Prognostic value of KRAS G12V mutation in lung adenocarcinoma stratified by stages and radiological features.

OBJECTIVE: KRAS G12V is one of the most common KRAS mutation variants in lung adenocarcinoma (LUAD), and yet its prognostic value is still unrevealed. In this study, we investigated the clinicopathologic characteristics and prognostic value of the KRAS G12V mutation in LUAD. METHODS: Data of 3829 patients who underwent LUAD resection between 2008 and 2020 were collected. Mutations were classified as wild-type, G12V, or non-G12V. The clinicopathologic characteristics, postoperative outcomes, and recurrence pattern were analyzed among groups. RESULTS: In total, 3554 patients were wild-type and 275 patients harbored a KRAS mutation: 60 patients with G12V (22.2%) and 215 patients with non-G12V (77.8%). The KRAS G12V mutation was more frequent in male patients, older patients (≥60 years), former/current smokers, those patients with radiologic solid nodules, and those with highly invasive histologic subtypes. Tumors carrying KRAS G12V mutation exhibited elevated programmed death-ligand 1 expression in comparison with wild-type tumors. KRAS G12V was more prevalent in older patients and had less lymphovascular invasion compared with other mutation types. FGF3, RET, and KDR co-mutations occurred more frequently in the KRAS G12V group. Multivariate analysis demonstrated that the KRAS G12V mutation was an independent prognostic factor in stage Ⅰ tumors, whereas the KRAS non-G12V mutation was not. KRAS G12V was associated with early recurrence and locoregional recurrence. CONCLUSIONS: The KRAS G12V mutation was associated with aggressive clinical-pathologic phenotype and early recurrence. To note, this mutation exhibited a significantly worse prognosis in patients with part-solid and stage Ⅰ lung adenocarcinoma. Meanwhile, the prognostic significance of KRAS G12C and G12V variants was comparable.

Systemic immune index predicts tumor-infiltrating lymphocyte intensity and immunotherapy response in small cell lung cancer.

Background: Despite recent progresses in immune checkpoint blockade (ICB) in small-cell lung cancer (SCLC), a lack of understanding regarding the systemic tumor immune environment (STIE) and local tumor immune microenvironment (TIME) makes it difficult to accurately predict clinical outcomes and identify potential beneficiaries from ICB therapy. Methods: We enrolled 191 patients with stage I-III SCLC and comprehensively evaluated the prognostic role of STIE by several quantitative measurements, and further integrate it with a local immune score system (LISS) established by eXtreme Gradient Boosting (XGBoost) machine learning algorithm. We also test the value of STIE in beneficiary selection in our independent advanced SCLC cohort receiving programmed cell death 1 ligand 1 (PD-L1) blockade therapy. Results: Among several systemic immune markers, the STIE as assessed by prognostic nutritional index (PNI) was correlated with disease-free survival (DFS) and overall survival (OS), and remained as an independent prognostic factor for SCLC patients [hazard ratio (HR): 0.473, 95% confidence interval (CI): 0.241-0.929, P=0.030]. Higher PNI score was closely associated with inflamed SCLC molecular subtype and local tumor-infiltrating lymphocytes (TILs). We further constructed a LISS which combined top three important local immune biomarkers (CD8+ T-cell count, PD-L1 expression on CD8+ T-cell and CD4+ T-cell count) and integrated it with the PNI score. The final integrated immune risk system was an independent prognostic factor and achieved better predictive performance than Tumor Node Metastasis (TNM) stages and single immune biomarker. Furthermore, PNI-high extensive-stage SCLC patients achieved better clinical response and longer progression-free survival (PFS) (11.8 vs. 5.9 months, P=0.012) from PD-L1 blockade therapy. Conclusions: This study provides a method to investigate the prognostic value of overall immune status by combining the PNI with local immune biomarkers in SCLC. The promising clinical application of PNI in efficacy prediction and beneficiary selection for SCLC immunotherapy is also highlighted.

Exploring diverse programmed cell-death patterns to develop a novel gene signature for predicting the prognosis of lung adenocarcinoma patients.

