Survival In Non-small Cell Lung Cancer Research Articles

Osimertinib induced cardiac failure and atrial flutter in a patient with advanced pulmonary adenocarcinoma: A case report and review of the literature

<b>Background: </b>Osimertinib-induced cardiotoxicity is a significant but rare condition. This article reports a case of an elderly patient who developed cardiac failure and atrial flutter due to Osimertinib treatment, potentially related to both the drug and the patient’s underlying factors.<br /> <b>Case presentation:</b> A 63-year-old man diagnosed with advanced non-small cell lung cancer (NSCLC) with bone metastasis was found to have an epidermal growth factor receptor mutation (exon 19 deletion). He had undergone four prior treatment regimens, including afatinib and bevacizumab. After two years, he developed resistance and experienced brain and bone metastases, prompting a switch to Osimertinib (80 mg/day). Before starting Osimertinib, he had a history of coronary artery disease and hypertension, with a normal electrocardiogram (ECG) and a left ventricular ejection fraction (LVEF) of 53%. However, nearly two months after initiating Osimertinib, he was presented with cardiac failure symptoms, with LVEF decreasing to <53% and atrial flutter observed on ECG. Suspecting drug-induced cardiotoxicity, Osimertinib was discontinued. Following cessation of the drug, his cardiac function improved, and the ECG abnormalities resolved. This case represents the first reported instance of concurrent cardiac failure and atrial flutter associated with Osimertinib treatment.<br /> <b>Conclusions: </b>As Osimertinib continues to significantly enhance survival in NSCLC, there remains a need for active monitoring of cardiac adverse events in patients undergoing Osimertinib treatment. These events can be life-threatening but are usually reversible after discontinuation of the drug.

Genetic variants of FER and SULF1 in the fibroblast-related genes are associated with non-small-cell lung cancer survival.

Fibroblasts are important components in the tumor microenvironment and can affect tumor progression and metastasis. However, the roles of genetic variants of the fibroblast-related genes (FRGs) in the prognosis of non-small-cell lung cancer (NSCLC) patients have not been reported. Therefore, we investigated the associations between 26,544 single nucleotide polymorphisms (SNPs) in 291 FRGs and survival of NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In Cox regression multivariable analysis, we found that 661 SNPs were associated with NSCLC overall survival (OS). Then we validated these SNPs in another independent replication dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. Finally, we identified two independent SNPs (i.e., FER rs7716388 A>G and SULF1 rs11785839 G>C) that remained significantly associated with NSCLC survival with hazards ratios (HRs) of 0.87 (95% confidence interval [CI] = 0.77-0.98, p = 0.018) and 0.88 (95% CI = 0.79-0.99, p = 0.033), respectively. Combined analysis for these two SNPs showed that the number of protective alleles was associated with better OS and disease-specific survival. Expression quantitative trait loci analysis indicated that the FER rs7716388 G allele was associated with the up-regulation of FER mRNA expression levels in lung tissue. Our results indicated that these two functional SNPs in the FRGs may be prognostic biomarkers for the prognosis of NSCLC patients, and the possible mechanism may be through modulating the expression of their corresponding genes.

Clinico-pathological characteristics and treatment outcome in non-small cell lung cancer in Greenland 2015-2020 - a comparison with the cohort from 2004 to 2010.

