EGFR

This study investigated additional genetic alterations in MET-amplified gastric cancers (GCs), which are associated with poor prognosis and limited response to targeted therapies. Researchers found that MET amplification is frequently accompanied by co-amplifications of other oncogenes located on chromosome 7, such as BRAF, CDK6, and EGFR, in 54% of cases. These co-amplifications exhibit significant intra- and intertumoral heterogeneity. This complex heterogeneity may explain the diagnostic and therapeutic challenges, subclonal evolution, and the failure of targeted therapies in MET-amplified GCs.

Homozygous MTAP loss is frequently observed in oncogene-driven non-small-cell lung cancers (NSCLC), particularly in EGFR, ALK, and RET altered subtypes. While this loss did not significantly impact the response to first-line targeted therapies, it creates a selective vulnerability to PRMT5 inhibitors. Preclinical studies demonstrated that the PRMT5 inhibitor BMS-986504 is active in MTAP-deleted NSCLC models and can enhance the efficacy of existing targeted therapies. These findings suggest a novel combined therapeutic strategy for NSCLC patients with MTAP loss.

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 prospective observational study assessed the utility of circulating tumor DNA (ctDNA) for mutational profiling and dynamic monitoring in 33 patients with metastatic colorectal cancer receiving palliative chemotherapy. ctDNA was detected in most patients at baseline, revealing frequent mutations in APC, TP53, KRAS, and PIK3CA. Good concordance was observed between plasma ctDNA profiles and tissue data. Longitudinal analysis showed the emergence of acquired mutations, particularly RAS mutations under anti-EGFR therapy, and correlated high ctDNA levels with shorter overall survival. These findings highlight ctDNA's potential to guide personalized treatment strategies and monitor resistance.

The phase II ORCHARD study investigated the efficacy and safety of combining osimertinib with datopotamab deruxtecan (Dato-DXd) in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who had progressed on first-line osimertinib. Two Dato-DXd doses (4 mg/kg and 6 mg/kg) were evaluated. Both cohorts demonstrated clinical benefit, with objective response rates (ORR) of 43% and 36% respectively. Median progression-free survival (PFS) was 9.5 months for the 4 mg/kg dose and 11.7 months for 6 mg/kg, while median overall survival (OS) reached 19.8 months and 26.2 months. Although the 6 mg/kg dose was associated with higher toxicity, it was manageable, and this dose is suggested as the preferred starting dose given the overall benefit-risk profile.

The prospective, multicenter ELIOS study characterized acquired resistance mechanisms to first-line osimertinib in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). By analyzing paired tumor biopsies taken pre-treatment and post-progression, the study identified frequent alterations including MET amplification, CDKN2A/CDKN2B and MTAP deletions, and the EGFR C797S mutation. Proteogenomic analysis also revealed high TROP2 expression, irrespective of genetic alterations. The findings highlight the heterogeneous nature of resistance and the complementary utility of tissue and liquid biopsies for alteration detection. This study emphasizes the need for therapeutic strategies targeting multiple resistance pathways.

This study characterizes Epstein-Barr virus (EBV)-positive small cell neuroendocrine carcinoma of the nasopharynx (SCNEC-nasopharynx), a rare and aggressive entity. By analyzing 15 cases, it described their distinct clinicopathological and molecular features. Patients typically presented with advanced-stage disease and had a median overall survival of 33 months following multimodal therapy. Molecular profiling revealed a higher mutational burden and unique alterations in cell cycle and DNA damage pathways compared to non-keratinizing carcinomas. These findings provide an essential foundation for precise diagnosis and the future development of targeted therapies.

This study identified invasion/metastasis-related differentially methylated genes (DMGs) with prognostic relevance in diffuse gliomas. A risk model was constructed using two marker genes, ERRFI1 and MYO1G, demonstrating robust predictive performance in both training and independent validation cohorts. Patients classified as high-risk exhibited worse overall survival and altered immune infiltration. In vitro functional validation showed that knockdown of ERRFI1 or MYO1G inhibited glioma cell proliferation, invasion, and migration, with potential involvement of the EGFR/MAPK/ERK pathway.

This single-center retrospective study assessed the clinical utility of comprehensive genomic profiling (CGP) in 108 patients with advanced or recurrent non-small cell lung cancer (NSCLC) after standard treatments. CGP detected druggable genetic aberrations in 37% of patients, with EGFR mutations being the most common. Resistance mechanisms were identified in nearly half of patients re-biopsied after targeted therapy. Although CGP-guided therapy was recommended for 35.2% of patients, only 16.6% received it, showing a trend towards prolonged overall survival for this subgroup. The study concludes that CGP can identify actionable mutations missed by conventional diagnostics, thus providing additional therapeutic opportunities in NSCLC.

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 observational study, conducted using the Italian ATLAS Registry, evaluated the efficacy and safety of amivantamab in 119 patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. Most patients had previously received platinum-based chemotherapy, with or without immunotherapy. Amivantamab, administered as a single agent in subsequent lines, demonstrated an objective response rate of 37.5%, a median progression-free survival of 9.6 months, and a median overall survival of 16.9 months. The safety profile was manageable, with grade 3-4 treatment-related adverse events reported in 10.9% of patients, confirming data from the CHRYSALIS trial in a heavily pretreated real-world population.

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.