Progression-free Survival In Non-small Cell Lung Cancer Patients Research Articles

Cancer cachexia as a predictor of adverse outcomes in patients with non-small cell lung cancer: A meta-analysis

IntroductionCancer cachexia is a complex problem characterized by weight loss due to skeletal muscle and adipose tissue reduction. The purpose of this meta-analysis is to examine the association between cancer cachexia and adverse outcomes in patients with non-small cell lung cancer (NSCLC). MethodsA comprehensive search was conducted in the PubMed, Web of Science, and Embase databases from their inception to January 15, 2024. Retrospective or prospective studies that investigated the cancer cachexia as a predictor of overall survival (OS), progression-free survival (PFS), overall response rate (ORR), or disease control rate (DCR) in NSCLC patients were included in this analysis. ResultsSixteen studies, comprising 5,919 NSCLC patients, were identified. The pooled prevalence of cachexia in NSCLC patients was 39%, with individual studies reporting rates ranging from 19% to 63.8%. A meta-analysis using a random effects model showed that cachexia was associated with reduced OS (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.54-2.21) and PFS (HR 1.49; 95% CI 1.27-1.73).Subgroup analysis indicated that cancer cachexia significantly predicted OS, regardless of study design, NSCLC subtypes, cancer stage, definitions of cachexia, or follow-up duration. However, there was no clear association between cancer cachexia and ORR or DCR. ConclusionsCancer cachexia emerges is a negative prognostic factor for OS and PFS in NSCLC patients. Assessing cancer cachexia can improve risk classification for survival outcomes in this patient population.

Nomograms integrating CT radiomic and deep learning signatures to predict overall survival and progression-free survival in NSCLC patients treated with chemotherapy

ObjectivesThis study aims to establish nomograms to accurately predict the overall survival (OS) and progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who received chemotherapy alone as the first-line treatment.Materials and methodsIn a training cohort of 121 NSCLC patients, radiomic features were extracted, selected from intra- and peri-tumoral regions, and used to build signatures (S1 and S2) using a Cox regression model. Deep learning features were obtained from three convolutional neural networks and utilized to build signatures (S3, S4, and S5) that were stratified into over- and under-expression subgroups for survival risk using X-tile. After univariate and multivariate Cox regression analyses, a nomogram incorporating the tumor, node, and metastasis (TNM) stages, radiomic signature, and deep learning signature was established to predict OS and PFS, respectively. The performance was validated using an independent cohort (61 patients).ResultsTNM stages, S2 and S3 were identified as the significant prognosis factors for both OS and PFS; S2 (OS: (HR (95%), 2.26 (1.40–3.67); PFS: (HR (95%), 2.23 (1.36–3.65)) demonstrated the best ability in discriminating patients with over- and under-expression. For the OS nomogram, the C-index (95% CI) was 0.74 (0.70–0.79) and 0.72 (0.67–0.78) in the training and validation cohorts, respectively; for the PFS nomogram, the C-index (95% CI) was 0.71 (0.68–0.81) and 0.72 (0.66–0.79). The calibration curves for the 3- and 5-year OS and PFS were in acceptable agreement between the predicted and observed survival. The established nomogram presented a higher overall net benefit than the TNM stage for predicting both OS and PFS.ConclusionBy integrating the TNM stage, CT radiomic signature, and deep learning signatures, the established nomograms can predict the individual prognosis of NSCLC patients who received chemotherapy. The integrated nomogram has the potential to improve the individualized treatment and precise management of NSCLC patients.

Efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitors treatment failure

Objective: To investigate the efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer (NSCLC) who failed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. Methods: A retrospective analysis was made on the clinical data of 60 NSCLC patients who were treated with immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure in the Affiliated Cancer Hospital of Shandong First Medical University from January 2019 to March 2022. Patients were followed up by telephone or outpatient review up to October 1, 2022, with a median follow-up of 8.2 months (95%CI: 7.1-9.3). All 60 patients were followed up. The response evaluation criteria in solid tumors were used to evaluate the short-term efficacy. The adverse reactions of patients were evaluated according to the common terminology criteria for adverse events. The survival curve was drawn by Kaplan-Meier method. Cox proportional hazard regression models were utilized to analyze the influencing factors of progression-free survival (PFS). Results: Among the 60 NSCLC patients, 22 were males. The age ranged from 41 to 75 years, with a median age of 61 years. Eleven patients had partial response, 19 patients had stable disease and 30 patients had progressive disease. The median PFS was 8.2 months (95%CI: 7.2-9.2). The median PFS of patients with low expression of programmed death receptor-ligand 1 (PD-L1) [Tumor cell Proportion Score (TPS)<1%], moderate expression of PD-L1 (1%≤TPS≤49%), and high expression of PD-L1 (TPS≥50%) were 6.4 (95%CI: 4.8-8.0), 8.3 (95%CI: 7.3-9.3) and 10.6 months (95%CI: 7.2-14.1), respectively, and there were statistically significant differences (χ2=13.58, P<0.001). Multivariate Cox proportional risk regression model analysis showed that age>65 years old (HR=4.017, 95%CI: 1.468-10.992, P=0.007) was a risk factor for PFS in NSCLC patients who received immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure. Moderate expression of PD-L1 (HR=0.360, 95%CI: 0.139-0.930, P=0.035) and high expression of PD-L1 (HR=0.155, 95%CI: 0.039-0.625, P=0.009) were protective factors for PFS. Most of the treatment-related adverse reactions in the whole group were grade 1-2, including bone marrow suppression (n=24), nausea (n=25), decreased appetite (n=24), fatigue (n=22), vomiting (n=18), abnormal liver function (n=17), blood creatinine increased (n=10), and so on. These were tolerated by the patients. Conclusions: NSCLC patients who failed EGFR-TKIs treatment can tolerate adverse reactions related to immunotherapy combined with chemotherapy and bevacizumab treatment. PFS is significantly prolonged in those aged≤65 years and those with moderate and high expression of PD-L1.

Radiation-induced eosinophil increase ratio predicts patient outcomes in non-small celllung cancer.

Background and purposeRadiotherapy (RT) is a double-edged sword in regulating immune responses. This study aimed to investigate the impact of thoracic RT on circulating eosinophils and its association with patient outcomes in non-small cell lung cancer (NSCLC).Materials and methodsThis retrospective study included 240 patients with advanced NSCLC treated with definitive thoracic RT from January 2012 to January 2020. Statistics included Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS), multivariate Cox analyses to identify significant variables, and Spearman’s correlation to qualify the relationship between dose-volume histogram (DVH) parameters and EIR.ResultsAbsolute eosinophil counts (AECs) showed an increasing trend during RT and an obvious peak in the 1st month after RT. Thresholds of eosinophil increase ratio (EIR) at the 1st month after RT for both OS and PFS were 1.43. Patients with high EIR above 1.43 experienced particularly favorable clinical outcomes (five-year OS: 21% versus 10%, P<0.0001; five-year PFS: 10% versus 8%, P=0.014), but may not derive PFS benefit from the addition of chemotherapy to RT. The higher a patient’s EIR, the larger the potential benefit in the absence of chemotherapy. DVH parameters including heart mean dose and heart V10 were negatively associated with EIR. None of these DVH parameters was correlated with the clinical outcomes.ConclusionEIR may serve as a potential biomarker to predict OS and PFS in NSCLC patients treated with RT. These findings require prospective studies to evaluate the role of such prognostic marker to identify patients at risk to tailor interventions.

The Efficacy of Immune Checkpoint Inhibitors vs. Chemotherapy for KRAS-Mutant or EGFR-Mutant Non-Small-Cell Lung Cancers: A Meta-Analysis Based on Randomized Controlled Trials.

Objective To assess and compare the effectiveness of immune checkpoint inhibitors vs. chemotherapy for KRAS-mutant or EGFR-mutant non-small-cell lung cancers. Methods Until February 19, 2022, Cochrane Library, PubMed, Web of Science, and Embase were searched for relevant randomized controlled trials (RCTs) in NSCLC. Progression-free survival (PFS) and overall survival (OS) were used as outcome measures. The studies were conducted using the Cochrane methodology for meta-analyses, and all statistical analyses were made with Review Manager Software (RevMan version 5.4). Results Our meta-analysis included nine clinical trials including 5633 participants with NSCLC. Immune checkpoint drugs extended OS (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.60–0.76) and PFS (HR, 0.44; 95% CI, 0.35-0.56) in patients with EGFR wild-type compared to chemotherapy alone, whereas programmed cell death 1 ligand 1 (PD-L1)/programmed cell death-1 (PD-1) inhibitors with chemotherapy versus chemotherapy extended PFS in NSCLC patients with EGFR mutations (HR, 0.63; 95% CI, 0.42-0.94). Meanwhile, immune checkpoint inhibitors vs. chemotherapy improved the OS (HR, 0.65; 95% CI, 0.48–0.88) and PFS (HR, 0.49; 95% CI, 0.36–0.66) of NSCLC patients with KRAS mutation. NSCLCs with KRAS G12C mutation had a much better PFS with ICIs than with chemotherapy (HR, 0.38; 95% CI, 0.21–0.71). Conclusion This research revealed that individuals with EGFR wild-type NSCLC or KRAS mutation may benefit from PD-L1/PD-1 inhibitors and that PD-L1/PD-1 inhibitors in combination with chemotherapy seem to be more successful than chemotherapy alone in NSCLC patients with EGFR mutation.

