Overall Survival In Non-small Cell Lung Cancer Patients Research Articles

Physical performance and plasma metabolic profile as potential prognostic factors in metastatic lung cancer patients.

Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non-small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells. This prospective cohort study included 55 metastatic NSCLC patients and seven age-matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis. We observed a higher survival rate in NSCLC patients with high performance in the timed up-and-go (+320%; p = .007), sit-to-stand (+256%; p = .01) and six-minute walking (+323%; p = .002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p > .05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (-54.2%; p < .0001) and cell proliferation (-44.9%; p = .007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance. These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.

Circ_0060060 Accelerates Metastasis of Non-Small-Cell Lung Carcinoma by Upregulating FUT8

We aimed to elucidate the diagnostic and prognostic values of Circ_0060060 in non-small-cell lung cancer (NSCLC), and its regulatory effect on FUT8. Relative levels of Circ_0060060 and FUT8 were examined in NSCLC and adjacent tissues. Clinical information of recruited NSCLC patients was collected for assessing the prognostic value of Circ_0060060. Regulatory effects of Circ_0060060 and FUT8 on in vitro proliferative and migratory abilities of NSCLC were examined by cell counting kit-8 (CCK-8) and transwell assay, respectively. Finally, the interaction between Circ_0060060 and FUT8 was determined via dual-luciferase reporter assay and Pearson correlation test. Circ_0060060 and FUT8 were upregulated in NSCLC tissues. High level of Circ_0060060 or FUT8 predicted higher incidences of distant metastasis and worse overall survival in NSCLC patients. in vitro evidences have shown the roles of Circ_0060060 and FUT8 in stimulating proliferative and migratory abilities of PC-9 and SPC-A1 cells. Circ_0060060 directly targeted FUT8 and positively regulated its level. Circ_0060060 and FUT8 are effective diagnostic markers of NSCLC. Circ_0060060 stimulates proliferative and migratory abilities of NSCLC by regulating FUT8.

A deep learning approach for overall survival prediction in lung cancer with missing values

Background and Objective:In the field of lung cancer research, particularly in the analysis of overall survival (OS), artificial intelligence (AI) serves crucial roles with specific aims. Given the prevalent issue of missing data in the medical domain, our primary objective is to develop an AI model capable of dynamically handling this missing data. Additionally, we aim to leverage all accessible data, effectively analyzing both uncensored patients who have experienced the event of interest and censored patients who have not, by embedding a specialized technique within our AI model, not commonly utilized in other AI tasks. Through the realization of these objectives, our model aims to provide precise OS predictions for non-small cell lung cancer (NSCLC) patients, thus overcoming these significant challenges. Methods:We present a novel approach to survival analysis with missing values in the context of NSCLC, which exploits the strengths of the transformer architecture to account only for available features without requiring any imputation strategy. More specifically, this model tailors the transformer architecture to tabular data by adapting its feature embedding and masked self-attention to mask missing data and fully exploit the available ones. By making use of ad-hoc designed losses for OS, it is able to account for both censored and uncensored patients, as well as changes in risks over time. Results:We compared our method with state-of-the-art models for survival analysis coupled with different imputation strategies. We evaluated the results obtained over a period of 6 years using different time granularities obtaining a Ct-index, a time-dependent variant of the C-index, of 71.97, 77.58 and 80.72 for time units of 1 month, 1 year and 2 years, respectively, outperforming all state-of-the-art methods regardless of the imputation method used. Conclusions:The results show that our model not only outperforms the state-of-the-art’s performance but also simplifies the analysis in the presence of missing data, by effectively eliminating the need to identify the most appropriate imputation strategy for predicting OS in NSCLC patients.

The efficacy and safety of furmonertinib in patients with advanced EGFR-mutated NSCLC and leptomeningeal metastases.

