Search Results (640)

Background/Objectives: Most cases of non-small cell lung cancer (NSCLC) are diagnosed at advanced stages, where prognosis remains poor. Machine learning (ML) offers new opportunities for patient stratification. This study aimed to identify distinct subgroups of patients with advanced-stage NSCLC using unsupervised ML techniques and to evaluate their association with survival outcomes and biomarker expression. Methods: 400 patients with advanced-stage NSCLC were analyzed using the k-prototypes algorithm. Clinical, demographic, and analytical variables, including smoking history and comorbidities, were incorporated. Identified clusters were compared in terms of molecular biomarkers and overall survival. A multivariable Cox proportional hazards model was performed to assess the association between cluster membership and overall survival. Results: Five patient profiles were identified. Cluster F, characterized by a predominance of women, relatively low smoking exposure, and a higher frequency of epidermal growth factor receptor (EGFR) mutations, showed the most favorable survival profile. Cluster S comprised mainly male heavy smokers with poorer performance status and high metastatic burden, whereas Cluster Y consisted predominantly of younger men without comorbidities but with frequent M1c disease. Clusters E and O showed intermediate outcomes and were characterized by older age with pleural effusion and by an older predominantly male smoking profile, respectively. In the multivariable Cox model, compared with Cluster F, a higher risk of death was observed for Cluster S (HR 1.62, 95% CI 1.01–2.60; p = 0.045) and Cluster Y (HR 1.55, 95% CI 1.09–2.21; p = 0.015), although the association for Cluster S should be interpreted cautiously. Differences in molecular biomarker distribution were also observed across clusters, particularly for EGFR mutations and programmed death-ligand 1 (PD-L1) expression. Conclusions: In this single-centre retrospective pilot study, unsupervised ML identified distinct patient profiles associated with differences in survival outcomes and molecular characteristics. These findings support the potential of data-driven approaches to characterize heterogeneity in advanced-stage NSCLC, although external validation is required before clinical application. Full article

Background/Objectives: Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Conventional computed tomography (CT) is the preferred imaging modality for evaluating pulmonary nodules because of its high spatial resolution; however, it primarily provides morphological information, including lesion size, shape, and density. Dual-energy CT (DECT), a more recent imaging technique, uses two different energy levels to enable material decomposition and quantitative parameter assessment. These parameters may provide additional information regarding tumor perfusion, vascularization, and tissue composition. This rapid review aimed to evaluate the current evidence regarding the clinical utility of DECT in the detection, characterization, and staging of lung tumors. Methods: This rapid review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed in the PubMed and Cochrane Library databases for studies published between 2005 and 2026. Studies were included if they evaluated the detection, characterization, or staging of lung tumors using quantitative DECT parameters. Case reports, editorials, duplicate studies, and studies without quantitative DECT data were excluded. Descriptive data analysis was performed using Microsoft Excel. Results: A total of 24 studies were included, comprising 18 retrospective (75%) and 6 prospective studies (25%). Only one study evaluated the role of DECT in lung tumor detection, demonstrating improved detection of mixed ground-glass nodules and invasive adenocarcinoma. Significant correlations were found between iodine uptake and tumor perfusion, highlighting the potential of DECT to improve differentiation between benign and malignant lesions. Several studies also demonstrated associations between DECT parameters and tumor biomarkers, including Ki-67 Proliferation Index (Ki-67) expression, Epidermal Growth Factor Receptor (EGFR) mutation status, Programmed Death-Ligand 1 (PD-L1) expression, and treatment response in non-small cell lung cancer. In addition, DECT provided complementary metabolic information regarding tumor malignancy and showed correlations between iodine uptake and fluorodeoxyglucose (FDG) parameters. Associations between iodine volume and tumor differentiation grade were also reported. One study demonstrated the potential role of DECT in tumor staging by predicting mediastinal lymph node metastasis. Across all included studies, iodine-based parameters (50%), radiomics and material decomposition parameters (16.67% each), and spectral attenuation parameters (12.50%) were the most frequently investigated DECT metrics. Conclusions: DECT appears to be a promising complementary imaging technique that provides quantitative perfusion-related and compositional surrogate information beyond the morphological assessment offered by conventional CT. However, the current evidence remains heterogeneous and is largely based on retrospective studies with relatively small patient cohorts. Larger prospective studies with standardized imaging protocols are necessary to further establish the clinical utility of DECT in lung tumors. Full article

