Abstract Background: After progression on first-line (1L) EGFR-TKI in EGFR-mutant non-small cell lung cancer(NSCLC), detecting the T790M resistance mutation is pivotal to guide third-generation EGFR-TKIs. Bronchial washing fluid (BWF) digital droplet PCR (ddPCR) may improve detection versus plasma, yet its clinical utility and outcomes require clarification. Methods: The Leclaza IIT 020 was an open-label, multicenter, single-arm, exploratory study evaluating patients with advanced NSCLC who experienced progression on 1L EGFR-TKI and underwent bronchoscopy for ddPCR-based T790M testing in BWF with paired plasma. Key eligibility included 1L EGFR-TKI failure and T790M positivity on bronchial washing by ddPCR. Patients with BWF T790M positivity received lazertinib 80 mg once daily. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS),disease control rate (DCR), and descriptive concordance across modalities. Results: Among 26 consecutively tested patients, BWF T790M was positive in 10 (38.5%) and negative in 16. Baseline demographics were statistically comparable between the BWF-positive and -negative groups (median age 72.5 years [IQR 66.0-77.8]; female 76.9%). Most patients had stage IV disease at diagnosis (92.3%) and prior exposure to afatinib (∼65%); smoking history and comorbidity profiles were also similar between the groups. Detection rates by modality were: plasma 6/26 with a detectable ddPCR signal (23.1%), but all plasma samples remained below the clinical reporting threshold (0/26 reportable), and BWF 10/26 (38.5%). Concordance analyses showed higher agreement for BW compared with initial tumor genotyping and moderate concordance with plasma, supporting the added yield of bronchoscopic sampling when plasma is negative or below threshold. Ten BWF-positive patients received lazertinib; best overall responses were partial response in 5 (50.0%), stable disease in 4 (40.0%), and progressive disease in 1 (10.0%), yielding an ORR of 50.0% and a DCR of 90.0%. Median PFS was 12.8 months (95% CI, 6.1-not estimable), with 6- and 12-month PFS of 72.7% and61.4%, respectively. Median follow-up was 9.4 months (95% CI, 3.7-12.4). Conclusions: In patients progressing on 1L EGFR-TKI, ddPCR on BWF identifies T790M more frequently than clinically reportable plasma testing and enriches for candidates who achieve favorable outcomes on lazertinib (ORR ∼50.0%, median PFS ∼12.8 months). BWF testing provides a practical escalation pathway when plasma is negative or below threshold, particularly inpatients with limited extra-thoracic disease burden. Prospective validation in larger cohorts is warranted. Citation Format: Chi Young Kim, Se Hyun Kwak, Eun Hye Lee, Sang Hoon Lee, Eun Young Kim, Yoon Soo Chang. Detection of EGFR T790M mutation in bronchial washing fluid and therapeutic efficacy of lazertinib in T790M-positive NSCLC patients after first-line EGFR-TKI failure: An open-label, multicenter, single-arm exploratory study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT249.

Genetic regulation of splicing uniquely contributes to trait-associated genome-wide association studies (GWAS) signals. However, quantitative trait loci (QTL) analysis using short-read sequencing of bulk tissues fails to capture full-length and cell-type-specific isoforms. Here, we present an isoform-level lung cell atlas from 129 never-smoking Korean women using single-cell long-read RNA-sequencing, identifying abundant unannotated and cell-type-specific isoforms. Isoform-level signatures of 37 lung cell types display a larger difference and therefore improve cell-type classification compared to gene-level expression. Notably, isoform-QTLs (isoQTLs) detect unannotated and/or cell-type-specific isoforms with independent genetic regulation from expression-QTL (eQTL), supported by enriched splicing functional elements. IsoQTLs nominate susceptibility isoforms from previously unexplained lung function and cancer GWAS loci, via eQTL-independent signals. We highlight a potentially functional novel variant of PPIL6 in multiciliated cells underlying lung cancer risk through alternative splicing. This isoform-level resource advances our understanding of cell-type-specific isoform regulation and its contribution to lung traits and diseases.