e20525 Background: Leptomeningeal metastasis (LM) is a common and fatal complication in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR) mutation. This retrospective study aimed to evaluate the efficacy and safety of furmonertinib in patients with advanced EGFR-mutated ( EGFRm) NSCLC and LM. Methods: Eligible patients with confirmed advanced EGFRm NSCLC and LM were treated with furmonertinib. The primary endpoints were LM response rate and progression-free survival (PFS). Secondary endpoints were overall survival (OS) and adverse events (AEs). Results: This retrospective study analyzed the efficacy and safety of 31 EGFRm advanced NSCLC patients with LM at two hospitals between February 2020 to March 2023. The median age was 56 years (rang: 31-75), 22 (71.0%) were females. 19 (61.3%) patients had ECOG PS≥2 and all 31 patients (100%) had adenocarcinoma histology. For the treatment of LM, 19 (61.3%) patients received furmonertinib as first-line treatment, 8 (25.8%) patients as second-line treatment. 16 (51.6%) patients were treated with 240 mg of furmonertinib and 12 (38.7%) patients with 160 mg of furmonertinib. The median follow-up duration was 16.80 months (95% CI 12.71-20.89 months). LM objective response rate (ORR) was 75.0% and LM disease control rate (DCR) was 95.0% according to RANO-LM radiologic criteria. Overall ORR was 22.6% and DCR was 96.8%. Median LM duration of response (DoR) was 12.00 months (95% CI 7.40-16.60 months) and median overall DoR was 7.20 months (95% CI 3.60-10.80 months). 23 (74.2%) of the 31 patients had progressed or died by data cutoff. The median PFS was 11.70 months (95% CI 9.48-13.92 months) and the median OS was 18.40 months (95% CI 12.49-24.21 months). There was no significant difference in survival (median PFS: 11.70 months vs 10.90 months, p = 0.335; median OS: 18.40 months vs 13.50 months, p = 0.196) between the 19 patients who treated with furmonertinib as first-line therapy and those who treated with furmonertinib as second-line therapy. Although data on cerebrospinal fluid (CSF) clearance were not available, we observed improved neurologic function in 18 (75%) of 24 patients with baseline neurologic abnormalities. Logistic regression analysis showed that the therapeutic dose of furmonertinib was a positive predictor of OS in NSCLC patients harboring EGFR mutation with LM [HR: 2.679 (1.004-7.147), P = 0.049]. The most common AEs were rash, diarrhea and decreased appetite. However, most AEs were grade 1-2. Conclusions: Our study provides real-world clinical evidence that furmonertinib shows an encouraging efficacy and a manageable safety profile in patients with EGFRm NSCLC and LM.

Is neoadjuvant immunotherapy necessary in patients with programmed death ligand 1 expression-negative resectable non-small cell lung cancer? A systematic review and meta-analysis

ObjectivesThe aim of this study was to investigate the clinical benefit and necessity of neoadjuvant programmed cell death (or ligand) (PD-(L)1) blockades in resectable non-small cell lung cancer (NSCLC) patients with negative PD-L1 expression. Materials and methodsRandomized control trials (RCTs) that compared event-free survival (EFS), overall survival (OS), major pathological response (MPR), and/or pathological complete response (pCR) between neoadjuvant chemo-immunotherapy (nCIT) and neoadjuvant chemotherapy (nCT) for patients with resectable NSCLC stratified by PD-L1 expression were eligible for inclusion in the study. Data regarding the pathological response and EFS were evaluated by the odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) using random and fixed models. ResultsA total of six RCTs involving 3,194 patients with resectable NSCLC with or without neoadjuvant immunotherapy were included. Compared with nCT alone, nCIT significantly improved pCR (18.3 % vs. 3.0 %; OR, 5.64; 95 % CI, 3.22–9.89; P < 0.001), MPR (38.9 % vs. 15.5 %; OR, 3.57; 95 % CI, 2.10–6.05; P < 0.001), and EFS (HR, 0.75; 95 % CI, 0.62–0.90; P = 0.002) in PD-L1 <1 % NSCLC patients. In addition, PD-L1 ≥1 % was associated with higher rates of pCR (32.8 % vs. 18.3 %; OR, 2.28; 95 % CI, 1.40–3.73; P = 0.001) and MPR (53.9 % vs. 38.9 %; OR, 1.84; 95 % CI, 1.22–2.79; P = 004) and longer EFS (HR, 0.44 vs. 0.75) in the setting of nCIT compared with PD-L1 <1 %. nCIT improved only OS in NSCLC patients with PD-L1 ≥1 % but not in patients with PD-L1 <1 %. ConclusionsThe use of nCIT should be recommended for resectable NSCLC patients with negative PD-L1 expression, as nCIT significantly improved the pathological response and EFS in these patients. The benefit to PD-L1-negative patients treated with nCIT on OS remains to be validated.

