Translational lung cancer research最新文献

Background: With advances in multimodal treatment, the importance of identifying biomarkers by bronchoscopy has increased, even in potentially resectable non-small cell lung cancer (NSCLC). However, it remains unclear whether next-generation sequencing (NGS) using bronchoscopic specimens is as useful in potentially resectable NSCLC as in unresectable cases. The objective of this study was to evaluate the feasibility of performing NGS using bronchoscopic specimens obtained from patients with potentially resectable NSCLC.

Methods: The patients diagnosed with NSCLC via bronchoscopy at National Cancer Center Hospital who underwent NGS were retrospectively analyzed. We allocated all N0-2 and M0 and N3 and/or M1 cases to the potentially resectable and unresectable groups, respectively. Patients were divided into three subgroups according to the target: endobronchial, peri-tracheal/bronchial, and lung lesions. The NGS analytical success rates for potentially resectable NSCLC were compared with unresectable cases for each subgroup to investigate the feasibility of NGS-targeted bronchoscopy.

Results: Among the 644 patients, 184 had potentially resectable disease, and 460 had unresectable disease. The overall NGS analytical success rate was significantly lower in the potentially resectable group than in unresectable group (81.0% vs. 87.8%, P=0.03). Concerning endobronchial and peri-tracheal/bronchial lesions, there were no significant differences in the NGS analytical success rates (85.7% vs. 100%, P=0.48; and 84.9% vs. 88.2%, P=0.44). The NGS analytical success rate for lung lesions was significantly lower in the potentially resectable group (73.4% vs. 86.4%, P=0.03). Inner-located tumors (P=0.04) were significant factors associated with analytical success.

Conclusions: The overall rate of successful NGS analysis using bronchoscopic specimens were lower in potentially resectable NSCLC cases, especially in lung lesions. To improve NGS feasibility, it is important to adequately harvest lung lesions and prioritize targeting endobronchial or peri-tracheal/bronchial lesions.

Background: The current standard of care for unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT) followed by durvalumab. There are no reliable biomarkers predicting the response to this treatment. We aimed to analyze the relationship between soluble immune mediators and treatment response and to identify biomarkers predicting the treatment response in patients with unresectable stage III NSCLC.

Methods: We prospectively enrolled 48 patients diagnosed with stage III NSCLC who underwent thoracic radiotherapy (cohort A). Of these patients, 29 received durvalumab after CCRT (cohort B). Peripheral blood samples were collected before radiotherapy and 6 weeks after durvalumab treatment. To identify soluble immune mediators associated with progression-free survival (PFS) and overall survival (OS), we examined the levels of 83 soluble immune mediators using a bead-based multiplex assay and calculated the concordance index (C-index).

Results: At baseline, the high matrix metalloproteinase (MMP)-2 group exhibited the longest PFS and OS in cohort A (C-index: 0.70 and 0.75, respectively), whereas the high IFN-γ group had the worst PFS and OS in cohort B (C-index: 0.75 and 0.71, respectively). Furthermore, patients with greater increases in CXCL9, CXCL10, and CCL23 levels after durvalumab treatment had poor PFS and OS in cohort B (C-index >0.70).

Conclusions: Our results suggest that PFS and OS are negatively affected by elevated CXCL9, CXCL10, and CCL23 levels after CCRT followed by durvalumab treatment. These soluble mediators may be useful tools for the clinical management of locally advanced NSCLC treated with PD-L1 therapy after CCRT.

Background: Combination immunotherapy has become a standard first-line treatment for advanced non-small cell lung cancer (NSCLC). However, its application in patients with checkpoint inhibitor-related pneumonitis (CIP) remains challenging due to the risk of treatment-related pulmonary toxicity. While first-line outcomes in CIP patients are increasingly reported, data on the efficacy and safety of subsequent therapies are lacking. This study aimed to evaluate treatment patterns, survival outcomes, and the risk of pulmonary toxicity associated with second-line therapy in NSCLC patients with prior CIP after first-line immunotherapy.

