Prognostic Factor For Non-small Cell Lung Cancer Patients Research Articles

The prognostic factors of clinical outcomes in non-small cell lung cancer patients receiving subsequent treatments after progression on initial immunotherapy.

The standard of care for non-small cell lung cancer (NSCLC) patients who encounter progression on initial immune checkpoint inhibitor (ICI) based treatment is uncertain. In the real world, there are various subsequent treatment options, but how to find the most suitable treatment for different patients is still unknown. The present study aimed to explore prognostic factors of subsequent treatment after progression (STAP) (defined as the next treatment after progression from the initial immunotherapy) of initial immunotherapy. In this retrospective cohort study, NSCLC patients received regimens after progression of initial immunotherapy at Beijing Chest Hospital, Capital Medical University, between March 2016 and May 2023 were retrieved. The major efficacy endpoint was progression-free survival 2 (PFS2), defined as the time from the initiation of next treatment after initial immunotherapy failure to disease progression or death from any cause. Subgroup analyses were conducted according to baseline characteristics, some subsequent regimens beyond progression, etc. for prognostic factors exploration. The Cox proportional hazards model was used for multivariate analysis. There were 176 patients enrolled. Median age was 64 years. There were 36 (20.5%) females, and 123 (69.9%) were smokers. Adenocarcinoma (99, 56.2%) was the major histological subtype. There were 95 (54.0%) patients with negative expression for programmed cell death ligand 1 (PD-L1). After progressive disease, 92 (52.3%) patients reused ICI-based treatment after progressive disease. Median PFS2 was 3.6 months [95% confidence interval (CI): 2.8-4.4]. Longer PFS2 was observed in patients with PD-L1 positive expression [hazard ratio (HR) =0.672, 95% CI: 0.477-0.947, P=0.023] or PFS ≥6 months in initial immunotherapy (HR =0.543, 95% CI: 0.358-0.824, P=0.004). Besides, patients switching to new ICI-based treatments without radiotherapy gained better PFS2 compared with patients receiving prior regimens (P=0.019). PD-L1 positive expression, and longer PFS in initial immunotherapy would be good prognostic factors for NSCLC patients undergoing STAP on first immunotherapy. Besides, compared with original regimen, changing ICI would prolong PFS2 for NSCLC patients reusing ICI.

The AST/ALT ratio predicts survival and improves oncological therapy decisions in patients with non-small cell lung cancer receiving immunotherapy with or without radiotherapy.

Immunotherapy, with or without radiotherapy (iRT or ICIs-nonRT), is the standard treatment for non-small cell lung cancer (NSCLC). Nonetheless, the response to the treatment varies among patients. Given the established role of aspartate aminotransferase/alanine transaminase (AST/ALT) ratio in predicting cancer prognosis, we sought to identify whether the pre-treatment AST/ALT ratio has the potential to serve as a prognostic factor for NSCLC patients receiving ICIs-nonRT and iRT. We retrospectively analyzed NSCLC patients who received immunotherapy between April 2018 and March 2021. Patients were classified into iRT group and ICIs-nonRT group and further classified based on AST/ALT ratio cut-off values. The Kaplan-Meier (KM) method estimated the time-to-event endpoints (progression-free survival (PFS) and overall survival (OS). Of the cohort, 239 underwent ICIs-nonRT and 155 received iRT. Higher AST/ALT ratios correlated with worse outcomes in the ICIs-nonRT group but indicated better outcomes in those who received iRT. Multivariate analysis validated AST/ALT ratio as an independent prognostic factor. For AST/ALT ratios between 0.67-1.7, both ICIs-nonRT and iRT yielded similar treatment outcomes; with AST/ALT ratios greater than 1.7, iRT could be a more favorable treatment option (P=0.038). Conversely, for ratios less than 0.67, ICIs-nonRT could be a more favorable treatment option (P=0.073). The pre-treatment AST/ALT ratio demonstrates potential as a prognostic marker for treatment outcomes in NSCLC patients receiving either ICIs-nonRT or iRT. This finding could help guide clinicians in selecting more effective treatment protocols, thereby enhancing patient prognosis.

Evaluation of the association between predictive factors and the development of immune-related adverse events and prognostic factors for chemoimmunotherapy in patients with non-small cell lung cancer: A multicenter retrospective study.