Lung cancer is the leading cause of cancer-related mortality in Greenland. Since 2004, medical treatment of lung cancer has been available in Greenland. However, both diagnostic work-up and treatment logistics are hampered by the lack of medical services in smaller settlements, the infrastructure, and extreme arctic weather conditions. Clinico-pathological data and assessment of treatment outcome in lung cancer in Greenland have not been carried out since 2015. This study aims to provide an analysis of Greenlandic patients with non-small cell lung cancer (NSCLC) from 2015 to 2020, compared to the cohort from the 2015 study. We focus on diagnostics, patient and treatment characteristics, and survival rates. Additionally, we include new data on treatment-related factors and diagnostic delays. Patients/material: Clinical-, pathological-, genomic data, tuberculosis status and survival were retrieved from the medical journal. A total of 163 patients were identified. Survival had improved in stage I, III, and IV, and early-stage disease was more often diagnosed as compared to the 2015 cohort. Molecular alterations and PD-L1 expressing tumors were comparable between Greenlandic and Danish patients. Diagnostic delay was a major concern. While NSCLC survival in Greenland has improved over the past decade, significant challenges remain. The trend towards diagnosing more stage IA-IIIA patients and the recent improvements in diagnostic and therapeutic options in Greenland are expected to translate into a better prognosis in the coming years. Addressing diagnostic delays and enhancing treatment options are crucial steps toward improving outcomes for NSCLC patients in Greenland.

Comparative evaluation of negative lymph node count, positive lymph node count, and lymph node ratio in prognostication of survival following completely resection for non-small cell lung cancer: a multicenter population-based analysis

ObjectiveLung cancer is the leading cause of cancer-related mortality. Lymph node involvement remains a crucial prognostic factor in non-small cell lung cancer (NSCLC), and the TNM system is the current standard for staging. However, it mainly considers the anatomical location of lymph nodes, neglecting the significance of node count. Metrics like metastatic lymph node count and lymph node ratio (LNR) have been proposed as more accurate predictors.MethodsWe used data from the SEER 17 Registry Database (2010–2019), including 52,790 NSCLC patients who underwent lobectomy or pneumonectomy, with at least one lymph node examined. Primary outcomes were overall survival (OS) and cancer-specific survival (CSS). Cox regression models assessed the prognostic value of negative lymph node (NLN) count, number of positive lymph node (NPLN), and LNR, with cut-points determined using X-tile software. Model performance was evaluated by the Akaike information criterion (AIC).ResultsThe Cox proportional hazards model analysis revealed that NLN, NPLN, and LNR are independent prognostic factors for OS and LCSS (P < 0.0001). Higher NLN counts were associated with better survival (HR = 0.79, 95% CI = 0.76–0.83, P < 0.0001), while higher NPLN (HR = 2.19, 95% CI = 1.79–2.67, P < 0.0001) and LNR (HR = 1.64, 95% CI = 1.79–2.67, P < 0.0001) values indicated worse outcomes. Kaplan-Meier curves for all three groups (NLN, NPLN, LNR) demonstrated clear stratification (P < 0.0001). The NLN-based model (60,066.5502) exhibited the strongest predictive performance, followed by the NPLN (60,508.8957) and LNR models (60,349.4583), although the differences in AIC were minimal.ConclusionsNLN count, NPLN, and LNR were all identified as independent prognostic indicators in patients with NSCLC. Among these, the predictive model based on NLN demonstrated a marginally superior prognostic value compared to NPLN, with NPLN outperforming the LNR model. Notably, higher NLN counts, along with lower NPLN and LNR values, were consistently associated with improved survival outcomes. The relationship between these prognostic markers and NSCLC survival warrants further validation through prospective studies.

A two-phase epigenome-wide four-way gene-smoking interaction study of overall survival for early-stage non-small cell lung cancer.

High-order interactions associated with non-small cell lung cancer (NSCLC) survival may elucidate underlying molecular mechanisms and identify potential therapeutic targets. Our previous work has identified a three-way interaction among pack-year of smoking (the number of packs of cigarettes smoked per day multiplied by the number of years the person has smoked) and two DNA methylation probes (cg05293407TRIM27 and cg00060500KIAA0226). However, whether a four-way interaction exists remains unclear. Therefore, we adopted a two-phase design to identify the four-way gene-smoking interactions by a hill-climbing strategy on the basis of the previously detected three-way interaction. One CpG probe, cg16658473SHISA9, was identified with FDR-q ≤ 0.05 in the discovery phase and P ≤ 0.05 in the validation phase. Meanwhile, the four-way interaction improved the discrimination ability for the prognostic prediction model, as indicated by the area under the receiver operating characteristic curve (AUC) for both 3- and 5-year survival. In summary, we identified a four-way interaction associated with NSCLC survival among pack-year of smoking, cg05293407TRIM27, cg00060500KIAA0226 and g16658473SHISA9, providing novel insights into the complex mechanisms underlying NSCLC progression.

