Prognostic impact of ALK rearrangement in surgically treated stage I lung adenocarcinoma: a retrospective cohort study

Introduction

Lung cancer remains the deadliest malignancy worldwide, with lung adenocarcinoma (LUAD) being the most common subtype (1). The adoption of low-dose computed tomography (LDCT) screening has driven a significant stage shift in lung cancer (2), increasing stage I diagnoses by 5.9–11.3% between 2010 and 2017 (3,4), renewing attention to this early-stage population and emphasizing the need to reassess and optimize treatment strategies to improve long-term outcomes.

The prognosis of stage I LUAD patients was generally favorable, with the 5-year survival rate ranging from 65.3% to 74.9% (5). However, significant heterogeneity still exists. For example, patient characteristics (6), along with tumor radiological and pathological features—such as the presence of solid components on computed tomography (CT) (7) or micropapillary patterns in LUAD (8)—are associated with poorer survival. Recently, studies have highlighted that certain gene mutations can drive distinct tumor behavior and significantly influence prognosis (9,10), which has been emphasized as a key focus for future lung cancer prognosis stratification (11).

Among the identified mutations in LUAD, anaplastic lymphoma kinase (ALK) rearrangement is a key actionable driver (12). The wild-type ALK gene encodes an orphan receptor tyrosine kinase (RTK) that regulates key pathways, including MAPK, PI3K-AKT, and JAK-STAT, but when rearranged, it produces aberrant fusion proteins that drive uncontrolled cell proliferation and survival through constitutive downstream signaling (13). A real-world study in China found that ALK rearrangement occurs in 8.2% of advanced LUAD cases, with ALK-positive patients more likely to be female, younger, and never smoker (14). Evidence has demonstrated that patients with ALK rearrangement were often diagnosed at advanced stage, accompanied by distant metastases, resulting in a poor prognosis (15,16). Fortunately, the introduction of ALK tyrosine kinase inhibitors (TKIs) has significantly benefited patients with advanced ALK-positive patients (17,18), as demonstrated by pivotal trials such as PROFILE 1014 (19), which confirmed the superiority of crizotinib over standard chemotherapy, and ALEX (20), ALTA-1L (21), and CROWN (22), which showed the enhanced efficacy of second- and third-generation ALK-TKIs. More recently, trials such as ALNEO (23) and ALINA (24) have extended the application of ALK inhibition to localized and resectable non-small cell lung cancer (NSCLC), reflecting a growing interest in the role of ALK-targeted therapy in earlier disease stages. However, the prevalence of ALK rearrangement in early-stage LUAD, its connection with tumor characteristics, and its influence on patient prognosis remain unexplored, leaving a critical gap in our understanding.

Therefore, this study seeks to uncover the prognostic significance of ALK rearrangement in surgically treated stage I LUAD patients by examining demographics, tumor characteristics, and patterns of postoperative recurrence and treatment patterns, supporting better management strategies for this group of patients. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1049/rc) (25).

Methods

Study design and data source

A retrospective cohort study was conducted on surgically treated, stage I LUAD patients who underwent ALK rearrangement test at West China Hospital, Sichuan University, between January 2014 and March 2021. Data were obtained from the West China Lung Cancer Database (WCLCD), a prospective, hospital-based registry established by the Department of Thoracic Surgery, West China Hospital, Sichuan University. The database integrates clinical, pathological, and follow-up information of patients undergoing lung cancer surgery and is continuously maintained and updated by dedicated research personnel. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Biomedical Research, West China Hospital, Sichuan University (approval No. 1704 [2024]). Informed consent was waived in this retrospective study.

Population

The inclusion criteria for the initial patient cohort were: (I) pathologically diagnosed as stage I (the 8^th edition) LUAD after surgery; and (II) with a definitive ALK gene rearrangement status. In West China Hospital, Sichuan University, ALK status was assessed uniformly by immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) was not routinely performed for ALK determination. Patients with multiple primary lung cancers were excluded. The initial cohort was analyzed for baseline characteristics, followed by screening for eligibility for survival analysis. The inclusion and exclusion criteria are outlined below. Inclusion: (I) older than 18 years; and (II) underwent R0 resection and lymph node dissection/sampling. Exclusion: (I) comorbid with other malignancy or with previous lung surgery; (II) underwent emergency operation; (III) underwent intraoperative emergent events, including massive bleeding (>500 mL), cardiac arrest and conversion to thoracotomy; (IV) reoperation due to postoperative bleeding or other emergent conditions; (V) lack of follow-up information or with a follow-up duration of less than 6 months; and (VI) death within 1 month.