Single-cell expression quantitative trait loci (sc-eQTL) analyses are powerful in identifying context-specific susceptibility genes from genome-wide association studies (GWAS) loci. However, few studies have comprehensively investigated cells of lung cancer origin in non-European populations. Here, we built a lung sc-eQTL dataset from 129 Korean women never-smokers with epithelial cell enrichment. eQTL mapping identified 2,229 genes with an eQTL in 33 cell types, including East Asian-specific findings when compared to predominantly European datasets. Integration with single-cell chromatin accessibility data demonstrated an enrichment of cell-type specific eQTLs in cell-type matched candidate enhancers, while shared eQTLs were more frequently found near promoters. Colocalization and transcriptome-wide association study unveiled 36 susceptibility genes from 22 cell types in 22 lung cancer loci, including 10 loci not achieving genome-wide significance in prior GWAS. Around 47% of these genes were from cells of the alveoli, underscoring their importance, especially in lung adenocarcinoma (LUAD) susceptibility. Focusing on the trajectory of alveolar epithelial cell regeneration, we detected 785 cell-state-interacting QTLs, which overlapped with 28% (10) of the identified susceptibility genes. Finally, we experimentally validated East Asian- and alveolar type 2 cell-specific eQTL of TCF7L2 underlying East Asian LUAD locus, 10q25.2. Consistent with its role as a Wnt/β-catenin effector, TCF7L2 displayed significant effect on lung adenocarcinoma cell growth. Our data highlighted context-specific susceptibility genes, especially from alveolar cells of lung, contributing to lung cancer etiology.

OBJECTIVES:To evaluate the impact of consolidative surgery and radiotherapy (RT) on survival outcomes in patients with advanced or metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). METHODS:This retrospective, multicenter cohort study included 864 patients with EGFR-mutant advanced or metastatic NSCLC receiving first-line EGFR-TKIs. Patients were categorized into EGFR-TKI monotherapy (n = 616), TKI plus surgery (n = 100), and TKI plus RT (n = 148). Propensity score matching (PSM) and overlap weighting were applied to balance baseline characteristics. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox proportional hazards models and restricted mean survival time (RMST). RESULTS:After PSM, 97 matched pairs were generated for TKI versus TKI plus surgery and 148 pairs for TKI versus TKI plus RT. Compared with TKI alone, consolidative surgery significantly improved OS (hazard ratio [HR], 0.36; 95% CI, 0.20-0.65; p < 0.001) and PFS (HR, 0.48; 95% CI, 0.34-0.67; p < 0.001), with RMST gains of 10.7 and 10.6 months.Consolidative RT showed a trend toward longer OS (HR, 0.61; 95% CI, 0.39-0.93; p = 0.023)without significant PFS or consistent RMST benefit. Subgroup analyses showed surgery benefit in younger patients with good performance, lower metastatic burden, and no brain metastasis, whereas RT effects were heterogeneous. CONCLUSION:In this real-world cohort, consolidative surgery combined with EGFR-TKI was associated with a clear survival benefit in advanced EGFR-mutant NSCLC while the effect of consolidative RT was less consistent, highlighting the importance of careful patient selection and multidisciplinary management.