Chemoimmunotherapy is widely used as the first-line management of advanced non-small cell lung cancer (NSCLC) in clinical settings. However, predictive factors associated with the development of immune-related adverse events (irAEs) and prognostic factors for NSCLC patients undergoing chemoimmunotherapy remains largely unexplored. Therefore, in this study, we aimed to evaluate predictive factors for irAE development and prognostic factors associated with chemoimmunotherapy in NSCLC patients. This study enrolled 199 patients with advanced and recurrent NSCLC who underwent chemoimmunotherapy across eight institutions in Nagano prefecture from December 2018 to January 2023. We examined predictive factors associated with irAE development and prognostic factors associated with overall survival (OS). Among the patients, 106 experienced irAEs, while 93 patients did not. A total of 44 (22.1%) patients developed multiple irAEs. High serum albumin levels (Alb >3.5 g/dL) emerged as an independent predictive factor associated with irAE development in logistic regression analysis (odds ratio; 2.35, 95% confidence interval 1.27-4.34, p = 0.007). Furthermore, the development of multiple irAEs (p = 0.016), lower lactate dehydrogenase level (<223 U/L, p = 0.002), and decreased neutrophil-to-lymphocyte ratio (<3, p = 0.049) were identified as independent favorable prognostic factors associated with OS in multivariate Cox hazard analyses. The study results suggest that high serum Alb is a predictive factor for irAE development and that the presence of multiple irAEs is a favorable prognostic indicator for NSCLC patients undergoing chemoimmunotherapy.

The clinical features and prognostic implications of the co-mutated TP53 gene in advanced non-small cell lung cancer.

TP53 is a frequently mutated oncogene within non-small cell lung cancer (NSCLC). However, the clinical and prognostic significance of co-mutations in TP53 in patients with advanced NSCLC has not been fully elucidated. A total of 174 patients with advanced NSCLC were enrolled in this study. All patients were subjected to sequencing analysis of tumor-related genes and information such as PD-L1 expression, TMB, and co-mutation changes were collected. Patients were categorized into TP53 mutant and TP53 wild-type groups according to their TP53 mutation status and then statistically analyzed. TP53 mutations were the most common among all patients, accounting for 56.32%, followed by epidermal growth factor receptor mutations at 48.27%. The most common mutation sites in the TP53 mutation group were exons 5-8.TP53 mutations were significantly associated with PD-L1 and TMB levels. Univariate Cox analysis showed that gender and EGFR mutation affected the prognosis of TP53-mutated NSCLC patients, and multivariate Cox regression analysis identified EGFR mutation as an independent risk factor. The OS of NSCLC patients in the TP53 mutation group was significantly shorter than that of the TP53wt group. Survival curves in the TP53/EGFR combined mutation group showed that patients with combined EGFR mutation had a lower survival rate. TP53 mutations are associated with different clinical indicators and have important implications in clinical treatment. TP53 is a poor prognostic factor for NSCLC patients, and TP53/EGFR co-mutation will affect the survival time of patients. TP53/EGFR co-mutation may be a new prognostic marker for NSCLC.

Treatment Strategies for Non-Small-Cell Lung Cancer with Comorbid Respiratory Disease; Interstitial Pneumonia, Chronic Obstructive Pulmonary Disease, and Tuberculosis.

Non-small cell lung cancer (NSCLC) patients are often complicated by other respiratory diseases, including interstitial pneumonia (IP), chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB), and the management of which can be problematic. NSCLC patients with IP sometimes develop fatal acute exacerbation induced by pharmacotherapy, and the establishment of a safe treatment strategy is desirable. For advanced NSCLC with IP, carboplatin plus nanoparticle albumin-bound paclitaxel is a relatively safe and effective first-line treatment option. Although the safety of immune checkpoint inhibitors (ICIs) for these populations remains controversial, ICIs have the potential to provide long-term survival. The severity of COPD is an important prognostic factor in NSCLC patients. Although COPD complications do not necessarily limit treatment options, it is important to select drugs with fewer side effects on the heart and blood vessels as well as the lungs. Active TB is complicated by 2-5% of NSCLC cases during their disease course. Since pharmacotherapy, especially ICIs, reportedly induces the development of TB, the possibility of developing TB should always be kept in mind during NSCLC treatment. To date, there is no coherent review article on NSCLC with these pulmonary complications. This review article summarizes the current evidence and discusses future prospects for treatment strategies for NSCLC patients complicated with IP, severe COPD, and TB.

The value of lung function assessment and Testin expression detection in clinicopathological features and prognosis of NSCLC patients.