Data collection

Baseline data were collected and standardized, covering patient demographics, tumor characteristics, treatment-related information, and additional biomarker data. Demographic variables included age, sex, body mass index (BMI), smoking history, and comorbidities. Tumor characteristics comprised CT radiomic features, such as ground-glass opacity (GGO) or solid components, and other morphological traits, alongside pathological data detailing tumor size, location, stage, histology type, differentiation extent, cancer embolus, tumor spread through air space (STAS), and visceral pleural invasion (VPI). Treatment-related information encompassed surgical approach, resection extent, number of resected lymph nodes, adjuvant and post-recurrence treatment, as well as targeted drugs. In principle, patients with preoperative CT findings suggesting pleural adhesions or calcified hilar lymph nodes were considered for thoracotomy based on multidisciplinary team (MDT) discussions. Peripherally located, GGO-dominant nodules ≤2 cm were treated with wedge resection, whereas those measuring 2–3 cm were treated with segmentectomy if an adequate surgical margin could be achieved. Post-recurrence treatment plans were discussed by an MDT (including thoracic surgery, oncology, and biological therapy departments) and were based on patient preferences and financial considerations to determine the most appropriate approach. Additionally, biomarker and driver gene data, including the mutation status of epidermal growth factor receptor (EGFR), c-ros oncogene 1 (ROS1), and the expression level of programmed death-ligand 1 (PD-L1), were gathered. Postoperative follow-up was performed according to national (26) and institutional guidelines, with standardized intervals and imaging protocols. All follow-up data were updated through December 31, 2024.

Outcomes

The primary outcome of the study was recurrence-free survival (RFS), defined as the time from surgery to the first documented recurrence or lung cancer-specific death (LCSD), with censoring at the last follow-up for recurrence-free patients and the time of those who died of other causes. Locoregional recurrence was identified based on imaging findings from chest CT, positron emission tomography (PET)/CT, or biopsy confirmation when applicable. Distant metastases were diagnosed using PET-CT, bone scintigraphy, magnetic resonance imaging (MRI), or CT scans, supplemented by biopsy if clinically indicated. All imaging evaluations were performed according to the treating physician’s discretion and institutional practice, and recurrence or metastasis was confirmed by an MDT consensus when necessary. Additionally, clinicopathologic characteristics, mutational profiles, and targeted therapy patterns in ALK-positive patients were analyzed.

Statistical analysis

Continuous variables were summarized as mean ± standard deviation (SD) for normally distributed data and as median with interquartile range (IQR) for non-normally distributed data. Baseline characteristics were compared by Student’s t-test, Wilcoxon rank-sum test, Chi-squared test, or Fisher’s exact test using the “tableone” R package. RFS was assessed using the Kaplan-Meier method, and group differences in survival were evaluated using the log-rank test. Cox proportional hazards regression was used to identify risk factors for RFS, and logistic regression was applied to estimate odds ratios (ORs) for LCSD, locoregional recurrence, and distant metastasis. All statistical tests were two-sided, with a significance threshold set at P<0.05. Data analysis was performed using R software (version 4.3.3).

Results

Baseline characteristics

A total of 3,775 patients with stage I LUAD who underwent surgical treatment were included in the initial cohort (Figure 1), comprising 2,415 females (63.97%) and 1,360 males (36.03%), with a mean (SD) age of 56.87 (11.20) years. Most patients were never-smokers (2,962, 78.46%), and 707 (18.73%) had a family history of cancer. Nearly all underwent minimally invasive surgery (3,737, 98.99%), and more than half received lobectomy (2,160, 57.22%). Regarding pathological stage, 2,461 patients (65.19%) were diagnosed as stage IA and 1,314 (34.81%) as stage IB (Table 1).

Figure 1 Flowchart illustrating the patient screening process, outlines the inclusion and exclusion criteria applied to identify the initial patient cohort and survival analysis cohort. +, positive; −, negative. AJCC, American Joint Committee on Cancer; ALK, anaplastic lymphoma kinase; LUAD, lung adenocarcinoma.

Mutational profiles

Among the 3,775 patients, 165 (4.37%) tested positive for ALK rearrangement, while 3,610 were negative. We then analyzed ALK positivity across subgroups (Table 2) and found significantly higher rates in females (4.89% vs. 3.46%, P=0.048), stage IB patients (6.09% vs. 3.45%, P<0.001), and those without EGFR mutations (10.64% vs. 3.52%, P<0.001). Younger patients (<60 years) and never-smokers also showed a trend toward higher ALK positivity, though the differences were not statistically significant.