Abstract Background: Lung cancer is one of the most prevalent and life-threatening cancers worldwide. Genetic factors contribute to lung cancer risk in smokers and non-smokers, and genome-wide association studies (GWAS) identified > 50 genomic loci from diverse populations. Expression quantitative trait loci (eQTL) and splicing QTL (sQTL) analyses can reveal distinct genetic effects on gene- or transcript isoform-level regulation contributing to GWAS signals to identify target genes and elucidate etiology. However, current sQTL studies using short-read sequencing of bulk tissues fail to capture full-length and novel isoforms or cell-type-specific splicing events contributing to tumorigenesis.Methods: We present an isoform-level lung cell atlas from 129 never-smoking Korean women using single-cell long-read RNA-sequencing. Epithelial cells, where lung cancer originate, were enriched by FACS sorting. Isoform signatures of each lung cell type were identified by differential analysis. We mapped isoform-level QTLs (isoQTLs) using jaxQTL negative binomial model of pseudo-bulk counts. Colocalization and transcriptome-wide association study (TWAS) with GWAS were performed to prioritize susceptibility isoforms.Results: We identified 325,865 full-length isoforms from 360,133 lung cells, where 83% are novel isoforms not annotated in GENCODE v32. We identified isoform-level signatures of 37 lung cell types, where 67.2% of differential isoforms display larger differences than in gene levels. Isoform-QTLs (isoQTLs) identified unreported genes in bulk tissue-based sQTL studies attributed to cell-type-specific and unannotated isoforms. Compared to the barcode-matched short-read expression data, 46% of isoQTLs did not colocalize with eQTLs in the same cell type. Consistently, isoQTLs were distinctly enriched in the functional elements of splicing and post-transcriptional regulation. Colocalization of isoQTLs with lung cancer and trait GWAS signals nominated candidate isoforms, where 69% were previously unreported at the gene level. Moreover, 71% of GWAS-colocalized isoforms were independent from eQTLs, including PPIL6-207 for lung cancer. TWAS of ancestry-matched lung adenocarcinoma identified 12 isoforms from the sub-threshold GWAS regions, which include lineage or cell-type-specific genes.Conclusions: We established an isoform-level lung cell atlas using single-cell long-read sequencing and detected isoQTLs that are cell-type-specific and independent from eQTLs. This isoform-level resource advances our understanding of cell-type-specific isoform regulation and its contribution to lung cancer and diseases. Citation Format: Bolun Li, Thong Luong, Elelta Sisay, Jinhu Yin, Zixuan Zhang, Ju Hye Shin, Jinyoung Byun, Yoon Soo Chang, Maria Teresa Landi, Nat Rothman, Erping Long, Qing Lan, Christopher I. Amos, Tongwu Zhang, Jianxin Shi, Nicholas Mancuso, Haoyu Zhang, Jin Gu Lee, Eon Young Kim, Jiyeon Choi. Single-cell full-length transcriptome of lung cells reveals genetic effects on isoform regulation beyond eQTL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5924.

Purpose The triggering receptor expressed on myeloid cells 2 (TREM2) creates an immunosuppressive environment, but the effects of anticancer treatment on TREM2 and the tumor microenvironment (TME) are not well established. This study investigates the impact of chemotherapy on TREM2-expressing macrophages within the lung adenocarcinoma TME. Materials and Methods Using single-cell RNA sequencing datasets of paired normal-appearing lung tissue (NL) and tumor (Tu), human and mouse lung cancer tissue, and THP-1 cells, we observed the effects of anticancer drugs on them. Results Myeloid cells (MY) were the second-most abundant non-epithelial component in the Tu, though less prevalent than in NL. Specific MY subclusters abundant in Tu showed overexpression of TREM2. In lung cancer-induced Kras-G12D mice, M2 proportion increased in Tu compared to NL; cisplatin increased TREM2+ M2 proportion in Tu. TREM2+ cells in Tu showed interactions with cell clusters showing characteristics of interstitial macrophage such as mo-lineage, mono-Mc, and CD163/LGMN cells via FN:CD44 and MIF:CD74+CXCR4, suggesting that they influence the recruitment of those cells to Tu and TME reshape. In M0-state THP-1 cells, cisplatin and osimertinib treatments induced polarization towards M1 and M2 states and increased TREM2 expression. Cisplatin promoted uptake of phosphatidylserine-coated latex beads by M0 cells, whereas osimertinib reduced uptake by polarized macrophages. These findings suggest anticancer treatments impact the lung immune microenvironment by altering the TREM2+ cells. Conclusion Given TREM2's central inhibitory role in the tumor immune environment, effects of chemotherapeutic agents should be considered in developing TREM2-targeting therapies.

Tobacco smoking remains a major global health concern, causing preventable deaths and economic strain. Although new tobacco products such as heat-not-burn (HnB) are safer alternatives to traditional cigarettes, research on their associated risks remains limited. This study aimed to investigate the effects of HnB smoke exposure on the lungs compared to those of traditional cigarettes and the combined use of HnB and cigarettes using experiments with a mouse model. We quantitatively analyzed changes in the levels of 92 blood plasma proteins using the proximity extension assay method and observed significant changes in their levels in mice exposed to different smoke conditions; specifically, the levels of certain proteins, including Ccl20, Cxcl1, and Pdgfb, increased in the HnB smoke-exposed group, suggesting activation of nicotine pathways. Comparative analysis with traditional cigarette smoke-exposed mice further highlighted similarities and differences in their protein expression profiles. This study contributes to an improved understanding of the biological mechanisms underlying the harmful effects of alternative nicotine delivery systems and identifies potential biomarkers associated with the harmful effects of HnB smoke exposure. However, the precise impact of nicotine on the immune system may be influenced by various factors, necessitating further research.

