Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers.

BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

Molecular profile of driver genes in lung adenocarcinomas of Brazilian patients who have never smoked: implications for targeted therapies.

INTRODUCTION: Lung cancer in never-smoker (LCINS) patients accounts for 20% of lung cancer cases, and its biology remains poorly understood, particularly in genetically admixed populations. We elucidated the molecular profile of driver genes in Brazilian LCINS. METHODS: The mutational and gene fusion status of 119 lung adenocarcinomas from self-reported never-smoker patients, was assessed using targeted sequencing (NGS), nCounter, and immunohistochemistry. A panel of 46 ancestry-informative markers determined patients' genetic ancestry. RESULTS: The most frequently mutated gene was EGFR (49.6%), followed by TP53 (39.5%), ALK (12.6%), ERBB2 (7.6%), KRAS (5.9%), PIK3CA (1.7%), and less than 1% alterations in RET, NTRK1, MET∆ex14, PDGFRA, and BRAF. Except for TP53 and PIK3CA, all other alterations were mutually exclusive. Genetic ancestry analysis revealed a predominance of European (71.1%), and a higher African ancestry was associated with TP53 mutations. CONCLUSION: Brazilian LCINS exhibited a similar molecular profile to other populations, except the increased ALK and TP53 alterations. Importantly, 73% of these patients have actionable alterations that are suitable for targeted treatments.

Complete response to capmatinib in a patient with metastatic lung adenocarcinoma harboring CD47-MET fusion: a case report.

Comprehensive genomic profiling is highly recommended for treatment decision in nonsquamous, non-small cell lung cancer (NSCLC). However, rare genomic alterations are still being unveiled, with scarce data to guide therapy. Herein, we describe the treatment journey of a 56-year-old, never-smoker Caucasian woman with a metastatic NSCLC harboring a CD47-MET fusion, initially classified as a variant of unknown significance. She had undergone 3 lines of therapy over the course of 3 years, including chemotherapy, immunotherapy, and anti-angiogenic therapy. After reanalysis of her next-generation sequencing data in our service, the fusion was reclassified as likely oncogenic. The patient was started with fourth-line capmatinib, with a good tolerance so far and a complete metabolic response in the active sites of disease, currently ongoing for 18 months. In conclusion, we highlight the sensitivity of a novel MET fusion to capmatinib and emphasize the need for comprehensive panels in NSCLC and molecular tumor board discussions with specialized centers when rare findings arise.

Projecting long-term clinical outcomes with larotrectinib compared with immune checkpoint inhibitors in metastatic nonsmall cell lung cancer and differentiated thyroid cancer.

BACKGROUND: Larotrectinib is approved for patients with advanced NTRK gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with other systemic therapy. However, comparisons to checkpoint inhibitors, such as nivolumab or pembrolizumab, have not been done. OBJECTIVE: To estimate and compare expected life-years (LYs) and quality-adjusted LYs (QALYs) for patients with nonsmall cell lung cancer (NSCLC) eligible for larotrectinib vs patients with unknown NTRK gene fusion status on nivolumab or pembrolizumab. We also assessed patients with metastatic differentiated thyroid cancer (DTC), as pembrolizumab may be considered in certain circumstances. METHODS: We developed partitioned survival models to project long-term comparative effectiveness of larotrectinib vs nivolumab or pembrolizumab. Larotrectinib survival data were derived from an updated July 2021 analysis of 21 adult patients (≥18 years of age) with metastatic NTRK gene fusion-positive NSCLC and 21 with DTC. Survival inputs for nivolumab and pembrolizumab were obtained from published articles. Progression-free and overall survival were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal). Exponential fits were chosen based on goodness-of-fit and clinical plausibility. RESULTS: In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 and 3.56 QALYs. In DTC, larotrectinib resulted in a gain of 5.23 LYs and 4.24 QALYs compared to pembrolizumab. CONCLUSIONS: In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors. Additional data with longer follow-up will further inform this comparison.

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS: In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Real-World Impact of Comprehensive Genomic Profiling on Biomarker Detection, Receipt of Therapy, and Clinical Outcomes in Advanced Non-Small Cell Lung Cancer.