Soluble programmed death ligand 1 as prognostic biomarker in non-small cell lung cancer patients receiving nivolumab, pembrolizumab or atezolizumab therapy

Many studies have focused on the prognostic role of soluble programmed death ligand 1 (sPD-L1) in non-small cell lung cancer (NSCLC), but outcomes are ambiguous and further investigations are needed. We addressed the matter by studying sPD-L1 in baseline samples and in longitudinal samples taken prior to three subsequent cycles of anti-PD-1/anti-PD-L1 treatments. Eighty patients with NSCLC were enrolled. Median sPD-L1 level at baseline was 52 pg/mL [95% confidence interval (CI) 49–57]. In patients treated with pembrolizumab and nivolumab, the concentration of sPD-L1 remained rather stable throughout treatment. In contrast, sPD-L1 rose by 50-fold following the first cycle of atezolizumab therapy. We found the baseline level of sPD-L1 to be related to overall survival (OS) after two years of follow-up in simple Cox analysis (p = 0.006) and multiple Cox Regression, hazard ratio 1.02 (95% CI 1.00–1.03) (p = 0.033). There was no association between sPD-L1 and tissue PD-L1 expression, overall response rate, or progression free survival. In conclusion, sPD-L1 measured in baseline serum samples may be associated with OS in NSCLC patients receiving anti-PD1/anti-PD-L1 treatment. Importantly, the results signify that further research is warranted to explore the clinical utility of sPD-L1 in patients treated with anti-PD-L1.

LncRNA RGMB-AS1 inhibits HMOX1 ubiquitination and NAA10 activation to induce ferroptosis in non-small cell lung cancer

Ferroptosis, an iron-dependent regulated cell death caused by excessive lipid peroxide accumulation, has emerged as a promising therapeutic target in various cancers, including non-small cell lung cancer (NSCLC). In this study, we identified the long non-coding RNA RGMB-AS1 as a key regulator of ferroptosis in NSCLC. Mechanistically, RGMB-AS1 interacted with heme oxygenase 1 (HMOX1) and prevented its ubiquitination by the E3 ligase TRC8, leading to increased HMOX1 stability and enhanced ferroptosis. Additionally, RGMB-AS1 bound to the 82–87 amino acid region of N-alpha-acetyltransferase 10 (NAA10), stimulating its acetyltransferase activity and promoting the conversion of acetyl-CoA to HMG-CoA, further contributing to ferroptosis. The RGMB-AS1-HMOX1 and RGMB-AS1-NAA10 axes synergistically inhibited NSCLC growth both in vitro and in vivo. Clinically, low RGMB-AS1 expression was associated with advanced tumor stage and poor overall survival in NSCLC patients. Furthermore, adeno-associated virus-mediated RGMB-AS1 overexpression significantly suppressed tumor growth in mouse xenograft models. Our findings uncover a novel lncRNA-mediated regulatory mechanism of ferroptosis and highlight the potential of RGMB-AS1 as a prognostic biomarker and therapeutic target in NSCLC.

Abstract 208: FGFR2 splice variant as a cell fate adjudicator determines clinical outcomes in non-small cell lung cancer

Abstract The splice variants specific protein expression in tumor cells presents promising targets for cancer therapy. The concept is supported by the recent introduction of the splice variant-specific antibody against FGFR2 IIIb (FGFR2b) in gastric cancer. Indeed, signaling of the two FGFR2 splice variants FGFR2b and FGFR2 IIIc (FGFR2c), whose expression is mutually exclusive on a cellular level, is mediated by different ligands and distinct downstream responses that can contribute to many aspects of tumorigenesis. Our study aimed to characterize the expression FGFR2b and 2c in non-malignant lung and non-small cell lung cancer (NSCLC) tissue and relate splice variant-specific expression to the histological and molecular background of cancer and its clinical impact.FGFR2b/FGFR2c isoforms expression was determined in RNA-seq data from 180 NSCLC patients and 19 tissues from normal lung (patient-matched). Cell-type specific expression and pan-cancer analysis of FGFR2 were explored using a public database, including DBTSS (NSCLC: 26, normal lung epithelium: 1, normal lung fibroblast 1) and CCLE (Total: 1019, NSCLC: 131), GTEx (normal lung tissue: 578) and HPA (scRNAseq for lung).Our results confirm a cell-specific expression in normal cells with dominance of FGFR2b in epithelial cells and FGFR2c in mesenchymal cells. In normal lung tissue, the FGFR2b variant showed high abundance. Pan-cancer analysis revealed FGFR2c dominant cancers (e.g., CNS tumors, kidney, liver) as well as FGFR2b dominant cancer types (e.g., breast, colon, lung cancer). The RNAseq data from our NSCLC cohort showed a chief expression of FGFR2b in 116 cases (64%), FGFR2c in 31 cases (17%), and a mixed FGFR2c/FGFR2b transcriptomics (18%). The ratio of FGFR2b/FGFR2c as a metric for splice variant dominance was associated with squamous histology, higher stage, and KRAS mutations. Differential gene expression analysis of cancer tissue and cell lines revealed an association of the splice variant FGFR2c to epithelial-mesenchymal transition (EMT) and the regulation of genes (ZEP1, ERSP1, CDH1) involved in the TGF-beta signal pathway. Finally, the ratio of FGFR2b/FGFR2c demonstrated a strong association with overall survival in NSCLC patients with the FGFR2c variant as unfavorable predictors (High vs low ratio, p = 0.01). Our study indicates cell-specific splice variant expression in non-malignant and malignant cells. The prognostic unfavorable impact of the FGFR2c variant on NSCLC patient survival might be explained by its association with TGF signaling and EMT. The observed clinical and biological difference between FGFR2b and FGFR2c dominated cancers gives further rationale to exploit splice variants as therapeutical targets. Citation Format: Hui Yu, Masafumi Horie, Amanda Lindberg, Max Backman, Neda Hekmati, Johanna Mattsson, Naoya Miyashita, Hans Brunnström, Fredrik Ponten, Akira Saito, Carina Strell, Patrick Micke. FGFR2 splice variant as a cell fate adjudicator determines clinical outcomes in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 208.