Methods: This retrospective study analyzed 159 patients with advanced or recurrent NSCLC treated with first-line combination immunotherapy at Fukuoka University Hospital between January 2019 and March 2024, including those who had previously received molecular targeted therapy for driver gene mutations. Patients were stratified based on baseline CIP status. Among them, 91 patients (19 prior CIP and 72 non-prior CIP) who received second-line therapy were evaluated for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and drug-induced pneumonitis onset during second-line treatment.

Results: Baseline CIP was present in 32 patients (20.1%). The transition rate to second-line therapy was 73% in the prior CIP group and 64% in the non-prior CIP group, with no statistically significant difference observed between the two groups (P=0.49), indicating that the presence of prior CIP did not clearly affect the likelihood of receiving secondary therapy. PFS following second-line treatment was similar between patients with and without prior CIP. However, OS tended to be shorter in the prior CIP group (6.4 vs. 10.3 months), although the difference was not statistically significant (P=0.07), a trend that persisted after propensity score matching. Drug-induced pneumonitis development during second-line therapy occurred more frequently in patients with prior CIP (26% vs. 3%, P<0.01).

Conclusions: Second-line cytotoxic chemotherapy following combination immunotherapy may be associated with shorter survival and increased pulmonary toxicity in NSCLC patients with prior CIP. Careful clinical decision-making, multidisciplinary consultation, and close monitoring are essential when initiating second-line treatment in this population.

Background and objective: Recent studies have increasingly highlighted the critical role of the microbiome in lung cancer initiation, progression, metastasis, and therapeutic resistance. Microbial dysbiosis has been identified as a significant risk factor for lung cancer progression. Beyond the gut, emerging evidence shows that microorganisms also colonize the lungs and even inside tumors, suggesting a broader role of the microbiome in the disease. This review explores the immune-oncology-microbiome (IOM) axis by examining microbial communities across different anatomical sites, their interactions with the tumor immune microenvironment, and their impact on immunotherapy efficacy in lung cancer.

Methods: We conducted a systematic literature search using PubMed and Web of Science databases for English-language articles published between 2014 and 2025, using key terms related to lung cancer and microbiome.

Key content and findings: The microbiome associated with lung cancer encompasses gut microbiota, lower respiratory tract microbiota, and intratumor microbiota. Different microbial communities maintain microecological homeostasis and modulate antitumor immune responses by shaping the tumor immune microenvironment. Meanwhile, certain microbiota can enhance or hinder the effectiveness of immunotherapy.

Conclusions: The IOM axis reveals dynamic interactions between immune cells, cancer cells, and microbes. Specific microbe-derived metabolites show promise as lung cancer biomarkers. Current microbiome-based therapy shows great potential in lung cancer treatment.

Background: Immune checkpoint inhibitors (ICIs) are a mainstay in the treatment of non-small cell lung cancer (NSCLC). Although accurate predictive biomarkers are required for treatment selection-considering the risk of serious immune-related adverse events-such predictors remain limited. In this study, we aimed to evaluate the association between the expression of p53, LKB1, and NRF2 proteins and ICI efficacy.

Methods: This retrospective analysis included patients with NSCLC who received first-line ICI-based therapy or epidermal growth factor receptor-tyrosine kinase inhibitors between 2017 and 2025 at our institute. Immunohistochemistry was performed on diagnostic samples to assess p53, LKB1, and NRF2 expression and tumor-infiltrating lymphocytes (TILs). Additionally, the associations between biomarker expression and clinical outcomes were examined.

Results: Among the 43 evaluable cases in the ICI group, aberrant p53 expression was observed in 46.5%, LKB1 loss in 13.9%, and nuclear-dominant NRF2 expression in 34.9% of cases. Aberrant p53 expression was associated with increased TILs and improved progression-free survival (PFS), while the loss of LKB1 was correlated with an immunosuppressive microenvironment and shorter PFS. Nuclear-dominant NRF2 expression was associated with poorer overall survival.