Sex-based differences in CEACAM5 expression in lung cancer.

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is expressed in 20-25% of non-small cell lung cancer (NSCLC) and there is interest in CEACAM5 as a biomarker given its potential for blood-based detection and investigational study as a drug target. Increased expression of CEACAM5 has been observed in semi-solid lung adenocarcinoma lesions, which have an increased prevalence in women and never smokers. Given this association, sex-based differences in CEACAM5 were evaluated. The Cancer Genome Atlas (TCGA) data on CEACAM5 expression in NSCLC tumors (n=994) in women (n=398) and men (n=596) were analyzed for differences in expression of CEACAM5 based on sex and histologic subtypes of adenocarcinoma and for correlations with overall survival (OS). Among all stages of NSCLC, mean expression of CEACAM5 was 143.3 fragments per kilobase of transcript per million (FPKM) with differences observed between female and male patients (194.5 vs. 109.2 FPKM, P<0.0001) and between adenocarcinoma and squamous cell carcinoma (239.3 vs. 46.2 FPKM, P<0.0001). Differences persisted among combined sex and histology subgroups. High CEACAM5 was not predictive of survival in NSCLC or adenocarcinoma overall, but was associated with worse survival among stage I female patients with adenocarcinoma (5-year OS CEACAM5 high =33% vs. low =64%, log-rank P=0.008). Higher levels of CEACAM5 expression are observed in NSCLC tumors in female patients and adenocarcinoma histology. High CEACAM5 expression in lung adenocarcinoma is associated with worse survival among female patients. The biologic impact of sex on CEACAM5 as a biomarker warrants further study.

Mitochondrial-associated programmed-cell-death patterns for predicting the prognosis of non-small-cell lung cancer.

Mitochondria are the convergence point of multiple pathways that trigger programmed cell death (PCD). Mitochondrial-associated PCD (mtPCD) is involved in the pathogenesis of several diseases. However, the role of mtPCD in the prognostic prediction of cancers including non-small-cell lung cancer (NSCLC) remains to be investigated. Here, 12 mtPCD patterns were analyzed in transcriptomics, genomics, and clinical data collected from 4 datasets containing 977 patients. A risk-score assessment system containing 18 genes was established. We found that NSCLC patients with a high-risk score had a poorer prognosis. A nomogram was constructed by incorporating the risk score with clinical features. The risk score was further associated with clinicopathological information, tumor-mutation frequency, and immunotherapy responses. NSCLC patients with a high risk score had more Treg cells infiltration. However, these patients had higher tumor-mutation burden scores and may be more sensitive to immunotherapy. Moreover, receptor-interacting serine/threonine protein kinase 2 (RIPK2) was selected from mtPCD gene model for validation. We found that RIPK2 exhibited oncogenic function, and its expression level was inversely associated with the overall survival of NSCLC. Taken together, our results indicated the accuracy and practicability of the mtPCD gene model and RIPK2 in predicting the prognosis of NSCLC.

Polyol pathway-generated fructose is indispensable for growth and survival of non-small cell lung cancer.

Despite recent treatment advances, non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide, and therefore it necessitates the exploration of new therapy options. One commonly shared feature of malignant cells is their ability to hijack metabolic pathways to confer survival or proliferation. In this study, we highlight the importance of the polyol pathway (PP) in NSCLC metabolism. This pathway is solely responsible for metabolizing glucose to fructose based on the enzymatic activity of aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD). Via genetic and pharmacological manipulations, we reveal that PP activity is indispensable for NSCLC growth and survival in vitro and in murine xenograft models. Mechanistically, PP deficiency provokes multifactorial deficits, ranging from energetic breakdown and DNA damage, that ultimately trigger the induction of apoptosis. At the molecular level, this process is driven by pro-apoptotic JNK signaling and concomitant upregulation ofthe transcription factors c-Jun and ATF3. Moreover, we show that fructose, the PP end-product, as well as other non-glycolytic hexoses confer survival to cancer cells and resistance against chemotherapy via sustained NF-κB activity as well as an oxidative switch in metabolism. Given the detrimental consequence of PP gene targeting on growth and survival, we propose PP pathway interference as a viable therapeutic approach against NSCLC.