PURPOSE: Therapeutic decision making for patients with advanced non-small cell lung cancer (aNSCLC) includes a growing number of options for genomic, biomarker-guided, targeted therapies. We compared actionable biomarker detection, targeted therapy receipt, and real-world overall survival (rwOS) in patients with aNSCLC tested with comprehensive genomic profiling (CGP) versus small panel testing (SP) in real-world community health systems. METHODS: Patients older than 18 years diagnosed with aNSCLC between January 1, 2015, and December 31, 2020, who received biomarker testing were followed until death or study end (September 30, 2021), and categorized by most comprehensive testing during follow-up: SP (≤52 genes) or CGP (>52 genes). RESULTS: Among 3,884 patients (median age, 68 years; 50% female; 73% non-Hispanic White), 20% received CGP and 80% SP. The proportion of patients with ≥one actionable biomarker (actionability) was significantly higher in CGP than in SP (32% v 14%; P < .001). Of patients with actionability, 43% (CGP) and 38% (SP) received matched therapies (P = .20). Among treated patients, CGP before first-line treatment was associated with higher likelihood of matched therapy in any line (odds ratio, 3.2 [95% CI, 1.84 to 5.53]). CGP testing (hazard ratio [HR], 0.80 [95% CI, 0.72 to 0.89]) and actionability (HR, 0.84 [95% CI, 0.77 to 0.91]) were associated with reduced risk of mortality. Among treated patients with actionability, matched therapy receipt showed improved median rwOS in months in CGP (34 [95% CI, 21 to 49] matched v 14 [95% CI, 10 to 18] unmatched) and SP (27 [95% CI, 21 to 43] matched v 10 [95% CI, 8 to 14] unmatched). CONCLUSION: Patients who received CGP had improved detection of actionable biomarkers and greater use of matched therapies, both of which were associated with significant increases in survival.

Prediction of Prognostic Features Based on Neutrophil-Related Genes for Lung Squamous Cell Carcinoma Reveals Immune Landscape and Drug Candidates.

UNASSIGNED: Background: Since to the prognosis of lung squamous cell carcinoma is generally poor, there is an urgent need to innovate new prognostic biomarkers and therapeutic targets to improve patient outcomes. Objectives: Our goal was to develop a novel multi-gene prognostic model linked to neutrophils for predicting lung squamous cell carcinoma prognosis. Methods: We utilized messenger RNA expression profiles and relevant clinical data of lung squamous cell carcinoma patients from the Cancer Genome Atlas database. Through K-means clustering, least absolute shrinkage and selection operator regression, and univariate/multivariate Cox regression analyses, we identified 12 neutrophil-related genes strongly related to patient survival and constructed a prognostic model. We verified the stability of the model in the Cancer Genome Atlas database and gene expression omnibus validation set, demonstrating the robust predictive performance of the model. Results: Immunoinfiltration analysis revealed remarkably elevated levels of infiltration for natural killer cells resting and monocytes in the high-risk group compared to the low-risk group, while macrophages had considerably lower infiltration in the high risk group. Most immune checkpoint genes, including programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4, exhibited high expression levels in the high risk group. Tumor immune dysfunction and exclusion scores and immunophenoscore results suggested a potential inclination toward immunotherapy in the "RIC" version V2 revised high risk group. Moreover, prediction results from the CellMiner database revealed great correlations between drug sensitivity (e.g., Vinorelbine and PKI-587) and prognostic genes. Conclusion: Overall, our study established a reliable prognostic risk model that possessed significant value in predicting the overall survival of lung squamous cell carcinoma patients and may guide personalized treatment strategies. (Rev Invest Clin. 2024;76(2):116-31).

Exploration of efficacy of different therapy regimens for advanced NSCLC patients with KRAS mutation in the first-line treatment.