Given the marked discrepancy in ALK rearrangement rates by EGFR mutational status, we examined the co-alteration patterns of these two genes and found a concomitant mutation rate of 2.32%. Comparative analysis with previous studies on driver mutations in Chinese LUAD patients supported our findings (Table 3). Notably, ALK rearrangement prevalence appeared to increase with disease stage, while its co-occurrence with EGFR mutations declined, particularly in patients with unifocal disease, suggesting a trend that warrants further investigation.

Patients with coexisting ALK and EGFR or ALK and ROS-1 alterations were rare. Therefore, we further summarized their clinicopathological characteristics in Table S1. The data indicated that patients harboring concurrent ALK and EGFR alterations were more likely to have a family history of cancer and to present with larger, more aggressive tumors.

Tumor characteristics

To investigate tumor characteristics associated with ALK rearrangement, we first identified several CT-based radiologic and pathological features as risk factors for RFS, including solid components, pleural retraction, lobulated or spiculated margins, and cavitation on CT; and invasive adenocarcinoma (IAC), presence of micropapillary or solid components and lack of lepidic components (MP/S⁺Lep⁻) (8), cancer emboli, and VPI on pathology (Table S2). ALK-positive patients were more likely to exhibit these high-risk features, particularly among those with stage IA disease, a group traditionally considered low risk (Figure 2).

Figure 2 Dumbbell plot presenting the proportion of stage I LUAD patients with high-risk CT radiomic and pathological features cross different ALK gene rearrangement statuses in (A) overall cohort, and (B) stage IA subgroup. ALK, anaplastic lymphoma kinase; CT, computed tomography; IAC, invasive adenocarcinoma; LUAD, lung adenocarcinoma; MP/S⁺Lep⁻, presence of micropapillary or solid components and lack of lepidic components; STAS, spread through air space; VPI, visceral pleural invasion.

Survival analysis

After eligibility screening, 2,982 patients were included in the survival analysis cohort (Table S3), with a median follow-up of 70.0 months (IQR, 59.0–81.0 months). RFS was significantly shorter in ALK-positive patients compared to ALK-negative ones (log-rank P=0.009; Figure 3A). Univariate Cox regression revealed a significantly increased risk of recurrence associated with ALK rearrangement [hazard ratio (HR) =2.15; 95% confidence interval (CI): 1.19–3.88; P=0.01]. However, after adjustment for potential confounders, including sex, age, smoking history, comorbidity, lung function [ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) (% predicted)], resection extent, number of resected lymph node stations, pathological stage, and adjuvant treatment, the association was attenuated and no longer statistically significant (HR =1.72; 95% CI: 0.92–3.21; P=0.09) (Table S4).

Figure 3 RFS curve by ALK gene rearrangement status in (A) OS-analysis cohort, and (B) subgroup of patients with high-risk pathological features. ALK, anaplastic lymphoma kinase; CI, confidence interval; HR, hazard ratio; OS, overall survival; RFS, recurrence-free survival.

Therefore, we assessed the impact of ALK rearrangement on specific postoperative outcomes (Table 4). ALK-positive patients had a significantly higher likelihood of developing metastases (OR =2.15; 95% CI: 1.02–4.53; P=0.045), particularly to the bone (OR =5.38; 95% CI: 2.20–13.16; P<0.001), and brain (OR =2.88; 95% CI: 1.04–7.93; P=0.041), after adjustment for potential confounders as stated above (Tables S5-S7). Of note, the distinct metastatic pattern associated with ALK rearrangement remained significant in subgroup analyses for both stage IA and IB patients (Tables S8,S9).

We further performed subgroup survival analysis to investigate the distinguishing ability of high-risk pathological features in patients with different ALK rearrangement status. High-risk features included VPI, cancer embolus, STAS, or poorly differentiated tumors. The analysis involved 2,122 patients with available data. Those with high-risk features had significantly shorter RFS than those without, in both ALK-positive and ALK-negative groups (Figure S1). Moreover, within the high-risk subgroup, ALK-positive patients showed significantly poorer RFS 24 months postoperatively compared to ALK-negative patients (log-rank P=0.006, Figure 3B). These findings highlight the importance of considering both pathological features and ALK status in long-term prognosis assessments.