The aim of this study is to investigate the clinical value and potential prognostic significance of lung function assessment and Testin expression in non-small cell lung cancer (NSCLC) patients. The NSCLC patients were classified into three groups according to lung function: group of normal lung function, group of PRISm (preserved ratio impaired spirometry) (FEV1, forced expiratory volume during the first second < 80% predicted and FEV1/FVC (forced vital capacity) ≥ 70%) and group of COPD (chronic obstructive pulmonary disease) (FEV1/FVC < 70%). The pre-operational clinicopathological characteristics of these patients were recorded and the markers of systemic inflammatory response, including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and eosinophils (EOS), were compared between three groups. The expression of Testin in NSCLC samples was detected by IHC and we further explored the correlation between Testin expression and clinicopathological characteristics and prognosis of NSCLC patients. Finally, Cox regression analysis was conducted to study the prognostic factors of NSCLC patients. Of the 158 NSCLC patients, percentages of normal lung function, PRISm and COPD were 41.4%, 22.8% and 36.1%, respectively. Patients with tumor in the left lung were more likely to have pulmonary dysfunction (PRISm and COPD) than the right lung. The markers of systemic inflammatory response showed differences to various degree in the three groups and NSCLC patients with PRISm or COPD presented more unfavorable prognosis than patients with normal function. The expression of Testin correlated with lymph node metastasis, TNM stage and tumor invasion of NSCLC patients. Moreover, patients with low Testin expression exhibited poorer disease-free survival and overall survival than those with high Testin expression. In Cox regression analysis, we found that PRISm, COPD and Testin expression served as prognostic factors in NSCLC patients. The presence of COPD or PRISm influenced systemic inflammatory response and prognosis of NSCLC patients. Testin expression correlated with clinicopathological features and could be potentially used as a prognostic marker in NSCLC.

Assessing EGFR-mutated NSCLC with bone metastasis: Clinical features and optimal treatment strategy.

This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non-small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR-tyrosine kinase inhibitors (TKIs). The study included patients with stage IV EGFR-mutated NSCLC who were receiving first-line treatment with EGFR-TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression-free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p < 0.001). The incidence of T790M was higher in patients with BoM than in those without (47.4% vs. 33.9%, p = 0.042). Multivariate Cox regression analysis revealed that sequential osimertinib treatment and the addition of antiangiogenic therapy (AAT) and denosumab therapy improved OS in patients with BoM. The presence of BoM is a negative prognostic factor for NSCLC patients with an EGFR mutation, possibly due to the presence of extrathoracic metastases. However, adding AAT and denosumab, along with sequential osimertinib, to the treatment regimen for patients with BoM can improve survival outcomes.

Abstract 5065: Integrating blood based liquid biopsies with TNM stage improves survival prediction model for non-small cell lung cancer

Abstract Introduction:Stage is the most important prognostic factor for survival in non-small cell lung cancer (NSCLC). The current TNM (Tumor, Node, Metastasis) staging system for NSCLC uses physical exam, histology, imaging, and surgical findings to define the extent and spread of a patient’s cancer. Despite advances in molecular testing which can impact treatment and prognosis for NSCLC patients, the current system does not incorporate molecular data into staging. We proposed a novel predictive model for survival analysis which integrates molecular analysis of liquid biopsies (B) into the TNM staging system (1). In this study, we tested this new staging system and our predictive model shows TNM + B (TNMB) provides a better predictive model for survival compared to TNM alone. Methods:176 patients were identified at Atrium Health Wake Forest Baptist with Guardant 360 liquid biopsies sent at diagnosis for NSCLC. Clinical data was obtained through retrospective chart review. Molecular analysis was performed on 81 genes across all Guardant 360 liquid biopsies. Using Cox proportional hazards model, we identified significant gene mutations or genes with significant magnitude of variant allele frequency (VAF) that improved survival prediction. We then designed a novel staging system incorporating whether a patient had a positive liquid biopsy test (B1), defined by the presence of these impact gene variables, to TNM stage. Results: Three impact genes STK11 (p=0.0253), NFE2L2 (p = 0.0025), TP53 (p=0.0129) and one gene with a magnitude of VAF, ARID1A (p=0.0082) was identified which significantly improved the predictive model for survival. Patients with negative liquid biopsy test, B0, had improved survival compared to patients with a positive liquid biopsy test, B1 (p&amp;lt;0.005). In our cohort, TNM staging alone did not show a significant survival difference between stage II and III (p = 0.19). Whereas TNMB staging showed a significant survival difference between stage II, III and IV. Conclusions: While TNM stage remains a major prognostic factor for NSCLC patients, it fails to incorporate molecular data which has a critical impact on management and prognosis. We designed a novel method to analyze molecular data obtained by liquid biopsy to identify significant gene mutations and gene magnitude of VAF that impacts survival prediction. In our cohort, we showed 4 impact genes which we used to create a new TNMB staging system which led to improved survival prediction compared to TNM alone. Acknowledgments: Research partly supported by NIH T32 Grant (T32CA247819) and Cancer Center Support Grant (P30CA012197) Reference: (1) Yang M, Forbes ME, Bitting RL, O'Neill SS, Chou PC, Topaloglu U, Miller LD, Hawkins GA, Grant SC, DeYoung BR, Petty WJ, Chen K, Pasche BC, Zhang W. Incorporating Blood-based Liquid Biopsy Information into Cancer Staging: Time for a TNMB System? Ann Oncol. 2018 Feb 1;29(2):311-323. Citation Format: Lauren Schmalz, Cetin Urtis, Liang Liu, Elizabeth Forbes, Fang-Chi Hsu, Nury Steuerwald, Alberto de Hoyos, Thomas Lycan, Jimmy Ruiz, William Petty, Wei Zhang. Integrating blood based liquid biopsies with TNM stage improves survival prediction model for 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 5065.