Impact of probiotics use on clinical outcomes of immune checkpoint inhibitors therapy in cancer patients.

Dysbiosis of the gut microbiota can lead to impaired therapeutic effect of immune checkpoint inhibitors (ICIs). This study aimed to investigate the use of probiotics on the clinical outcomes of cancer patients receiving ICIs therapy. PubMed, EMBASE, and the Cochrane Library database were searched to retrieve relevant studies that exploring the relationship between probiotics and the efficacy of ICIs. The primary endpoints included overall survival (OS) and progression-free survival (PFS), evaluated by the hazard rations (HRs) with 95% confidence intervals (CI), and the secondary endpoint was objective response rate (ORR), evaluated by the odd ratio (OR) with a 95% CI. A total of five studies including 1031 patients were eligible for analysis. Our results indicated that the use of probiotics was associated with a superior OS (HR=0.50, 95% CI: 0.30-0.85, p=0.01) and PFS (HR=0.51, 95% CI: 0.42-0.61, p< 0.01), but had no relationship with ORR (OR=2.11, 95%CI: 0.51-8.65, p=0.30) in non-small cell lung cancer (NSCLC) patients. Probiotics were positively correlated with OS and PFS in NSCLC patients administrated with ICIs, but had no relationship with ORR.

NLRP4 negatively regulates type I interferon response and influences the outcome in anti-programmed cell death protein (PD)-1/PD-ligand 1 therapy.

The challenge to improve the clinical efficacy and enlarge the population that benefits from immune checkpoint inhibitors (ICIs) for non‐small‐cell lung cancer (NSCLC) is significant. Based on whole‐exosome sequencing analysis of biopsies from NSCLC patients before anti‐programmed cell death protein‐2 (PD‐1) treatment, we identified NLRP4 mutations in the responders with a longer progression‐free survival (PFS). Knockdown of NLRP4 in mouse Lewis lung cancer cell line enhanced interferon (IFN)‐α/β production through the cGAS‐STING‐IRF3/IRF7 axis and promoted the accumulation of intratumoral CD8+ T cells, leading to tumor growth retardation in vivo and a synergistic effect with anti‐PD‐ligand 1 therapy. This was consistent with clinical observations that more tumor‐infiltrating CD8+ T cells and elevated peripheral IFN‐α before receiving nivolumab treatment were associated with a longer PFS in NSCLC patients. Our study highlights the roles of tumor‐intrinsic NLRP4 in remodeling the immune contextures in the tumor microenvironment, making regional type I IFN beneficial for ICI treatment.

Avoiding Absolute Quantification Trap: A Novel Predictive Signature of Clinical Benefit to Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer.

Immunotherapy has been focused on by many oncologists and researchers. While, due to technical biases of absolute quantification, few traditional biomarkers for anti-PD-1 immunotherapy have been applied in regular clinical practice of non-small cell lung cancer (NSCLC). Therefore, there is an urgent and unmet need for a feasible tool—immune to data source bias—for identifying patients who might benefit from ICIs in clinical practice. Using the strategy based on the relative ranking of gene expression levels, we herein proposed the novel BRGP index (BRGPI): four BRGPs significantly related with progression-free survival of NSCLC patients treated with anti-PD-1 immunotherapy in the multicohort analysis. Moreover, stratification and multivariate Cox regression analyses demonstrated that BRGPI was an independent prognostic factor. Notably, compared to PD-L1, BRGPI exerted the best predictive ability. Further analysis showed that the patients in the BRGPI-low and PD-L1-high subgroup derived more clinical benefits from anti-PD-1 immunotherapy. In conclusion, the prospect of applying the BRGPI to real clinical practice is promising owing to its powerful and reliable predictive value.