Brain metastases represent a major clinical challenge in the management of non-small-cell lung cancer, particularly in patients with epidermal growth factor receptor mutations, constituting a leading cause of morbidity and mortality. In recent years, significant advancements have been made in both local therapies and systemic treatments. Nevertheless, managing central nervous system disease remains complex, encompassing challenges such as optimal therapy sequencing, resistance mechanisms, oligoprogression, the role of the blood–brain barrier, diagnostic strategies, and the influence of the brain tumor microenvironment. Despite advances, brain metastases in non-small-cell lung cancer remain an unmet need. Local treatments like radiotherapy are effective but carry risks of long-term neurological side effects, while the number and burden of brain metastases remain key prognostic factors. Surgical resection may be considered even in patients with multiple brain metastases to improve clinical status, enable further therapy, and enhance survival and quality of life. With the extension of survival afforded by systemic therapies, optimizing the balance between treatment efficacy and quality of life has become critical. Integrating patient perspectives is essential in navigating these complex clinical decisions. Full article

Background: Lung adenocarcinoma (LUAD) is the most prevalent histologic subtype of non-small cell lung cancer (NSCLC) and exhibits considerable molecular heterogeneity. Among the most clinically significant driver alterations are mutations in EGFR and KRAS, both of which influence treatment selection and oncologic outcomes. The prevalence of these mutations varies by race, yet racial minority populations remain underrepresented in genomic studies. EGFR alterations are more frequently observed in Asian patients, while KRAS mutations predominate in non-Asian cohorts. This study aimed to characterize race-associated differences in driver mutation prevalence among Asian, Black, and White patients with LUAD. Methods: A retrospective secondary cohort analysis was performed using publicly available clinicogenomic data from the Lung Adenocarcinoma Met Organotropism cohort, accessed via cBioPortal, comprising 2653 tumor samples. Patients were stratified by self-reported race into Asian, Black, and White cohorts; cases with missing race data were denoted as either other or unknown. Mutation frequencies for EGFR, KRAS, and TP53 were extracted from OncoPrint cohort study views and compared descriptively across groups. Results: Distinct race-associated differences in driver mutation prevalence were observed. Asian patients exhibited the highest frequency of EGFR alterations (64%), compared with Black (41%) and White (28%) cohorts. In contrast, KRAS mutations were least prevalent in Asian patients (10%) and more frequent in White (33%) and Black (23%) cohorts, indicating an inverse distribution between Asian and non-Asian populations. TP53 mutation prevalence was similar in Asian (52%) and White (53%) cohorts but was notably higher in Black patients (65%). Conclusions: Asian patients with LUAD exhibit a distinct molecular profile characterized by EGFR predominance, with direct implications for eligibility for EGFR-targeted tyrosine kinase inhibitor therapy. Black patients may also benefit from EGFR-based targeted therapies, but lack of large genomic data on Black populations warrants further investigation. White cohorts display a KRAS-dominant mutation pattern, suggesting divergent tumorigenic pathways and the potential need for alternative therapeutic strategies. The elevated TP53 frequency in Black patients remains to be further characterized. These findings support integrating race-associated genomic profiling into precision oncology frameworks to improve treatment selection and reduce disparities in outcomes. Full article

