Search Results (3,211)

Background/Objectives: Outcomes in non–small cell lung cancer (NSCLC) remain heterogeneous, even within stage and molecular subtypes. We evaluated whether a Computational Histology Artificial Intelligence (CHAI) biomarker, derived solely from the diagnostic hematoxylin-and-eosin (H&E) whole-slide image (WSI), provides prognostic information independent of established clinicopathologic factors. Methods: Using The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) projects, 914 patients with an evaluable diagnostic digitized whole-slide images (WSI) and outcomes data were stratified by stage and histology and randomly split into a development set (30%, N = 270) and a held-out validation set (70%, N = 644). A CHAI histologic signature was developed and locked on the development set and applied without modification to the validation set. In development, image features were extracted from H&E-stained WSIs and used to train a Cox proportional hazards model to output a CHAI prognostic biomarker score and then dichotomized into high (CHAI positive (+))- and low (CHAI negative (−))-risk groups. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free interval (PFI). Associations were assessed by Kaplan–Meier and Cox proportional-hazards models and adjusted for traditional clinicopathologic and genomic variables. Results: A total of 644 patients were included in the validation cohort. Median age was 68 (IQR: 60–74), 388 (60%) were male, 317 (49%) had LUAD, 327 (51%) had LUSC, and 57 (9%) were never smokers. CHAI-positive patients had significantly worse OS than CHAI-negative patients (3-year OS: 53% vs. 69%; log-rank p < 0.001). The biomarker remained significantly associated with OS (HR 1.70, 95% CI 1.29–2.24, p < 0.001) and PFI (HR 1.39, 95% CI 1.05–1.84, p = 0.023) in multivariable analysis. The effect was consistent across both histologies, and a model combining the CHAI score with clinicopathologic variables was well-calibrated in validation. The biomarker was not associated with stage, age, sex, or histologic subtype, and its adjusted prognostic effect was unchanged after relevant genomic alterations were added to the model. CHAI-positive tumors were, however, enriched for KRAS mutations (21% vs. 11% wild-type, p adjusted = 0.005). Conclusions: An H&E-only CHAI NSCLC biomarker was developed and provided independent prognostic stratification in a held-out NSCLC validation cohort. Such a biomarker has the potential to refine risk stratification in NSCLC. Full article

Background: Patients presenting with concurrent lung and brain lesions pose a unique diagnostic and therapeutic challenge. The role of neurosurgical resection in the management of de novo non-small-cell lung cancer brain metastases (NSCLC-BM) remains poorly defined. Methods: Consecutive patients undergoing resection for NSCLC-BM between February 2018 and October 2025 were retrospectively analyzed. De novo NSCLC-BM was defined as radiographic detection of pulmonary and intracranial lesions concurrently or within 1 month during the initial diagnostic work-up. Clinical characteristics and outcomes were compared between de novo and metachronous brain metastases (BM). Multivariable Cox regression identified factors associated with overall survival (OS). Factors associated with long-term postoperative survival in the de novo subgroup were further explored using Firth logistic regression. Results: Among 248 surgically treated patients, 113 (45.6%) presented with de novo BM. Compared with metachronous BM, de novo patients more frequently presented with symptomatic and multifocal intracranial disease. Among 73 de novo patients with evaluable survival, median postoperative OS was 57.0 months (95% CI, 22.9–not reached). Postoperative OS and intracranial progression-free survival (iPFS) did not differ significantly between the two groups, and de novo presentation was not independently associated with postoperative survival. Driver-positive status and lower intracranial tumor burden were associated with durable postoperative survival in the de novo subgroup. Conclusions: Neurosurgical resection represents a reasonable option for appropriately selected patients with de novo NSCLC-BM. These findings provide real-world evidence to inform multidisciplinary, individualized decision-making in patients presenting with concurrent lung and brain lesions. Full article

