzed DFS, PFS and OS as main outcome parameters. Variables with a P value less than 0.05 in univariable analysis were entered into multivariable survival analysis. The statistical analysis was conducted in R Statistical Language (version 4.1.2).

Results

Frequency and distribution of EGFR mutation subtypes

A total of 2,160 patients with EGFR-mutant invasive LADC undergoing complete resection were enrolled in this study. Patient tumors were successfully reclassified into one of the invasive LADC grades outlined in the IASLC grading system: grade 1 (N=68), grade 2 (N=1,137) and grade 3 (N=955). The clinicopathologic features stratified by each grade were summarized in Table 1. Consistent with previous study (4), higher IASLC grades were significantly correlated with male (P<0.001), smokers (P=0.002), radiologic solid feature (P<0.001), more extensive surgeries (P<0.001), higher pathologic TNM stages (P<0.001) and presence of visceral pleural invasion (P<0.001) and lymphovascular invasion (P<0.001).

Classical EGFR mutations L858R and exon 19 deletions occurred in 941 (43.6%) and 900 (41.7%) cases, respectively, followed by uncommon mutations (N=116, 5.4%), exon 20 insertions (N=94, 4.3%), T790M mutations (N=23, 1.1%) and other rare mutations (Figure 1A). The distribution of the different types of EGFR mutations in each IASLC grade was shown in Figure 1B and Table S1. Again, we observed variations in the incidence of EGFR mutation subtypes within different grades. Exon 19 deletions had a significantly higher prevalence of grade 3 (46.9%) while exon 21 L858R was more frequent in grade 1 (44.1%) and grade 2 (47.6%) adenocarcinomas (P<0.001). The proportion of atypical EGFR mutations did not differ among the grades when compared with classical mutations (P=0.86, Table S1).

Figure 1 The frequency and distribution of EGFR mutations within different IASLC grades in the entire cohort. (A) Pie chart of the frequency of EGFR mutations in the entire cohort; (B) Correlation between EGFR mutations and IASLC grades. IASLC, International Association for the Study of Lung Cancer.

Stratification value of the IASLC grading system for adjuvant EGFR-TKI benefit

Six hundred and twenty patients with p-TNM stage Ib–III LADC received adjuvant systemic treatment after surgery (ADJUVANT subgroup, Table S2). This subgroup was comprised of four grade 1, 116 grade 2 and 500 grade 3 adenocarcinomas; 94 patients were treated with adjuvant EGFR-TKI (average duration of treatment: 16.98±10.52 months) and the remaining 526 patients received ACT. Among the former 94 patients, gefitinib was the most frequently applied EGFR-TKI (N=73, 77.6%), followed by osimertinib (N=11, 11.7%), icotinib (N=5, 5.3%) and erlotinib (N=5, 5.3%).

We investigated the adjuvant EGFR-TKI efficacy stratified by the IASLC grading system. A significant benefit was seen from EGFR-TKI compared to ACT in the entire ADJUVANT subgroup for DFS [HR 0.76, 95% confidence interval (CI): 0.61–0.95, P=0.01] but not OS (P=0.47; Figure 2A,2B). Interestingly, the mDFS (P=0.94) and mOS (P=0.42) was similar with adjuvant EGFR-TKI than ACT in the IASLC grade 1–2 group (Figure 2C,2D). However, there was still a significant DFS benefit from adjuvant EGFR-TKI in the IASLC grade 3 group (HR 0.69, 95% CI: 0.52–0.91, P=0.007; Figure 2E), with no OS benefit observed (P=0.48; Figure 2F). Of note, 31.3% (21/67) patients of this group had pathological stage Ib tumors (Figure S2). Multivariable analysis further confirmed that adjuvant EGFR-TKI was an independent prognostic factor for DFS (HR 0.74, 95% CI: 0.56–0.98, P=0.04) in the IASLC proposed grade 3 group regardless of pathological tumor stages, but not in the entire ADJUVANT subgroup (P=0.12, Table 2). The survival curves stratified by tumor stages were also provided in Figure S3. Though there was a significant DFS benefit from adjuvant EGFR-TKI in p-TNM stage II–III patients, the effect was not statistically significant after adjustment for clinicopathologic variables (HR 0.80, 95% CI: 0.62–1.05, P=0.10; Table S3).