Dual network analysis of transcriptome data for discovery of new therapeutic targets in non-small cell lung cancer

The drug therapy for non-small cell lung cancer (NSCLC) have always been issues of poisonous side effect, acquired drug resistance and narrow applicable population. In this study, we built a novel network analysis method (difference- correlation- enrichment- causality- node), which was based on the difference analysis, Spearman correlation network analysis, biological function analysis and Bayesian causality network analysis to discover new therapeutic target of NSCLC in the sequencing data of BEAS-2B and 7 NSCLC cell lines. Our results showed that, as a proteasome subunit coding gene in the central of cell cycle network, PSMD2 was associated with prognosis and was an independent prognostic factor for NSCLC patients. Knockout of PSMD2 inhibited the proliferation of NSCLC cells by inducing cell cycle arrest, and exhibited marked increase of cell cycle blocking protein p21, p27 and decrease of cell cycle driven protein CDK4, CDK6, CCND1 and CCNE1. IPA and molecular docking suggested bortezomib has stronger affinity to PSMD2 compared with reported targets PSMB1 and PSMB5. In vitro and In vivo experiments demonstrated the inhibitory effect of bortezomib in NSCLC with different driven mutations or with tyrosine kinase inhibitors resistance. Taken together, bortezomib could target PSMD2, PSMB1 and PSMB5 to inhibit the proteasome degradation of cell cycle check points, to block cell proliferation of NSCLC, which was potential optional drug for NSCLC patients.

Labyrinthin Expression Is Associated with Poor Prognosis in Patients with Non-Small-Cell Lung Cancer.

To determine Labyrinthin (LAB) expression in non-small-cell lung cancer (NSCLC), we immunostained and scored for LAB immunohistochemistry (IHC) expression on sections of tissue microarrays (TMAs) prepared from 256 archival tissue blocks of NSCLC. Propensity-score-weighted Kaplan-Meier curves and weighted Cox models were used to associate LAB expression with overall survival. LAB mRNA expression was assessed in The Cancer Genome Atlas (TCGA) and correlated with clinical phenotype and outcome. Positive LAB IHC expression (>5% of tumor cells) was detected in 208/256 (81.3%) of NSCLC samples, and found in both lung adenocarcinomas (LUAD) and lung squamous cell cancer (LUSC). LAB positivity was associated with poor overall survival (HR = 3.56, 95% CI: 2.3-5.4; p < 0.0001) and high tumor differentiation grade or metastasis compared with negative LAB expression. Univariant and multivariate survival analyses demonstrated LAB expression as an independent prognostic factor for NSCLC patients. LAB RNA expression in TCGA-LUAD was higher in primary and advanced-stage tumors than in normal tissue, and was associated with poorer overall survival. No significant differences or associations were found with LAB RNA expression in TCGA-LUSC. The LAB IHC assay is being used to identify candidate cancer patients for the first-in-human phase I trial evaluating the LAB vaccines (UCDCC#296, NCT051013560).