Real-World Efficacy and Safety of Anlotinib With and Without Immunotherapy in Advanced Non-Small Cell Lung Cancer

AimsCombination of anti-angiogenesis therapy and immunotherapy has showed synergistic effects in non-small cell lung cancer (NSCLC). The aim of this retrospective study was to investigate the efficacy and safety of anlotinib with and without immunotherapy in NSCLC.MethodsPathologically confirmed NSCLC patients (stage IIIB-IV) receiving anlotinib between November 2018 and February 2020 were enrolled for retrospective analysis. The outcomes and safety of overall patients were evaluated, and the efficacies of anlotinib plus immunotherapy and anlotinib alone was compared. The primary endpoint was progression-free survival (PFS).ResultsA total of 80 patients (median age: 62 years, range: 29-86 years) were included. Overall median PFS was 4.3 months (95% confidence interval (CI): 2.7-5.9 months). In univariate analysis, patients without EGFR mutation, previous EGFR target therapy, and brain metastasis had significantly longer PFS. Cox regression analysis showed that only brain metastasis was an independent predictor of PFS. The median PFS of patients receiving anlotinib plus immunotherapy was slightly longer than that of patients receiving anlotinib alone (4.2 vs 3.1 months); however, the difference was not statistically significant. A tendency of longer median PFS was observed in patients with adenocarcinoma, EGFR wild type, stage IV, no liver metastasis, former smoker, ≥2 previous treatment lines, no previous VEGF or EGFR target therapies in anlotinib plus immunotherapy group. Treatments with anlotinib alone or anlotinib plus immunotherapy were well tolerable. The most common adverse events were fatigue, decreased hemoglobin count, hypertension, hand-foot syndrome, oral mucositis and hoarseness.ConclusionAnlotinib is well tolerable and effective in advanced NSCLC patients. Brain metastasis is an independent predictor of PFS in NSCLC patients receiving anlotinib. Future prospective studies with larger sample size and extended follow-up are needed to confirm the clinical benefit in NSCLC patients treated with anlotinib combined with immunotherapy.

Evaluation of the roles and regulatory mechanisms of PD-1 target molecules in NSCLC progression.

BackgroundTargeted programmed cell death protein 1 (PD-1) therapy could effectively improve the long-term prognosis of patients with non-small cell lung cancer (NSCLC). The role of PD-1 targets in the progression of NSCLC has not been fully revealed.MethodsThe differentially expressed genes (DEGs) in patients’ blood after NSCLC treatment with PD-1 blocker nivolumab in the GSE141479 dataset were analyzed by GEO2R and identified in the TCGA database. The mechanism of action involved in the PD-1 target molecules via the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein-protein interaction (PPI) network shows the relationship between PD-1 target molecules. The factors affecting the prognosis of NSCLC patients were identified via the COX regression analysis and survival analysis to build the risk model and nomogram.ResultsThere were 64 DEGs in patients’ blood after nivolumab treatment and 48 DEGs in NSCLC tissues. The PD-1 target molecules involved cell proliferation, DNA replication, cell cycle, lung cancer, and other cellular processes. The prognostic factors CCNA2, CHEK1, DLGAP5, E2F8, FOXM1, HIST1H2BH, HJURP, MKI67, PLK1, TPX2, and TYMS, and the independent factors HIST1H2BH and PLK1, influenced the prognosis of NSCLC patients. HIST1H2BH and PLK1 were overexpressed in LUAD and LUSC tissues. The elevated expression levels of HIST1H2BH and PLK1 were related to the overall survival (OS) and the progression-free survival of NSCLC patients. High-risk NSCLC patients had a poor prognosis and were an independent factor influencing the poor prognosis of NSCLC patients. The high-risk model group was enriched with signaling mechanisms such as cell cycle, DNA replication, and homologous recombination.ConclusionsThe risk model based on PD-1 target molecules was helpful to assess the prognosis of NSCLC patients. HIST1H2BH and PLK1 might become prognostic biomarkers of NSCLC patients.