This review examines the current status and recent progress in lung cancer screening programs, focusing on low-dose computed tomography (LDCT) and emerging liquid biopsy technologies. In Korea, the National Lung Cancer Screening Program has shown promising results in reducing lung cancer mortality since its implementation in 2019. This review discusses the LDCT screening in Korea, including reductions in short-term mortality, increased screening uptake, and enhanced smoking cessation rates. Results from major international trials, including the National Lung Screening Trial, Nederlands–Leuvens Longkanker Screenings Onderzoek trial, and Multicenter Italian Lung Detection studies, demonstrating the efficacy of LDCT in reducing lung cancer mortality, are reviewed. The potential of liquid biopsy as a complement to LDCT is explored, with a focus on multi-cancer early detection technologies. Notable advances include the Circulating Cell-free Genome Atlas study and the Galleri® test, which have shown promise in detecting cancer at early stages through blood-based screening. We also highlight the challenges and limitations of current screening methods, including the need to improve strategies for screening non-smokers and the importance of balancing benefits against risks. As lung cancer screening continues to advance, combining LDCT and liquid biopsy is anticipated to provide more comprehensive and effective early detection strategies.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function. Multiple genetic loci are associated with lung cancer risk, but the underlying genetic mechanisms remain poorly understood. Here, the authors perform single-cell RNA-seq and ATAC-seq analyses of lung cells from ever- and never-smokers; they report candidate cis-regulatory elements that colocalise with candidate causal variants in lung cancer risk loci and potential susceptibility genes.

Abstract Background: Triggering receptor expressed on myeloid cells (TREM2) serves as an immune signaling hub that senses and interacts with a wide range of ligands arising from damaged tissues in pathologic conditions. Despite TREM2’s diverse role in casting immune suppressive environment, the effects of chemotherapy on tumor microenvironment (TME), TREM2 and their interactions are not well established. In this study, we aimed to investigate the characteristics of TREM2 (+) Mφ within the lung TME (Tu), focusing on the impact of chemotherapy on the immune dynamics of lung adenocarcinoma (LUAD). Method: Changes in the number and distribution of Mφ subclusters in normal appearing lung tissue (NL) and Tu were examined using open-source single cell RNA sequencing (scRNA-seq) datasets and immunofluorescent staining of lung cancer-induced Kras-G12D mouse tissue. Clinical measures affecting the expression of TREM2 were explored using the TCGA-LUAD and -LUSC datasets, and the effects of anticancer drugs and the apoptotic cells on Mφ were observed by differentiating THP1 cells into M0, M1, and M2. Results: scRNA-seq analysis on LUAD datasets showed that Mφ were the second most abundant cell population that constitutes the lung TME, and the proportion of Mφ in the Tu decreases compared to NL. Among the Mφ subclusters in Tu, a subcluster which specifically increased in Tu shows enrichment of apoptotic cell clearance gene sets, including TREM2. In lung cancer induced Kras-G12D mouse, compared to NL the Tu has an increase in M2 proportion, showing the characteristics of interstitial Mφ in addition with overexpression of TREM2 and enrichment of monocyte chemotaxis gene set enrichment. Among TCGA-LUAD, the high TMB group has low TREM2 expression, and the proportion of TREM2 (+) M2 in the Tu decreases in cisplatin-treated Kras-G12D mouse Tu, suggesting the expression of TREM2 in M2 is suppressed by either cisplatin treatment itself or active immunity in Tu. Additionally, we are going to observe the effect on TREM2 expression by adding cisplatin treated A549-GFP cells or cisplatin alone, to the THP-1 cells that were differentiated into M0, M1, or M2 state. Conclusion: In addition to changes in the lung immune environment due to the tumor, anticancer treatment changes in the characteristics of M2 in TME, in terms of decrease in TREM2 (+) Mφ fraction. Considering that TREM2 plays a central inhibitory role in the tumor immune environment, the effect of anticancer chemotherapeutic agents should be considered in the development TREM2 targeting agents. Citation Format: Yoon Jin Cha, Min Kyung Park, Yoon Soo Chang. Chemotherapeutic agent, cisplatin, influences the proportion of TREM2 (+) M2 macrophages in the TME of LUAD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 171.

