Prevalence and clinical outcomes of anaplastic lymphoma kinase rearrangements in surgically resected adenocarcinoma lung cancer: a retrospective cohort study

Introduction

Despite advances in screening and treatment, lung cancer remains the leading cause of cancer-related mortality worldwide, posing a substantial global health burden (1,2). According to the National Cancer Institute, over 226,000 new cases and 124,000 deaths are projected in the United States in 2025 (3). With the implementation of lung cancer screening and advances in diagnostic modalities, approximately 40–50% of patients with non-small cell lung cancer (NSCLC) are now diagnosed at early or locally advanced stages amenable to curative-intent therapy (4,5). For resectable cases, surgical resection remains the cornerstone of treatment, often supplemented by neoadjuvant or adjuvant therapies to improve survival (6-8). Nevertheless, despite complete resection, many patients experience disease recurrence, underscoring the need for more effective perioperative strategies tailored to specific molecular subtypes.

Among these subtypes, anaplastic lymphoma kinase (ALK) rearrangements are distinct oncogenic drivers, accounting for approximately 3–7% of NSCLC cases (9,10). Clinically, patients with ALK-positive NSCLC are typically younger and never-smokers or light smokers (11,12). They are frequently diagnosed at advanced stages and have a high propensity for central nervous system (CNS) metastases (13,14). Since the introduction of crizotinib, a first-generation ALK inhibitor, subsequent generations of ALK tyrosine kinase inhibitors (TKIs) have revolutionized treatment and markedly improved outcomes (15-18). This has transformed ALK-positive NSCLC into a highly treatable subtype associated with prolonged survival. However, until recently, these targeted therapies were largely restricted to advanced or metastatic disease settings.

A paradigm shift followed the phase III ALINA trial, which showed that adjuvant alectinib significantly improves disease-free survival (DFS) and CNS DFS compared with platinum-based chemotherapy in patients with resected ALK-positive NSCLC (19). Consequently, major clinical practice guidelines now recommend adjuvant alectinib as standard care (7). With adjuvant ALK TKI therapy emerging as a new standard of care, quantifying the real-world burden of ALK-positive resected lung cancer is increasingly important. While studies have investigated the prevalence and prognostic value of ALK positivity in early-stage NSCLC, most rely on historical data that may not reflect the current clinical landscape (9,10,20). Given the evolution of surgical practices, molecular testing, and the availability of later-generation ALK TKIs, up-to-date real-world data are needed to define a contemporary surgical baseline for ALK-positive resected NSCLC as adjuvant ALK-directed therapy enters routine practice.

Therefore, this study aimed to analyze the prevalence and clinical outcomes of ALK rearrangements in a contemporary, single-center surgical cohort. We focused on patients with pathologic stage I–III resected lung adenocarcinoma, thereby providing a targeted assessment of those most likely to benefit from the evolving adjuvant treatment strategies. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0957/rc).

Methods

Study design and patient eligibility

This single-center, retrospective cohort study was conducted at Asan Medical Center, Seoul, Korea. Consecutive adult patients who underwent curative-intent surgical resection for NSCLC between January 2019 and December 2023 were screened. Patients upstaged to pathologic stage IV on postoperative pathologic evaluation were excluded.

For primary analyses of ALK rearrangement prevalence and postoperative outcomes, the study population was limited to patients with pathologically confirmed lung adenocarcinoma. Patients were excluded if ALK test results were unavailable, medical records were insufficient for chart review, or follow-up was <6 months from initial diagnosis. Among eligible patients, those with ALK rearrangements were identified for outcome analyses; Figure 1 shows the cohort selection process.

Figure 1 Study flowchart illustrating patient inclusion and exclusion. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board (IRB) of Asan Medical Center (IRB No. 2025-0805), and informed consent was waived due to the retrospective nature of the study.

Data collection and ALK assessment

Clinicopathological data were retrieved retrospectively from electronic medical records. Key variables included age, sex, smoking history, Eastern Cooperative Oncology Group performance status, and pathologic findings. Pathologic staging followed the 8th edition of the American Joint Committee on Cancer (AJCC) system. Treatment details, including neoadjuvant or adjuvant chemotherapy and radiotherapy, were also recorded. The extent of resection was classified as lobectomy (including bilobectomy) or sublobar resection (segmentectomy or wedge resection). ALK rearrangement was assessed using immunohistochemistry with the Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Tucson, AZ, USA), which shows strong concordance with fluorescence in situ hybridization (21).