Background: Programmed cell death (PCD) plays a critical role in tumor progression and malignancy, and exploring its relationship with lung adenocarcinoma (LUAD)'s survival outcomes is important for personalized diagnosis and treatment. This study aimed to identify survival-related genes and construct an effective prognostic indicator for LUAD based on 12 forms of PCD. Methods: A total of 1,933 candidate genes related to PCD were collected from published studies and public data center. A prognostic gene signature, called the cell death index (CDI), was established based on RNA-Seq and immunohistochemistry (IHC). IHC staining on tissue microarray was applied for the validation of protein level. Moreover, GSE42127, GSE72094 were used as validation datasets. Results: The CDI based on expression level of nine genes (CCNB2, HMGA1, CACNA2D2, BUB1B, BTG2, KIF14, PTGDS, SERPINB5, BRCA1) was highly predictive for overall survival (OS) of LUAD in our cohort [36-month area under the curve (AUC): 0.750, 60-month AUC: 0.809]. The CDI was further validated in independent cohorts (GSE72094, 36-month AUC: 0.717, 60-month AUC: 0.737; GSE42127, 12-month AUC: 0.829, 60-month AUC: 0.663). And the CDI was found to be an independent prognostic factor after adjusting for other clinical characteristics. Furthermore, the high-CDI group was associated with upregulated tumor immune infiltration compared to the low-CDI group. Conclusions: This study identified a 9-gene signature (CDI) based on PCD-related genes that accurately predicted the prognosis of LUAD patients. The CDI could serve as a valuable prognostic indicator and guide personalized therapeutic strategies for LUAD.

Evolutionary proteogenomic landscape from pre-invasive to invasive lung adenocarcinoma.

Lung adenocarcinoma follows a stepwise progression from pre-invasive to invasive. However, there remains a knowledge gap regarding molecular events from pre-invasive to invasive. Here, we conduct a comprehensive proteogenomic analysis comprising whole-exon sequencing, RNA sequencing, and proteomic and phosphoproteomic profiling on 98 pre-invasive and 99 invasive lung adenocarcinomas. The deletion of chr4q12 contributes to the progression from pre-invasive to invasive adenocarcinoma by downregulating SPATA18, thus suppressing mitophagy and promoting cell invasion. Proteomics reveals diverse enriched pathways in normal lung tissues and pre-invasive and invasive adenocarcinoma. Proteomic analyses identify three proteomic subtypes, which represent different stages of tumor progression. We also illustrate the molecular characterization of four immune clusters, including endothelial cells, B cells, DCs, and immune depression subtype. In conclusion, this comprehensive proteogenomic study characterizes the molecular architecture and hallmarks from pre-invasive to invasive lung adenocarcinoma, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease.

A Shift in Paradigm: Selective Lymph Node Dissection for Minimizing Oversurgery in Early Stage Lung Cancer.

Systematic lymph node dissection has been widely accepted and turned into a standard procedure for lung cancer surgery. In recent years, the concept of "minimal invasive surgery (MIS)" has greatly changed the surgical paradigm of lung cancer. Previous studies revealed that excessive dissection of lymph nodes without metastases had uncertain clinical benefit. Meanwhile, it leads to the elevated risk of postoperative complications including chylothorax and laryngeal nerve injury. In addition, dissection of nonmetastatic lymph nodes may disturb systematic immunity, resulting in the secondary effect on primary tumor or latent metastases. The past decades have witnessed the innovative strategies such as lobe-specific lymph node dissection and selective lymph node dissection. On the basis of evolution of lymph node dissection strategy, we discuss the negative effects of excessive nonmetastatic lymph node dissection and summarize the recent advances in the optimized dissection strategies, hoping to provide unique perspectives on the future directions.

Residual tumor descriptors proposed by the International Association for the Study of Lung Cancer may not be applicable to stage I and ground-glass opacity-featured non-small cell lung cancer.

Background: The International Association for the Study of Lung Cancer (IASLC) has proposed a residual tumor descriptor, essential for subsequent treatments. This study aimed to validate the prognostic effect of the proposed R descriptor and restrict its scope of clinical application in a large-scale cohort with non-small cell lung cancer (NSCLC). Methods: Patients, who underwent lobectomy from January 2010 to May 2019, were retrospectively reviewed. Patients were categorized according to the different R classification standards proposed by Union for International Cancer Control (UICC) and IASLC. Results: Among 5,200 enrolled patients with NSCLC, 1,727 and 9 cases of UICC-R0 were re-evaluated as uncertain resection [R(un)] and R1, respectively. After reclassification, there were 3,228 (62.1%) cases of R0, 1,727 (33.2%) cases of R(un), 151 (2.9%) cases of R1, and 94 (1.8%) cases of R2. Not performing rigorous systematic nodal dissection (SND) or lobe-specific SND (68.3%) was the main reason for the alteration from R0 to R(un). Patients with R(un) showed intermediate survival between those with R0 and R1. Further multivariable Cox analysis indicated that the proposed R descriptor was an independent prognostic factor for overall survival (OS) and recurrence-free survival (RFS). However, subgroup analysis of OS and RFS revealed that there was no significant difference between R0 and R(un) in patients with ground-glass opacity (GGO) or patients with tumor-node-metastasis stage I. Conclusions: R(un) represented an intermediate type between R0 and R1. Our study provided an external validation for new residual tumor descriptors for NSCLC proposed by IASLC. Proposed residual tumor descriptors were applicable in radiologic solid NSCLC and stage II-III NSCLC, but were ineffective for GGO-featured or stage I NSCLC.

