Translational lung cancer research最新文献

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide. Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) presents unique clinical challenges, including frequent central nervous system (CNS) metastases. At present, comparative real-world data on ALK inhibitors remain limited. This study aimed to compare real-world progression-free survival (PFS) and overall survival (OS) among patients with ALK-positive NSCLC treated with first-line alectinib or brigatinib using nationwide South Korean data.

Methods: This retrospective cohort study analyzed anonymized data from South Korea's Health Insurance Review and Assessment Service, covering January 2007 to December 2023. Patients diagnosed with ALK-positive NSCLC (ICD-10: C34x) and treated with either alectinib or brigatinib as first-line monotherapy were included. Patients with prior lung surgery or other malignancies were excluded. Baseline demographics and comorbidities were collected. The primary outcomes were PFS and OS, as measured from ALK inhibitor initiation.

Results: The final cohort included 1,009 patients with ALK-positive NSCLC. The mean age was 61.6 years, and 49.5% were male. Alectinib was associated with a significantly longer PFS. Brigatinib showed a higher OS in the unadjusted analysis; however, this difference was not statistically significant after multivariable adjustment. Transition to lorlatinib was associated with extended survival in both groups, reflecting its use as a later-line therapy following resistance.

Conclusions: In this real-world cohort of ALK-positive NSCLC patients, both alectinib and brigatinib were associated with extended survival, with alectinib showing longer PFS. Findings should be interpreted descriptively. Alectinib demonstrated superior disease control in terms of PFS. Further research is warranted to optimize treatment sequence strategies for ALK inhibitors.

Background: Recent evidence highlights the importance of lipid metabolic reprogramming in lung adenocarcinoma (LUAD) progression. Due to the limitations of conventional techniques, the fine structure of lipids cannot be identified. The metabolic changes of lipid structural features-particularly carbon-carbon double bond (C=C) positional isomers-remain underexplored. This study aims to characterize the structural alterations of lipids, especially C=C positional isomers, in LUAD tissues to elucidate their potential roles in tumor progression.

Methods: We performed deep structural lipidomic profiling on paired normal lung (N) and LUAD (T) tissue samples using a combination of photochemical reaction-based structural analysis (Ω Analyzer) and liquid chromatography-mass spectrometry (LC-MS). Lipid species were characterized at three structural levels: lipid class, molecular species, and C=C positional isomer. Relative quantitative analyses were conducted to identify differences in total composition, unsaturation levels, and the distribution of C=C isomers between N and T groups.

Results: A total of 794 phospholipid species were identified at the C=C isomer level, with the T group exhibiting a slightly higher overall number of identified lipids compared to the N group. Polyunsaturated lipids displayed notable upregulation in the T group and facilitated robust clustering between normal and cancer tissues. Furthermore, analyzing C=C positional isomers revealed significant differences in their relative abundances between the two groups: lipids enriched in C18:1(Δ9) were predominantly upregulated in T group samples, whereas those carrying C18:1(Δ8) were generally downregulated.

Conclusions: Our findings demonstrate that deep structural lipidomic analysis yields crucial insights into the lipid reprogramming of LUAD. In particular, the relative abundances of C=C positional isomers hold promise as novel diagnostic markers and therapeutic targets for LUAD.

Background: Time-to-surgery is used as a surrogate quality indicator within lung cancer care. However, its definition is not clearly defined in the literature. This study aimed to explore the evidence on optimal time-to-surgery interval with no negative impact on disease progression or oncological outcomes.

Methods: A systematic search was performed in January 2025 through MEDLINE, EMBASE, and Cochrane databases. Studies about lung cancer patients with treatment interval description until surgery were included.

Results: Eighty-six studies were included with a clear definition of the treatment interval until surgery. Starting points of the interval varied widely, of which pathological diagnosis was reported most often. Thirty-six studies also included associations of time-to-surgery with oncological outcomes. Overall, 47% of the included studies associated a delay in treatment interval with worse outcomes, 33% found no association, and in 19% the association differed per lung cancer stage or type of outcome. Inconsistency was seen in the definition of timely surgery, ranging from 21 to 90 days, influencing the reported outcome measures and comparability. Most studies chose the tipping point for delayed surgery at or beyond 6 weeks, and the most reported outcome was overall survival (OS). For OS, two thirds of the included study groups associated a delay in time-to-surgery with worse survival, with a very heterogeneous cut-off point between timely and delayed surgery.