Conclusions: The immunohistochemical profiles of p53 and LKB1 are associated with distinct immune microenvironment features. These markers may serve as surrogate predictors of ICI efficacy in patients with NSCLC.

Background: RET gene fusions define a distinct molecular subset of non-small cell lung cancer (NSCLC) that commonly affects younger and non-smoking individuals. Selective RET inhibitors such as pralsetinib have shown favorable outcomes in advanced or metastatic settings; however, their role in perioperative or locally advanced disease remains poorly defined. Integrating targeted therapy into a multidisciplinary "sandwich" strategy, which includes neoadjuvant, surgical, and adjuvant components, may offer improved outcomes and requires further exploration.

Case description: We report the case of a 34-year-old male patient with a 15-year smoking history, who presented with persistent right-sided chest pain. Imaging revealed a 3.4 cm × 2.4 cm × 4.4 cm mass in the right middle lobe with mediastinal and left supraclavicular lymphadenopathy. Supraclavicular node biopsy confirmed metastatic poorly differentiated adenocarcinoma. Immunohistochemistry supported a pulmonary origin, and molecular testing via amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) detected a RET exon 12 fusion. The clinical stage was cT2N3M0 (stage IIIB). The patient declined chemotherapy and underwent neoadjuvant pralsetinib therapy. After 3 months, a partial response (PR) was observed. On April 13, 2023, the patient underwent video-assisted thoracoscopic surgery (VATS) with right middle lobectomy. Postoperative pathology revealed a pathological complete response (pCR) with 0% viable tumor cells. Pralsetinib was resumed as adjuvant therapy post-surgery. The patient also began elective regional radiotherapy targeting bilateral supraclavicular drainage areas, but the treatment was terminated early due to grade 3 acute esophagitis. At the 24-month follow-up, the patient remained disease-free on pralsetinib maintenance with preserved performance status.

Conclusions: This case highlights the potential benefit of pralsetinib-based "sandwich" therapy in the treatment of RET fusion-positive NSCLC. Incorporating targeted therapy with surgery and tailored adjuvant treatment may lead to durable remission in selected patients with locally advanced disease. Prospective studies need to be conducted to further define the treatment sequencing and validate this multi-modal approach.

Background and objective: Checkpoint inhibitors have revolutionised cancer treatment over the past few decades; however, their successes in clinical trials and real-world settings have been tempered by immune-related adverse events (IrAEs). Checkpoint inhibitor pneumonitis (CIP), the leading cause of IrAE-related mortality, poses a significant challenge to clinicians due to non-specific clinical features and unpredictable disease trajectory. Bronchoalveolar lavage (BAL) is a diagnostic procedure that offers insight into the immune and molecular processes underlying CIP. This review presents the current role and application of BAL in the evaluation of CIP, explores current literature, and discusses how recent advances in research and technology may shape future approaches to its diagnosis and management.

Methods: A comprehensive literature search using PubMed, EMBASE, and Cochrane databases was performed to identify recent literature evaluating BAL findings in CIP. This review synthesizes findings from these studies to provide an up to date and comprehensive overview of the role of BAL in CIP management.

Key content and findings: Current guidelines recommend BAL in symptomatic patients when the diagnosis of CIP remains uncertain, primarily to exclude infection and other disease processes. However, the unpredictable clinical course of CIP narrows the window of opportunity to safely perform BAL. Variable utilisation of BAL in clinical practice may also be attributed to the lack of clinically reliable and applicable biomarkers that could improve diagnostic clarity. Beyond lymphocytosis, a well-recognised finding in BALs of patients with CIP, the role of specific immune cell populations and molecular drivers in shaping a proinflammatory microenvironment has been highlighted in multiple emerging studies. Advances in molecular profiling, immunogenomics, and lung microbiome research hold promise for enhancing our understanding of CIP pathogenesis and guiding future approaches to its diagnosis and management.