Background:The introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has revolutionized advanced non-small cell lung cancer (NSCLC) treatment. However, their efficacy can be compromised by concurrent use of gastric acid suppressants (GASs), such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). This study aimed to update the evidence on the impact of GASs on the overall survival (OS) and progression-free survival (PFS) in patients on EGFR-TKI treatment. Methods:A systematic review and meta-analysis were conducted using data from PubMed, Embase, Cochrane Library, Web of Science, Scopus, KoreaMed, and preprint repositories. Data from 13 retrospective studies, involving 10,814 patients, were analyzed. Results:Overall, 34.6% of the patients used GASs, with most being Asian females and non-smokers. Most patients had EGFR-mutated adenocarcinoma, reflecting typical EGFR-TKI usage scenarios. Concurrent use of GASs was significantly associated with reduced OS [hazard ratio (HR) =1.34, 95% confidence interval (CI): 1.26-1.42], and PFS (HR =1.52, 95% CI: 1.25-1.86). In subgroup analysis, PPIs had a more negative impact on OS (HR =1.64, 95% CI: 1.51-1.79) than did H2RAs (HR =1.11, 95% CI: 0.95-1.31). Longer overlap times of GASs correlated with a higher trend in HRs for OS. However, the results for PFS were not significant in both subgroup analyses. Conclusions:Concurrent use of GASs with EGFR-TKIs is linked to poorer OS and PFS in patients with advanced NSCLC. Careful consideration is advised when prescribing GASs, including adjusting administration timing, minimizing overlap duration, or opting for H2RAs over PPIs. Further research is needed to optimize treatment protocols, specifically addressing the duration of overlap time, to improve patient outcomes.

Abstract Lung cancer is one of the most prevalent and deadly forms of cancer worldwide. Whilst smoking is the main determinant, genetic factors also play a crucial role as genome-wide association studies (GWAS) have identified >50 loci associated with lung cancer risk. Yet, for most of these loci, it is still unknown how they contribute to lung cancer risk. Expression quantitative trait loci (eQTL) studies have been powerful in linking GWAS variants to potential target genes, providing genetic mechanisms underlying common diseases such as cancers. However, the current eQTL resources lack ancestral diversity and are primarily based on bulk tissues. Emerging single-cell eQTL (sc-eQTL) approaches can detect context-specific gene regulation but are mainly of blood samples or cultured cells and still representing European populations. This limits our abilities to test GWAS variants in cancer-relevant cell types as well as in diverse populations. To generate a resource to characterize lung cancer GWAS loci, we are building a lung sc-eQTL dataset of Asian population while addressing common challenges of tissue sc-eQTL. Namely, processing fresh tissue in a population scale is logistically challenging and costly, and epithelial cells (including cell types of lung cancer origin) are vulnerable to the dissociation and freezing/thawing process. To address these issues, we incorporated sample multiplexing and cell type balancing. We collected fresh tumor-distant normal lung tissues from 131 never-smoking Korean women and dissociated them before cryopreservation. We then performed single-cell RNA sequencing (scRNA-seq) using 10x Chromium Single Cell 3’ v3.1 chemistry with multiplexing of ~6 samples/batch. To enrich for epithelial cells, we utilized flow cytometry with surface markers of four major lung cell types (epithelial: EpCAM+/CD45-, immune: EpCAM-/CD45+, endothelial and stromal: EpCAM-/CD45-) before 10X library preparation. Concurrently, we performed DNA genotyping and imputation using matched blood samples. Following scRNA-seq (~36,000 reads/cell) we performed a genotype-based sample demultiplexing using Demuxlet. By integrating Demuxlet and Scrublet, we identified ~89% of the detected cells as singlets. After applying QC to filter empty droplets and low-quality cells, we obtained 428,619 cells or 3,272 cells/patient. Cell annotation guided by Azimuth label transfer using the Human Lung Cell Atlas, identified 28 cell types including 7 of epithelial origins. We will further perform eQTL analyses for individual cell types using pseudo-bulk and LIMIX (linear mixed model) or SAIGE-qtl (poisson regression) methods followed by aggregation across the cell types. By incorporating lung cancer GWAS data, we will identify cell-type specific susceptibility genes. Our dataset will provide a unique resource for lung cancer research. Citation Format: Thong Luong, Erping Long, Jinhu Yin, Bolun Li, Ju Hye Shin, Elelta Sisay, Alexander Kane, Alyxandra Golden, Yoon Soo Chang, Nicholas Banovich, Nathaniel Rothman, Jinyoung Byun, Qing Lan, Christopher Amos, Jianxin Shi, Jin Gu Lee, Eun Young Kim, Jiyeon Choi. Establishing a single-cell eQTL dataset of lung tissues from Asian never-smokers to identify cell-type specific lung cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7331.