METTL3-mediated the m6A modification of SF3B4 facilitates the development of non-small cell lung cancer by enhancing LSM4 expression.

Splicing factor B subunit 4 (SF3B4) has been confirmed to participate in the progression of many cancers and is considered to be a potential target for non-small cell lung cancer (NSCLC). Thus, the role and molecular mechanism of SF3B4 in NSCLC progression deserves further study. Quantitative real-time PCR and western blot were employed to detect the mRNA and protein levels of SF3B4, Sm-like protein 4 (LSM4) and methyltransferase-like 3 (METTL3). Cell proliferation, apoptosis, invasion, migration and stemness were tested by cell counting kit-8, colony formation, flow cytometry, transwell, wound healing, and sphere formation assays. The interaction between SF3B4 and METTL3 or LSM4 was confirmed by MeRIP, RIP and Co-IP assays. Mice xenograft models were constructed to assess the effects of METTL3 and SF3B4 on NSCLC tumorigenesis. SF3B4 had high expression in NSCLC tissues and was associated with the shorter overall survival of NSCLC patients. Knockdown of SF3B4 suppressed NSCLC cell proliferation, invasion, migration and stemness, while inducing apoptosis. METTL3 promoted SF3B4 mRNA stability by m6A modification, and its knockdown inhibited NSCLC cell growth, metastasis and stemness by downregulating SF3B4. SF3B4 could interact with LSM4, and sh-SF3B4-mediated the inhibition on NSCLC cell functions could be reversed by LSM4 overexpression. In addition, reduced METTL3 expression restrained NSCLC tumor growth, and this effect was reversed by SF3B4 overexpression. METTL3-stablized SF3B4 promoted NSCLC cell growth, metastasis and stemness via positively regulating LSM4.

CircNOX4 activates an inflammatory fibroblast niche to promote tumor growth and metastasis in NSCLC via FAP/IL-6 axis

BackgroundCancer-associated fibroblasts (CAFs) orchestrate a supportive niche that fuels cancer metastatic development in non-small cell lung cancer (NSCLC). Due to the heterogeneity and plasticity of CAFs, manipulating the activated phenotype of fibroblasts is a promising strategy for cancer therapy. However, the underlying mechanisms of fibroblast activation and phenotype switching that drive metastasis remain elusive.MethodsThe clinical implications of fibroblast activation protein (FAP)-positive CAFs (FAP+CAFs) were evaluated based on tumor specimens from NSCLC patients and bioinformatic analysis of online databases. CAF-specific circular RNAs (circRNAs) were screened by circRNA microarrays of primary human CAFs and matched normal fibroblasts (NFs). Survival analyses were performed to assess the prognostic value of circNOX4 in NSCLC clinical samples. The biological effects of circNOX4 were investigated by gain- and loss-of-function experiments in vitro and in vivo. Fluorescence in situ hybridization, luciferase reporter assays, RNA immunoprecipitation, and miRNA rescue experiments were conducted to elucidate the underlying mechanisms of fibroblast activation. Cytokine antibody array, transwell coculture system, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the downstream effectors that promote cancer metastasis.ResultsFAP+CAFs were significantly enriched in metastatic cancer samples, and their higher abundance was correlated with the worse overall survival in NSCLC patients. A novel CAF-specific circRNA, circNOX4 (hsa_circ_0023988), evoked the phenotypic transition from NFs into CAFs and promoted the migration and invasion of NSCLC in vitro and in vivo. Clinically, circNOX4 correlated with the poor prognosis of advanced NSCLC patients. Mechanistically, circNOX4 upregulated FAP by sponging miR-329-5p, which led to fibroblast activation. Furthermore, the circNOX4/miR-329-5p/FAP axis activated an inflammatory fibroblast niche by preferentially inducing interleukin-6 (IL-6) and eventually promoting NSCLC progression. Disruption of the intercellular circNOX4/IL-6 axis significantly suppressed tumor growth and metastatic colonization in vivo.ConclusionsOur study reveals a role of the circRNA-induced fibroblast niche in tumor metastasis and highlights that targeting the circNOX4/FAP/IL-6 axis is a promising strategy for the intervention of NSCLC metastasis.