Integrating radiomic and 3D autoencoder-based features for Non-Small Cell Lung Cancer survival analysis

Background and objectivesThe aim of this study is to develop a radiomic and deep learning-based signature for survival analysis of patients with Non-Small Cell Lung Cancer. MethodsFour-hundred twenty-two patients from “Lung1” dataset were included in the study. A 3D convolutional autoencoder (AE) was built and features from the latent space extracted for further analysis. Radiomic features were derived from the 3D volume of the tumor region using PyRadiomics. Both radiomic and AE-based features underwent feature selection, by removing: i) highly correlated and ii) constant features. The selected variables were then used to derive both mono-domain (radiomics, AE and clinic) and multi-domain signatures fitting a Cox Proportional Hazard model with LASSO penalization and evaluated considering the concordance (C)-index as performance metric. ResultsBoth mono-domain and multi-domain signatures could significantly differentiate high risk from low risk patients. Among the mono-domain signatures, the highest hazard ratio (HR) in the test set was obtained using radiomics (HR = 1.5428) followed by the AE-based signature (HR = 1.5012) and the clinical signature (HR = 1.4770). The best overall performance was achieved by combining all three signatures, resulting in the highest HR (HR = 1.7383), while the combination of AE-based and clinical signatures yielded the highest C-index (C-index = 0.6309). ConclusionsThese preliminary results show that combining information carried by AE, radiomic and clinical domain shows potential for improving the prediction of overall survival in NSCLC patients.

Evaluation of albumin and lactate dehydrogenase in comparison with cytokeratin 19 fragments and neuron‐specific enolase as diagnostic biomarkers for non‐small cell lung cancer

AbstractBackgroundThe diagnosis of non‐small cell lung cancer (NSCLC) is a clinical issue that requires attention, and more practical and effective biomarkers need to be selected to assist in diagnosis. This study aimed to examine the diagnostic value of serum albumin (ALB), lactate dehydrogenase (LDH), cytokeratin 19 fragments (CYFRA21‐1), and neuron‐specific enolase (NSE) for NSCLC.MethodsThe clinical data of 1048 NSCLC patients and 1125 healthy subjects were extracted from electronic medical records. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic significance of ALB, LDH, CYFRA21‐1, and NSE for NSCLC. The Cancer Genome Atlas (TCGA) data, which included mRNA profiles for ALB and LDH expression, were acquired from TCGA Program. Finally, interactive survival scatter plots and survival analyses for NSCLC patients were evaluated using the Human Protein Atlas and Kaplan–Meier Plotter.ResultsSignificant differences were noted in the levels of ALB and LDH between NSCLC patients and healthy controls. The areas under the ROC curves (AUCs) for ALB and LDH were 0.754 (95% CI: 0.734–0.774) and 0.681 (95% CI: 0.658–0.704), respectively. Moreover, the combination of ALB and LDH raised the AUC to 0.804 (95% CI: 0.785–0.823), and the incorporation of CYFRA21‐1 and NSE further increased the AUC to 0.903 (95% CI: 0.890–0.916). Notably, ALB and LDH might be related to the overall survival of NSCLC patients.ConclusionThis study revealed that ALB and LDH in NSCLC patient serum could improve the diagnostic accuracy of conventional biomarkers for NSCLC.

Prognostic significance of the modified Glasgow Prognostic Score in NSCLC patients undergoing immune checkpoint inhibitor therapy: a meta-analysis.