Modeling the dynamics of three tumor cell populations, i.e., sensitive, persister, and resistant tumor cells, during molecularly targeted therapy with tyrosine kinase inhibitors (TKIs) would be valuable for adjusting treatment plans for patients with epidermal growth factor receptor-mutated non-small cell lung cancer (EGFR-mt NSCLC). We hypothesized the time-variant tumor growth trajectories (TGTs) of patients with stage IV EGFR-mt NSCLC for the three tumor cell populations could be expressed using differential models after several follow-up computed tomography examinations. We aimed to propose differential models for TGTs in three cell populations from patients with EGFR-mt NSCLC treated with an EGFR-TKI (osimertinib). We selected two differential equations—Bertalanffy–Pütter (BP) and Gompertz—to develop TGT models. The parameters of the models were optimized based on a dual annealing method within parameter ranges determined using synthetic patient data. Using CT examinations that were not employed for model fitting, the mean absolute percentage errors (MAPEs) for BP-based and Gompertz-based models were 36.1 ± 40.2% and 43.9 ± 60.1%, respectively, for three follow-up computed tomography (FCT) examinations, which indicated no statistically significant difference (p = 0.61). This study suggests that the proposed BP-based and Gompertz-based differential models could have the potential to express TGTs in patients with stage IV EGFR-mt NSCLC treated with EGFR-TKIs after three follow-up CT examinations, although MAPEs should be mitigated in future works. Full article

Background: Sensitive detection of EGFR mutations in liquid biopsies of advanced non-small-cell lung cancer (aNSCLC) is vital for guiding targeted treatments. Real-time PCR offers a quick turnaround time but relatively low sensitivity while Next-Generation Sequencing (NGS) offers broader EGFR coverage, co-mutation evaluation and high sensitivity. Methods: This study evaluated the amplicon-based NGS Plasma-SeqSensei™ Solid Cancer In Vitro Diagnostics (IVD) Kit (Sysmex) against the real-time PCR-based cobas^® EGFR Mutation Test v2 (Roche), the current routine standard at the Veneto Institute of Oncology IOV-IRCCS. We enrolled 130 patients with aNSCLC in the RARE Study between April 2022 and August 2025 who were referred to our institute. Liquid biopsies were taken at diagnosis or at progression and analyzed using two methods with the primary objective of assessing diagnostic concordance for EGFR profiling. Sysmex NGS libraries were sequenced on a NextSeq 550 sequencer (Illumina), with the NextSeq 500/550 Mid Output Kit v2.5 (150 Cycles) in single-end mode. Results: Among 129 evaluable samples, the NGS assay demonstrated a marginally higher EGFR mutation detection rate, identifying mutations in 31/129 cases (24.0%, 95% CI: 17–33), versus 28/129 (21.7%, 95% CI: 15–30) by cobas, specifically for variants covered by both assays. Overall concordance was almost perfect (Cohen’s Kappa = 0.89, 95% CI: 0.80–0.98), confirming the high reliability of both methods. Furthermore, we identified a cfDNA input threshold of at least 20 ng as critical for ensuring optimal assay sensitivity and reliable mutation detection (Odds Ratio = 4.41 for inputs ≥ 20 ng, p = 0.006). Conclusions: Ultimately, the Sysmex NGS proved to be a robust and highly sensitive assay. It delivers performance comparable to that of standard RT-PCR while providing the clinical advantage of concurrently detecting a broader spectrum of EGFR variants and actionable mutations in other genes. Full article