Abstract 376: Prognostic significance of Glasgow prognostic score in NSCLC patients treated with immunotherapy after platinum-based cytotoxic chemotherapy

Abstract Introduction: The Glasgow prognostic score (GPS) reflects the host systemic inflammatory response and is validated prognostic factor in lung cancer. However, little is known about the prognostic role in non-small cell lung cancer (NSCLC) patients treated with immunotherapy after platinum-based cytotoxic chemotherapy. Patient and Methods: This study used a lung cancer cohort of the Catholic Medical Center of Korea between January 2018 and June 2020. We included the patients who were diagnosed with unresectable advanced stage NSCLC or recurrent disease after pulmonary resection and had received at least one regimen of platinum-based chemotherapy before being administered immunotherapy. The patients with NSCLC treated with anti-PD1 or anti-PD-L1 (pembrolizumab, nivolumab, or atezolizumab) and assessed the prognostic value of the GPS. The GPS was calculated using C-reactive protein and albumin concentrations within 1 week before starting anti-PD1 or anti-PD-L1 treatment. Results: A total of 78 patients with NSCLC treated with immunotherapy as 2nd or 3rd line therapy after platinum-based chemotherapy. Kaplan-Meier analyses revealed that higher GPS was significant predictors of shorter progression free survival (PFS) (Log rank &amp;lt; 0.001) and overall survival (OS) (Log rank &amp;lt; 0.001). In cox-regression multivariate analysis, the hazard ratios for disease progression were 2.146 (95% CI: 0.814-5.656; P = 0.123) for a GPS of 1 and 9.73 (95% CI: 2.931-32.298, P &amp;lt; 0.001) for a GPS of 2 relative to a GPS of 0. Older age (P = 0.033), lower PD-L1 expression (P = 0.036) and higher GPS (P = 0.007) were independently associated with shorter OS. Conclusion: Higher GPS were identified as one of poor prognostic factor for OS and PFS in NSCLC patients received immunotherapy as 2nd or 3rd line therapy after platinum-based chemotherapy. Citation Format: Hye Seon Kang, In Kyoung Kim, Jin Woo Kim. Prognostic significance of Glasgow prognostic score in NSCLC patients treated with immunotherapy after platinum-based cytotoxic chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 376.

Silencing ZIC2 abrogates tumorigenesis and anoikis resistance of non-small cell lung cancer cells by inhibiting Src/FAK signaling

Aberrant expression of the zinc finger protein (ZIC) family has been extensively reported to contribute to progression and metastasis in multiple human cancers. However, the functional roles and underlying mechanisms of ZIC2 in non-small cell lung cancer (NSCLC) are largely unknown. In this study, ZIC2 expression was evaluated using qRT-PCR, western blot, and immunohistochemistry, respectively. Animal experiments in vivo and functional assays in vitro were performed to investigate the role of ZIC2 in NSCLC. Luciferase assays and chromatin immunoprecipitation (ChIP) were carried out to explore the underlying target involved in the roles of ZIC2 in NSCLC. Here, we reported that ZIC2 was upregulated in NSCLC tissues, and high expression of ZIC2 predicted worse overall and progression-free survival of NSCLC patients. Silencing ZIC2 repressed tumorigenesis and reduced the anoikis resistance of NSCLC cells. Mechanical investigation further revealed that silencing ZIC2 transcriptionally inhibited Src expression and inactivated steroid receptor coactivator/focal adhesion kinase signaling, which further attenuated the anoikis resistance of NSCLC cells. Importantly, our results showed that the number of circulating tumor cells (CTCs) was positively correlated with ZIC2 expression in NSCLC patients. Collectively, our findings unravel a novel mechanism implicating ZIC2 in NSCLC, which will facilitate the development of anti-tumor strategies in NSCLC.

Quantification of HER family dimers by proximity ligation assay and its clinical evaluation in non–small cell lung cancer patients treated with osimertinib