Significance of Pulmonary Artery Dilatation in Lung Cancer Patients With Chronic Obstructive Pulmonary Disease Who Underwent Pulmonary Resection

BackgroundThe significance of pulmonary artery (PA) diameter in patients with non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) who undergo pulmonary resection has not been elucidated. MethodsData of 357 patients with NSCLC and COPD who underwent pulmonary resection were retrospectively reviewed. The main PA diameter, determined by preoperative computed tomography, relative to the body surface area (PBR), was used as an index of PA dilatation, and patients were divided into 2 groups using median values. The relationship between the PBR and short- and long-term outcomes was also analyzed. ResultsThe mean age was 70.8 years, and 82% of the patients were men. The median main PA diameter was 24 mm (range, 17-43 mm), and the median PBR was 14.5 (range, 10.4-28.6). Lobectomy or more was performed in 276 patients (78%) and sublobar resection in 81 patients (22%). The postoperative complication rates did not differ between the low- and high-PBR groups (33% vs 32%, P = .91). The relapse-free survival (RFS) and overall survival (OS) rates of the low-PBR group were significantly better than those of the high-PBR group (5-year RFS: 76% vs 59%, P = .0003; 5-year OS: 88% vs 72%, P = .0010). A multivariable analysis identified high PBR as a poor prognostic factor for both RFS and OS. ConclusionsPA dilatation was associated with poor long-term outcomes and was an independent poor prognostic factor for both RFS and OS in NSCLC patients with COPD who underwent pulmonary resection.

Enhancing brain metastasis prediction in non-small cell lung cancer: a deep learning-based segmentation and CT radiomics-based ensemble learning model

BackgroundBrain metastasis (BM) is most common in non-small cell lung cancer (NSCLC) patients. This study aims to enhance BM risk prediction within three years for advanced NSCLC patients by using a deep learning-based segmentation and computed tomography (CT) radiomics-based ensemble learning model.MethodsThis retrospective study included 602 stage IIIA-IVB NSCLC patients, 309 BM patients and 293 non-BM patients, from two centers. Patients were divided into a training cohort (N = 376), an internal validation cohort (N = 161) and an external validation cohort (N = 65). Lung tumors were first segmented by using a three-dimensional (3D) deep residual U-Net network. Then, a total of 1106 radiomics features were computed by using pretreatment lung CT images to decode the imaging phenotypes of primary lung cancer. To reduce the dimensionality of the radiomics features, recursive feature elimination configured with the least absolute shrinkage and selection operator (LASSO) regularization method was applied to select the optimal image features after removing the low-variance features. An ensemble learning algorithm of the extreme gradient boosting (XGBoost) classifier was used to train and build a prediction model by fusing radiomics features and clinical features. Finally, Kaplan‒Meier (KM) survival analysis was used to evaluate the prognostic value of the prediction score generated by the radiomics–clinical model.ResultsThe fused model achieved area under the receiver operating characteristic curve values of 0.91 ± 0.01, 0.89 ± 0.02 and 0.85 ± 0.05 on the training and two validation cohorts, respectively. Through KM survival analysis, the risk score generated by our model achieved a significant prognostic value for BM-free survival (BMFS) and overall survival (OS) in the two cohorts (P < 0.05).ConclusionsOur results demonstrated that (1) the fusion of radiomics and clinical features can improve the prediction performance in predicting BM risk, (2) the radiomics model generates higher performance than the clinical model, and (3) the radiomics-clinical fusion model has prognostic value in predicting the BMFS and OS of NSCLC patients.