Background: The Lung Immune Prognostic Index (LIPI), based on the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase, may reflect systemic inflammation and tumor-related metabolic burden. This study evaluated the prognostic value of pretreatment LIPI and its relationship with programmed death-ligand 1 (PD-L1) expression in patients with advanced non-small cell lung cancer (NSCLC) receiving nivolumab after first-line therapy. Methods: A total of 158 patients were included in this retrospective, single-center study. Patients were classified into LIPI 0, LIPI 1, or LIPI 2 groups according to their pretreatment LIPI scores. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier analysis and multivariable Cox regression. The prognostic value of LIPI was also evaluated within PD-L1-negative and PD-L1-positive subgroups, and LIPI × PD-L1 interactions were explored. Harrell’s concordance index was used to examine whether adding LIPI improved model discrimination beyond clinical variables and PD-L1 expression. PD-L1 data were available for 145 patients. Results: Median PFS was 566, 340, and 109 days for the LIPI 0, LIPI 1, and LIPI 2 groups, respectively, while median OS was 841, 760, and 201 days, respectively; the differences were statistically significant for both outcomes (both p < 0.001). The objective response rate (ORR) was 55.6%, 36.5%, and 4.9%, whereas the disease control rate (DCR) was 75.9%, 65.1%, and 14.6% in the LIPI 0, LIPI 1, and LIPI 2 groups, respectively (both p < 0.001). In multivariable analyses, higher LIPI remained independently associated with shorter PFS and OS, with the strongest association observed in the LIPI 2 group. LIPI also differentiated survival outcomes within both PD-L1-negative and PD-L1-positive subgroups, although no significant LIPI × PD-L1 interaction was identified for PFS or OS. The addition of LIPI increased the C-index from 0.583 to 0.698 for PFS (ΔC-index, 0.115; p < 0.001) and from 0.588 to 0.697 for OS (ΔC-index, 0.109; p = 0.003). Conclusions: Pretreatment LIPI was independently associated with PFS and OS in patients with advanced NSCLC receiving nivolumab after first-line therapy. Its association remained after adjustment for available PD-L1 expression data, and its addition improved model discrimination. These findings suggest that LIPI may provide prognostic information complementary to PD-L1 expression and routinely available clinical factors. Full article

Aptamer-functionalized liposomes are a promising strategy to improve the selectivity of anticancer therapies. AT11-L2 is a G-quadruplex (G4)-forming aptamer with high affinity for nucleolin (NCL), which is overexpressed at the surface of non-small cell lung cancer (NSCLC) cells. Here, we developed AT11-L2-functionalized liposomes loaded with doxorubicin (DOX) or BRACO-19 for targeted delivery to NSCLC cells. The effects of both compounds on AT11-L2 stability and the ability of the aptamer to retain G4 folding after liposome conjugation were evaluated. Liposomes were characterized for size, polydispersity, surface charge, stability, encapsulation efficiency, and release profile. Biological activity was assessed in A549 and MRC-5 cells. Liposomes had an average size of approximately 110 nm, with a slight size increase and reduced surface charge after AT11-L2 functionalization. The aptamer retained G4 folding in 100 mM KCl after conjugation. Encapsulation efficiency was approximately 90%. DOX showed substantial release within 72 h, whereas BRACO-19 exhibited a more sustained profile. AT11-L2-DOX liposomes showed preferential effects in A549 cells, while BRACO-19 formulations displayed lower selectivity and cytotoxicity. Additionally, the NCL-dependent internalization of AT11-L2-functionalized liposomes was supported by a protein-blocking assay using an anti-NCL antibody. These results support AT11-L2-functionalized liposomes as a versatile NCL-targeted delivery system for NSCLC. Full article

Lung cancer is the leading cause of cancer-related mortality worldwide, yet the majority of cases are diagnosed at advanced stages when a cure is rarely achievable. Low-dose computed tomography (LDCT) screening in high-risk populations reduces lung cancer mortality by 20–24% in randomised trials, but fewer than 20% of eligible adults in the United States undergo annual screening. We conducted a structured narrative review of PubMed, Embase, and the Cochrane Library for studies published between January 2002 and March 2026, supplemented by review of current clinical guidelines from the USPSTF, NCCN, ACS, CHEST, and ERS. Evidence from the National Lung Screening Trial (NLST) and the NELSON trial establishes the mortality benefit of LDCT screening, though both trials have important methodological limitations that affect generalisability. The NLST predominantly detected non-small cell lung cancer (NSCLC), particularly adenocarcinoma and squamous cell carcinoma, while small cell lung cancer (SCLC) was infrequently screen detected and showed no survival benefit from early detection. Guideline eligibility criteria have progressively broadened, and multivariable risk model-based selection using the PLCOm2012 now demonstrates superiority over categorical smoking thresholds in prospective validation cohorts, with the added benefit of reducing racial and ethnic eligibility disparities. Overdiagnosis estimates have declined substantially with extended follow-up, reaching 7% when observation exceeds five years. Implementation remains critically deficient: patient stigma, provider knowledge gaps, structural barriers, and inadequate electronic health record infrastructure collectively account for screening uptake below 20%. Integrating smoking cessation into screening encounters is evidence-based and cost-effective. Artificial intelligence tools show promising performance in nodule detection and risk prediction, but lack the prospective external validation required for routine clinical deployment. The field has established efficacy; the urgent challenge is now effectiveness at scale. Transitioning to risk model-based eligibility, expanding access to underserved populations, and mandating cessation integration represent the three highest-priority actions. A research agenda addressing never-smoker screening, personalised intervals, and robust AI validation must proceed in parallel. Full article