Epidermal growth factor receptor (EGFR)-targeted therapy represents one of the earliest and most established examples of precision oncology in non-small-cell lung cancer (NSCLC), with more than 10 approved agents, including tyrosine kinase inhibitors, bispecific antibodies and antibody–drug conjugates. Over the past two decades, the diagnostic and therapeutic landscape of EGFR-mutant NSCLC has evolved from empiric treatment to mutation subtype-guided strategies, from advanced disease to earlier-stage interventions, and from monotherapy to rational combination regimens. Somatic EGFR mutations remain key predictive biomarkers guiding treatment selection, therapeutic intensification, resistance mechanism-directed treatment, and disease monitoring through plasma circulating tumor DNA burden. In parallel, germline EGFR alterations are increasingly recognized as contributors to inherited lung cancer susceptibility, particularly among never-smokers and familial clusters. Germline EGFR T790M is the best-characterized pathogenic variant, creating a permissive background for multifocal lung nodules and lung adenocarcinoma development, often following acquisition of a second somatic EGFR driver mutation. Recent familial, regional, and paired tumor–normal sequencing studies have expanded the evidence beyond isolated case reports and support an emerging hereditary lung cancer predisposition phenotype. Clinically, germline EGFR should be suspected when EGFR T790M is detected prior to TKI exposure, particularly at variant allele fractions near 50%, or in patients with multifocal ground-glass nodules, multiple primary lung adenocarcinomas, early-onset disease, never/light smoking history, or family history of lung cancer. Confirmation requires germline testing and genetic counseling. This review highlights the current knowledge, recent advances, and future directions in somatic and germline EGFR-mutant NSCLC, emphasizing translational relevance for clinicians and researchers. Full article

The discovery of activating epidermal growth factor receptor (EGFR) mutations transformed the management of non-small cell lung cancer and has driven two decades of therapeutic advances in precision oncology across metastatic, resectable, and unresectable locally advanced disease, including central nervous system (CNS) control. Consequently, treatment outcomes for patients with tumors harboring classical EGFR mutations have markedly improved. Despite these advances, many questions remain unanswered, and the expanding number of treatment options has created new challenges in treatment selection and sequencing. This narrative review summarizes contemporary data on the management of classical EGFR-mutant NSCLC, encompassing novel therapeutic approaches across disease stages, biomarker-informed resistance strategies, multimodality treatment integrating radiotherapy, CNS-directed management, and challenging scenarios such as small-cell transformation. We also discuss emerging fourth-generation inhibitors, nucleic-acid delivery platforms, and data-enabled personalized treatment. We highlight evolving standards of care, unresolved knowledge gaps, and research priorities for the next decade. Full article

The emergence of antibody-drug conjugates (ADCs) targeting trophoblast cell-surface antigen 2 (TROP2) represents a potential paradigm shift in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), a setting historically characterized by limited therapeutic options following progression on EGFR tyrosine kinase inhibitors (TKIs). This review examines the biological rationale and clinical challenges underpinning the development of anti-TROP2 ADCs in EGFR-mutated NSCLC. From a mechanistic standpoint, TROP2 occupies a unique and dynamic role in EGFR-mutated NSCLC, providing strong biological rationale for clinical development of anti-TROP2 ADCs in this population. Three TROP2-directed ADCs are currently in clinical development in this setting. Available clinical data in previously treated EGFR-mutated patients are critically reviewed here, focusing on efficacy, toxicity profiles, clinical challenges and potential future perspectives. Full article

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), limiting the durability of targeted therapy. Bardoxolone methyl (CDDO-Me) has been reported to exert anti-inflammatory and anti-cancer activities. However, its role in acquired EGFR-TKI resistance remains unclear. Here, we found that CDDO-Me significantly enhanced sensitivity of resistant NSCLC cells to gefitinib, with combination index analysis confirming a synergistic interaction between CDDO-Me and gefitinib. Mechanistically, CDDO-Me induced mitochondrial dysfunction and reactive oxygen species (ROS) accumulation, thereby activating Caspase-3 mediated apoptosis and GSDME-dependent pyroptosis, as evidenced by increased lactate dehydrogenase (LDH) release. Network pharmacology and molecular docking analyses identified Src as a potential target of CDDO-Me. Cellular thermal shift assay (CETSA) confirmed cellular engagement between CDDO-Me and Src, and Western blot analysis showed that CDDO-Me suppressed Src/STAT3 signaling. Consistently, Src knockdown reduced the inhibitory effect of combined CDDO-Me and gefitinib treatment on colony formation and attenuated changes in apoptosis and pyroptosis regulatory proteins induced by the combination treatment. Collectively, these findings suggest that CDDO-Me enhances gefitinib sensitivity by targeting Src and suppressing Src/STAT3 signaling, leading to apoptosis and pyroptosis in gefitinib-resistant NSCLC cells. This study provides mechanistic evidence for further investigation of CDDO-Me-based combination strategies for gefitinib-resistant NSCLC. Full article