Pretreatment Platelet Count is a Prognostic Marker in Lung Cancer: A Danish Registry-based Cohort Study

BackgroundThrombocytosis has been associated with a poor prognosis in a wide range of malignancies. However, the results have been conflicting for lung cancer. Therefore, we evaluated the prognostic value of platelet count in a large cohort of lung cancer patients. Patients and MethodsAll lung cancer patients diagnosed in The Central Denmark Region from 2009 to 2018 were included in the study. Data from the Danish Lung Cancer Registry were combined with data from the clinical laboratory information system on pretreatment platelet count. Platelet count was defined as low, normal, or high based on being below, within, or above the reference intervals. The prognostic value of platelet count was assessed by the Cox proportional hazard model. C-statistics were conducted to investigate if the platelet count added additional prognostic value to existing prognostic markers. ResultsTotally, 6,758 patients with non–small-cell lung cancer (NSCLC) and 1150 patients with small-cell lung cancer (SCLC) were included. Low and high platelet count were significantly associated with decreased overall survival (OS) in NSCLC patients (low: adjusted hazard ratio (HR)=1.75 (95% confidence interval [CI]: 1.49-2.06); high: adjusted HR=1.24 (95% CI: 1.16-1.33)). In SCLC patients, only low platelet count was significantly associated with decreased OS (adjusted HR = 2.71 [95% CI: 2.02-3.65]). C-statistics showed that the prognostic models were significantly improved by the addition of platelet count for both NSCLC and SCLC patients (P < .0001). ConclusionLow and high platelet count were adverse prognostic factors in NSCLC patients, while only low platelet count was a prognostic marker in SCLC patients.

Glucose-Regulated Protein 94 Expression in Patients with Non- Small Cell Lung Cancer and Prognostic Significance

The researchers aimed to study the correlations of expression of glucose-regulated protein 94 (GRP94) with clinicopathological characteristics and prognosis of patients with non-small cell lung cancer (NSCLC). NSCLC tissue specimens were collected from January 2016 to January 2018. The prognostic factors of NSCLC patients were analyzed. Survival curves were plotted. Logistic multivariate regression analysis was performed to explore the factors influencing prognosis. GRP94 protein was mainly expressed in the nucleus in NSCLC and para-carcinoma tissues. The high expression rates of GRP94 in NSCLC tissues were significantly different in patients with and without tumor metastasis after surgery (P&lt;0.05). GRP94-positive NSCLC patients had significantly longer mean survival time than GRP94-negative ones (P&lt;0.01). Positive GRP94 expression, maximum diameter of tumor, pathological type, lymph node metastasis, T stage and postoperative TNM stage were independent risk factors affecting prognosis. GRP94 is an independent factor influencing the prognosis of NSCLC, as a potential target for treatment.

Construction of a B cell-related gene pairs signature for predicting prognosis and immunotherapeutic response in non-small cell lung cancer.

Accumulating evidence indicates that the B cells play important roles in anti-tumor immunity and shaping tumor development. This study aimed to explore the expression profiles of B cell marker genes and construct a B cell-related gene pairs (BRGPs) signature associated with the prognosis and immunotherapeutic efficiency in non-small cell lung cancer (NSCLC) patients. B cell-related marker genes in NSCLC were identified using single-cell RNA sequencing data. TCGA and GEO datasets were utilized to identify the prognostic BRGPs based on a novel algorithm of cyclically single pairing along with a 0-or-1 matrix. BRGPs signature was then constructed using Lasso-Cox regression model. Its prognostic value, associated immunogenomic features, putative molecular mechanism and predictive ability to immunotherapy were investigated in NSCLC patients. The BRGPs signature was composed of 23 BRGPs including 28 distinct B cell-related genes. This predictive signature demonstrated remarkable power in distinguishing good or poor prognosis and can serve as an independent prognostic factor for NSCLC patients in both training and validation cohorts. Furthermore, BRGPs signature was significantly associated with immune scores, tumor purity, clinicopathological characteristics and various tumor-infiltrating immune cells. Besides, we demonstrated that the tumor mutational burden scores and TIDE scores were positively correlated with the risk score of the model implying immune checkpoint blockade therapy may be more effective in NSCLC patients with high-risk scores. This novel BRGPs signature can be used to assess the prognosis of NSCLC patients and may be useful in guiding immune checkpoint inhibitor treatment in our clinical practice.