Background: Precision oncology has significantly transformed the management of non-small cell lung cancer (NSCLC) through the integration of molecular diagnostics, targeted therapies, and biomarker-driven treatment selection. Advances in next-generation sequencing (NGS) and liquid biopsy have improved the identification of actionable molecular alterations and enabled dynamic monitoring of tumor evolution. Objective: To provide a structured narrative review of current evidence regarding actionable molecular biomarkers, diagnostic methodologies, targeted therapies, and future directions in NSCLC precision oncology, with a specific focus on conceptualizing acquired resistance mechanisms. Methods: A structured narrative literature review was conducted by searching PubMed and Google Scholar for English-language studies published between 2015 and 2026. Eligible publications included clinical trials, cohort studies, translational research, reviews, and clinical guidelines addressing molecular profiling, targeted treatments, diagnostic approaches, and resistance mechanisms in NSCLC. Results: A total of 99 foundational studies and clinical documents were analyzed. Key actionable biomarkers included EGFR (Epidermal Growth Factor Receptor), ALK (Anaplastic Lymphoma Kinase), ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase), KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog), RET (Rearranged during Transfection), MET (Mesenchymal–Epithelial Transition Factor), HER2 (Human Epidermal Growth Factor Receptor 2) and NTRK (Neurotrophic Tyrosine Receptor Kinase) alterations, along with emerging targets such as NRG1 (Neuregulin 1) fusions. NGS emerged as the cornerstone of comprehensive molecular profiling, while liquid biopsy enabled longitudinal monitoring of tumor dynamics and resistance development. To organize the biological complexity of treatment failure, acquired resistance mechanisms were categorized into a three-tiered conceptual framework: target-centric genetic evolution (Tier 1), cellular plasticity and intratumoral heterogeneity (Tier 2), and non-genetic/microenvironmental adaptation (Tier 3). Targeted therapies significantly improved clinical outcomes compared with conventional chemotherapy; however, acquired resistance remained a major challenge across all tiers. Conclusions: Precision oncology in NSCLC is evolving from a biomarker-focused approach toward a dynamic framework integrating molecular diagnostics, targeted therapies, and continuous resistance monitoring. The proposed three-tiered resistance framework provides a structured basis for understanding treatment failure, guiding molecular reassessment at progression, and informing future adaptive therapeutic strategies to improve long-term patient outcomes. Full article

Background/Objectives: In recent years, neoadjuvant chemoimmunotherapy followed by surgery has improved outcomes in patients with stage II/III non-small cell lung cancer (NSCLC). However, the prognostic impact of residual mediastinal nodal disease after chemoimmunotherapy remains insufficiently defined, particularly with the introduction of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) 9th edition nodal subclassification. Methods: In this retrospective study, 90 consecutive patients with clinically node-positive (cN1-2) resectable locally advanced NSCLC who underwent neoadjuvant chemoimmunotherapy followed by curative-intent resection were included. Disease-free survival (DFS) was analyzed according to postoperative pathologic nodal status. Nodal status was assessed using the UICC/AJCC 8th edition (ypN0, ypN1, ypN2) and reclassified according to the 9th edition (ypN0, ypN1, ypN2a, ypN2b). Residual postoperative nodal disease was defined as residual pathologic nodal involvement (ypN+) in patients with clinically node-positive (cN+) disease at baseline. Results: The cohort comprised 90 patients (60% male, median age 63 years [interquartile range (IQR) 58–69]). Following neoadjuvant therapy, surgery revealed pathologic nodal clearance in 53 (58.9%) and residual nodal disease in 37 (41.1%) patients (ypN1, n = 16 [17.8%]; ypN2a, n = 15 [16.7%]; and ypN2b, n = 6 [6.7%]). DFS differed significantly by postoperative nodal status (global log-rank p < 0.001), with progressively poorer outcomes with increasing residual nodal burden. Conclusions: Residual nodal disease after neoadjuvant chemoimmunotherapy and surgery is associated with progressively inferior DFS according to its anatomic extent. The UICC/AJCC 9th-edition staging system provides clinically relevant prognostic granularity, supporting further investigation of mediastinal restaging and postoperative treatment strategies. Full article