Conclusions: Within lung cancer care, there is no clear definition of treatment interval until surgery, nor consensus on the definition of timely surgery. The relation between treatment interval and outcomes is inconsistent and requires more structured evidence. We suggest using pathological diagnosis as a starting point, and a 6-week timeframe as a basis to define timely surgery instead of "as soon as possible", without significantly compromising oncological safety. Defining an interval can reframe waiting time into structural preoperative preparation time, unlocking the opportunity to implement prehabilitation and optimize patient outcomes.

Background and objective: Lung cancer is the leading cause of global cancer mortality. Multiple primary lung cancer (MPLC) represents a clinically challenging subtype characterized by independent tumor foci. Distinguishing MPLC from intrapulmonary metastases is crucial for prognosis and treatment. This review integrates current evidence on MPLC's etiology, molecular mechanisms, diagnosis, and management, aiming to provide a clinical reference and highlight future precision medicine directions.

Methods: We searched PubMed/MEDLINE, Web of Science, and Google Scholar for articles published between January 2000 and September 2024. Search terms included "multiple primary lung cancer", "diagnosis", "molecular characteristics", and "treatment". The selection focused on English-language research and reviews addressing MPLC pathogenesis, diagnosis, or management.

Key content and findings: The review delineates the multifactorial pathogenesis of MPLC, encompassing genetic susceptibility, somatic heterogeneity, clonal evolution, and epigenetic dysregulation. It frames these mechanisms against a backdrop of "field cancerization" and dynamic tumor microenvironment interactions. The evolution of diagnosis from histology to integrated molecular-artificial intelligence (AI) models is detailed, alongside treatment strategies that must overcome the challenge of inter-lesional heterogeneity.

Conclusions: MPLC is a distinct entity arising from genetic, epigenetic, and microenvironmental interplay. Advancing its management requires multi-omics integration to decipher pathology and identify biomarkers. Future work should develop AI-enhanced diagnostics and lesion-specific treatment strategies. This review synthesizes current evidence to inform and direct future research and clinical innovation in MPLC.

Background: Plasma-based circulating tumor DNA (ctDNA) analysis has emerged as a promising tool to complement tissue genotyping in non-small cell lung cancer (NSCLC), particularly when tissue acquisition is limited. We investigated the clinical applicability of ctDNA analysis in Korean patients with recurrent or metastatic NSCLC.

Methods: We retrospectively analyzed 132 patients with NSCLC who underwent plasma ctDNA testing between June 2017 and December 2021 in the K-MASTER project. Mutation detection rates, concordance between tissue and plasma results, and survival outcomes according to targeted therapy administration were evaluated. Clinical characteristics of plasma-only mutations were further examined.

Results: Actionable mutations were identified in 43.2% of patients through combined tissue and plasma analyses. Plasma ctDNA testing revealed actionable mutations in 11.4% of patients not detected by tissue genotyping, seven of whom received targeted therapy based on plasma results. Rare co-occurring actionable alterations were found in three patients, including concurrent EGFR and KRAS or ALK and EGFR mutations, suggesting intratumoral heterogeneity or possible multiple primary cancers. Among the three cases with plasma-positive but tissue-negative results, one had biopsies from bone and one from liver, suggesting possible effects of sampling bias or clonal evolution. Patients who received targeted therapy-guided by either tissue or plasma results-demonstrated significantly improved survival compared with those who did not (P=0.03).

Conclusions: Plasma-based ctDNA analysis broadens detection of actionable genomic alterations and facilitates access to targeted therapies in NSCLC, particularly when tissue biopsy is limited. These findings support integrating liquid biopsy into routine practice to optimize patient outcomes.

