Translational lung cancer research最新文献

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.

Background: Oligometastatic disease, i.e., disease with limited metastatic spread (LMS), is increasingly recognised as a distinct clinical entity as it differs from disease with extensive metastatic spread (polymetastatic disease) in terms of treatment and prognosis. This retrospective observational study aimed to characterise a population-based cohort of non-small-cell lung cancer (NSCLC) patients with synchronous metastatic disease, stratified by the extent of metastatic spread.

Methods: NSCLC patients [≥18 years, diagnosed 2016-2020, ICD-10 C34, Union for International Cancer Control (UICC) stage IV at primary diagnosis] were identified from three German population-based cancer registries covering approximately 27% of the national population. The extent of metastatic disease was classified according to the 8^th edition of the tumour-node-metastasis (TNM) system and further subclassified by the number of organ systems involved. We differentiated between patients with TNM-M stage M1a (intra-thoracic LMS), M1b [one single extra-thoracic metastasis or extra-thoracic LMS (ET-LMS)], M1c and ≤3 [limited multi-organ involvement (LMOI)] and >3 organ systems involved or with generalised metastatic disease [extensive multi-organ involvement (EMOI)]. The intent of the statistical analysis was mainly descriptive.

Results: The cohort included 8,033 NSCLC patients with distant metastasis at diagnosis of the primary tumour (1,767 with intra-thoracic LMS, 1,314 with ET-LMS, 4,196 with LMOI and 756 with EMOI). Patients with EMOI were younger (median: 64 vs. 66-70 years), more often female (45.0% vs. 40.6-41.4%), had a higher proportion of adenocarcinomas (83.7% vs. 72.2-78.7%) and showed more frequent N3 lymph node involvement (37.8% vs. 22.9-30.4%) than patients with LMS (subgroups: intra-thoracic LMS, ET-LMS or LMOI). Patients in the ET-LMS subgroup most often presented with one brain, osseous or adrenal metastasis (in descending order), patients in the LMOI subgroup most often with osseous, brain and/or pulmonal metastases, while patients in the EMOI subgroup presented most often with osseous, hepatic and/or pulmonal metastases. Patients were followed-up for a median time of 7 months (interquartile range, 3-16 months), during which every fourth patient with initially LMS experienced a new metastasis with mainly limited spread, usually in another organ than at primary diagnosis. Brain and osseous metastases were most frequently observed during follow-up.

Conclusions: We were able to identify patients with LMS in a population-based real-world dataset. This large data source forms the basis of a study series, in which subsequent analyses will assess survival prospects and optimal treatment strategies for this therapeutically relevant patient group.

Background: Rearranged during transfection (RET) fusion is a key driver in non-small cell lung cancer (NSCLC). Accurate detection is essential for targeted therapeutic strategies, and its reliability varies with the diagnostic methods employed. This study systematically compares the concordance of various molecular profiling techniques for identifying RET fusions in early-stage NSCLC.

Methods: This retrospective study included 40 NSCLC patients with RET fusions (RET+) identified by DNA sequencing (DNA-seq). Comprehensive detection was conducted using fluorescence in situ hybridization (FISH) and RNA sequencing (RNA-seq), incorporating both targeted RNA-seq and whole-transcriptome sequencing (WTS). Clinical and molecular features were evaluated for associations with fusion types.

Results: Patients were predominantly female (67.5%) and never-smokers (87.5%), with a median age of 53 years. All patients underwent FISH, while 39 cases underwent RNA-seq, with one excluded due to RNA quality control failure. The most common fusions were KIF5B::RET and CCDC6::RET (89.7%), alongside noncanonical fusion partners such as ERC1 (5.0%) and CCDC186 (2.5%). WTS achieved a 79.5% (31/39) RET+ detection rate. Targeted RNA-seq uncovered an additional five RET+ cases missed by WTS. Concordance rates for fusion detection were 92.3% between DNA-seq and RNA-seq, 84.6% between RNA-seq and FISH, and 82.5% between DNA-seq and FISH. Interestingly, patients exhibiting nonreciprocal RET translocations were significantly younger (P=0.03) and presented a lower Ki67 proliferation index (P=0.03).

Conclusions: Our findings underscore the complexity of RET fusion characterization and the necessity for a comprehensive diagnostic approach, which enhances the identification of both canonical and noncanonical alterations. This supports precision oncology initiatives aimed at optimizing treatment outcomes for RET+ NSCLC patients.

Background: The phase III PACIFIC trial demonstrated that one year of durvalumab maintenance therapy after concurrent chemoradiotherapy (CCRT) significantly improved overall survival (OS) in unresectable stage III non-small cell lung cancer (NSCLC), reducing the risk of death by 32% compared with observation. Durvalumab therapy administered for up to 12 months is currently the standard of care for patients with locally advanced NSCLC. This study aimed to identify the factors influencing the completion of durvalumab therapy.

Methods: This retrospective study analyzed patients who initiated durvalumab therapy for unresectable NSCLC at Niigata University Medical and Dental Hospital between August 2018 and December 2022. Patients who discontinued the treatment for reasons unrelated to disease progression or adverse events were excluded. The patients were divided into durvalumab completion and non-completion groups, and the clinical factors influencing durvalumab completion were analyzed.

Results: Among the 65 enrolled patients, 46.2% completed one year of durvalumab maintenance therapy. The completion rate was significantly lower in patients who received low-dose carboplatin as part of CCRT (20% vs. 54%, P=0.04), and higher in patients with adenocarcinoma (P=0.03). Older patients were more frequently treated with low-dose carboplatin CCRT (median age: 78 vs. 66 years, P<0.001). Patients receiving low-dose carboplatin had a significantly shorter time to treatment failure (median: 3.8 months vs. not reached, P=0.002) and tended to have a shorter OS (median: 47 months vs. not reached, P=0.06).

Conclusions: Low-dose carboplatin CCRT is associated with lower durvalumab completion rates and worse outcomes, particularly in older patients. Alternative CCRT regimens may warrant consideration, particularly for older patients who are less likely to complete durvalumab maintenance.