ObjectivesThe epidermal growth factor receptor (EGFR, also known as Her1) is a member of the human epidermal growth factor receptor (HER) family of proteins and a target of tyrosine kinase inhibitors (TKIs) in the treatment of non–small cell lung cancer (NSCLC) positive for activating mutations ofEGFR. Signal transduction by HER family proteins is dependent on their homo- or heterodimerization, but little is known of the relation between the relative proportions of such dimers of Her1 and sensitivity to EGFR-TKIs. We here investigated the feasibility of assessing this relation with the in situ proximity ligation assay (PLA) technique, which is able to detect the interaction of two proteins of interest when they are in close proximity. Materials and methodsIn situ PLA was applied to detect Her1 homodimers and Her1 heterodimers in NSCLC cell lines and tissue specimens positive for EGFR activating mutations. ResultsIn situ PLA allowed visualization and quantitative assessment of Her1 homodimers as well as of Her1 heterodimers with Her2, Her3, or Her4 not only in NSCLC cell lines but also in NSCLC tissue specimens obtained from various anatomic sites and by different collection methods. Treatment of NSCLC cell lines with EGFR-TKIs resulted in a decrease in the number of Her1 dimers, with the effect on homodimers being greater than that on heterodimers. A high ratio of Her1 heterodimers to homodimers was associated with poor progression-free survival in NSCLC patients treated with osimertinib. ConclusionIn situ PLA allows the detection of HER family dimers in NSCLC tissue, and quantitative assessment of Her1 homo- and heterodimers may prove informative for prediction of the response of NSCLC patients to EGFR-TKI treatment.

Prognostic value of morphological characteristics assessed by CT scan in patients with non‐small cell lung cancer treated with nivolumab

BackgroundNivolumab is known to demonstrate superior overall survival compared with docetaxel in pretreated non‐small cell lung cancer (NSCLC) patients. Programmed death‐ligand 1 (PD‐L1) expression is reported to predict the outcome of treatment by nivolumab in lung cancer patients. However, the significance of the morphological characteristics of chest computed tomography (CT) as predictors of nivolumab efficacy for advanced NSCLC patients remains unknown.MethodsWe performed a multicenter retrospective trial from April 2013 to March 2017, to assess the significance of CT morphological characteristics as predictors of nivolumab efficacy for advanced NSCLC patients. A total of 78 NSCLC patients pretreated with nivolumab were enrolled. A chest radiologist used chest CT to assess the following morphological characteristics of each patient's main tumor and intrathoracic status prior to nivolumab treatment; interstitial septal thickening, peritumoral ground‐glass opacity, spiculated margin, air bronchogram, cavity or necrosis, adjacent organ invasion, bulky lymph node, and accumulation of small lymph nodes. Logistic regression and Cox proportional hazards regression models were used to analyze outcomes.ResultsA total of 60 (77%) patients were male and 72 (92%) had a performance status (PS) of 0 or 1. The objective response rates of male patients and heavy smokers were significantly higher than those of female patients and light or never smokers, respectively. Multivariate analysis identified light or never smoking, poor PS, histological type of squamous cell carcinoma, and interstitial septal thickening as independent negative predictors of progression free survival (PFS).ConclusionsInterstitial septal thickening was a significant and independent predictor of PFS in NSCLC patients treated with nivolumab.Key pointsSignificant findings of the studyInterstitial septal thickening is an independent predictor of progression free survival in non‐small lung cancer patients treated with nivolumab.What this study addsThe current study reveals the significance of morphological characteristics obtained via chest computed tomography as a predictor of nivolumab efficacy for advanced non‐small cell lung cancer patients.

MAGI1-IT1 stimulates proliferation in non-small cell lung cancer by upregulating AKT1 as a ceRNA.

This study aims to illustrate the potential role of MAGI1-IT1 in the progression of non-small cell lung cancer (NSCLC) and the underlying mechanism. The relative level of MAGI1-IT1 in normal lung tissues and NSCLC tissues was determined. Its level in NSCLC patients with different tumor sizes (<5 cm or >5 cm), metastatic statues (positive or negative), and tumor staging (stage I+II or stage III+IV) was detected as well. The prognostic potential of MAGI1-IT1 in evaluating the overall survival (OS) and progression-free survival (PFS) of NSCLC patients was assessed by the Kaplan-Meier method. In A549 and PC-9 cells, the regulatory effect of MAGI1-IT1 on the proliferative ability was examined by the cell counting kit-8 (CCK-8), colony formation, and 5-Ethynyl-2'-deoxyuridine (EdU) assay. The target miRNA of MAGI1-IT1 and the target gene binding to miRNA-512-3p were predicted using the Diana database. The interactions among MAGI1-IT1/miRNA-512-3p/AKT1 regulatory loop were tested by the Dual-luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. At last, the rescue experiments were carried out to uncover the regulatory effect of MAGI1-IT1/AKT1 axis on NSCLC progression. MAGI1-IT1 was upregulated in NSCLC tissues. Its level was higher in NSCLC patients with larger tumor size, positive metastasis, or advanced stage. High level of MAGI1-IT1 predicted worse OS and PFS in NSCLC patients. The knockdown of MAGI1-IT1 remarkably attenuated the proliferative ability in A549 and PC-9 cells. MAGI1-IT1 could target miRNA-512-3p, and AKT1 was the target gene of miR-512-3p. The overexpression of AKT1 stimulated lung cancer cells to proliferate. Of note, the elevated proliferative rate in lung cancer cells overexpressing AKT1 was reversed by the silence of MAGI1-IT1. MAGI1-IT1 is upregulated in NSCLC tissues and cell lines, and predicts a poor prognosis in NSCLC patients. MAGI1-IT1 stimulates proliferative ability in NSCLC by upregulating the AKT1 level by binding to miRNA-512-3p.