An autophagy-associated lncRNAs model for predicting the survival in non-small cell lung cancer patients

Long non-coding RNAs (lncRNAs) can influence the proliferation, autophagy, and apoptosis of non-small cell lung cancer (NSCLC). LncRNAs also emerge as valuable prognostic factors for NSCLC patients. Consequently, we set out to discover more autophagy-associated lncRNAs. We acquired autophagy-associated genes and information on lncRNAs from The Cancer Genome Atlas database (TCGA), and the Human Autophagy Database (HADb). Then, the prognostic prediction signature was constructed through using co-expression and Cox regression analysis. The signature was constructed including 7 autophagy-associated lncRNAs (ABALON, NKILA, LINC00941, AL161431.1, AL691432.2, AC020765.2, MMP2-AS1). After that, we used univariate and multivariate Cox regression analysis to calculate the risk score. The survival analysis and ROC curve analysis confirmed good performances of the signature. GSEA indicated that the high-risk group was principally enriched in the adherens junction pathway. In addition, biological experiments showed that ABALON promoted the proliferation, metastasis and autophagy levels of NSCLC cells. These findings demonstrate that the risk signature consisting of 7 autophagy-associated lncRNAs accurately predicts the prognosis of NSCLC patients and should be investigated for potential therapeutic targets in clinic.

991P EGFR exon 20 insertions in non-small cell lung cancer (NSCLC): Impact of TP53 mutation status and value of immune checkpoint blockade (ICB)

About 4% of all EGFR mutations account as exon 20 insertions, which convey resistance to the first three generations of EGFR-tyrosine kinase inhibitors (TKIs). Recent research has revealed new drugs to target these mutations specifically. However, little is known about the impact of immune-checkpoint blockade (ICB) in this subgroup, especially in patients with co-occurring TP53 mutations. We analyzed co-occurring mutations in patients with EGFR exon 20 insertions and their influence on the efficacy of systemic treatment. The main focus was impact of ICB on overall survival (OS) in these patients with or without TP53 mutations. Co-mutational status was assessed using next-generation-sequencing (NGS) panels. TP53 mutations were further divided into truncating vs. non-truncating mutations. Real-world-data (RWD) of 159 advanced NSCLC patients with EGFR exon 20 insertion in the timeframe of 2014-2020 were analyzed. TP53 mutation was the most common co-occurring mutation in 69 (43.6%) patients. OS of TP53 wildtype patients was significantly longer with 851 vs. 444 days (p=0.003, Log Rank). No difference of OS referring to the subtype of TP53 mutations was observed (p=0.703). In total, 66 pts were treated with ICB in one of the treatment lines and trended towards longer OS of 824 vs. 479 days, without reaching significance (p=0.402). In patients with co-occurring TP53, patients who received ICB (n=33) had longer OS than those without ICB exposure (507 vs. 369 days, p=0.086). Lack of significance might be explainable by a median follow-up time of 1498 days (4.1 years). Regardless of subtype, TP53 co-occurring mutation seems to be a strong negative prognostic factor in NSCLC patients with EGFR exon 20 insertions. However, these patients seem to benefit from the ICB, especially at the beginning of their treatment pathway.

PAK4 expression is associated with the prognosis in non-small cell lung cancer.

This study attempted to determine the expression of p21-activated kinase 4 (PAK4) in non-small cell lung cancer (NSCLC) tissues and the normal lung tissues. The correlation between PAK4 expression and prognosis of NSCLC patients was also evaluated in the present study. The expression level of PAK4 was measured by high-performance liquid chromatography method. Chi-square test was adopted to explore the relationship of PAK4 expression and clinical features. Kaplan-Meier survival curves were plotted to delineate the overall survival rate of NSCLC patients. Cox regression analysis was performed to evaluate the prognostic significance of PAK4 expression in NSCLC. The PAK4 expression in NSCLC tissue samples was significantly higher than that in normal lung tissues (P<0.001) and shared significant correlation with Eastern Cooperative Oncology Group score, histological type, and distant metastasis (P<0.05). Survival curve revealed that NSCLC patients with high PAK4 expression had relatively higher mortality than those with low PAK4 expression (P = .001). Cox regression analysis explained that PAK4 expression was associated with the prognosis of NSCLC patients (P = .024; HR, 3.104; 95% CI, 1.164–8.278). In a word, PAK4 was highly expressed in NSCLC tissues and could act as a prognostic factor for NSCLC patients.