Background/Objectives: Clinical outcomes with immune checkpoint inhibitors (ICIs), such as nivolumab, vary among patients with metastatic non-small cell lung cancer (NSCLC). The Lung Immune Prognostic Index (LIPI) may help stratify prognosis. This study evaluated the prognostic significance of LIPI in patients receiving second- or third-line nivolumab and developed a nomogram for individualized survival estimation. Methods: This single-center retrospective study included 142 patients with metastatic NSCLC who received second- or third-line nivolumab between February 2022 and December 2024, after progression on platinum-based chemotherapy. LIPI was calculated from baseline values obtained within 14 days before nivolumab initiation, based on a derived neutrophil-to-lymphocyte ratio (dNLR) > 3 and lactate dehydrogenase (LDH) > 225 U/L (institutional upper limit of normal), classifying patients as good-, intermediate-, or poor-risk (0, 1, or 2 factors, respectively). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method; independent prognostic factors were assessed by multivariable Cox regression, and a prognostic nomogram combining ECOG performance status, serum albumin, and LIPI was developed and internally validated. Results: By LIPI, 34.5%, 45.1%, and 20.4% of patients were at good, intermediate, and poor risk, respectively. Objective response and disease control rates were 29.6% and 55.6%. Median OS and PFS were 19.3/8.0/3.1 and 8.6/3.1/2.5 months across good, intermediate, and poor LIPI groups (log-rank p < 0.001). In multivariable analysis, ECOG 2 (hazard ratio [HR], 4.94), albumin per 1 g/dL (HR 0.27), and poor versus good LIPI (HR 3.74) were independently associated with OS. A nomogram combining these three factors showed acceptable discrimination (optimism-corrected Harrell C-statistic 0.742). Conclusions: LIPI was independently associated with prognosis in this cohort. Combining LIPI with ECOG and albumin may aid individualized risk assessment, pending external validation. Full article

Background: Host-related factors such as skeletal muscle and adipose tissue characteristics are increasingly recognized as determinants of outcome in advanced non-small cell lung cancer (aNSCLC). However, the prognostic relevance of integrated body composition phenotypes in patients receiving first-line immunotherapy-based treatment remains unclear. Methods: We retrospectively analyzed patients with aNSCLC treated with first-line immune checkpoint inhibitors (ICI) alone or combined with chemotherapy (ICI–CT) between October 2018 and December 2023 at LMU University Hospital. AI-derived CT biomarkers included skeletal muscle volume index (SMVI), skeletal muscle density (SMD), visceral adipose volume index (VAVI), and subcutaneous adipose volume index (SAVI), normalized for height. Individual body composition parameters were analyzed as standardized continuous variables. For exploratory phenotype analyses, SMVI and VAVI were categorized using cohort-specific sex-stratified median values. An integrated body composition phenotype was defined as “high-muscle/low-visceral-adiposity” (high SMVI/low VAVI) or “low-muscle/high-visceral-adiposity” (low SMVI/high VAVI), with patients not meeting either definition classified as having an intermediate phenotype. Multivariable Cox regression adjusted for age, sex, treatment modality, and metastatic burden evaluated associations with progression-free survival (PFS) and overall survival (OS). Results: Of 116 screened patients, 103 with evaluable baseline CT imaging were included. The cohort predominantly comprised ever-smokers (81.6%) and patients with adenocarcinoma (62.1%). Higher SMD (per one standard deviation increase) was associated with improved overall survival (HR 0.72, 95% CI 0.52–1.00; p = 0.047), and higher VAVI was associated with a higher risk of death (HR 1.29, 95% CI 1.00–1.65; p = 0.048). Neither SMD nor VAVI was significantly associated with PFS, and SMVI and SAVI were not significantly associated with OS or PFS. In the exploratory integrated phenotype analysis, median OS was 29.5 months in the high-muscle/low-visceral-adiposity group, 16.2 months in the intermediate group, and 19.3 months in the low-muscle/high-visceral-adiposity group; however, the overall Kaplan–Meier comparison was not statistically significant (log-rank p = 0.385). Conclusions: AI-derived CT body composition assessment may provide complementary prognostic information in patients with aNSCLC receiving first-line immunotherapy-based treatment. Higher skeletal muscle density was associated with a lower risk of death, whereas higher visceral adiposity was associated with a higher risk of death. The exploratory integrated phenotype analysis did not demonstrate a consistent risk gradient across phenotype categories. These findings require validation in larger prospective cohorts before clinical implementation. Full article