Figure 2 Survival curves for predicting adjuvant EGFR-TKI benefit after tumor resection in the entire ADJUVANT subgroup (A,B), IASLC proposed grade 1–2 cohort (C,D) and IASLC proposed grade 3 cohort (E,F). The 95% CIs are shown as shaded areas. Chemo, chemotherapy; CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; IASLC, International Association for the Study of Lung Cancer; mDFS, median disease-free survival; mOS, median overall survival; NR, not reached; OS, overall survival; TKI, tyrosine kinase inhibitor.

Clinical outcomes of patients with post-operative recurrence

Follow up information upon palliative systemic treatment with EGFR-TKI and chemo therapy for patients developing post-operative recurrence was collected; 319 patients were treated with either EGFR-TKI (N=270) or chemotherapy (N=49) as 1L therapy (Tables S4,S5); 55 patients received second-line (2L) therapy and 17 patients received 3L therapy. In total, data from 391 different therapies regardless of treatment lines were available for survival analysis (RECURRENCE subgroup).

In this entire subgroup, median PFS (mPFS) and median OS (mOS) were both significantly longer upon treatment with EGFR-TKI compared to chemotherapy in 1L [mPFS: 24.4 vs. 10.3 months, P<0.001; mOS: not reached (NR) vs. 48.5 months, P=0.008; Table S5, Figure 3]. This effect was similar when all line treatments were considered for PFS analysis (HR, 0.63, 95% CI: 0.54–0.74, P<0.001; Figure 3A, Table S5).

Figure 3 Survival curves for predicting EGFR-TKI benefit after tumor relapse in the entire RECURRENCE subgroup (A,B), IASLC proposed grade 1–2 subgroup (C,D) and IASLC proposed grade 3 subgroup (E,F). The 95% CIs are shown as shaded areas. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; IASLC, International Association for the Study of Lung Cancer; mOS, median overall survival; mPFS, median progression-free survival; NR, not reached; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

In IASLC grade 1–2 group, mPFS was still significantly longer with EGFR-TKI compared to chemotherapy considering either 1L (24.1 vs. 8.3 months, P=0.004) or all line treatments (21.2 vs. 8.3 months, P<0.001; Figure 3C, Table S5). However, the PFS advantage did not translate into an OS advantage with 1L treatment (HR 0.64, 95% CI: 0.37–1.13, P=0.11; Figure 3D). Interestingly, both PFS and OS benefit favoring EGFR-TKI vs. chemotherapy were observed in IASLC grade 3 group, regardless of treatment lines (Figure 3E,3F, Table S5). Very similar conclusions have been drawn from the survival curves stratified by tumor stages (Figure S4).

Frequency of co-mutations and their effect on EGFR-TKI efficacy

Customized NGS panel was tested for 1,158 patients in the entire cohort (53.6%) and co-mutations occurred in 55.6% of these patients (N=644, Figure 4A). TP53 mutation was reported as the most frequent co-mutations (N=436, 67.7%), among which 133 patients (30.5%) were accompanied by other mutations such as PIK3CA (22/133, 16.5%), PTEN (14/133, 10.5%), CTNNB1 (12/133, 9.0%) and others (Figure 4A). PIK3CA was the 2^nd most frequently occurring co-mutations (N=45, 7.0%). Interestingly, significantly more co-mutations as well as TP53 mutations were reported in IASLC high-grade group (Figure 4B,4C), suggesting that part of rare EGFR mutations in this group may represent passenger mutations.

Figure 4 Co-mutations. (A) Pie chart indicating distribution of non-co-mutations and several most frequent genes. (B,C) Boxplots indicating frequency of co-mutations per IASLC grades (B) and TP53 mutations per IASLC grades (C). (D,E) Kaplan-Meier plots for response to EGFR-TKI by TP53 mutational status in ADJUVANT subgroup (D) and in RECURRENCE subgroup (E). The 95% CIs are shown as shaded areas. CI, confidence interval; DFS, disease-free survival; IASLC, International Association for the Study of Lung Cancer; NGS, next-generation sequencing; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; WT, wild type.