The Effect of Epidermal Growth Factor Receptor Mutation on Intracranial Progression-Free Survival of Non-Small Cell Lung Cancer Patients with Brain Metastasis Underwent Gamma Knife Radiosurgery

BackgroundThe aim of this study was to survey prognostic factors, particularly those focusing on epidermal growth factor receptor (EGFR) mutations, of patients with non-small cell lung cancer (NSCLC) after Gamma Knife Radiosurgery (GKRS) for metastatic brain tumors.MethodsWe retrospectively reviewed the medical records of 98 patients with NSCLC who underwent GKRS for brain metastases from August 2010 to July 2017. The primary endpoint was progression-free survival (PFS) of the intracranial disease. We analyzed variables such as age, sex, Karnofsky Performance Status, recursive partitioning analysis (RPA) class, smoking status, primary cancer pathology, EGFR mutations, and time to brain metastases as prognostic factors.ResultsThe median overall survival (OS) of the patients was 16 months [95% confidence interval (CI), 13–21 months]. Median systemic PFS and intracranial PFS were 9 months (95% CI, 8–11 months) and 11 months (95% CI, 7–14 months), respectively. Kaplan-Meier survival analysis revealed that the patients with EGFR mutations had longer intracranial PFS than those without EGFR mutation (median intracranial PFS: 19 vs. 10 months with p=0.01) while they had no benefits in OS and systemic PFS. Furthermore, the patients harboring adenocarcinoma had longer OS (p<0.01) and intracranial PFS (p<0.01) and the patients with lower RPA class had longer OS (p=0.02) and intracranial PFS (p=0.03).ConclusionEGFR mutations, primary cancer pathology, and RPA class may be proposed as prognostic factors for intracranial PFS in NSCLC patients after GKRS for brain metastasis in this study.

Total metabolic tumor volume by 18F-FDG PET/CT for the prediction of outcome in patients with non-small cell lung cancer.

Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are imaging parameters derived from 18F-FDG PET/CT that have been proposed for risk stratification of cancer patients. The aim of our study was to test whether these whole-body volumetric imaging parameters may predict outcome in patients with non-small cell lung cancer (NSCLC). Sixty-five patients (45 men, 20 women; mean age ± SD, 65 ± 12years), with histologically proven NSCLC who had undergone 18F-FDG PET/CT scan before any therapy, were included in the study. Imaging parameters including SUVmax, SUVmean, total MTV (MTVTOT) and whole-body TLG (TLGWB) were determined. Univariate and multivariate analyses of clinical and imaging variables were performed using Cox proportional hazards regression. Survival analysis was performed using Kaplan-Meier method and log-rank tests. A total of 298 lesions were analyzed including 65 primary tumors, 114 metastatic lymph nodes and 119 distant metastases. MTVTOT and TLGWB could be determined in 276 lesions. Mean value of MTVTOT was 81.83ml ± 14.63ml (SE) whereas mean value of TLGWB was 459.88g ± 77.02g (SE). Univariate analysis showed that, among the variables tested, primary tumor diameter (p = 0.0470), MTV of primary tumor (p = 0.0299), stage (p < 0.0001), treatment (p < 0.0001), MTVTOT (p = 0.0003) and TLGWB (p = 0.0002) predicted progression-free survival in NSCLC patients, while age (p = 0.0550), MTV of primary tumor (p = 0.0375), stage (p < 0.0001), treatment (p < 0.0001), MTVTOT (p = 0.0001) and TLGWB (p = 0.0008) predicted overall survival. At multivariate analysis age, TLGWB and stage were retained in the model for prediction of progression-free survival (p < 0.0001), while age, MTVTOT and stage were retained in the model for prediction of overall survival (p < 0.0001). Survival analysis showed that patients with TLGWB ≤ 54.7g had a significantly prolonged progression-free survival as compared to patients with TLGWB > 54.7g (p < 0.0001). Moreover, overall survival was significantly better in patients showing a MTVTOT ≤ 9.5ml as compared to those having MTVTOT > 9.5ml (p < 0.0001). Similar results were obtained in a subgroup of 43 patients with advanced disease (stages III and IV). Whole-body PET-based volumetric imaging parameters are able to predict outcome in NSCLC patients.