A Comprehensive Bioinformatic Analysis for Identification of Myeloid-Associated Differentiation Marker as a Potential Negative Prognostic Biomarker in Non-Small-Cell Lung Cancer

Objectives: This study aimed to identify a molecular marker associated with the prognosis of non-small-cell lung cancer (NSCLC). Materials and Methods: The RNA sequencing data and clinical information of NSCLC patients were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). The weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression gene modules and differentially expressed genes (DEGs) by comparing gene expression between NSCLC tumor tissues and normal tissues. Subsequently, the functional enrichment analysis of the DEGs was performed. Kaplan-Meier survival analysis and the GEPIA2 online tool were performed to investigate the relationship between the expression of these genes of interest and the survival of NSCLC patients, and to validate one most survival-relevent hub gene, as well as validated the hub gene using independent datasets from the GEO database. Further analysis was carried out to characterize the relationship between the hub gene and tumor immune cell infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and other known biomarkers of lung cancer. The related genes were screened by analyzing the protein-protein interaction (PPI) network and the survival model was constructed. GEPIA2 was applied in the potential analysis of pan-cancer biomarker of hub gene. Results: 57 hub genes were found to be involved in intercellular connectivity from the 779 identified differentially co-expressed genes. Myeloid-associated differentiation marker (MYADM) was strongly associated with overall survival (OS) and disease-free survival (DFS) of NSCLC patients, and high MYADM expression was associated with poor prognosis. Thus, MYADM was identified as a risk factor. Additionally, MYADM was validated as a survival risk factor in NSCLC patients in two independent datasets. Further analysis showed that MYADM was nagetively associated with TMB, and was positively correlated with macrophages, neutrophils, and dendritic cells, suggesting its role in regulating tumor immunity. The MYADM expression differed across many types of cancer and had the potential to serve as a pan-cancer marker. Conclusion: MYADM is an independent prognostic factor for NSCLC patients, which can predict the progression of cancer and play a role in the tumor immune cell infiltration in NSCLC.

Mitochondrial ROS drive resistance to chemotherapy and immune-killing in hypoxic non-small cell lung cancer

BackgroundSolid tumors subjected to intermittent hypoxia are characterized by resistance to chemotherapy and immune-killing by effector T-lymphocytes, particularly tumor-infiltrating Vγ9Vδ2 T-lymphocytes. The molecular circuitries determining this double resistance are not known.MethodsWe analyzed a panel of 28 human non-small cell lung cancer (NSCLC) lines, using an in vitro system simulating continuous and intermittent hypoxia. Chemosensitivity to cisplatin and docetaxel was evaluated by chemiluminescence, ex vivo Vγ9Vδ2 T-lymphocyte expansion and immune-killing by flow cytometry. Targeted transcriptomics identified efflux transporters and nuclear factors involved in this chemo-immuno-resistance. The molecular mechanism linking Hypoxia-inducible factor-1α (HIF-1α), CCAAT/Enhancer Binding Protein-β (C/EBP-β) isoforms LAP and LIP, ABCB1, ABCC1 and ABCA1 transporters were evaluated by immunoblotting, RT-PCR, RNA-IP, ChIP. Oxidative phosphorylation, mitochondrial ATP, ROS, depolarization, O2 consumption were monitored by spectrophotometer and electronic sensors. The role of ROS/HIF-1α/LAP axis was validated in knocked-out or overexpressing cells, and in humanized (Hu-CD34+NSG) mice bearing LAP-overexpressing tumors. The clinical meaning of LAP was assessed in 60 NSCLC patients prospectively enrolled, treated with chemotherapy.ResultsBy up-regulating ABCB1 and ABCC1, and down-regulating ABCA1, intermittent hypoxia induced a stronger chemo-immuno-resistance than continuous hypoxia in NSCLC cells. Intermittent hypoxia impaired the electron transport chain and reduced O2 consumption, increasing mitochondrial ROS that favor the stabilization of C/EBP-β mRNA mediated by HIF-1α. HIF-1α/C/EBP-β mRNA binding increases the splicing of C/EBP-β toward the production of LAP isoform that transcriptionally induces ABCB1 and ABCC1, promoting the efflux of cisplatin and docetaxel. LAP also decreases ABCA1, limiting the efflux of isopentenyl pyrophosphate, i.e. the endogenous activator of Vγ9Vδ2 T-cells, and reducing the immune-killing. In NSCLC patients subjected to cisplatin-based chemotherapy, C/EBP-β LAP was abundant in hypoxic tumors and was associated with lower response to treatment and survival. LAP-overexpressing tumors in Hu-CD34+NSG mice recapitulated the patients’ chemo-immuno-resistant phenotype. Interestingly, the ROS scavenger mitoquinol chemo-immuno-sensitized immuno-xenografts, by disrupting the ROS/HIF-1α/LAP cascade.ConclusionsThe impairment of mitochondrial metabolism induced by intermittent hypoxia increases the ROS-dependent stabilization of HIF-1α/LAP complex in NSCLC, producing chemo-immuno-resistance. Clinically used mitochondrial ROS scavengers may counteract such double resistance. Moreover, we suggest C/EBP-β LAP as a new predictive and prognostic factor in NSCLC patients.

