Lung Adenocarcinoma

This study investigates a simplified approach to identify lung origin in cancers of unknown primary (CUP). Researchers found that the presence of SMARCA4 mutations, combined with a history of smoking, is strongly associated with lung-origin CUP (CUP-Lung). This combination offers a 76% probability of lung origin, even without detectable pulmonary involvement. This method could serve as a surrogate for whole-genome sequencing (WGS) to guide organ-directed treatments.

This retrospective study evaluated the efficacy and prognostic factors of first-line bevacizumab plus chemotherapy in elderly patients (≥65 years) with advanced lung adenocarcinoma lacking driver gene alterations. Among 169 included patients, the bevacizumab-treated group demonstrated a median overall survival of 47 months and a median progression-free survival of 24 months. Multivariate analysis identified bevacizumab as an independent favorable prognostic factor for both progression-free and overall survival. Biomarkers related to inflammation, nutrition, and tumor burden were also associated with prognosis.

This study investigated the mechanisms and therapeutic targets of distant metastasis in lung adenocarcinoma (LUAD), with a focus on organotropism. By integrating digital spatial profiling (DSP), multiplex immunofluorescence (mIF), and clinical data, researchers developed highly accurate random forest models predicting organ-specific metastases to the brain, liver, adrenal gland, and bone. Key compartment-specific gene expression signatures were identified in tumor, immune, and stromal cells, including FKBP1A for brain and MOCOS for liver metastasis. The study also revealed distinct biological pathways and prognostic factors related to post-metastasis survival, providing promising new biomarkers and therapeutic targets.

This study identifies ERO1A as a novel and promising biomarker for early-stage lung adenocarcinoma (esLUAD). High ERO1A expression is associated with poor prognosis, yet paradoxically, it correlates with an immune-activated tumor microenvironment. Tumors with elevated ERO1A levels demonstrate a superior response to immune checkpoint inhibitors. This biomarker could therefore aid in patient stratification and guide peri-operative therapeutic decisions.

This study investigates histologic transformation to lung squamous cell carcinoma (LUSC) in EGFR-mutant lung adenocarcinoma (LUAD) patients, an underrecognized resistance mechanism. Multiomic analyses revealed that patients with transforming or adenosquamous (LUAS) phenotypes experienced shorter overall survival on first-line osimertinib. Inactivation of the retinoblastoma (Rb) pathway, particularly via CDKN2A/B deletions, was identified as a key driver of this transformation. Furthermore, MET pathway upregulation was observed, and combined EGFR and MET inhibition demonstrated efficacy in preclinical models. These findings suggest novel strategies to counteract this aggressive form of resistance.

This retrospective study investigated eight cases of multifocal micronodular pneumocyte hyperplasia (MMPH) associated with tuberous sclerosis complex (TSC), a rare benign pulmonary lesion. Patients typically presented with multiple ground-glass nodules in the lungs on CT scans and various clinical manifestations of TSC. A significant diagnostic challenge was highlighted, as intraoperative frozen sections were often misdiagnosed as early-stage lung adenocarcinoma. Next-generation sequencing revealed TSC1 or TSC2 gene mutations in most patients, confirming the association with TSC. All followed-up patients showed a favorable overall survival.

This prospective study evaluated gene expression profiling of seven genes (EGFR, FGFR2, PIK3CA, PTEN, SMAD4, STK11, TP53) in cell-free RNA (cfRNA) from exhaled breath condensate (EBC) in patients with advanced lung adenocarcinoma. Results indicated that PIK3CA showed the best diagnostic performance in distinguishing patients from healthy controls. High expression of FGFR2 and PIK3CA was associated with significantly shorter overall survival, highlighting their prognostic relevance. EGFR expression demonstrated a strong correlation between EBC and plasma, and low EGFR expression was linked to longer survival in patients receiving chemotherapy alone. This non-invasive EBC-based approach offers potential for molecular characterization and patient stratification.

This retrospective study analyzed 120 cases of lung adenocarcinoma (LUAD) with malignant serous effusions (MSE) to characterize their clinicopathologic, molecular, and prognostic features. Pleural effusions were most common, but pericardial involvement was associated with the shortest overall survival. Molecular profiling revealed TP53 mutations and actionable alterations in genes such as EGFR, KRAS, BRAF, ALK, and ROS1. NKX2-1 (TTF-1) negativity and the absence of actionable alterations were independent adverse prognostic factors, with dual NKX2-1/CD274 (PD-L1) negativity defining the poorest prognosis subgroup. Immunotherapy-based regimens and tyrosine kinase inhibitors showed varying survival benefits.

This study characterized the molecular architecture of the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) with somatic BRCA1/2 mutations, using single-cell sequencing and multi-omics data. BRCA1/2 mutations are linked to increased genomic instability and poor prognosis, yet predict better clinical outcomes with immune checkpoint blockade (ICB) treatment. BRCA1 mutations correlate with an upregulated type I IFN/IFN-γ signature and CD8+ T cell activation, while BRCA2 mutations are associated with inflammatory responses and enhanced MHC-II antigen presentation, influencing CD4+ T cell differentiation. The study also identified tissue-resident memory T cell (Trm) subsets as predictors of ICB response and found that a cancer-promoting program activated by BRCA1 is vulnerable to histone deacetylase inhibitors.