PURPOSE: The treatment of the advanced non-small cell lung cancer (NSCLC) with KRAS mutation has been closely paid more attention. The aim of this study is to investigate the efficacy of different first-line regimens in advanced KRAS-mutated non-small cell lung cancer. METHODS: In our retrospective study, we collected patients with advanced NSCLC with KRAS mutation in Zhejiang Cancer Hospital between January 2015 and May 2023. We analyzed the benefit of different first-line therapy according to theraputic methods and the differential effect of the same treatment method among KRAS-mutated subtypes. We divided the patients into group A (A1, chemotherapy alone; A2, immunotherapy alone) and group B (B1, chemotherapy plus immunotherapy; B2, chemotherapy combined with antiangiogenic therapy; B3, chemotherapy combined with immunotherapy plus antiangiogenic therapy). The Kaplan-Meier survival curve was used to reflect the PFS and OS of different methods. The objective response rate (ORR) and the disease control rate (DCR) were used to evaluated the response. RESULTS: We enrolled 227 patients including eighty-two with KRAS G12C mutation. The ORR and DCR of first-line treatment in the overall population were 32.2% and 80.6% respectively. The median PFS was 6.7 months and the median OS was 17.4 months for the overall population. The PFS of the Group B was significantly better than that of the Group A (7.7 months vs 5.4 months, P = 0.003), while no significant difference in OS was observed (19.4 months vs 15.0 months, P = 0.077). In the Group B, chemotherapy combined immunotherapy with antiangiogenic therapy showed better PFS than chemotherapy plus immunotherapy (14.1 months vs 7.7 months, P = 0.049), and OS also showed that tendency of difference (31.9 months vs 19.3 months, P = 0.158). There was no statistically significant difference between KRAS G12C and non-G12C mutation according to first-line treatment methods, whereas patients with TP53 co-mutation showed a better survival benefit (OS, 23.7 vs 12.5 months, P = 0.023). CONCLUSION: In the first-line treatment, combination regimen has advantages over single regimen. Among them, chemotherapy combined with immunotherapy plus antiangiogenic therapy can achieve significant efficacy benefits.

Prognostic model based on B cell marker genes for NSCLC patients under neoadjuvant immunotherapy by integrated analysis of single-cell and bulk RNA-sequencing data.

BACKGROUND: Neoadjuvant immunotherapy has evolved as an effective option to treat non-small cell lung cancer (NSCLC). B cells play essential roles in the immune system as well as cancer progression. However, the repertoire of B cells and its association with clinical outcomes remains unclear in NSCLC patients receiving neoadjuvant immunotherapy. METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data for LUAD samples were accessed from the TCGA and GEO databases. LUAD-related B cell marker genes were confirmed based on comprehensive analysis of scRNA-seq data. We then constructed the B cell marker gene signature (BCMGS) and validated it. In addition, we evaluated the association of BCGMS with tumor immune microenvironment (TIME) characteristics. Furthermore, we validated the efficacy of BCGMS in a cohort of NSCLC patients receiving neoadjuvant immunotherapy. RESULTS: A BCMGS was constructed based on the TCGA cohort and further validated in three independent GSE cohorts. In addition, the BCMGS was proven to be significantly associated with TIME characteristics. Moreover, a relatively higher risk score indicated poor clinical outcomes and a worse immune response among NSCLC patients receiving neoadjuvant immunotherapy. CONCLUSIONS: We constructed an 18-gene prognostic signature derived from B cell marker genes based on scRNA-seq data, which had the potential to predict the prognosis and immune response of NSCLC patients receiving neoadjuvant immunotherapy.

Clinical difference on the variants and co-mutation in a Chinese cohort with ALK-positive advanced non-small cell lung cancer.