Hybrid deep multi-task learning radiomics approach for predicting EGFR mutation status of non-small cell lung cancer in CT images.

Objective.Epidermal growth factor receptor (EGFR) mutation genotyping plays a pivotal role in targeted therapy for non-small cell lung cancer (NSCLC). We aimed to develop a computed tomography (CT) image-based hybrid deep radiomics model to predict EGFR mutation status in NSCLC and investigate the correlations between deep image and quantitative radiomics features.Approach.First, we retrospectively enrolled 818 patients from our centre and 131 patients from The Cancer Imaging Archive database to establish a training cohort (N= 654), an independent internal validation cohort (N= 164) and an external validation cohort (N= 131). Second, to predict EGFR mutation status, we developed three CT image-based models, namely, a multi-task deep neural network (DNN), a radiomics model and a feature fusion model. Third, we proposed a hybrid loss function to train the DNN model. Finally, to evaluate the model performance, we computed the areas under the receiver operating characteristic curves (AUCs) and decision curve analysis curves of the models.Main results.For the two validation cohorts, the feature fusion model achieved AUC values of 0.86 ± 0.03 and 0.80 ± 0.05, which were significantly higher than those of the single-task DNN and radiomics models (allP< 0.05). There was no significant difference between the feature fusion and the multi-task DNN models (P> 0.8). The binary prediction scores showed excellent prognostic value in predicting disease-free survival (P= 0.02) and overall survival (P< 0.005) for validation cohort 2.Significance.The results demonstrate that (1) the feature fusion and multi-task DNN models achieve significantly higher performance than that of the conventional radiomics and single-task DNN models, (2) the feature fusion model can decode the imaging phenotypes representing NSCLC heterogeneity related to both EGFR mutation and patient NSCLC prognosis, and (3) high correlations exist between some deep image and radiomics features.

Tumor-derived Vimentin as a novel biomarker for distinct subtypes predicting adjuvant chemotherapy resistance and T-cell-inflamed phenotype in small cell lung cancer.

Despite recent progress in subtype classification for small cell lung carcinoma (SCLC), little is known about the biomarker for triple-negative (ASCL1, NEUROD1, and POU2F3 negative) tumors. The long-term survival, adjuvant chemotherapy (ACT) response, and immune milieu in different SCLC subtypes have also not been well established. Here, we retrospectively collected a large cohort of 192 primary SCLC tumors and reported that ASCL1-, NEUROD1- and POU2F3-dominant subtypes counted for 61.38%, 19.31%, and 6.21%, respectively. Subtype intra-tumoral heterogeneity and co-expression at the single-cell level existed substantially. The expression of tumor-derived Vimentin (VIM) was nearly restricted to triple-negative SCLC tumors (15/19, 78.9%) while YAP1 expression was distributed widely in other subtypes. The SCLC subtyping model was independently prognostic of OS and RFS (p <  0.001 and p = 0.043). In particular, patients with ASCL1-positive SCLC tumors can benefit more from ACT, and VIM-positive tumors did the opposite. Compared with other subtypes, the VIM-dominant SCLC subtype was associated with abundant but functionally impaired CD4+ and CD8+ T-cells, which highly expressed inhibitory checkpoints and potentially benefit from PD-L1 blockade therapy. Our study showed that tumor-derived SCLC-V subtype could independently predict ACT response. The distinct immune landscape between subtypes may help inform personalized immune therapeutic approaches.

Prognostic Factors for Survival of Stage IB Non-small Cell Lung Cancer Patients: A 10-Year Follow-Up Retrospective Study.