Lymph Node Ratio Enhances Predictive Value for Treatment Outcomes in Patients with Non-Small Cell Lung Cancer Undergoing Surgery: A Retrospective Cohort Study.

Purpose: To compare the prognostic value of lymph node ratio (LNR) and pN in patients with non-small cell lung cancer (NSCLC) undergoing surgery. Materials and methods: NSCLC patients were investigated between 2004 and 2015 from the Surveillance, Epidemiology, and End Results databases. The X-tile software was used to determine LNR cut-off values. Kaplan-Meier analysis was employed to assess cancer-specific survival (CSS) and overall survival (OS). Results: The identified cut-off values of LNR were 0.19 and 0.73. Median CSS for LNR1 (LNR < 0.19), LNR2 (0.19 ≤ LNR ≤ 0.73), and LNR3 (LNR > 0.73) were 71, 41, and 17 months. Both LNR2 (HR = 1.46, 95% CI: 1.36-1.57; P < 0.001) and LNR3 (HR = 2.85, 95% CI: 2.58-3.15; P < 0.001) demonstrated poorer median CSS compared to LNR1. Similarly, median OS for LNR1, LNR2, and LNR3 were 50, 35, and 16 months. LNR2 (HR = 1.36, 95% CI: 1.27-1.45; P < 0.001) and LNR3 (HR = 2.60, 95% CI: 2.37-2.85; P < 0.001) exhibited worse median OS compared to LNR1. A revised pN (r-pN) classification incorporating LNR and pN demonstrated superior penalized goodness-of-fit and discriminative ability in predicting CSS and OS compared to both LNR and pN. Conclusion: LNR outperformed pN in predicting CSS and OS in NSCLC patients undergoing surgery, potentially leading to more precise adjuvant treatment decisions.

Tailoring Therapeutic Strategies in Non-Small-Cell Lung Cancer: The Role of Genetic Mutations and Programmed Death Ligand-1 Expression in Survival Outcomes

Background: This study aims to assess the real-world impact of advancements in first-line systemic therapies for non-small-cell lung cancer (NSCLC), focusing on the role of driver gene mutations and programmed death-ligand 1 (PD-L1) expression levels. Methods: Conducted across eight medical facilities in Japan, this multicenter, retrospective observational research included 863 patients diagnosed with NSCLC and treated between January 2015 and December 2022. The patients were categorized based on the type of systemic therapy received: cytotoxic agents, molecular targeting agents, immune checkpoint inhibitors, and combination therapies. Comprehensive molecular and immunohistochemical analyses were conducted, and statistical evaluations were performed. Results: The median overall survival (OS) shows significant variations among treatment groups, with targeted therapies demonstrating the longest OS. This study also revealed that high PD-L1 expression was common in the group treated with immune checkpoint inhibitors. Multivariate analysis was used to identify the type of anticancer drug and the expression of PD-L1 at diagnosis as the impactful variables affecting 5-year OS. Conclusions: This study underscores the efficacy of targeted therapies and the critical role of comprehensive molecular diagnostics and PD-L1 expression in affecting OS in NSCLC patients, advocating for their integration into routine clinical practice.

SERPINE1 and SERPINB7 as potential biomarkers for intravenous vitamin C treatment in non-small-cell lung cancer

High dose intravenous vitamin C (IVC) has been proposed as a pro-oxidant anticancer agent. However, there is a lack of biomarkers that are specific for this treatment. Here, we explored profiles of gene expression responding to IVC treatment in non-small cell lung cancer (NSCLC) cells as an effort for potential biomarker discovery. Genome-wide RNA-seq was performed in human NSCLC cell lines treated with pharmacological concentrations of vitamin C(VitC) for differential expression of genes. The identified genes were analyzed for correlations with patient prognosis using data from the Kaplan-Meier Plotter and the Human Protein Atlas databases. Further, tumor samples from a retrospective study of 153 NSCLC patients were analyzed with immunohistochemistry for expression of targeted genes, and patient prognosis was correlated to these genes. Two genes, namely SERPINE1 and SERPINB7 were found to be downregulated in NSCLC cells following VitC treatment. Combined patient data from the cohort analysis and online databases revealed that these 2 genes presented an unfavorable prognostic prediction of overall survival (OS) in NSCLC patients receiving standard of care. However, high expression level of these 2 genes were associated with prolonged OS in NSCLC patients receiving IVC in addition to standard of care. These data revealed that SERPINE1 and SERPINB7 have the potential to serve as predictive factors indicating favorable responses to IVC treatment in patients with NSCLC. Further validations are warranted.