The Effect of Next-Generation TKI in Non-Small Cell Lung Cancer after Failure of First-Line Treatment: a Meta-Analysis.

Resistance develops against first-generation tyrosine kinase inhibitors (TKIs), which target the epidermal growth factor receptor (EGFR), after a while for non-small-cell lung cancer (NSCLC). Recently, researchers have developed specific inhibitors against them. Among those inhibitors, next-generation EGFR-TKIs have gained prominence due to the greater efficacy and more favorable tolerability. Today, the efficacy of next-generation EGFR-TKIs in patients with advanced NSCLC after failure on first-generation EGFR-TKIs still remains under investigation. The aim of this meta-analysis was to systematically assess the efficacy and safety profiles of next-generation EGFR-TKIs in advanced NSCLC after failure on first-generation EGFR-TKIs. We performed a comprehensive search of the several electronic databases to September, 2018 to identify clinical trials. The primary endpoint was overall survival (OS), progression-free survival (PFS), disease controlled rate (DCR), objective response rate (ORR), and adverse events (AEs). Severe adverse events (AEs) (grade ≥ 3) based on the EGFR-TKIs were analysed. Odds Ratio (OR) along with 95% confidence interval (95% CI) were utilized for the main outcome analysis. In total, we had 3 randomized controlled trials in this analysis. The group of next-generation EGFR-TKIs was significantly improved PFS (OR = 0.34,95%CI = 0.29-0.40, P < 0.00001), as well with the ORR (OR = 10.48,95%CI = 3.87-28.34, P < 0.00001) and DCR (OR = 6.03,95%CI = 4.41-8.25, P < 0.00001), respectively. However, there is no significant difference in overall survival with next-generation EGFR-TKIs (OR = 1.05,95%CI = 0.85-1.31, P = 0.66). While, the OR for the treatment-related AEs of grade 3 or 4 (diarrhoea, rash/acne, nausea, vomiting, anemia) between the patients who received next-generation EGFR-TKIs and chemotherapy did not show safety benefit (P>0.05). Next-generation EGFR-TKIs was shown to be the better agent to achieve higher response rate and the longer PFS in NSCLC patients as the later-line therapy for previously treated patients with first-generation EGFR-TKIs. While, the benefit of the OS and safety compared with the chemotherapy did not achieved. Further research is needed to develop a database of all EGFR mutations and their individual impact on the differing treatments.

KCNQ1OT1 facilitates progression of non-small-cell lung carcinoma via modulating miRNA-27b-3p/HSP90AA1 axis.

Long noncoding RNA KCNQ1OT1 participates in the regulation of imprinted genes within the kcnq1 domain. But its roles in carcinogenesis and metastasis remain largely elusive. Herein, we evaluated its potential in non-small-cell lung cancer (NSCLC) progression. We demonstrated that the KCNQ1OT1 level was upregulated in NSCLC tissues and cell lines. High KCNQ1OT1 level correlated with poor overall and progression-free survival in NSCLC patients. KCNQ1OT1 facilitated proliferation, migration, and invasion in H460 cells. Furthermore, knockdown of KCNQ1OT1 reduced the expression of HSP90AA1. KCNQ1OT1 presented a positive correlation with HSP90AA1 which predicted the tumor progression in NSCLC from The Cancer Genome Atlas database. Intriguingly, KCNQ1OT1 modulated HSP90AA1 expression by sponging miR-27b-3p. MiR-27b-3p counteracted the effect of KCNQ1OT1 on HSP90AA1 expression, H460 cell migration, and invasion. These data revealed a role for KCNQ1OT1 as an oncogene through miR-27b-3p/HSP90AA1 axis during NSCLC progression.

MiR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1.

Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics invitro and invivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.