PurposeIn cases where rebiopsy fails to find the epidermal growth factor receptor (EGFR) T790M mutation, the criteria for selecting patients for repeated rebiopsy remains unclear. This study aimed to assess the impact of repeated rebiopsy on T790M mutation detection in non-small cell lung cancer (NSCLC) patients.MethodsPatients with advanced EGFR-mutated NSCLC between January 2018 and December 2021 at three-referral hospitals in South Korea underwent retrospective review. Of 682 patients who had rebiopsy after disease progression, T790M mutation status was assessed in plasma circulating tumor DNA (ctDNA) and/or tumor tissues.ResultsThe overall T790M positivity rate increased from 40.8% after the first rebiopsy to 52.9% following multiple rebiopsies in the entire study population. Longer duration of initial EGFR TKI use (OR 1.792, ≥8 months vs. <8 months, p=0.004), better EGFR TKI responses (OR 1.611, complete or partial response vs. stable disease, p=0.006), presence of bone metastasis (OR 2.286, p<0.001) were correlated with higher T790M positivity. Longer EGFR TKI use and better responses increased T790M positivity in repeated tissue rebiopsy, while bone metastasis favored liquid rebiopsy. Additionally, T790M status has been shown to be positive over time through repeated rebiopsies ranging from several months to years, suggesting its dynamic nature.ConclusionIn this study, among patients who initially tested negative for T790M in rebiopsy, repeated rebiopsies uncovered an additional 23.5% T790M positivity. Particularly, it is suggested that repeated rebiopsies may be valuable for patients with prolonged EGFR TKI usage, better responses to treatment, and bone metastasis.

AbstractBackgroundAbout 3%–5% of non‐small cell lung cancer (NSCLC) presents positive anaplastic lymphoma kinase (ALK). Recently, several target agents have been approved as a treatment for ALK‐positive NSCLC. This study aimed to analyze the real‐world efficacy and outcome when administered crizotinib, the first approved target agent for ALK‐positive NSCLC, according to first‐ or late‐line treatment.MethodsA total of 290 patients with ALK‐positive advanced NSCLC who were treated with crizotinib in 15 institutions in South Korea from January 2009 to December 2018 were enrolled.ResultsThe median age of patients was 57.0 years, and 50.3% were male. The median follow‐up duration was 29.3 months. Among them, 113 patients received crizotinib as first‐line therapy. The objective response rate (ORR) was 60.1% (57.0% for first‐line recipients, 61.8% for second−/later‐line). Median (95% CI) progression‐free survival (PFS) was 13.7 (11.6–17.0) months. For first‐line recipients, overall survival (OS) was 26.3 (17.6–35.0) months. No significant difference in ORR, PFS and OS, according to the setting of crizotinib initiation, was observed. In a multivariate Cox regression analysis, old age, male gender, initially metastatic, and number of metastatic organs were associated with poor PFS and OS. The most common adverse events were nausea and vomiting, and severe adverse event leading to dose adjustment was hepatotoxicity.ConclusionsORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials. Our findings could aid in the efficient management of ALK‐positive lung cancer patients.