Prognostic Significance of Serum Lipids in Patients with Non-Small Cell Lung Cancer Treated with Radiotherapy: A Multicenter Prospective Study

Although lipids have been assessed for their possible roles in cancer survival prediction, studies on the association between serum lipids levels and the prognosis of non-small cell lung cancer (NSCLC) patients are limited. This study aimed to evaluate whether serum lipids are associated with outcomes in patients with NSCLC treated with radiotherapy. We conducted a multicenter prospective study on patients diagnosed with NSCLC between January 2018 and February 2021. Participants received thoracic radiotherapy of 60ཞ80 Gy to the primary lung tumor and positive lymph node metastases. We measured patients' serum lipids levels (serum triglyceride, TGs; total cholesterol, TC, high density lipoprotein cholesterol, HDL-C; low density lipoprotein cholesterol, LDL-C) before radiotherapy. The association between serum lipids levels and overall survival (OS) was evaluated using hazard ratios. We sought to determine a threshold point using optimal stratification. Survival analysis was performed using Kaplan-Meier curves. Of the 300 participants diagnosed with NSCLC treated with radiotherapy, 165 (55.0%) were men. Median follow-up time was 24.4 months (range 1.0- 101.9 months). Using univariate and multivariate Cox proportional hazard analysis, among those serum lipids, only serum TG was shown to be independent prognostic factors for OS (hazard ratio: 1.203, 95% confidence interval: 1.038 - 1.393, p = 0.014). The cut-off for TG associated with OS was 2.04 mmol/L. Based on the TG cut-off value, 55 NSCLC patients were categorized into the high TG group (>2.04 mmol/L) and 245 in the low TG group (<2.04 mmol/L). The NSCLC patients in the low TG group exhibited higher OS than the high group (median OS, not reach vs 41.4 months, p = 0.025). TG levels were found to be a significant negative prognostic biomarker for OS in NSCLC patients treated with radiotherapy.

The value of CRP-albumin-lymphocyte index (CALLY index) as a prognostic biomarker in patients with non-small cell lung cancer.

The C-reactive protein-albumin-lymphocyte (CALLY) index is a new index related to inflammation, immunity, and nutrition. We investigated whether it can predict the prognosis of patients with non-small cell lung cancer (NSCLC) and developed a prognostic model including CALLY index. Data from patients with NSCLC who were followed up in the INSCOC database from May 2013 to December 2018 were retrospectively analyzed. Simple random sampling by splitting these patients into training (n = 1307) and validation cohorts (n = 557) resulted in a sample size ratio of 7:3. Using the results of COX regression analysis of the training cohort, a nomogram model for predicting 3- and 5-year overall survival (OS) was established and validated internally. The calibration and clinical decision curve were used to evaluate the prediction accuracy and clinical application ability of the nomogram and compared with the TNM staging system for lung cancer. Sex, TNM stage, surgical treatment, BMI, CALLY, and HGS were independent risk factors for the prognosis of NSCLC patients. The OS of NSCLC patients with a low CALLY index score was significantly worse than that of patients with a high CALLY index (P < 0.001). The CALLY-based nomogram had a good predictive prognostic power, with a C-index of 0.697. Compared with the traditional TNM staging system, our prognostic nomogram had better resolution and accuracy in predicting the 3-year and 5-year OS. Decision curve analysis showed that this prognostic model has a clinical application value. The CALLY index is a valuable biomarker for evaluating the prognosis of patients with lung cancer. The nomogram based on the CALLY index is highly effective in predicting OS in patients with NSCLC. The results of this study provide a reference tool for clinicians to guide the personalized treatment of patients with lung cancer.