Because of the low number of other co-mutations, we chose to analyze only the effect of TP53 co-mutations on both adjuvant and palliative EGFR-TKI efficacy. The results showed no effect of TP53 co-mutations on DFS in patients with adjuvant EGFR-TKI or PFS in EGFR-TKI treated patients all treatment lines (Figure 4D,4E), which may be due to insufficient sample size.

Discussion

This study involving the largest retrospective cohort, to our knowledge, of EGFR-mutant invasive LADCs undergoing complete resection has confirmed the clinical relevance of the IASLC grading system, which was adapted for the fifth edition [2021] of the World Health Organization (WHO) thoracic tumor classification (17). Our results showed that patients with IASLC proposed high-grade invasive adenocarcinoma had an improved DFS (which did not translate to OS benefit) with adjuvant EGFR-TKI compared to ACT. Moreover, in patients who developed post-operative recurrence, the effect of systemic EGFR-TKI vs. chemotherapy was significantly different in IASLC low-grade (grade 1–2) and high-grade (grade 3) groups. Therefore, we have shown the first evidence to our knowledge that the IASLC grading system may be a stratification marker for potential beneficiaries from adjuvant EGFR-TKI in DFS in invasive LADC after tumor resection, and from systemic EGFR-TKI in both PFS and OS after tumor relapse. However, more analyses are needed to confirm these findings.

To date, clinical trial designations for NSCLC concerning EGFR-TKI therapy remain based on tumor stages. Identifying predictive markers for TKI efficacy beyond stage is crucial to select additional patients who may benefit from targeted therapy and optimize clinical outcomes. There have been intensive studies on predictive biomarkers such as programmed death-ligand 1 (PD-L1) expression (18-20) and mutant allele frequency (21), but so far, no markers have been sufficiently validated for routine clinical use. The correlation between molecular alternations and histologic patterns has been well studied in multiple works (14,22). The current study further revealed EGFR exon 19 deletions had a significantly higher prevalence of high grade while exon 21 L858R was more frequent in low-grade adenocarcinomas, and potential benefit from TKIs existed only in high-grade adenocarcinomas, which suggests a potential role of grading in future targeted clinical trials.

Despite that osimertinib has become the standard adjuvant therapy for stage Ib to III resected EGFR-mutant LADCs, our finds suggest a broader role of earlier generation EGFR TKIs in such patients. For example, gefitinib is currently only approved for the treatment of stage II–III EGFR-mutant LADCs in China and some other regions. Based on our findings, however, gefitinib might also be an adjuvant option for stage Ib patients with high-grade LADC, which greatly extend the indicated populations since 71.9% of stage Ib patients had high-grade tumors in our study, whereas osimertinib may still not available for most families due to economic burden and drug accessibility. However, given the limited sample size of stage Ib patients in our TKI cohort, further prospective validation is required before clinical implementation. In addition, there has been ongoing debate about the priority of drug choice. Despite that osimertinib achieved better survival than earlier generation TKIs, part of patients eventually develop resistance and no efficient drug are available for them. That is, osimertinib may be the best but also the last choice. On the other hand, 50–60% of patients receiving first/second-generation TKIs developed T790M mutation, and these patients could still derive survival benefit from 2L third-generation TKIs. In addition, our findings provide a biological rationale that remains relevant in the era of osimertinib. The significant benefit seen in grade 3 tumors suggests that these high-grade components are highly dependent on EGFR signaling. Therefore, the IASLC grading system could potentially identify patients at high risk who might require the more potent inhibition provided by third-generation TKIs, or even combination therapies. Nevertheless, further prospective investigation is still warranted to confirm the selection role of IASLC grading system in EGFR-TKI treatment.