Background Ubiquitin C-terminal hydrolase L1 (UCHL1), which encodes thiol protease that hydrolyzes a peptide bond at the C-terminal glycine residue of ubiquitin, regulates cell differentiation, proliferation, transcriptional regulation, and numerous other biological processes and may be involved in lung cancer progression. UCHL1 is mainly expressed in the brain and plays a tumor-promoting role in a few cancer types; however, there are limited reports regarding its role in lung cancer. Methods Single-cell RNA (scRNA) sequencing using 10X chromium v3 was performed on a paired normal-appearing and tumor tissue from surgical specimens of a patient who showed unusually rapid progression. To validate clinical implication of the identified biomarkers, immunohistochemical (IHC) analysis was performed on 48 non-small cell lung cancer (NSCLC) tissue specimens, and the correlation with clinical parameters was evaluated. Results We identified 500 genes overexpressed in tumor tissue compared to those in normal tissue. Among them, UCHL1, brain expressed X-linked 3 (BEX3), and midkine (MDK), which are associated with tumor growth and progression, exhibited a 1.5-fold increase in expression compared to that in normal tissue. IHC analysis of NSCLC tissues showed that only UCHL1 was specifically overexpressed. Additionally, in 48 NSCLC specimens, UCHL1 was specifically upregulated in the cytoplasm and nuclear membrane of tumor cells. Multivariable logistic analysis identified several factors, including smoking, tumor size, and high-grade dysplasia, to be typically associated with UCHL1 overexpression. Survival analyses using The Cancer Genome Atlas (TCGA) datasets revealed that UCHL1 overexpression is substantially associated with poor survival outcomes. Furthermore, a strong association was observed between UCHL1 expression and the clinicopathological features of patients with NSCLC. Conclusion UCHL1 overexpression was associated with smoking, tumor size, and high-grade dysplasia, which are typically associated with a poor prognosis and survival outcome. These findings suggest that UCHL1 may serve as an effective biomarker of NSCLC.

Differences in treatment response among patients with EGFR mutant lung cancer indicate the need for a treatment approach that involves molecular subgrouping. The response to EGFR-tyrosine kinase inhibitor (TKI) treatment is anticipated to have a strong association with compound EGFR mutations and other co-mutations. We investigated the contribution of compound EGFR mutations and other co-mutations to efficacy of EGFR-TKI in EGFR mutant lung adenocarcinoma.

Birt-Hogg-Dube (BHD) is a rare genetic disorder characterized by multiple lung cysts, typical skin manifestations, and renal tumors. We prospectively enrolled thirty-one subjects from four South Korean institutions with typical lung cysts, and next-generation sequencing was conducted. We prospectively enrolled thirty-one subjects from four Korean institutions with typical lung cysts. Next-generation sequencing was performed to investigate mutations in the following genes: FLCN, TSC1, TSC2, CFTR, EFEMP2, ELN, FBLN5, LTBP4, and SERPINA1. BHD was diagnosed in 11 of the 31 enrolled subjects (35.5%; FLCN mutations). Notably, we identified three novel mutations (c.1098G>A, c.139G>T, and c.1335del) that have not been previously reported. In addition to FLCN mutations, we also observed mutations in CFTR (16.1%), LTBP4 (9.7%), TSC2 (9.7%), TSC1 (3.2%), ELN (3.2%), and SERPINA1 (3.2%). According to a systematic review of 45 South Korean patients with BHD, the prevalence of pneumothorax (72.7%) was greater in South Korea than in the rest of the world (50.9%; p = 0.003). The prevalence of skin manifestations (13.6%) and renal tumors (9.1%) was lower in Korea than in the rest of the world, at 47.9% [p < 0.001] and 22.5% [p = 0.027], respectively). This study confirmed a significant prediction model for BHD based on age, number of lung cysts (>40), and maximal diameter of lung cysts (>2 cm) regardless of skin manifestations and renal tumors. Importantly, three novel mutations (c.1098G>A, c.139G>T, and c.1335del) were identified. In conclusion, South Korean patients with BHD display characteristics that are different from those observed in patients of other nationalities. Detailed characterization of lung cysts is needed to define BHD, especially in South Korea, even if patients do not present with skin or renal lesions.

Lung cancer ranks first in cancer mortality in Korea and cancer incidence in Korean men. More than half of Korean lung cancer patients undergo chemotherapy, including adjuvant therapy. Cytotoxic agents, targeted therapy, and immune checkpoint inhibitors are used in chemotherapy according to the biopsy and genetic test results. Among chemotherapy, the one that has developed rapidly is targeted therapy. The National Comprehensive Cancer Network (NCCN) guidelines have been updated recently for targeted therapy of multiple gene mutations, and targeted therapy is used not only for chemotherapy but also for adjuvant therapy. While previously targeted therapies have been developed for common genetic mutations, recently targeted therapies have been developed to overcome uncommon mutations or drug resistance that have occurred since previous targeted therapy. Therefore, this study describes recent, rapidly developing targeted therapies.