BACKGROUND: This study aimed to determine the prognostic factors for the long-term outcome of stage IB non-small cell lung cancer (NSCLC). METHODS: Surgically resected patients with stage IB NSCLC diagnosed (based on TNM 8th edition) between April 2008 and December 2013 were retrospectively reviewed. The prognosis and possible risk factors among the stage IB NSCLC patients were evaluated. RESULTS: Of the 349 patients identified for the study, 80 (22.9%) received post-surgery adjuvant chemotherapy (ACT). The median follow-up time after surgery was 123.3 months. The 10-year overall survival (OS) rate was 69.6%, and the 10-year recurrence-free survival (RFS) rate was 62.8%. The patients in this cohort were divided into three groups (T1 with visceral pleural invasion [VPI], T2a without VPI, and T2a with VPI), and no significant differences in OS or RFS were found among the groups. Furthermore, survival analysis indicated that the absence of ground-glass opacity (GGO) components portends an adverse long-term OS and RFS. In a subgroup of patients with solid nodules, age older than 65 years (hazard ratio [HR] 1.987; 95% confidence interval [CI] 1.312-3.010; p = 0.001) and ACT (HR 0.392; 95% CI 0.225-0.684; p < 0.001) were independent prognostic factors for OS, whereas lymphovascular invasion (HR 1.792; 95% CI 0.995-3.227; p = 0.052) should be considered as an independent unfavorable prognostic factor for RFS. CONCLUSIONS: As an upstaging factor, VPI did not further stratify prognosis for the stage IB patients in our cohort. The presence of GGO components had a notable impact on a favorable prognosis in stage IB NSCLCs.

Long-Term Outcomes of Selected Patients with IIIA-N2 Non-small Cell Lung Cancer Receiving Upfront Surgical Resection.

BACKGROUND: Stage IIIA non-small cell lung cancer (NSCLC) is a diverse group that requires multimodality treatment. The aim of this study was to report the long-term outcomes for patients with IIIA-N2 disease. METHODS: We conducted a retrospective review of cases with IIIA-N2 (T1-2N2) NSCLC who underwent upfront surgery. Kaplan-Meier curves and Cox proportional hazard analyses were used to assess the impact of various variables on survival. RESULTS: A total of 475 patients were ultimately included. With a median follow-up time of 108 months, the 5- and 10-year overall survival (OS) rates were 42.2% and 27.7%, respectively. R0 resection was found to be associated with improved progression-free survival (PFS) and OS compared with R1/R2 resection (p = 0.041 for PFS; p = 0.015 for OS). Patients with single-station N2 disease demonstrated significantly better PFS and OS than those with multiple-station N2 disease (p < 0.001 for PFS; p = 0.002 for OS). Following surgical resection, adjuvant therapy was significantly correlated with prolonged PFS and OS compared with those patients without any treatment. However, there was no significant difference in PFS and OS between chemotherapy and radiochemotherapy (p = 0.915 for PFS; p = 0.287 for OS). Patients with EGFR exon 19 deletion had significantly improved OS compared with those with L858R (p = 0.040). CONCLUSIONS: Our study shows promising long-term outcomes for selected patients with stage IIIA-N2 NSCLC treated with upfront surgery followed by adjuvant therapy, especially those with R0 resection and single-station N2. This study sheds light on the potential management and treatment options for this challenging population.

Prognostic effect of ground-glass opacity in subcentimeter invasive lung adenocarcinoma.

Background: Although subcentimeter nodules represent precursor or minimally invasive lung cancer in most cases, there are still a few that are subcentimeter invasive adenocarcinoma (IAC). The aim of this study was to investigate the prognostic effect of ground-glass opacity (GGO) and the optimal surgical procedure in this special group. Methods: Patients with subcentimeter IAC were enrolled and were categorized into pure GGO, part-solid, and solid nodules based on the radiological appearance. Cox proportional hazards model and the Kaplan-Meier method were used for survival analyses. Results: A total of 247 patients were enrolled. Among them, 66 (26.7%) were in the pure-GGO group, 107 (43.3%) were in the part-solid group, and 74 (30.0%) were in the solid group. Survival analysis demonstrated a significantly worse survival in the solid group. Cox multivariate analyses confirmed that the absence of GGO component was an independent risk factor for worse recurrence-free survival (RFS) and overall survival (OS). As for surgical procedures, lobectomy did not provide a significant better RFS or OS than sublobar resection in the whole cohort or in a subgroup of patients with solid nodules. Conclusions: The radiological appearance stratified the prognosis of IAC with size of smaller than or equal to 1 cm. Sublobar resection may be feasible for subcentimeter IAC, even for those appearing as solid nodules; however, caution should be taken when applying wedge resection.