ERβ overexpression may not be a direct prognostic factor in patients with NSCLC: A meta-analysis.

Overall survival of non-small cell lung cancer (NSCLC) patients remains disappointingly low. The estrogen receptor (ER) was considered a promising therapeutic target for NSCLC. Numerous studies have linked expression of ERβ to lung cancer outcome. However, results are conflicting regarding the association of ERβ with surviving lung cancer. The aim of this meta-analysis was to evaluate the prognostic aspect of ERβ expression on survival among NSCLC patients. We performed a final analysis of prognostic value of overexpression ERβ on 3500 patients from 18 evaluable studies (from January 1, 2000 to May 1, 2021). The reference category is specified as low ERβ expression levels. Summarized hazard ratios were calculated. Our study showed that the pooled hazard ratios of ERβ overexpression for overall survival in NSCLC was 0.81 (95% confidence interval (CI): 0.64-1.02, P = 0.07) by univariate analysis and 1.06 (95% CI: 0.83-1.36, P = 0.63) by multivariate analysis. Pooled hazard ratio by univariate analysis in Asian studies was 0.73 (95%CI: 0.59-0.89, P = 0.002). Pooled hazard ratio by univariate analysis was 0.75 (95% CI: 0.61-0.93, P = 0.009) from seven studies reported for nuclear ERβ. No significant results were found in subgroups by multivariate analysis. No significant results were found in studies outside Asia or in studies reported for cytoplasmic ERβ. Our results suggested that expression of ERβ might not be a direct prognostic factor for NSCLC patients. More detailed prospective studies are needed to identify direct prognostic factors in these patients.

Signature based on B cells-related gene pairs could predict prognosis and immunotherapeutic response in NSCLC.

e21051 Background: Tumor-infiltrating B cells accompanying several widely used B cell-related biomarkers, such as CD19 and CD20, have inconsistent clinical prognostic values in non-small-cell lung cancer (NSCLC) patients. Considering only one B cell-related biomarker could not distinguish the anti-tumor and pro-tumor B cell subsets in tumor, we aimed to construct a more accurate B-cells related gene pairs (BRGPs) prognostic model and evaluate its potential predictive ability to immunotherapy in NSCLC patients. Methods: Using public single-cell RNA sequencing data, the B cells-related genes (BRGs) in NSCLC samples were identified. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were utilized to construct the BRGPs model which was not affected by the technical bias of different platforms. With no dependence upon specific gene expression levels, a novel signature based on BRGPs was established in this study. In addition, the prognostic value and immunotherapeutic response for this signature with regard to the TME components and potential molecular mechanism were explored. Results: Based on the TCGA database, we built a novel prognostic signature of 23 BRGPs comprising 28 unique BRGs. This risk model showed significant power in distinguishing good or poor prognosis and could serve as an independent prognostic factor for NSCLC patients in the TCGA cohort. The prognostic accuracy of the model was further verified in the GSE31210 dataset from the GEO database. Likewise, the prognostic value of the risk score for the BRGPs model was demonstrated in the GEO cohorts by the univariate and multivariate cox regression analysis. In addition, the risk model was significantly associated with sex, TNM stage, immune score, tumor purity and various tumor-infiltrating immune cells. GSEA analysis indicated that low-risk group enriched with several immune-related pathways, such as activation of immune response, antigen receptor mediated signaling pathway, B cell activation and B cell mediated immunity, whereas several proliferation-related pathways, such as nuclear chromosome segregation, sister chromatid segregation and mitotic sister chromatid segregation were most enriched in high-risk group. Besides, the tumor mutational burden (TMB) score rather than CD274(PD-L1 mRNA) expression was positively correlated with the risk score (P＜0.001; P = 0.94, respectively). NSCLC patients with high-risk exhibited significantly higher TMB score compared with low-risk patients (P &lt; 0.001). Correspondingly, we demonstrated that immune checkpoint blockade therapy may be more efficacious in high-risk group NSCLC patients according to TIDE method (P＜0.01). Conclusions: This novel BRGPs model can assess the prognosis of patients with NSCLC, and may be helpful to guide immune checkpoint inhibitors treatment in our clinical practice.