PURPOSE: Despite the generally favourable prognoses observed in patients with ALK-positive non-small cell lung cancer (NSCLC), there remains significant variability in clinical outcomes. The objective of this study is to enhance patient stratification by examining both the specific sites of gene fusion and the presence of co-occurring mutations. METHODS: We collected retrospective clinical and pathological data on ALK-positive patients with locally advanced or metastatic disease. ALK fusion variants and concomitant mutations were identified through next-generation sequencing technology. We then assessed treatment efficacy via tumor response and survival metrics. RESULTS: This study included a total of 59 patients, with 49 harboring echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions and 10 presenting with rare fusions. The median follow-up period was 33 months. Clinical outcomes between non-EML4-ALK and EML4-ALK patients were comparable. Among the EML4-ALK cohort, patients with longer variants (v1, v2, v8) demonstrated superior progression-free survival (PFS) (median PFS: 34 months vs. 11 months; hazard ratio [HR]: 2.28; P = 0.05) compared to those with shorter variants (v3, v5). Furthermore, patients treated with second-generation ALK inhibitors (ALKi) displayed a progression-free survival advantage (median PFS: not reached [NR] vs. 9 months; HR: 5.37; P = 0.013). Baseline TP53 co-mutation were linked with a substantially shorter OS (median OS,37 months vs. NR; HR 2.74; P = 0.047). CONCLUSIONS: In ALK+ NSCLC, longer EML4-ALK variants correlate with improved prognosis and enhanced response to second-generation ALKi, while TP53 co-mutations indicate a negative prognosis.

Identification and validation of an immune-derived multiple programmed cell death index for predicting clinical outcomes, molecular subtyping, and drug sensitivity in lung adenocarcinoma.

OBJECTIVES: Comprehensive cross-interaction of multiple programmed cell death (PCD) patterns in the patients with lung adenocarcinoma (LUAD) have not yet been thoroughly investigated. METHODS: Here, we collected 19 different PCD patterns, including 1911 PCD-related genes, and developed an immune-derived multiple programmed cell death index (MPCDI) based on machine learning methods. RESULTS: Using the median MPCDI scores, we categorized the LUAD patients into two groups: low-MPCDI and high-MPCDI. Our analysis of the TCGA-LUAD training cohort and three external GEO cohorts (GSE37745, GSE30219, and GSE68465) revealed that patients with high-MPCDI experienced a more unfavorable prognosis, whereas those with low-MPCDI had a better prognosis. Furthermore, the results of both univariate and multivariate Cox regression analyses further confirmed that MPCDI serves as a novel independent risk factor. By combining clinical characteristics with the MPCDI, we constructed a nomogram that provides an accurate and reliable quantitative tool for personalized clinical management of LUAD patients. The findings obtained from the analysis of C-index and the decision curve revealed that the nomogram outperformed various clinical variables in terms of net clinical benefit. Encouragingly, the low-MPCDI patients are more sensitive to commonly used chemotherapy drugs, which suggests that MPCDI scores have a guiding role in chemotherapy for LUAD patients. CONCLUSION: Therefore, MPCDI can be used as a novel clinical diagnostic classifier, providing valuable insights into the clinical management and clinical decision-making for LUAD patients.

Machine learning-driven prediction of brain metastasis in lung adenocarcinoma using miRNA profile and target gene pathway analysis of an mRNA dataset.

BACKGROUND: Brain metastasis (BM) is common in lung adenocarcinoma (LUAD) and has a poor prognosis, necessitating predictive biomarkers. MicroRNAs (MiRNAs) promote cancer cell growth, infiltration, and metastasis. However, the relationship between the miRNA expression profiles and BM occurrence in patients with LUAD remains unclear. METHODS: We conducted an analysis to identify miRNAs in tissue samples that exhibited different expression levels between patients with and without BM. Using a machine learning approach, we confirmed whether the miRNA profile could be a predictive tool for BM. We performed pathway analysis of miRNA target genes using a matched mRNA dataset. RESULTS: We selected 25 miRNAs that consistently exhibited differential expression between the two groups of 32 samples. The 25-miRNA profile demonstrated a strong predictive potential for BM in both Group 1 and Group 2 and the entire dataset (area under the curve [AUC] = 0.918, accuracy = 0.875 in Group 1; AUC = 0.867, accuracy = 0.781 in Group 2; and AUC = 0.908, accuracy = 0.875 in the entire group). Patients predicted to have BM, based on the 25-miRNA profile, had lower survival rates. Target gene analysis of miRNAs suggested that BM could be induced through the ErbB signaling pathway, proteoglycans in cancer, and the focal adhesion pathway. Furthermore, patients predicted to have BM based on the 25-miRNA profile exhibited higher expression of the epithelial-mesenchymal transition signature, TWIST, and vimentin than those not predicted to have BM. Specifically, there was a correlation between EGFR mRNA levels and BM. CONCLUSIONS: This 25-miRNA profile may serve as a biomarker for predicting BM in patients with LUAD.