Conclusions: In current clinical practice, BAL remains an important investigation to support a diagnosis of CIP; however, its diagnostic value remains uncertain. Enhanced understanding of the CIP immune landscape is fundamental to identifying robust diagnostic and predictive biomarkers that could improve diagnosis and patient outcomes in cancer patients treated with checkpoint inhibitors.

Background: Lung cancer is the leading cause of cancer-related mortality in the United States (U.S.). The United States Preventive Services Task Force (USPSTF) recommends lung cancer screening with low-dose computed tomography (LDCT) for individuals at high risk for lung cancer to improve early detection and survival rates. Despite strong evidence supporting lung cancer screening, its adoption remains low. Participation rates range from only 1% to 16% of those eligible across different geographic regions. Further, rural populations may face significant barriers to lung cancer screening access due to factors such as geographic isolation, socioeconomic status (SES), and health literacy.

Methods: We propose a systematic review to examine how rurality, SES, and health literacy independently and collectively influence lung cancer screening utilization rates in the U.S. Using the Sample, Phenomenon of Interest, Design, Evaluation and Research (SPIDER) framework, this review will synthesize findings from research studies published between the years 2014 to 2024. The review will explore the barriers to screening uptake, including limited healthcare infrastructure, financial constraints, and inadequate awareness or understanding of lung cancer screening guidelines.

Discussion: The findings of this systematic review are intended to influence policies that enhance accessibility, affordability, and education surrounding lung cancer screening to improve outcomes for rural populations.

Registration: PROSPERO Registration: CRD42025644774.

Background: Current standard of care for squamous non-small cell lung cancer (sqNSCLC) is not very effective, and FGFR2b-targeted therapy may be a new option for patients with sqNSCLC. The prevalence and clinical implications of fibroblast growth factor receptor 2b (FGFR2b) expression in Chinese patients with advanced sqNSCLC remain poorly characterized. This study evaluated FGFR2b expression patterns, their association with programmed death-ligand 1 (PD-L1) expression, and clinical outcomes in this population.

Methods: This retrospective cross-sectional analysis screened three hundred newly diagnosed advanced sqNSCLC patients from 2018 to 2024. Archival biopsy samples were assessed for FGFR2b expression via immunohistochemistry (IHC). A total of 266 patients, with histologically confirmed stage IIIB-IV sqNSCLC and valid FGFR2b protein expression status, were enrolled. Historical clinical data and PD-L1 detection reports were extracted from hospital records.

Results: Among the 266 patients, 117 (44.0%, 117/266) were diagnosed with IIIB/IIIC-stage cancer, and 149 (56%, 149/266) were diagnosed with IV-stage cancer. FGFR2b positivity (≥1+ in ≥1% tumor cells) was observed in 50.8% of patients, while overexpression (≥2+ in ≥1% tumor cells) occurred in 19.5%. FGFR2b expression was correlated significantly with sex (P=0.04), and cancer stage (P=0.01). Among 204 patients with valid FGFR2b and PD-L1 dual expression data, over 80% of FGFR2b-positive tumors demonstrated concurrent PD-L1 expression. In patients receiving first-line paclitaxel/nab-paclitaxel-platinum combined with anti-programmed cell death-1 (PD-1)/PD-L1 antibodies, FGFR2b-positive cohorts exhibited superior outcomes: higher objective response rate (57.4% vs. 41.9%) and prolonged median progression-free survival {11.3 months [95% confidence interval (CI): 6.6-17.9] vs. 6.5 months (95% CI: 5.0-17.3)} compared to FGFR2b-negative counterparts.

Conclusions: FGFR2b expression may serve as a predictive biomarker for therapeutic response of FGFR2b-targeted agents in sqNSCLC. The high co-expression rate of FGFR2b and PD-L1 supports the feasibility of combining FGFR2b-targeted agents with immune checkpoint inhibitors as a rational treatment strategy.