Identification of Germline Mutations in East-Asian Young Never-Smokers with Lung Adenocarcinoma by Whole-Exome Sequencing.

Recently, an increasing number of young never-smokers are diagnosed with lung cancer. The aim of this study is to investigate the genetic predisposition of lung cancer in these patients and discover candidate pathogenic variants for lung adenocarcinoma in young never-smokers. Peripheral blood was collected from 123 never-smoking east-Asian patients diagnosed with lung adenocarcinoma before the age of 40. Whole-exome sequencing (WES) was conducted on genomic DNA extracted from peripheral blood cells. As a result, 3,481 single nucleotide variants were identified. By bioinformatical tools and the published gene list associated with genetic predisposition of cancer, pathogenic variants were detected in ten germline genes: ATR, FANCD2, FANCE, GATA2, HFE, MSH2, PDGFRA, PMS2, SDHB, and WAS. Patients with pathogenic variants were more likely to occur in females (9/10, 90.0%) and have stage IV lung adenocarcinoma (4/10, 40%). Furthermore, germline mutations in 17 genes (ASB18, B3GALT5, CLEC4F, COL6A6, CYP4B1, C6orf132, EXO1, GATA4, HCK, KCP, NPHP4, PIGX, PPIL2, PPP1R3G, RRBP1, SALL4, and TTC28), which occurred in at least two patients, displayed potentially pathogenic effects. Gene ontology analysis further showed that these genes with germline mutations were mainly located in nucleoplasm and associated with DNA repair-related biological processes. The study provides spectrum of pathogenic variants and functional explanation for genetic predisposition of lung adenocarcinoma in young never-smokers, which sheds a light on prevention and early diagnosis of lung cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00062-1.

Selective Mediastinal Lymph Node Dissection Strategy for Clinical T1N0 Invasive Lung Cancer: A Prospective, Multicenter, Clinical Trial.

INTRODUCTION: We aimed to prospectively evaluate our previously proposed selective mediastinal lymph node (LN) dissection strategy for peripheral clinical T1N0 invasive NSCLC. METHODS: This is a multicenter, prospective clinical trial in China. We set six criteria for predicting negative LN stations and finally guiding selective LN dissection. Consolidation tumor ratio less than or equal to 0.5, segment location, lepidic-predominant adenocarcinoma (LPA), negative hilar nodes (stations 10-12), and negative visceral pleural invasion (VPI) were used separately or in combination as predictors of negative LN status in the whole, superior, or inferior mediastinal zone. LPA, hilar node involvement, and VPI were diagnosed intraoperatively. All patients actually underwent systematic mediastinal LN dissection. The primary end point was the accuracy of the strategy in predicting LN involvement. If LN metastasis occurred in certain mediastinal zone that was predicted to be negative, it was considered as an "inaccurate" case. RESULTS: A total of 720 patients were enrolled. The median number of LN dissected was 15 (interquartile range: 11-20). All negative node status in certain mediastinal zone was correctly predicted by the strategy. Compared with final pathologic findings, the accuracy of frozen section to diagnose LPA, VPI, and hilar node metastasis was 94.0%, 98.9%, and 99.6%, respectively. Inaccurate intraoperative diagnosis of LPA, VPI, or hilar node metastasis did not lead to inaccurate prediction of node-negative status. CONCLUSIONS: This is the first prospective trial validating the specific mediastinal LN metastasis pattern in cT1N0 invasive NSCLC, which provides important evidence for clinical applications of selective LN dissection strategy.

Impact of Prior Cancer History on Outcomes of Resected Lung Cancer.

BACKGROUND: Previous studies concerning the impact of prior cancer on newly diagnosed lung cancer are mainly based on databases and obtained mixed results. Utilizing a large study population, we aimed to reveal this impact. PATIENTS AND METHODS: Lung cancer patients from January 2008 to April 2021 were enrolled. The Kaplan-Meier method was used to perform survival analyses. To investigate the impact of prior cancer, a Cox proportional hazards model was conducted. To minimize the influence of the heterogeneity of prior cancer, stratified analyses were carried out. RESULTS: In total, 17,423 lung cancer patients were reviewed, among which we identified 1469 (8.4%) patients with a history of prior cancer. Cox regression analysis revealed that prior cancer was an independent poor prognostic factor on overall survival (HR = 1.430, 95% CI: 1.147-1.784, p = 0.001) but did not affect lung cancer-specific survival (HR = 1.120, 95% CI: 0.876-1.434, p = 0.366). Interestingly, in further stratified analyses, we found that prior cancer history affected overall survival only in pTNM stage 0/I patients (HR = 1.670, 95% CI: 1.247-2.237, p = 0.001), but not in pTNM stage II/III/IV patients (HR = 1.237, 95% CI: 0.877-1.743, p = 0.226). Similarly, prior cancer was an independent poor prognostic factor on overall survival only for pN0 patients. Subsequently, subgroup analyses indicated that the impact of prior cancer varied in pTNM stage 0/I patients according to the type of prior cancer and the interval time. CONCLUSIONS: Considering that prior cancer affects overall survival in patients with clinically curable lung cancer, clinicians should pay attention to this effect and improve the management of these patients to achieve a better prognosis.