Background: Neoadjuvant immuno-chemotherapy has been verified as a promising treatment for early-stage non-small-cell lung cancer (NSCLC). However, its risk of pre-operative treatment interruption was unclear. This study aimed to evaluate and compare the risk of pre-operative treatment interruption between different neoadjuvant therapy (NAT) strategies in early-stage NSCLC.

Methods: We searched MEDLINE, Embase, and the Cochrane Library for randomized controlled trials (RCTs) reporting on NAT in NSCLC up to July 3, 2024. Eligible studies reporting pre-operative treatment interruption were included. Paired meta-analysis and Bayesian network meta-analysis (NMA) were conducted to compare the risk between different NAT strategies. The primary outcome was pre-operative treatment interruption, which included neoadjuvant treatment discontinuation, surgery delay and surgery cancellation.

Results: Compared with neoadjuvant chemotherapy, neoadjuvant immuno-chemotherapy was associated with a higher risk of adverse event (AE)-related NAT discontinuation [risk ratio (RR), 1.32; 95% confidence interval (CI): 1.00-1.73; I²=4%] and a lower risk of progressive disease (PD)-related NAT discontinuation (RR, 0.53; 95% CI: 0.30-0.96; I²=0%), but there was no significant difference in the overall risk of NAT discontinuation. Neoadjuvant immuno-chemotherapy was also associated with a lower risk of overall surgery cancellation (RR, 0.79; 95% CI: 0.70-0.90; I²=26%). The NMA further corroborated the aforementioned findings.

Conclusions: Neoadjuvant immuno-chemotherapy did not increase the risk of NAT discontinuation and surgery delay. On the contrary, it is associated with a reduced risk of surgery cancellation, particularly in cases of cancellation due to PD. These findings suggested extra advantage of neoadjuvant immuno-chemotherapy in the management of early-stage NSCLC (CRD42024570066).

Background: Non-small cell lung cancer (NSCLC) patients with double-driver gene mutations are reported with poorer survival outcomes and reduced therapy responses compared to single-mutant (SM) patients. While substantial progress has been made in treating cancers with single-driver gene alterations, the therapeutic implications and tumor microenvironment of double-mutant (DM) NSCLC remain largely unexplored because of its rarity and poor prognosis. This study aims to delineate the landscape of the immune microenvironment within DM NSCLC.

Methods: We employed single-cell RNA sequencing (scRNA-seq) to generate a comprehensive transcriptomic atlas from 25 EGFR mutant NSCLC samples. To assess immune microenvironment changes over time, time-series scRNA-seq and multiplex immunofluorescence analyses were performed in two DM patients. In vitro, EGFR-mutant cell lines were constructed to assess potential therapeutic responses for future clinical applications.

Results: The scRNA-seq platform scFocuSCOPE accurately identified and characterized rare, mutation-bearing cancer cells at the single-cell level. DM cancer cells exhibited a strong tendency toward angiogenesis, suggesting an invasive phenotype. DM patients had a more suppressed immune microenvironment, with fewer dysfunctional T lymphocytes. The observation of fewer immune cells and high programmed death ligand-1 (PD-L1) expression in DM cases, probably related to immune evasion and poorer prognosis. In one DM patient, PD-L1 expression remained unchanged after targeted therapy but decreased after immunotherapy. In vitro, EGFR/ERBB2 DM cells showed greater sensitivity to dual-targeted therapies than to single-agent treatments.

Conclusions: scFocuSCOPE precisely delineated tumor heterogeneity and immune suppression in EGFR-DM NSCLC. The complex immune landscape of EGFR-DM tumors offers valuable insights for future mechanistic studies and personalized therapies.