Study endpoints

The primary objective was to evaluate the prevalence of ALK rearrangements in patients with resected stage I–III lung adenocarcinoma. Secondary objectives focused on clinical outcomes in the ALK-positive subpopulation, specifically DFS and overall survival (OS).

DFS was defined as the time from surgical resection to the first documented tumor recurrence or death from any cause. OS was defined as the time from surgical resection to death from any cause. Patients without events were censored at the last follow-up.

Recurrence was determined according to radiologic and/or pathologic confirmation during routine postoperative follow-up. Recurrence patterns were classified as locoregional or distant. Locoregional recurrence was defined as recurrence at the bronchial stump, within the ipsilateral lung, and/or regional (intrathoracic) lymph nodes. Distant recurrence was defined as recurrence in the contralateral lung, pleura (pleural seeding and/or effusion), or any extrathoracic organ.

We also evaluated the prognostic effect of clinicopathological factors—including patient demographics, tumor characteristics (T and N stage), and treatment details—on recurrence and survival.

Statistical analysis

Continuous variables were presented as mean ± standard deviation or median [interquartile range (IQR)], and categorical variables as frequencies and percentages (%). The Kaplan-Meier method was used to estimate DFS and OS, and differences between survival curves were assessed using the log-rank test. Prognostic factors for recurrence were evaluated using Cox proportional hazards models. First, univariate Cox proportional hazards models were performed to evaluate associations between clinicopathological variables and recurrence. Variables with P<0.20 in univariate analyses were considered candidates for the multivariate Cox regression model. To avoid multicollinearity between overall pathologic stage and its component variables, pathologic stage was not entered into the multivariate model; instead, T stage and N stage were included as separate variables. Subgroup analyses were performed to evaluate DFS according to nodal stage and pathologic stage. Statistical analyses were performed using R software version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria), and figures were generated using Python (version 3.13). A two-sided P<0.05 was considered statistically significant.

Results

Prevalence of ALK rearrangement and baseline characteristics

Between January 2019 and December 2023, 5,958 patients underwent curative-intent resection for NSCLC. After excluding 175 patients upstaged postoperatively to pathologic stage IV, 5,783 patients with stage I–III disease were included in the cohort (Figure 1). The median age at surgery was 65.0 years (range, 19–89 years), and 50.9% were male. Adenocarcinoma was the predominant histologic subtype (85.2%), followed by squamous cell carcinoma (11.1%) (Table S1).

Among the 4,927 patients with adenocarcinoma, 3,288 underwent ALK testing, and 150 (4.6%) had ALK rearrangements. The median follow-up for the ALK-positive cohort was 45.7 months (IQR, 30.5–58.4 months). Table 1 summarizes baseline clinicopathological characteristics of the 150 patients. The median age at surgery was 56 years (range, 19–83 years), and 56.0% were female. Never-smokers comprised 60.7% of the cohort.

Regarding pathologic stage, 87 (58.0%), 18 (12.0%), and 45 (30.0%) patients had stage I, II, and III disease, respectively. Most patients presented with T1 (66.7%) or T2 (30.0%) tumors. Nodal involvement was absent (N0) in 92 patients (61.3%), while N1 and N2 disease occurred in 15 (10.0%) and 43 (28.7%) patients, respectively. Lobectomy was the most frequent procedure (n=124, 82.7%), while sublobar resection was performed in 26 (17.3%) patients.

Of the 150 patients, 91 (60.7%), 54 (36.0%), and 5 (3.3%) underwent surgery alone, adjuvant treatment, and neoadjuvant chemoradiotherapy, respectively. Among those undergoing adjuvant therapy, most were treated with chemoradiotherapy (n=27, 18.0%) or cytotoxic chemotherapy (n=20, 13.3%). A small proportion received ALK TKIs (n=6, 4.0%) or radiotherapy alone (n=1, 0.7%).