Non-small-cell lung cancer (NSCLC) treatment is hampered by its complex pathogenesis and high heterogeneity. N6-methyladenosine (m⁶A) represents the most common post-transcriptional modification regulating RNA stability and function in eukaryotes. This methylation is catalyzed by methyltransferase complexes, with METTL14 being the core catalytic subunit. Abnormal expression of lncRNA MSTRG.292666.16 is related to poor prognosis of NSCLC. However, the mechanism by which it regulates NSCLC progression through m⁶A modification remains unclear. We employed cell function experiments, molecular mechanism analysis, RNA interaction experiments, and a nude mouse tumor model to explore the roles of METTL14-mediated MSTRG.292666.16 m⁶A modification in NSCLC and the potential MAPK signaling pathway involved. METTL14 was significantly upregulated in NSCLC cell lines and promoted m⁶A modification of MSTRG.292666.16 by forming a stable association with it. METTL14 knockdown significantly inhibited the viability, migration and invasion of A549 cells and promoted apoptosis, whereas MSTRG.292666.16 overexpression reversed these effects. Mechanistically, METTL14 upregulated the expression of MSTRG.292666.16 through m⁶A modification, thereby activating the MAPK pathway (manifested as elevated levels of MAPK8IP3 and p-ERK1/2). The use of a selective p38 MAPK inhibitor SB203580 stimulated the tumor-suppressive effect of METTL14 knockdown, whereas the activator U-46619 reversed it. In vivo experiments confirmed that METTL14 knockdown significantly inhibited tumor growth, whereas MSTRG.292666.16 overexpression partially restored the malignant phenotype of the tumor, which was associated with MAPK pathway activation. This study revealed that METTL14-dependent m⁶A modification of MSTRG.292666.16 may act as an upstream driver to activate the MAPK cascade and facilitate NSCLC progression. These findings clarify a key epitranscriptomic regulatory mechanism driving NSCLC development and offer preliminary molecular clues for exploring potential therapeutic targets in subsequent clinical NSCLC research. Full article

Actionable ALK, ROS1, RET, NTRK, and NRG1 fusions define biologically distinct subsets of advanced non-small cell lung cancer (NSCLC), yet real-world data across these rare populations remain limited. We retrospectively evaluated patients with advanced NSCLC treated at Memorial Healthcare System who received genotype-matched fusion-directed therapy; the first fusion-directed agent defined the index treatment, and survival was measured from its initiation. Progression was determined from radiographic reports and treating-oncologist documentation. After patient-level reconciliation, 59 unique patients were included: 29 ALK, 14 ROS1, 11 RET, 3 NTRK, and 2 NRG1. Median follow-up was 47.7 months (95% CI, 28.6–58.7), median progression-free survival was 44.8 months (95% CI, 17.1–not estimable), and median overall survival was not reached. No statistically significant survival differences were detected among ALK, ROS1, and RET subgroups, although limited sample sizes preclude exclusion of clinically meaningful differences. Later-line index therapy was not significantly associated with progression-free survival in exploratory unadjusted analysis. These findings provide descriptive real-world evidence of precision-oncology implementation across actionable fusion-defined NSCLC while underscoring that pooled outcomes should not be interpreted as evidence of equivalent efficacy across molecular subtypes or therapies. Full article

Circulating tumor cell (CTC) clustering is a key driver of metastatic progression in non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms remain largely unknown. Here, we performed single-cell proteomic sequencing on CTC clusters and individual CTCs isolated from lung cancer patients, identifying 912 proteins in total, of which 246 were significantly upregulated in clusters versus single CTCs. Enrichment analyses revealed a prominent involvement of lipid and cholesterol metabolism pathways. Apolipoprotein E (APOE) emerged as a central hub, exhibiting marked upregulation in CTC clusters. Functional experiments showed that cholesterol supplementation promoted cluster formation in NSCLC cell lines and accelerated metastatic dissemination in vivo, whereas APOE depletion impaired clustering capacity. Mechanistically, we identified USF2 as a potential transcriptional regulator of APOE through direct binding to the promoter, as supported by Chromatin Immunoprecipitation (ChIP) and reporter assays. Clinical validation in a cohort of 75 lung cancer patients demonstrated that elevated APOE expression was strongly associated with advanced pathological grade, distant metastasis, and poor survival. Taken together, these findings establish a novel USF2–APOE–cholesterol axis that governs CTC clustering and metastatic progression, positioning APOE as both a prognostic biomarker and a potential therapeutic target for NSCLC metastasis. Full article