Lung Cancer Clinical Trials in Latin America in the Era of Cooperative Groups: A 20-Year Analysis.

PURPOSE: The aim of this study is to characterize lung cancer treatment clinical trials in Latin America before (January 2001-December 2011) and after (January 2012-December 2021) the organization of major Latin American oncology cooperative groups. MATERIALS AND METHODS: Interventional clinical trials were identified in ClinicalTrials.gov using the search terms "lung cancer," country filters for 20 Latin American countries, and study start dates January 1, 2001-December 31, 2011, and January 1, 2012-December 31, 2021. Clinical trials were categorized as either originating in Latin America (LA) or outside Latin America (non-LA) with participation of Latin American countries. Descriptive statistics, two-sided Z-scores, and chi-square analyses with 95% CIs were calculated. RESULTS: Overall, 273 clinical trials involving Latin American countries between 2001 and 2021 were identified. Comparing 2001-2011 with 2012-2021, there was an increase in total clinical trials (100 v 173; P < .001). Only 9% (26 of 273) of all trials were LA trials. There was a marked decrease in the proportion of LA trials (14% v 7%, P = .058) and estimated enrollment to LA trials (3,245 v 1,190 patients; P < .001). Recruiting of patients with EGFR (29% v 7%; P < .01) and KRAS (18% v 2%; P < .01) driver mutations also decreased. Trial participation was highest in Brazil, Mexico, Argentina, Chile, and Peru and increased over time: Brazil (61 v 108; 77% increase), Mexico (40 v 88; 120% increase), Argentina (50 v 78; 56% increase), Chile (25 v 57; 128% increase), and Peru (14 v 37; 164% increase). CONCLUSION: There was a significant increase in clinical trial participation by Latin American countries, from 2001-2011 to 2012-2021. However, there were few clinical trials which originated in Latin America or focused on patients with driver mutations.

Comprehensive Analysis of Lung Adenocarcinoma and Brain Metastasis through Integrated Single-Cell Transcriptomics.

Lung adenocarcinoma (LUAD) is a highly prevalent and lethal form of lung cancer, comprising approximately half of all cases. It is often diagnosed at advanced stages with brain metastasis (BM), resulting in high mortality rates. Current BM management involves complex interventions and conventional therapies that offer limited survival benefits with neurotoxic side effects. The tumor microenvironment (TME) is a complex system where cancer cells interact with various elements, significantly influencing tumor behavior. Immunotherapies, particularly immune checkpoint inhibitors, target the TME for cancer treatment. Despite their effectiveness, it is crucial to understand metastatic lung cancer and the specific characteristics of the TME, including cell-cell communication mechanisms, to refine treatments. Herein, we investigated the tumor microenvironment of brain metastasis from lung adenocarcinoma (LUAD-BM) and primary tumors across various stages (I, II, III, and IV) using single-cell RNA sequencing (scRNA-seq) from publicly available datasets. Our analysis included exploring the immune and non-immune cell composition and the expression profiles and functions of cell type-specific genes, and investigating the interactions between different cells within the TME. Our results showed that T cells constitute the majority of immune cells present in primary tumors, whereas microglia represent the most dominant immune cell type in BM. Interestingly, microglia exhibit a significant increase in the COX pathway. Moreover, we have shown that microglia primarily interact with oligodendrocytes and endothelial cells. One significant interaction was identified between DLL4 and NOTCH4, which demonstrated a relevant association between endothelial cells and microglia and between microglia and oligodendrocytes. Finally, we observed that several genes within the HLA complex are suppressed in BM tissue. Our study reveals the complex molecular and cellular dynamics of BM-LUAD, providing a path for improved patient outcomes with personalized treatments and immunotherapies.

Personalizing non-small cell lung cancer treatment through patient-derived xenograft models: preclinical and clinical factors for consideration.