The modified Glasgow Prognosis Score (mGPS), which considers both inflammatory response and nutritional status, has been linked to the prognosis of various tumors. The relationship between mGPS and non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) is still a subject of debate. This meta-analysis aims to comprehensively assess the association between mGPS and survival in NSCLC treated with ICIs. A thorough review of studies from PubMed, Web of Science, Scopus, and Embase was conducted up to June 4, 2024. Fixed-effect or random-effect models were employed, combining hazard ratios (HRs) and 95% confidence intervals (CI), to assess the prognostic value of mGPS for OS and PFS in patients with NSCLC receiving immunotherapy. A total of 1,022 patients from 11 studies were recruited. Combined results showed that mGPS elevation was significantly associated with poor OS (HR = 1.63, 95%CI: 1.42-1.87, P < 0.01) and PFS (HR = 1.71, 95%CI: 1.31-2.24, P < 0.01). Subgroup analysis and sensitivity analysis further determined the predictive effect of elevated mGPS on OS and PFS deterioration in NSCLC patients receiving immunotherapy. mGPS can be used as a good noninvasive biomarker to demonstrate prognostic and clinical significance in patients with NSCLC undergoing immunotherapy. http://www.crd.york.ac.uk/prospero/ PROSPERO, identifier CRD42023432661.

Genetic variants of LRRC8C, OAS2, and CCL25 in the T cell exhaustion-related genes are associated with non-small cell lung cancer survival.

T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported. We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants. Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood. Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression.

Enhancing Non-Small Cell Lung Cancer Survival Prediction through Multi-Omics Integration Using Graph Attention Network.

Background: Cancer survival prediction is vital in improving patients' prospects and recommending therapies. Understanding the molecular behavior of cancer can be enhanced through the integration of multi-omics data, including mRNA, miRNA, and DNA methylation data. In light of these multi-omics data, we proposed a graph attention network (GAT) model in this study to predict the survival of non-small cell lung cancer (NSCLC). Methods: The different omics data were obtained from The Cancer Genome Atlas (TCGA) and preprocessed and combined into a single dataset using the sample ID. We used the chi-square test to select the most significant features to be used in our model. We used the synthetic minority oversampling technique (SMOTE) to balance the dataset and the concordance index (C-index) to measure the performance of our model on different combinations of omics data. Results: Our model demonstrated superior performance, with the highest value of the C-index obtained when we used both mRNA and miRNA data. This demonstrates that the multi-omics approach could be effective in predicting survival. Further pathway analysis conducted with KEGG showed that our GAT model provided high weights to the features that are associated with the viral entry pathways, such as the Epstein-Barr virus and Influenza A pathways, which are involved in lung cancer development. From our findings, it can be observed that the proposed GAT model leads to a significantly improved prediction of survival by exploiting the strengths of multiple omics datasets and the findings from the enriched pathways. Our GAT model outperforms other state-of-the-art methods that are used for NSCLC prediction. Conclusions: In this study, we developed a new model for the survival prediction of NSCLC using the GAT based on multi-omics data. Our model showed outstanding predictive values, and the KEGG analysis of the selected significant features showed that they were implicated in pivotal biological processes underlying pathways such as Influenza A and the Epstein-Barr virus infection, which are linked to lung cancer progression.

BUB1 Inhibition Overcomes Radio- and Chemoradiation Resistance in Lung Cancer.