Lung cancer is the leading cause of cancer related death worldwide and is typically categorised as either small cell lung carcinoma (SCLC) or non-small cell lung carcinoma (NSCLC). SCLC accounts for 15% of all lung cancer diagnoses while NSCLC accounts for 85%. In NSCLC, 70% of patients are at an advanced stage at diagnosis, which limits surgical options. A key management challenge is the high levels of drug resistance that occur over time, which impact treatment strategies. Transient receptor potential ankyrin-1 (TRPA1) is a nonselective ion channel with a high permeability for calcium which is involved in numerous physiological functions, including thermoregulation, nociception, phagocytosis, cell motility and inflammatory pain sensation. The TRPA1 receptor is present throughout the respiratory tract and its role in inflammatory conditions such as asthma and chronic obstructive pulmonary disease (COPD) have been well established. TRPA1 has been implicated in the pathogenesis of a variety of cancers, and interest in its role in the oncology setting is expanding. It has been implicated in the development of prostate cancer, breast cancer, oral squamous cell carcinoma, colorectal carcinoma and pancreatic ductal adenocarcinoma. However, the role of TRPA1 in lung cancer has yet to be fully investigated. In silico studies have suggested that TRPA1 messenger ribonucleic acid (mRNA) is upregulated in NSCLC, both in lung squamous cell carcinoma (SCC) lung adenocarcinoma (LUAD). Moreover, TRPA1 expression showed a positive correlation with increased lung cancer stages and risk of metastasis. Potential involvement in SCLC and SCC development have been demonstrated by a number of studies, however information regarding the role of TRPA1 in LUAD is scant. This represents an active research gap which should be addressed, given the role that TRPA1 appears to play in the inflammatory lung milieu and other malignancies. In this review, we outline the current knowledge surrounding the biological roles of TRPA1 in the lung, summarize the existing drug strategies to target this receptor, and discuss the potential for its targeting either as an anticancer strategy or alternatively for its use in pain management for patients suffering from lung cancer.

Background: Surgical resection remains the cornerstone of early-stage treatment for non-small cell lung cancer (NSCLC). However, the survival benefits of different surgical methods in clinical stage IA patients remain controversial. This systematic review aims to compare the efficacy of surgical methods-lobectomy, segmentectomy, and wedge resection-on survival outcomes in clinical stage IA NSCLC patients.

Methods: A systematic search was performed in PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases between January 2000 and November 30, 2024. Studies meeting the inclusion and exclusion criteria were identified, and hazard ratio (HR) for overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) were extracted from each study for pairwise and Bayesian network meta-analyses. This study protocol was registered on PROSPERO (CRD42024618659).

Results: A total of 58 retrospective studies and 3 randomized controlled trials (RCTs) were included. For patients with overall stage IA, network meta-analyses showed that both lobectomy and segmentectomy had significant advantages in OS, DFS, and RFS compared to wedge resection {HR_OS 0.67 [95% confidence interval (CI): 0.59-0.75], 0.75 (95% CI: 0.65-0.84); HR_DFS 0.69 (95% CI: 0.54-0.89), 0.71 (95% CI: 0.55-0.92); HR_RFS 0.57 (95% CI: 0.42-0.78), 0.53 (95% CI: 0.39-0.72)}. No significant differences were observed between lobectomy and segmentectomy. Based on ranking probabilities, lobectomy ranked first. In subgroup analyses, results for overall T1a/b patients were consistent with those of stage IA. When 0.5< consolidation-to-tumor ratio (CTR) <1, lobectomy and segmentectomy showed significant advantages in OS and RFS compared to wedge resection [HR_OS 0.57 (95% CI: 0.38-0.94), 0.52 (95% CI: 0.34-0.84); HR_RFS 0.53 (95% CI: 0.32-0.83), 0.51 (95% CI: 0.31-0.84)], while no significant differences were observed otherwise. Segmentectomy ranked first in this group. When CTR =1, no significant differences were found, with lobectomy ranking first. For overall T1c patients, lobectomy demonstrated significant advantages in OS compared to segmentectomy and wedge resection [HR 0.73 (95% CI: 0.60-0.91); HR 0.60 (95% CI: 0.44-0.77)], while no significant differences were observed otherwise. Lobectomy ranked first in this group. For patients with 0.5< CTR <1, no significant differences were found, with lobectomy ranked first.

Conclusions: Lobectomy and segmentectomy provide better OS benefits compared to wedge resection in stage IA NSCLC patients, with no significant differences between lobectomy and segmentectomy. However, the optimal surgical approach should still be determined based on tumor size and CTR.