Prognostic Potential of the Prognostic Nutritional Index in Non-Small Cell Lung Cancer Patients Receiving Pembrolizumab Combination Therapy with Carboplatin and Paclitaxel/Nab-Paclitaxel

Introduction: Pembrolizumab (Pemb) therapy in conjunction with carboplatin and paclitaxel (PTX)/nab-PTX has been efficacious in treating non-small cell lung cancer (NSCLC). However, the response predictors of this combination therapy (Pemb-combination) remain undetermined. We aimed to evaluate whether Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) are potential factors in prognosticating the response to Pemb-combination therapy in advanced NSCLC patients. Methods: We retrospectively recruited 144 NSCLC patients receiving first-line treatment with Pemb-combination therapy from 13 institutions between December 1, 2018, and December 31, 2020. GPS, NLR, BMI, PLR, and PNI were assessed for their efficacy as prognostic indicators. Cox proportional hazard models and the Kaplan-Meier method were used to compare the progression-free survival (PFS) and overall survival (OS) of the patients. Results: The treatment exhibited a response rate of 63.1% (95% confidence interval [CI]: 55.0–70.6%). Following Pemb-combination administration, the median PFS and OS were 7.3 (95% CI: 5.3–9.4) and 16.5 (95% CI: 13.9–22.1) months, respectively. Contrary to PNI, NLR, GPS, BMI, and PLR did not display substantially different PFS in univariate analysis. However, multivariate analysis did not identify PNI as an independent prognostic factor for PFS. Furthermore, univariate analysis revealed that GPS, BMI, and PLR exhibited similar values for OS but not NLR and PNI. Patients with PNI ≥45 were predicted to have better OS than those with PNI <45 (OS: 23.4 and 13.9 months, respectively, p = 0.0028). Multivariate analysis did not establish NLR as an independent prognostic factor for OS. Conclusion: The PNI evidently predicted OS in NSCLC patients treated with Pemb-combination as first-line therapy, thereby validating its efficiency as a prognostic indicator of NSCLC.

Machine learning-based establishment and validation of age-related patterns for predicting prognosis in non-small cell lung cancer within the context of the tumor microenvironment.

Lung cancer (LC) is a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 80% of cases. The impact of aging on clinical outcomes in NSCLC remains poorly understood, particularly with respect to the immune response. In this study, we explored the effects of aging on NSCLC using 307 genes associated with human aging from the Human Ageing Genomic Resources. We identified 53 aging-associated genes that significantly correlate with overall survival of NSCLC patients, including the clinically validated gene BUB1B. Furthermore, we developed an aging-associated enrichment score to categorize patients based on their aging subtypes and evaluated their prognostic and therapeutic response values in LC. Our analyses yielded two aging-associated subtypes with unique profiles in the tumor microenvironment, demonstrating varying responses to immunotherapy. Consensus clustering based on transcriptome profiles provided insights into the effects of aging on NSCLC and highlighted the potential of personalized therapeutic approaches tailored to aging subtypes. Our findings provide a new target and theoretical support for personalized therapeutic approaches in patients with NSCLC, offering insights into the potential impact of aging on cancer outcomes.

Pretreatment lymphocyte-to-monocyte ratio as a prognostic factor and influence on dose-effect in fractionated stereotactic radiotherapy for oligometastatic brain metastases in non-small cell lung cancer patients.

Studies on the prognostic factors for patients with brain oligo-metastasis treated with fractionated stereotactic radiotherapy (FSRT) usually focus on the size of metastatic tumor and radiation dose. Some inflammatory indicators have predictive value in non-small cell lung cancer (NSCLC) with brain metastasis receiving stereotactic radiotherapy. However, the prognostic value of inflammatory indicators in NSCLC patients with brain oligo-metastasis treated with FSRT, and their effect on radiotherapy dose is unknown. A total of 95 advanced NSCLC patients with brain oligo-metastasis who had undergone FSRT treatment at Ningbo Medical Center Lihuili Hospital between January 2015 and April 2022 were enrolled into the study. Neutrophil to lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), tumor diameter and biologically effective dose (BED10) were analyzed using Chi-square test. Univariate and multivariate Cox regressions were used to identify predictors of survival. Tumor diameter (< 2 cm), BED10 (≥ 48Gy) and LMR (≥ 4) were found to be independently associated with good intracranial local control survival (i-LCS) through multivariate analysis. The median i-LCS was longer in patients with 2 independent risk factors (tumor diameter ≥ 2 and LMR < 4) administered with BED10 > 53.6Gy compared with patients administered with BED10 ≤ 53.6Gy (20.7 months vs 12.0 months, P = 0.042). LMR ≥ 4 (P = 0.019) and positivity for driver gene mutations (P = 0.011) were independently associated with better overall survival (OS). LMR is an independent prognostic factor of i-LCS and OS in NSCLC patients with brain oligo-metastasis treated with FSRT. Patients with tumor diameter ≥ 2 and LMR < 4 should be treated with BED10 greater than 53.6Gy.