Pregnancy may have little influence on ground-glass opacities suspected for lung adenocarcinoma.

PURPOSE: Owing to the popularity of low-dose computed tomography in lung cancer screening, young women spotted with ground-glass opacities (GGO) is a growing subgroup in clinical practice. We aim to investigate the influence of pregnancy on GGOs suspected for lung adenocarcinoma. METHODS: This retrospective study collected a series of female patients who were pregnant in follow-up of GGO lesions. The last CT images of GGO before pregnancy (CT1) and the first CT images after pregnancy (CT2) were reviewed to assess any radiologic change. Young female patients who were not pregnant in long-term (> 12 months) follow-up of GGO were enrolled as a comparison group. We also enrolled patients who gave birth within 2 years before surgical resection of GGOs. RESULTS: Four patients were enrolled according to the criteria. There was no significant change of the GGOs in all four patients with a median follow-up duration of 45.5 (range 17-86) months. Two patients were diagnosed pathologically to be minimally invasive adenocarcinoma, one was invasive adenocarcinoma and one did not underwent surgery. Six patients were enrolled in the comparison group and no significant change was witnessed in all the nodules. In those patients who gave birth within two years before surgical resection of GGOs, we found that the majority present as preinvasive lesions, and those with invasive adenocarcinomas were bigger in size and possess more solid component radiologically. CONCLUSION: Pregnancy seems to have little impact on GGOs suspected for lung adenocarcinoma. Therefore, pregnancy might be safely planned during the follow-up of GGOs.

Clinical characteristics and progression of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET rearrangements: a retrospective cohort study.

Background: Patients harboring anaplastic lymphoma kinase (ALK) or rearranged during transfection (RET) rearrangements are usually diagnosed at a relatively late stage with nodal and distant metastasis, and rapid progression course of ALK/RET fusion-positive lung cancer were well-known. However, clinical characteristics and course of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET fusions are poorly described. Identifying patients with gene fusions at early stage may offer surgical options that could cure those patients. Methods: We retrospectively included patients with surgically resected pre-/minimally invasive lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations or ALK/RET rearrangements, and further compared the patient clinical characteristics, nodule natural course, and survival outcomes. Radiological characteristics including ground-glass component, cystic airspace, pleural attachment, etc. were specially assessed for this study. EGFR (exons 18-22) was detected by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the ALK/RET rearrangements. Lung cancer-specific survival (LCSS), relapse-free survival (RFS), and overall survival (OS) were all evaluated. Results: Of 238 patients with pre-/minimally invasive lung adenocarcinomas, 226 patients had EGFR mutations, 7 patients had ALK fusions, and 5 patients had RET fusions. Average age at surgery was 45.3 years for ALK/RET-positive group and 52.6 years for EGFR-positive group (P=0.049). Radiologically, among the 12 patients with ALK/RET fusions, the majority of lesions (10/12) manifested as mixed ground-glass opacities (mGGOs), which was significantly more prevalent when compared with patients with EGFR mutations (83.4% vs. 24.3%, P<0.001). Moreover, a substantial proportion of cystic airspace was found in ALK/RET-positive group but not in EGFR-positive group (66.7% vs. 14.2%, P<0.001). Among four patients with ALK/RET fusions undergoing surveillance over 1 year before surgery, two of them developed rapid radiologic progression. The 5-year LCSS and RFS were 100%, 100% for ALK/RET-positive group, and 100%, 100% for EGFR-positive group, respectively. Conclusions: ALK/RET-positive pre-/minimally invasive lung adenocarcinomas were mostly characterized as mGGOs with cystic airspace developing rapid nodule progression, and no recurrence occurred during long-term follow-up after resection. This provides insights into proper curative surgery timing in the management of patients with gene fusions. However, these findings must be treated with caution and validated in future multi-center studies with larger sample size.