PURPOSE: In the pursuit of creating personalized and more effective treatment strategies for lung cancer patients, Patient-Derived Xenografts (PDXs) have been introduced as preclinical platforms that can recapitulate the specific patient's tumor in an in vivo model. We investigated how well PDX models can preserve the tumor's clinical and molecular characteristics across different generations. METHODS: A Non-Small Cell Lung Cancer (NSCLC) PDX model was established in NSG-SGM3 mice and clinical and preclinical factors were assessed throughout subsequent passages. Our cohort consisted of 40 NSCLC patients, which were used to create 20 patient-specific PDX models in NSG-SGM3 mice. Histopathological staining and Whole Exome Sequencing (WES) analysis were preformed to understand tumor heterogeneity throughout serial passages. RESULTS: The main factors that contributed to the growth of the engrafted PDX in mice were a higher grade or stage of disease, in contrast to the long duration of chemotherapy treatment, which was negatively correlated with PDX propagation. Successful PDX growth was also linked to poorer prognosis and overall survival, while growth pattern variability was affected by the tumor aggressiveness, primarily affecting the first passage. Pathology analysis showed preservation of the histological type and grade; however, WES analysis revealed genomic instability in advanced passages, leading to the inconsistencies in clinically relevant alterations between the PDXs and biopsies. CONCLUSIONS: Our study highlights the impact of multiple clinical and preclinical factors on the engraftment success, growth kinetics, and tumor stability of patient-specific NSCLC PDXs, and underscores the importance of considering these factors when guiding and evaluating prolonged personalized treatment studies for NSCLC patients in these models, as well as signaling the imperative for additional investigations to determine the full clinical potential of this technique.

MET alterations in advanced non-small cell lung cancer.

Precision medicine has helped identify several tumor molecular aberrations to be treated with targeted therapies. These therapies showed substantial improvement in efficacy without excessive toxicity in patients with specific oncogenic drivers with advanced cancers. In metastatic lung cancers, the implementation of broad platforms for molecular tumor sequencing has helped oncology providers identify oncogenic drivers linked with better outcomes when treated upfront with targeted therapies. Mesenchymal-epithelial transition factor (MET) alterations are present in up to 60% of non-small cell lung cancer and are associated with a poor prognosis. Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Several agents are being developed to tackle an unmet need in patients with MET alterations. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.

MET overexpression correlated with prognosis of EGFR-mutant treatment­naïve advanced lung adenocarcinoma: a real­world retrospective study.

BACKGROUND: About 50-60% treatment-naïve advanced non-small-cell lung cancers were coexistence of epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) overexpression. However, few studies demonstrated the prognostic value of MET protein expression in untreated EGFR-mutant lung adenocarcinoma (LUAD). METHODS: A total of 235 EGFR-mutant untreated advanced LUAD patients were retrospectively enrolled. MET expression was determined using immunohistochemistry, and MET positivity was defined as 2 + or 3 + using the METmab scoring algorithm. Progression-free survival (PFS) and overall survival (OS) were analysed according to MET expression status. Independent factors predicting prognosis were identified using multivariate Cox regression analyses. RESULTS: Of the 235 patients, 113 (48.1%) harboured exon 19 deletion (19_del), 103 (43.8%) had exon 21 L858R mutations, and 19 (8.1%) had other mutation types, including exon 21 L861Q, exon 18 G719A/C, exon 20 S768I, and L858R/19_del double mutations. MET-positive expression was observed in 192 (81.7%) cases. There was no significant difference in baseline clinicopathological characteristics between MET positivity and MET negativity groups. Patients were stratified by different EGFR mutation subtypes. MET-positive patients in the L858R mutation subgroup had markedly shorter PFS and OS than MET-negative patients (median PFS: 13 versus 27.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.008), but no significant difference was observed in the 19_del subgroup. Multivariate Cox regression analyses indicated that MET positivity was an independent predictor for poor PFS and OS in L858R subgroup (PFS: HR = 3.059, 95% CI 1.552-6.029, p = 0.001; OS: HR = 3.511, 95% CI 1.346-9.160, p = 0.010). Additionally, an inferior survival outcome of MET positivity was observed in the L858R mutation subgroup when treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy as the first-line regimen (median PFS: 13 versus 36.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.012) but not with EGFR-TKI plus platinum doublet chemotherapy. CONCLUSIONS: MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.