In addition, as ALK and ROS-1 share approximately 70% homology in their kinase domains (28), and previous studies have reported similar epidemiological characteristics between ALK and ROS-1 rearranged patients (29). We therefore compared the prognosis of patients harboring these two alterations. Interestingly, our survival analysis showed that ALK⁺/ROS-1⁻ patients had significantly worse RFS than ALK⁻/ROS-1⁺ patients (P=0.001), and ALK positivity was consistently associated with inferior RFS regardless of ROS-1 status (P=0.02) (Figure S2). These findings suggest that although ALK and ROS-1 rearrangements may share similar clinicopathological profiles, their prognostic implications appear distinct.

Targeted treatment patterns among ALK-positive patients

Among ALK-positive LUAD patients, four individuals received adjuvant treatment, all at stage IB and with concurrent EGFR mutations. These patients were treated with EGFR-TKIs. At follow-up, one patient developed bone metastasis at 45 months post-surgery and died of lung cancer at 66 months, while the remaining three patients remained alive and recurrence-free at their most recent follow-ups (107, 85, and 69 months).

In the subgroup of ALK-positive patients who experienced recurrence or metastasis (n=12), ten received further treatment, including six who were treated with ALK-TKIs. Among these six patients, one developed bone and brain metastases 18 months after surgery and died 12 months following the initiation crizotinib treatment. The other five patients remained on ALK-TKI treatment and under active follow-up, with total follow-up durations ranging from 37 to 77 months since surgery and 11 to 55 months after recurrence. Among them, three initially received crizotinib (two of whom were later switched to alectinib due to resistance), while the remaining two started on alectinib and lorlatinib, respectively.

Discussion

In this study, we analyzed 3,775 resected stage I LUAD cases to provide the first comprehensive evaluation of the prevalence and clinicopathological significance of ALK rearrangements in early-stage disease. ALK fusions were identified in 4.37% of patients, with a significantly higher incidence observed in those with stage IB tumors and females and was mutually exclusive with EGFR mutations. Histopathological analysis revealed that ALK-positive tumors were associated with more aggressive features and a distinct tendency for distant metastases to the bone and brain, which highlight the potential prognostic value of ALK rearrangements in early-stage LUAD and underscore the need for further large-scale, prospective validation to guide risk stratification and treatment decisions.

Firstly, the ALK gene rearrangement rate (4.37%) observed in our cohort is slightly lower than the rates reported in later-stage patient cohorts, such as 6.2% in stage I–III surgically resected LUADs from the European Thoracic Oncology Platform Lungscape iBiobank (30), or 8.2% in advanced NSCLC patients from multi-center studies in China (14). Notably, the ALK rearrangement rate in our stage IB subgroup (6.09%) was similar to that found in these advanced-stage cohorts. This suggests that the lower overall prevalence in our study may not simply reflect sampling bias but instead point to the biological aggressiveness of ALK-positive tumors, which are more likely to be diagnosed at advanced stages due to rapid progression, with early lymph node (31) or distant metastasis. Moreover, our results support a significant gender difference in the occurrence of ALK rearrangements, although differences related to smoking status and age subgroup only showed a trend without reaching statistical significance. Regarding smoking status, it is important to note that this study exclusively included LUAD patients, a subtype that is more commonly observed in non-smokers (32), with only about 20% of our cohort being smokers. Therefore, the observed association between ALK rearrangement and smoking status may be biased. Concerning age, a genomic analysis based on a Latin American cohort (33) found a significant negative correlation between the age at diagnosis and the risk of ALK translocations in lung cancer patients (P=0.00003). For every 10-year increase in age, the risk of ALK translocation decreased by approximately 3% (OR =0.97; 95% CI: 0.96–0.99). Given the relationship between age and ALK rearrangements, further distinction between germline mutations and somatic ALK alterations is crucial (34). This differentiation not only aids in understanding tumor biology but also provides important insights for evaluating familial risk and developing personalized treatment strategies.

As for tumor features, our findings indicate that stage I ALK-positive LUADs were associated with higher-risk radiologic and pathologic features, consistent with prior studies. For example, a previous analysis of 198 resectable NSCLC patients identified lobulated margins, solid lesions, and hypoattenuation on contrast-enhanced CT as independent predictors of ALK rearrangement through multivariate analysis (35). In our cohort, further subgroup analysis of stage IA patients, who are generally considered low-risk, revealed that ALK-positive tumors had a significantly higher incidence of adverse pathological features related to postoperative recurrence, such as being IAC and poorly differentiated, compared to ALK-negative tumors.