KRAS G12C, long considered an undruggable oncogenic driver, has become one of the most consequential therapeutic targets in non-small cell lung cancer (NSCLC). The discovery of a cryptic binding pocket accessible in the GDP-bound state enabled covalent inhibitors—sotorasib and adagrasib—that have received regulatory approval for previously treated KRAS G12C-mutant NSCLC, with sotorasib demonstrating PFS and OS superiority over docetaxel in CodeBreaK 200 and adagrasib showing meaningful intracranial activity and a progression-free survival benefit over docetaxel in KRYSTAL-12. Yet response durability is limited by on-target switch-II pocket mutations, upstream RTK and SHP2-mediated bypass signaling, downstream MAPK and PI3K-AKT reactivation, phenotypic plasticity, and adverse modulation by co-occurring STK11, KEAP1, and TP53 alterations. Next-generation covalent inhibitors (divarasib, glecirasib, olomorasib), tri-complex RAS(ON) inhibitors (RMC-6291), pan-KRAS agents, and rationally designed combinations with EGFR, SHP2, SOS1, and PD-1 inhibitors are repositioning KRAS-directed therapy toward earlier lines of treatment. This review integrates the structural, signaling, and clinical biology of KRAS G12C with contemporary trial and real-world evidence to examine the emerging case for first-line KRAS G12C inhibition in genomically defined subsets of NSCLC. First-line use nonetheless remains investigational; platinum-based chemoimmunotherapy remains the standard of care outside of clinical trials, and a frontline indication will require confirmation from randomized phase III trials. Full article

Non-small cell lung cancer (NSCLC) comprises a diverse group of malignancies driven by distinct molecular alterations that have become critical targets for precision oncology. Among these, EGFR exon 20 insertion mutations and HER2 dysregulation, including HER2 mutations, amplification, and overexpression, define clinically important subsets of NSCLC characterized by unique biological behavior and historically limited treatment options. Although these alterations account for a relatively small proportion of NSCLC cases, their identification has become increasingly relevant due to advances in molecular diagnostics and the development of novel targeted therapies. This review provides a comprehensive overview of the epidemiology, molecular biology, and clinical characteristics of EGFR exon 20 insertion-mutated and HER2-deregulated NSCLC. We discuss current diagnostic approaches, including the role of next-generation sequencing and biomarker testing, and summarize the evolving therapeutic landscape encompassing conventional chemotherapy, immunotherapy, and targeted agents. Particular attention is given to recently approved therapies and emerging treatment strategies, including tyrosine kinase inhibitors and antibody-based therapies that have demonstrated clinically meaningful activity in these patient populations. We also address the major challenges associated with treatment resistance, molecular heterogeneity, and optimal therapeutic sequencing. Finally, we highlight ongoing research efforts and future perspectives aimed at improving outcomes for patients with these rare but clinically significant molecular subtypes of NSCLC. Full article