Survival outcomes and prognostic factors

At data cutoff, tumor recurrence occurred in 37 patients (24.7%). The median DFS was not reached for the cohort. The 1-, 3-, and 5-year DFS rates were 93.3%, 77.6%, and 65.7%, respectively (Figure 2).

Figure 2 DFS in patients with resected ALK-positive lung adenocarcinoma. (A) Overall DFS in the entire ALK-positive cohort. (B) DFS stratified based on nodal stage (N0, N1, N2). (C) DFS stratified based on pathologic stage (I, II, III). ALK, anaplastic lymphoma kinase; DFS, disease-free survival; Med, median; N, node; NR, not reached.

Univariate and multivariate Cox proportional hazards analyses were performed to identify prognostic factors for recurrence (Table 2). Univariate analysis revealed an increased recurrence risk with T2 stage [vs. T1; hazard ratio (HR) 2.60; 95% confidence interval (CI): 1.34–5.06; P=0.005], N2 nodal involvement (vs. N0; HR 7.23; 95% CI: 3.48–15.01; P<0.001), and pathologic stage III disease (vs. stage I, HR 8.24; 95% CI: 3.91–17.38; P<0.001). Univariate analysis also linked adjuvant therapy with higher recurrence risk (HR 2.79; 95% CI: 1.46–5.36; P=0.002). In a multivariate model incorporating T and N stages, N2 disease was the strongest independent predictor of recurrence (HR, 14.64; 95% CI: 4.59–46.76; P<0.001), while adjuvant therapy was associated with improved DFS (HR 0.36; 95% CI: 0.14–0.92; P=0.03). Conversely, T stage was not independently associated with recurrence after adjustment (T2: HR 1.27, P=0.53; ≥ T3: HR 4.13, P=0.07). Age and surgical extent (lobectomy vs. sublobar resection) were not significantly associated with recurrence.

Consistent with multivariate findings, Kaplan-Meier survival analysis revealed significant stratification based on nodal stage (log-rank P<0.001; Figure 2B). Patients with N2 disease had significantly inferior DFS than those with N0 or N1 disease. Recurrence rates increased with nodal involvement: 12.0% (11/92) in N0, 20.0% (3/15) in N1, and 53.5% (23/43) in N2 disease. Recurrence also differed significantly based on pathologic stage (log-rank P<0.001; Figure 2C). The median DFS was not reached for patients with stage I and II disease, whereas it was 36.5 months for stage III disease. Recurrence was highest in stage IIIA (56.8%, 25/44), followed by stage IB (28.6%, 4/14), IIB (12.5%, 2/16), and IA (8.2%, 6/73). No recurrence occurred among the two patients with stage IIA disease. At data cutoff, the median OS was not reached, with only a single death (0.7%) observed in the cohort.

Recurrence patterns and post-recurrence treatments

Table 3 shows recurrence patterns. Among the 37 patients with recurrence, distant recurrence was predominant in 30 patients (81.1%), while locoregional recurrence occurred in 7 patients (18.9%). Among distant recurrence sites, the brain was most common (29.7%, n=11), followed by the contralateral lung and pleura (each 21.6%, n=8). Other distant recurrence sites included bone (16.2%, n=6), adrenal gland (10.8%, n=4), and extrathoracic lymph nodes (10.8%, n=4).

Of the 37 patients with recurrence, 27 (73.0%) underwent first-line palliative systemic therapy, while the remaining patients underwent local salvage therapy, were observed, or were lost to follow-up. Among patients undergoing systemic treatment, second-generation ALK TKIs predominated, with alectinib most frequently prescribed (44.4%), followed by brigatinib (40.7%). Crizotinib (11.1%) and lorlatinib (3.7%) were also used in specific cases (Table S2).