Bevacizumab improved prognosis for advanced EGFR-mutant lung adenocarcinoma with brain metastasis receiving cerebral radiotherapy.

OBJECTIVE: This study aimed to determine whether the combined use of bevacizumab could improve overall survival (OS) in patients with brain metastasis (BM), epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) undergoing cerebral radiotherapy. MATERIALS AND METHODS: A total of 237 patients with EGFR-mutant lung adenocarcinoma and BM met the inclusion criteria for this retrospective study, including 102 patients in the bevacizumab treatment group and 135 in the non-bevacizumab group. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate analyses were performed to identify EGFR-mutated BM prognostic factors for these patients. RESULTS: At the end of the last follow-up period, 176 patients (74.3%) had died, and the median overall survival (OS) was 34.2 months. We observed a significant difference in the median OS between the bevacizumab and non-bevacizumab groups (45.8 months vs 30.0 months, P < 0.0001). Among the 178 (75.1%) patients who received cerebral radiotherapy, the median OS of patients in the bevacizumab + cerebral radiotherapy group was 45.8 months versus 32.0 months in the non-bevacizumab + cerebral radiotherapy group, respectively (P = 0.0007). Patients treated with bevacizumab after cerebral radiotherapy had a longer median OS than patients treated with bevacizumab before cerebral radiotherapy (59.4 months vs 33.7 months, P = 0.0198). In the univariate analysis, smoking status, Lung-molGPA scores, and bevacizumab therapy showed correlations (HR = 1.450, P = 0.045; HR = 0.700, P = 0.023; HR = 0.499, P < 0.001). Multivariate analysis showed that bevacizumab therapy alone (hazard ratio [HR] = 0.514; P < 0.001) was independently associated with improved OS. CONCLUSION: In patients with BM from EGFR-mutated NSCLC, cerebral radiotherapy with bevacizumab markedly improved OS. This improvement was more evident after cerebral radiotherapy.

The diagnostic and prognostic value of exosomal microRNAs in lung cancer: a systematic review.

BACKGROUND: Studies have shown that many exosomal microRNAs (miRNAs) can be used as non-invasive biomarkers of lung cancer, but their diagnostic and prognostic values need to be further clarified. METHODS: We conducted a systematic literature search in Web of Science, PubMed, and ScienceDirect databases, obtained relevant articles and extracted data, and used statistical methods and statistical software to comprehensively evaluate the diagnostic and prognostic value of exosomal miRNAs in lung cancer. REGISTRATION NUMBER: PROSPERO CRD42023447398. RESULTS: In terms of diagnosis, two exosomal miRNAs (miR-486-5p and miR-451a) were reported with the highest frequency in lung cancer patients, both of which had good diagnostic value. Compared with the control group, the pooled sensitivities of miR-486-5p and miR-451a were 0.80 (95% CI: 0.73-0.86) and 0.76 (95% CI: 0.60-0.87), specificities: 0.93 (95% CI: 0.63-0.99) and 0.85 (95% CI: 0.72-0.92), and AUCs: 0.85 (95% CI: 0.81-0.88) and 0.88 (95% CI: 0.84-0.90), for the respective miRNAs. For prognosis, in lung cancer patients with abnormally expressed exosomal miRNAs, miR-1290 was associated with PFS outcome; miR-382, miR-1246, miR-23b-3p, miR-21-5p, and miR-10b-5p were associated with OS outcome; miR-21 and miR-4257 were associated with DFS outcome; miR-125a-3p and miR-625-5p were associated with PFS and OS outcomes; miR-216b and miR-451a were associated with OS and DFS outcomes. CONCLUSIONS: Exosomal miRNAs are valuable biomarkers in lung cancer patients. Exosomal miR-486-5p and miR-451a can be used as new diagnostic biomarkers for lung cancer. Dysregulated exosomal miRNAs could serve as indicators of survival outcomes in lung cancer patients.