Background/Objectives: Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has undergone rapid therapeutic evolution. However, heterogeneous outcomes persist, driven by mutations, central nervous system (CNS) involvement, and dynamic tumor burden reflected in part by circulating tumor DNA (ctDNA). As such, this review aims to summarize the most recent risk stratification frameworks in treating EGFR-mutant NSCLC, evaluate evidence supporting treatment intensification strategies and managing adverse effects, and explore the evolving role of ctDNA in guiding personalized therapy. Methods: A comprehensive literature search was conducted using major medical databases with a focus on key relevant studies on the workup and management of EGFR-mutant NSCLC. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Molecular co-alterations, such as TP53 and RB1, as well as central nervous system (CNS) involvement, are consistently associated with inferior outcomes, supporting consideration of upfront treatment intensification. Combination strategies, including osimertinib plus chemotherapy or amivantamab-based regimens, demonstrate improved progression-free survival and delayed CNS progression when compared against osimertinib monotherapy. Intensification, however, is associated with a higher risk of increased toxicity, including dermatologic adverse events and infusion-related reactions. Finally, the utilization of circulating tumor DNA (ctDNA) has emerged as a strong prognostic marker, with ongoing trials investigating its predictive role for both escalation and de-escalation of therapy. Conclusions: The treatment paradigm for EGFR-mutant NSCLC is gradually evolving beyond first-line osimertinib to include a more integrated approach that considers molecular features, CNS involvement, and early ctDNA response. Although intensified regimens offer meaningful efficacy gains for high-risk patients, proactive toxicity management is essential to preserving quality of life. ctDNA-guided strategies represent a new and promising frontier for escalation and de-escalation of therapy, with results from ongoing trials poised to further refine personalized treatment algorithms. Full article

Background and Clinical Significance: Brain metastases in non-small cell lung cancer (NSCLC) carry a poor prognosis, particularly in patients lacking targetable driver mutations or significant programmed death-ligand 1 (PD-L1) expression. Durable intracranial control exceeding five years is uncommon in this population and the factors that determine exceptional therapeutic response remain incompletely understood; Case Presentation: We report a 59-year-old male with pathological stage pT3N1 solid-type pulmonary adenocarcinoma (EGFR wild-type, ALK wild-type, PD-L1 <1%) who developed two sequential brain metastases following right upper lobectomy and adjuvant pembrolizumab plus pemetrexed-carboplatin. The first lesion was treated with single-fraction stereotactic radiosurgery (SRS, 10 Gy); a second metastasis identified 18 months later was managed with focal radiotherapy (8 Gy, single fraction) followed by whole-brain radiotherapy (24 Gy in 12 fractions). Local progression of the second metastasis in 2024 prompted successful surgical resection via right occipital craniotomy. Over a follow-up exceeding five years, the patient achieved sustained intracranial disease control, preserved neurological function, and maintained quality of life. Notably, no clinically apparent neurocognitive deterioration was documented on routine clinical follow-up, despite whole-brain irradiation without hippocampal sparing; formal neuropsychological testing was not performed; Conclusions: This case demonstrates that durable intracranial control may be achievable through carefully sequenced multimodal therapy—including stereotactic radiosurgery, whole-brain radiotherapy, and neurosurgical resection—even in biologically unfavorable NSCLC. The absence of clinically apparent neurocognitive deterioration on routine follow-up after WBRT raises hypothesis-generating questions regarding interindividual variability in radiation tolerance; this observation must be interpreted in the absence of formal neuropsychological testing and prospective hippocampal dosimetry. A multidisciplinary, individualized approach integrating radiotherapy, systemic therapy, and neurosurgery remains essential in this setting. Full article

A 64-year-old Asian woman diagnosed with synchronous breast ductal carcinoma in situ (DCIS) and stage IV EGFR-mutated non-small cell carcinoma of the lung (NSCLC). A decision was made to defer management of the DCIS and initiate Osimertinib for lung cancer treatment, since this was a life-limiting diagnosis. At 9 months, restaging FDG-PET CT showed an interval response in the NSCLC and complete loss of FDG avidity at the biopsy-proven DCIS site. Breast MRI confirmed complete imaging resolution of the DCIS. The clinical resolution of breast DCIS during third-generation EGFR inhibitor therapy has not been previously reported in humans and highlights a potential role for the EGFR/HER2 (ERBB) pathway in pre-invasive breast cancer. Full article