Background: Despite advances in targeted therapies and immunotherapies, traditional treatments like microtubule stabilizers (paclitaxel, docetaxel), DNA-intercalating platinum drugs (cisplatin), and radiation therapy remain essential for managing locally advanced and metastatic lung cancer. Identifying novel molecular targets could enhance the efficacy of these treatments. Hypothesis: We hypothesize that BUB1 (Ser/Thr kinase) is overexpressed in lung cancers and its inhibition will sensitize lung cancers to chemoradiation. Methods: BUB1 inhibitor (BAY1816032) was combined with cisplatin, paclitaxel, a PARP inhibitor olaparib, and radiation in cell proliferation and radiation-sensitization assays. Biochemical and molecular assays evaluated the impact on DNA damage signaling and cell death. Results: Immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) compared to normal tissues. In NSCLC, BUB1 overexpression correlated directly with the expression of TP53 mutations and poorer overall survival in NSCLC and SCLC patients. BAY1816032 synergistically sensitized lung cancer cell lines to paclitaxel and olaparib and enhanced cell killing by radiation in both NSCLC and SCLC. Molecular analysis indicated a shift towards pro-apoptotic and anti-proliferative states, evidenced by altered BAX, BCL2, PCNA, and Caspases-9 and -3 expressions. Conclusions: Elevated BUB1 expression is associated with poorer survival in lung cancer. Inhibiting BUB1 sensitizes NSCLC and SCLC to chemotherapies (cisplatin, paclitaxel), targeted therapy (olaparib), and radiation. Furthermore, we present the novel finding that BUB1 inhibition sensitized both NSCLC and SCLC to radiotherapy and chemoradiation. Our results demonstrate BUB1 inhibition as a promising strategy to sensitize lung cancers to radiation and chemoradiation therapies.

Potentially functional variants of PARK7 and DDR2 in ferroptosis-related genes predict survival of non-small cell lung cancer patients.

Ferroptosis, a form of regulated cell death, is characterized by iron-dependent lipid peroxidation. It is recognized increasingly for its pivotal role in both cancer development and the response to cancer treatments. We assessed associations between 370,027 single-nucleotide polymorphisms (SNPs) within 467 ferroptosis-related genes and survival of non-small cell lung cancer (NSCLC) patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial served as our discovery dataset, while the Harvard Lung Cancer Susceptibility Study used as our validation dataset. For SNPs that remained statistically significantly associated with overall survival (OS) in both datasets, we employed a multivariable stepwise Cox proportional hazards regression model with the PLCO dataset. Ultimately, two independent SNPs, PARK7 rs225120 C>T and DDR2 rs881127 T>C, were identified with adjusted hazard ratios of 1.32 (95% confidence interval = 1.15-1.52, p = .0001) and 1.34 (95% confidence interval = 1.09-1.64, p = .006) for OS, respectively. We aggregated these two SNPs into a genetic score reflecting the number of unfavorable genotypes (NUG) in further multivariable analysis, revealing a noteworthy association between increased NUG and diminished OS (ptrend = .001). Additionally, an expression quantitative trait loci analysis indicated that PARK7 rs225120T genotypes were significantly associated with higher PARK7 mRNA expression levels in both whole blood and normal lung tissue. Conversely, DDR2 rs881127C genotypes were significantly associated with lower DDR2 mRNA expression levels in normal lung tissue. Our findings suggest that genetic variants in the ferroptosis-related genes PARK7 and DDR2 are associated with NSCLC survival, potentially through their influence on gene expression levels.

Perioperative PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer: A meta-analysis based on randomized controlled trials.

PD-1/PD-L1 inhibitors (PI) have shown promising results in both neoadjuvant and adjuvant therapies for resectable non-small cell lung cancer (NSCLC). However, substantial evidence from large-scale studies is still lacking for their use in the perioperative setting (neoadjuvant plus adjuvant). This meta-analysis aims to evaluate the integration of perioperative PI (PPI) with neoadjuvant chemotherapy for resectable NSCLC. To identify appropriate randomized controlled trials (RCTs), we thoroughly explored six different databases. The primary endpoint was survival, while the secondary measures included pathological responses and adverse events (AEs). Six RCTs involving 2941 patients were included. The PPI group significantly improved overall survival (OS) (hazard ratio [HR]: 0.62 [0.51, 0.77]), event-free survival (EFS) (HR: 0.57 [0.51, 0.64]), pathological complete response (risk ratio [RR]: 5.81 [4.47, 7.57]), and major pathological response (RR: 2.60 [1.77, 3.82]). Benefits in EFS were seen across all subgroups. OS rates at 12-48 months and EFS rates at 6-48 months were higher in the PPI cohort. Furthermore, the advantages in OS and EFS increased with prolonged survival times. The PPI group also exhibited higher rates of surgery and R0 resections. However, the PPI group experienced more grade 3-5 AEs, serious AEs, and treatment discontinuations due to AEs. The integration of perioperative PI with neoadjuvant chemotherapy can significantly improve survival and pathological responses for resectable NSCLC. However, the increased incidence of grade 3-5 AEs must be carefully evaluated.