Discussion

Current real-world data for ALK-positive lung adenocarcinoma are critical for the transition to the perioperative ALK TKI era, particularly data linking updated prevalence, nodal risk stratification, CNS-dominant recurrence patterns, and post-recurrence survival. In this single-center cohort of patients with pathologic stage I–III NSCLC, we evaluated the prevalence of ALK rearrangements and postoperative outcomes in resected ALK-positive lung adenocarcinoma between 2019 and 2023. Among the 3,288 ALK-tested patients, 4.6% had ALK rearrangements. In the ALK-positive resected cohort, the median DFS was not reached, and the 1-, 3-, and 5-year DFS rates were 93.3%, 77.6%, and 65.7%, respectively. Nodal stage was the dominant determinant of recurrence, with N2 disease linked to markedly inferior DFS, remaining the strongest independent prognostic factor in a multivariate analysis (HR, 14.64). The recurrences were predominantly distant and most frequently affected the brain, lungs, and pleura. The OS data were immature, with a single death recorded during follow-up.

The ALK prevalence of 4.6% in our ALK-tested resected adenocarcinoma cohort was broadly consistent with previous estimates. In the European Lungscape Project, ALK positivity was reported to be 6.2% by immunohistochemistry (IHC) and 2.2% by fluorescence in situ hybridization (FISH) (9). Similarly, ALK rearrangements have been detected in 3.9% to 10% of tested resected lung adenocarcinomas in Japanese nationwide and matched cohorts and in approximately 7.9% in a Chinese cohort (20,22). Many of these studies reflect earlier treatment contexts, before later-generation ALK TKIs became widely available for recurrent or metastatic diseases. Our study extended these observations to a more contemporary surgical cohort treated between 2019 and 2023 and showed a prevalence estimate comparable to those for earlier Asian and Western cohorts. ALK testing was performed in approximately two-thirds of resected adenocarcinomas in our study, suggesting that the observed prevalence was derived from relatively broad molecular screening rather than from highly selective testing. In the post-ALINA era, this prevalence has practical implications for estimating the expected number of patients who may be considered for adjuvant ALK-directed therapy. Based on the observed ALK prevalence and proportion of patients with stage II–III disease in our cohort, the potentially relevant population is expected to account for approximately 2% of patients with resected lung adenocarcinomas, underscoring the importance of upfront molecular profiling in routine surgical practice.

The prognostic impact of ALK rearrangements in surgically resected NSCLC remains controversial, with previous studies reporting conflicting results regarding recurrence risk and survival (9,10,23,24). A recent meta-analysis has suggested that surgically resected ALK-rearranged NSCLC is associated with an increased risk of recurrence and reduced DFS (25). In our study, the median DFS was not reached, and the 5-year DFS rate was 65.7%. These results were more favorable than those of Chaft et al., in which ALK-positive patients had a median recurrence-free survival (RFS) of 24.3 months and stage III disease accounted for 45% of cases (10). However, our findings were broadly in line with those of a Japanese matched-cohort study by Matsuura et al., who also reported a predominance of stage I disease and a 5-year time-to-recurrence rate of 75% in the ALK-rearranged group (22). These differences across studies may partly reflect differences in stage distribution, as stage I disease accounted for 58.0% of our cohort and stage-stratified analyses showed that the risk of recurrence was concentrated in stage III disease.

Importantly, nodal burden was effective for prognostic stratification in our cohort. N2 disease was associated with markedly inferior DFS and remained the strongest independent predictor of recurrence in a multivariate analysis (HR, 14.64), whereas T stage was not independently associated with DFS after adjustment. These findings suggest that mediastinal nodal involvement, rather than primary tumor extent alone, is the major determinant of postoperative recurrence risk in surgically treated ALK-positive adenocarcinomas. Our results align with recent data from a resectable ALK-positive NSCLC cohort in which pathologic nodal positivity was associated with a substantially lower 3-year DFS than that of nodal-negative disease (59.7% vs. 92.5%), and N2 disease conferred worse outcomes than those for N1 disease (HR, 2.734) (26). Although an advanced T stage showed a trend toward an increased risk of recurrence, it was not independently associated with DFS after adjustment. Given the small number of T3–T4 disease, this finding should be interpreted with caution. Nevertheless, together with prior data showing that tumor size has prognostic value mainly in node-negative ALK-positive disease, our results support the predictive value of nodal burden for recurrence risk in surgically treated ALK-positive adenocarcinoma (26). Given that only 4.0% of the patients in our cohort received adjuvant ALK-directed therapy, these outcomes largely reflect the period before the widespread adoption of adjuvant ALK TKIs. In this context, the strong prognostic impact of N2 disease is particularly relevant as it may help identify a high-risk subgroup for whom effective adjuvant ALK-directed strategies and intensified surveillance may be most clinically meaningful.