Background: The optimal first-line treatment for advanced BRAF V600-mutant non-small cell lung cancer (NSCLC) remains uncertain. We compared the real-world effectiveness of first-line Dabrafenib plus trametinib (Dab+Tram) with immunochemotherapy (ICT) and other systemic regimens. Methods: This single-centre retrospective cohort study included 142 patients with unresectable stage III/IV BRAF-mutant NSCLC treated between April 2017 and May 2024. Patients were grouped by first-line regimen Dab+Tram, ICT, chemotherapy alone, or others. Primary endpoint was real-world progression-free survival (rwPFS). Propensity score matching (PSM) and multivariable Cox regression were applied to reduce measured confounding. Results: Forty-seven patients received Dab+Tram and 30 received ICT. In unadjusted analysis, Dab+Tram yielded significantly longer median rwPFS than ICT (32.5 vs. 13.3 months; p = 0.004). After PSM (25 pairs), median rwPFS was 19.6 months for Dab+Tram versus 12.6 months for ICT (HR = 1.74, 95%CI 0.85–3.66, p = 0.12). Multivariable Cox regression showed ICT, chemotherapy alone, and other regimens were independently associated with worse rwPFS versus Dab+Tram (all p < 0.05). Overall survival showed no significant difference. Dab+Tram showed some antitumor activity in later-line settings. Findings regarding pyrexia and PD-L1 subgroups were exploratory. Conclusions: In this real-world cohort, first-line Dab+Tram suggested a potential rwPFS benefit over ICT and chemotherapy. The matched comparison did not reach statistical significance, but multivariable analysis consistently supported an association between Dab+Tram and improved rwPFS. These findings provide complementary real-world evidence and require prospective validation. Full article

Molecular residual disease (MRD) testing approaches with plasma next-generation sequencing (NGS) testing to identify circulating tumor DNA (ctDNA) in resectable-stage non-small cell lung cancer (NSCLC) are evolving. The MRD concept is to better guide perioperative systemic treatment and identify recurrent NSCLC before symptomatic radiographic recurrences. Multiple tumor-informed assays are available with technology driving lower levels of ctDNA detection. However, it remains unclear that individual patients derive survival outcome benefit from MRD testing. NSCLC tumor biology of spatial heterogeneity, early parallel metastases, and recurrence clonal evolution can impact tumor-informed approaches irrespective of specific assay level of ctDNA detection. Clinical decision making guided by tumor-informed MRD testing to date have been limited by recurrence risks of up to 20% when landmark MRD-negative, improved outcomes benefit of adjuvant treatment even when landmark MRD-negative, and lead times with longitudinal MRD-positive conversion of several months or longer before overt radiographic recurrences with no proven strategy of survival benefit with intervening treatment. Cautionary tumor biology and clinical issues remain in the clinical utility of tumor-informed MRD testing in resected NSCLC. These need to be clarified with certainty before MRD testing should step beyond a technology-driven prognostic recurrence risk indicator before becoming an absolute clinical guide to meaningfully impact individual patient management and outcomes. Full article

Acquired resistance to targeted therapies is inevitable in EGFR-mutant non-small cell lung cancer (NSCLC), yet the principles governing its emergence in vivo remain incompletely understood. In particular, how lesion-level response patterns vary across distinct EGFR allele contexts during therapy has not been systematically examined at single-lesion resolution. Here, we establish a longitudinal in vivo imaging platform enabling single-lesion resolution tracking of tumor behavior during therapy in genetically engineered mouse models representing clinically relevant EGFR alleles. Using high-resolution micro-computed tomography (micro-CT) and three-dimensional reconstruction, we monitor tumor growth, therapeutic response, and resistance during osimertinib treatment. EGFR genotype is associated with distinct patterns of tumor growth, response kinetics, and resistance timing. Therapeutic response is spatially heterogeneous, with coexisting lesions undergoing complete regression, persistence, or progression within the same lung. During treatment, spatially distinct lesion-level behaviors included persistent growth during therapy and initial regression followed by regrowth. These findings demonstrate the utility of longitudinal micro-CT imaging to investigate allele-associated differences in treatment response and resistance timing at single-lesion resolution in vivo. Full article