Consistent with the above findings, survival analysis indicated a higher risk of postoperative recurrence in ALK-positive patients, particularly with distant metastases to bone and brain. This observation aligns with the result of a retrospective study of 764 resected stage I–III NSCLC patients (73% diagnosed at stage I), in which ALK rearrangement was detected in 10 patients (1.08%). After adjusting for stage, ALK-positive patients showed significantly worse RFS compared to those with EGFR mutation (HR =1.8; 95% CI: 1.1–3.1) (36). Similarly, another study investigating occult nodal metastasis in early-stage, clinically node-negative LUAD identified ALK rearrangement as an independent predictor of pathological upstaging (OR =8.05; 95% CI: 3.12–20.76; P<0.001), along with the number of resected lymph nodes (OR =1.82; 95% CI: 1.21–2.72; P<0.001) (31). Taken together, these data suggest that incorporating clinical and imaging indicators into preoperative assessment may facilitate early identification of molecularly high-risk patients, even among those with clinically localized disease. For such patients, broader resection margins and more extensive lymph node dissection may be warranted to reduce the risk of residual disease or occult metastasis and to enhance the accuracy of pathologic staging, ultimately improving perioperative management and long-term outcomes.

Consequently, the potential efficacy of ALK-TKIs in early-stage patients has attracted considerable interest. A recent study compared alectinib with platinum-based chemotherapy as adjuvant therapy in resected ALK-positive NSCLC (stage IB–IIIA) (24), demonstrating significant improvements in disease-free survival (DFS; HR =0.24; 95% CI: 0.13–0.43; P<0.001) and central nervous system DFS (HR =0.22; 95% CI: 0.08–0.58). However, in the stage IB subgroup (n=26), the DFS benefit did not reach statistical significance (HR =0.21; 95% CI: 0.02–1.84), leaving the efficacy of ALK-TKIs in stage I disease inconclusive and in need of further prospective validation in larger cohort. In light of these uncertainties, several important clinical questions remain to be addressed. First, should all ALK-positive patients, including those with stage IA disease, receive adjuvant ALK-TKIs? The potential benefit must be weighed against the risk of overtreatment in patients with early-stage tumors. Based on our analysis, patients with high-risk pathological features may be suitable candidates for targeted adjuvant therapy, as ALK-positive patients with these features were found to exhibit the poorest RFS. This is further supported by another study of 63 patients with clinical T1–2 N0 ALK-positive LUAD, which found that high-grade tumors were significantly associated with postoperative upstaging, and that adjuvant treatment significantly improved DFS (HR =0.18; P=0.042) (37). Second, the optimal timing for initiating ALK-TKI therapy remains unclear. In our cohort, a subset of patients who received ALK-TKIs upon disease recurrence demonstrated potentially durable responses. This observation raises the question of whether immediate postoperative initiation may offer superior long-term outcomes compared to delayed treatment at recurrence. Third, the presence of concurrent ALK and EGFR mutations, though traditionally regarded as rare (38), presents important therapeutic dilemmas. The optimal sequencing or combination strategy for ALK- and EGFR-targeted agents remains undefined, and studies are needed to determine the most effective approach for managing this unique molecular subset.

This study has several limitations. Due to the retrospective design, detailed information on surgical decision-making and post-recurrence treatment selection was not fully available. Given the strong association between ALK rearrangement and certain demographic characteristics, propensity score matching was not applied; instead, multivariate analysis was used to evaluate its prognostic significance. Overall survival (OS) was not analyzed because the generally favorable prognosis of stage I LUAD limited the ability to detect meaningful survival differences within the available follow-up period. In addition, ALK fusion subtyping was performed in only about 20% of cases, and the absence of uniform NGS testing may have influenced co-alteration analyses (e.g., ALK and EGFR), which should be interpreted with caution.

Conclusions

In conclusion, ALK rearrangements were identified in a subset of resected, pathologically diagnosed stage I LUAD patients and were associated with more aggressive histologic features and a higher risk of distant metastases to bone and brain. These findings underscore the prognostic relevance of ALK in early-stage disease and highlight the importance of integrating molecular profiling into postoperative risk stratification and treatment planning to improve patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1049/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1049/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1049/prf

Funding: This work was supported by the Young Scientists Fund of the Natural Science Foundation of Sichuan Province of China (No. 2024NSFSC1906 to J.Z.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1049/coif). J.Z. reports receiving support from the Young Scientists Fund of the Natural Science Foundation of Sichuan Province of China (No. 2024NSFSC1906). 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 was approved by the Ethics Committee of Biomedical Research, West China Hospital, Sichuan University (approval No. 1704 [2024]). 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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