The association between postdiagnosis smoking cessation and survival in advanced non-small cell lung cancer patients in Southern Taiwan: A retrospective cohort study

ABSTRACT Objectives: Smoking is a major lung cancer risk factor. Studies show that smoking after lung cancer diagnosis is associated with an increased risk of developing other cancers and shorter survival. The purpose of this study was to examine the association between postdiagnosis smoking cessation and survival in patients with advanced non-small cell lung cancer (NSCLC). Materials and Methods: A retrospective cohort study was conducted. Data were collected between January 2014 and December 2019 in three hospitals in Southern Taiwan. Patient data were collected from the hospitals’ databases, and the correlation between smoking status and patient survival was analyzed using Kaplan–Meier curves and Cox proportional hazards regression modeling. Results: A total of 681 patients with advanced NSCLC were included in this study. The numbers (percentage) of ex-smokers and current smokers were 334 (49%) and 347 (51%), respectively. More than half of the patients in this study continued to smoke postdiagnosis advanced NSCLC. Furthermore, ex-smokers had lower mortality risk, even though this was not statistically significant (P = 0.212). The results of this study suggest that older than 65 years, men, Eastern Cooperative Oncology Group performance score of 3 and higher, history of chronic disease, receive chemotherapy, and targeted therapy are correlated with and have predictive effects on advanced NSCLC survival. Conclusion: There is no significant difference between postdiagnosis smoking cessation and survival in patients with advanced NSCLC. The reason for this finding may be due to lower survival rates after diagnosis with advanced NSCLC, and the benefits of smoking cessation cannot be seen immediately.

Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC)

BackgroundCancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC. MethodsIn vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome. ResultsIn vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts. DiscussionAlthough in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.

Brain Metastases as Inaugural Sign of Non-Small Cell Lung Carcinoma: Case Series and Review of Literature.

In the era of immune checkpoint inhibitors (ICI), managing non-oncogene driven non-small cell lung cancer (NSCLC) with brain metastases (BM) is challenging, especially when brain involvement is the initial sign. Patients with newly diagnosed brain metastatic NSCLC without epidermal growth factor receptor (EFGR) nor anaplastic lymphoma kinase (ALK) alterations were retrospectively included. Twenty-five patients were analyzed; 15 (60%) had symptomatic BM as the first sign (group 1), while 10 (40%) had BM discovered during complementary examinations (group 2). Fourteen patients (56%) had concomitant extracerebral metastases, primarily in group 2. Eight (32%) had oligometastatic disease, with seven in group 1. Over half received chemotherapy and pembrolizumab as first-line treatment. BM surgical resection occurred in twelve (80%) patients in group 1 and one in group 2. Median cerebral progression-free survival was 10 months: 12 in group 1 and 5 in group 2. Median overall survival was 25 months: not reached in group 1 and 6 months in group 2. This case series highlights survival outcomes for patients with inaugural BM, a demographic underrepresented in pivotal trials. Oligometastatic disease and symptomatic BM as initial signs seem associated with better prognosis due to increased use of multimodal local approaches. Combining local approaches with first-line ICI+/- chemotherapy appears to improve survival in brain metastatic NSCLC. A literature review was conducted to explore key questions regarding upfront ICI alone or in combination with systemic drugs or local approaches in brain metastatic NSCLC.

1378P Improvements in stage IV non-small cell lung cancer survival differ by race in the US

1378P Improvements in stage IV non-small cell lung cancer survival differ by race in the US