Postoperative recurrence often represents an incurable metastatic disease and is associated with a poor prognosis. In our cohort, distant recurrence occurred in >80% of patients who relapsed, whereas locoregional recurrence was relatively infrequent. The brain was the most common site of distant recurrence (29.7%). This finding is clinically relevant in the perioperative ALK TKI era because CNS recurrence is associated with neurological morbidity, potential interruption or modification of systemic treatment, and deterioration of quality of life. Moreover, the conventional postoperative strategies used in our cohort, mainly cytotoxic chemotherapy and/or radiotherapy, may not adequately address the risk of systemic and intracranial recurrence of ALK-positive disease. In the phase III ALINA trial, the brain was the most common site of recurrence, and adjuvant alectinib substantially reduced the risk of CNS disease recurrence or death (HR, 0.22) (19). Therefore, the recurrence pattern observed in our cohort provides real-world context for the clinical relevance of CNS-active adjuvant ALK-directed therapies, such as alectinib, particularly for patients at high risk of postoperative recurrence.

The OS outcomes also varied across previous surgical cohorts of ALK-positive NSCLC. In the Lungscape project, patients with ALK-positive adenocarcinoma showed a median OS of 72 months and a 5-year OS rate of 55.2% (9), and Chaft et al. reported a poor 5-year OS of 29% among patients with stage III ALK-positive disease (10). These studies preceded the widespread availability of later-generation ALK TKIs in post-recurrence settings. A recent Japanese matched-cohort study by Matsuura et al. reported excellent survival in the ALK-positive group, with a 5-year OS rate of 95%; post-recurrence therapies in this study included ALK TKI treatment and local ablative therapy, which may have contributed to the prolonged survival after recurrence (22). Similarly, mortality was extremely low in our cohort (0.7%), with only one death observed during follow-up despite a recurrence rate of 24.7%. Because the study period largely preceded the routine implementation of adjuvant ALK TKIs in resected NSCLC, the favorable OS observed in our cohort may reflect advances in post-recurrence management, including the widespread availability of second- and third-generation ALK TKIs. This observation is important when interpreting contemporary survival outcomes, as improvements in OS may occur even in the absence of adjuvant ALK-directed treatment. Therefore, the OS outcomes in contemporary ALK-positive cohorts should be interpreted in the context of evolving post-recurrence treatment strategies and the limited number of deaths observed during follow-up.

This study had some limitations. First, this was a retrospective, single-center study conducted exclusively in the Korean population, which may introduce selection bias and limit the generalizability of our findings to broader global populations, particularly because screening practices, molecular testing practices, and baseline patient characteristics vary across regions. Second, ALK testing was not performed systematically in all resected adenocarcinoma cases, especially in patients with pathological stage I disease without planned adjuvant therapy. Therefore, the observed ALK prevalence might not fully represent the true prevalence in all surgically resected lung adenocarcinomas. Third, because the study period was relatively recent, the OS data were not sufficient for determining the long-term impact of recurrence on survival. Fourth, although the overall ALK-tested cohort was large, the number of patients in certain ALK-positive subgroups, such as those with T3–T4 disease or death events, was small, limiting the statistical power and stability of the multivariate analyses. Finally, several potential confounders, including detailed histological risk features, molecular co-alterations, and surveillance intensities, were not considered. Nevertheless, our findings provide a real-world context for interpreting postoperative outcomes and recurrence patterns in patients with resected ALK-positive lung adenocarcinoma during the transition to the perioperative ALK TKI era.

Conclusions

In conclusion, these findings support routine ALK testing in resected lung adenocarcinoma and careful postoperative risk stratification based on nodal burden, particularly N2 disease. Despite favorable OS, the predominance of distant and intracranial recurrence supports consideration of CNS-active, risk-adapted perioperative ALK-directed strategies as adjuvant ALK-directed therapy enters routine practice.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0957/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0957/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0957/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0957/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 (IRB) of Asan Medical Center (IRB No. 2025-0805) and individual consent for this retrospective analysis was waived.

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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