The molecular mechanism responsible for this treatment efficacy relevance remains unknown. One possible hypothesis is the differential EGFR-TKI efficacy among EGFR mutation subtypes. The available retrospective and prospective studies appear to support that TKIs have better efficacy, at least in terms of PFS, in patients with exon 19 deletion than those with L858R mutation. Lee et al. analyzed seven randomized trials comparing 1L EGFR-TKIs with chemotherapy and revealed a 50% greater benefit in exon 19 deletion than those with L858R mutation (23). Furthermore, a combined analysis of two phase-III trials (LUX-Lung 3 and LUX-Lung 6) showed that OS was improved with afatinib as 1L setting in patients with exon 19 deletion but not those with L858R mutation (24). Nevertheless, due to sample size fragmentation when splitting by mutation subtypes and treatments, we could not directly compare the survival benefit these two groups. And patients with sensitive EGFR mutations (19Del and L858R) should still be the standard candidates for EGFR-TKI treatment, and IASLC grading system might become a better surrogate for patient selection.

It is worth noting that the DFS benefit from adjuvant EGFR-TKIs did not translate to an OS benefit in patients with high-grade adenocarcinoma. Several randomized trials revealed adjuvant EGFR-TKIs therapy could significantly prolong DFS but not OS in patients with early-stage EGFR-mutant NSCLC (8,25), while the long-term follow-up data for the phase III ADAURA trial proved the OS benefit in the adjuvant TKI group (9,10). In this study, this nonsignificant test for OS may be explained by lack of power, smaller number of events for OS compared with DFS, and dilution effect by noncancer deaths. In addition, the drug resistance and subsequent disease relapse may also partially explain the DFS curve crossover at around 5 years and subsequent no OS benefit.

Our data also confirmed the co-occurring mutations were more frequent in high-grade adenocarcinomas, which was in concordance with literature (26). Retrospective studies have also indicated that co-mutations such as TP53 combined with classical EGFR mutations and ALK-alterations can be detrimental for outcome with specific targeted therapies (27,28). However, our results did not indicate the detrimental effect of co-occurring TP53 mutations on outcome in EGFR-TKI treated patients, possibly due to low numbers and further analysis is warranted.

There were some limitations to this study. First, this was a retrospective, single-center study spanning a long period [2008–2021], during which the standard of care evolved. Although we adjusted for confounding factors, selection bias cannot be fully excluded. Second, the majority of EGFR-TKI applied in our study was the first-generation gefitinib. Considering that osimertinib has become the standard adjuvant therapy in patients with stage Ib to III resected EGFR-mutant lung cancer, and several 4^th-generation EGFR-TKIs are undergoing clinical trials, further exploration concerning the additional role of IASLC grading system is warranted. Third, the duration of adjuvant EGFR-TKI therapy was heterogeneous which might impact the patient survival outcomes. And the analysis of post-recurrence survival is limited by the heterogeneity of subsequent treatment lines. Finally, the analysis of TP53 co-mutations was constrained by the relatively small sample size in the subgroups.

Conclusions

In summary, this retrospective study confirmed that within different IASLC grades, variations existed in relation to EGFR mutation subtypes. More importantly, our study has shown a significant clinical value of IASLC grading system as a prognostic stratification factor to identify potential beneficiaries of EGFR-TKIs therapy in patients with EGFR-mutant adenocarcinoma. These results may provide rationale for its adoption not just in routine diagnostic reports but as a potential stratification factor in future clinical trials.

Acknowledgments

The abstract of this study has been published on J Thorac Oncology as Mini Oral Presentation [https://www.jto.org/article/S1556-0864(23)01065-1/fulltext].

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1419/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1419/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1419/prf

Funding: The study was supported by National Key R&D Program of China (No. 2022YFA1103900), National Natural Science Foundation of China (Nos. 82430099 and 82504099), the Clinical Research Special Project of Shanghai Municipal Health Commission (No. 202440070), and the Medical Research Special Project for Shanghai Science and Technology Innovation Action Plan (No. 24Y12800400).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1419/coif). The 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 was approved by the institutional review board (Fudan University Shanghai Cancer Center IRB 2008223-9, date: July 14, 2020). Informed consent was waived in this retrospective study.

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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