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

Management and Outcomes of Newly Diagnosed Non-Small Cell Lung Cancer Patients with Brain Metastases: A Real-World Study in Japan

Background:Brain metastases (BM) are one of the strongest negative prognostic factors in patients with non-small cell lung cancer (NSCLC). Molecularly targeted agents are standard of care for NSCLC patients with a driver mutation; however, their efficacy in patients with BM is not fully understood because patients with BM are usually excluded from clinical studies. This study investigated the current management and outcomes of newly diagnosed NSCLC patients with BM in Japanese clinical practice, focusing on their driver mutation status. Patients and Methods:We enrolled newly diagnosed, treatment-naïve NSCLC patients with BM between January 2012 and December 2015 from 4 institutions in Japan. The medical records of each patient were retrospectively reviewed, and the treatment details and outcomes were evaluated. Results:In total, 203 patients with BM were enrolled in this study and 73 (36%) were neurologically symptomatic. Regarding initial treatment, 110 patients (54%) received local therapy, including radiotherapy and surgery, whereas 77 (38%) received systemic therapy. The median overall survival (OS) was 14.3 months for all patients, and it was significantly longer among patients with a driver mutation (28.9 months; 95% confidence interval [CI], 20.9–41.0) than among patients without a driver mutation (9.9 months; 95% CI, 7.0–13.4) (hazard ratio [HR] 0.39; 95% CI, 0.27–0.57; p < 0.001). Multivariate analysis identified performance status (HR 1.78; 95% CI, 1.16–2.72; p = 0.009) and driver mutation status (HR 0.27; 95% CI, 0.17–0.44; p < 0.001) as significant prognostic factors. No significant difference in OS was noted according to the type of initial treatment, i.e., local versus systemic. Conclusion:The median OS of patients with a driver mutation was longer than 2 years, even of patients with BM, and it was significantly longer than that of patients without a driver mutation. Driver mutation status, in addition to performance status, was a significant prognostic factor in NSCLC patients with BM.

Advanced Non–Small Cell Lung Cancer Patients With Low Tumor Mutation Burden Might Derive Benefit From Immunotherapy

The aim of this study is to investigate the association between tumor mutation burden (TMB) and survival in non-small cell lung cancer (NSCLC) patients with anti-programmed cell death protein 1 and anti-programmed death-ligand 1 blockade. Two retrospective cohorts and The Cancer Genome Atlas NSCLC data set were included in this study. The restricted cubic spline analysis was used to explore the association between TMB and survival. The cutoff values for TMB were determined by X-tile software. Primary outcomes were overall survival (OS). The associations between TMB and intratumor heterogeneity, number of segments, fraction of genome alterations, aneuploidy score, and T-cell populations were also investigated. In the restricted cubic spline plots, TMB showed an inverted U-shaped curve with OS. The median OS in the low TMB group was significantly longer than those in the medium TMB group. In The Cancer Genome Atlas NSCLC data set, low TMB was also associated with longer OS in comparison with medium TMB. Furthermore, NSCLC patients with low TMB had significantly lower intratumor heterogeneity, number of segments, fraction of genome alterations, aneuploidy score, T-helper type 2 (Th2) cells, and CD8 T cells, but higher levels of Th1 and Th17 cells. Low TMB might be a prognostic factor for NSCLC patients receiving anti-programmed cell death protein 1/programmed death-ligand 1 immunotherapy.

Long-term survival analysis of patients with non-small cell lung cancer complicated with type 2 diabetes mellitus.

BackgroundThis study aimed to investigate the effect of type 2 diabetes mellitus on survival of patients with non‐small cell lung cancer (NSCLC).MethodsWe retrospectively analyzed NSCLC patients who had undergone radical lung cancer surgery from January 2011 to December 2014 in the Anhui Medical University affiliated Anhui Provincial Hospital. Kaplan‐Meier plots, log‐rank tests, and Cox proportional hazards regression models were used to describe the effect of type 2 diabetes mellitus on the overall survival of patients with NSCLC.ResultsA total of 769 patients with NSCLC were enrolled, including 126 in the diabetic mellitus group and 643 in the nondiabetic mellitus group. The one, three, and five‐year survival for patients with and without diabetes mellitus were 86.1% versus 89.6%, 49.5% versus 62.4%, and 33.3% versus 40.6%, respectively. The Cox model showed that type 2 diabetes mellitus was a poor independent prognostic factors for NSCLC patients. In addition, metformin is a good independent prognostic factor for patients with non‐small cell lung cancer with type 2 diabetes mellitus.ConclusionsNSCLC patients without type 2 diabetes mellitus have an increased survival rate compared with those with type 2 diabetes mellitus.

Caspase Recruitment Domain Containing Protein 9 Suppresses Non-Small Cell Lung Cancer Proliferation and Invasion via Inhibiting MAPK/p38 Pathway.

PurposeCaspase recruitment domain containing protein 9 (CARD9) has been demonstrated to be a pro-tumor factor in various cancers. However, our previous study found a significant decrease of CARD9 in malignant pleural effusion compared with benign pleural effusion. So we investigated the role of CARD9 in non-small cell lung cancer (NSCLC) and its working mechanism.Materials and MethodsImmunohistochemistry, western blot, and quantitative real-time polymerase chain reaction were used to detect the expression of CARD9 in specimens of NSCLC patients. The Cancer Genome Atlas (TCGA) databasewas also used to analyze the expression of CARD9 in NSCLC and its predicting value for prognosis. Immunofluorescence was used for CARD9 cellular location. Cell growth assay, clonal formation assay, wound healing assay, matrigel invasion assay, and flow cytometry were used to test cell proliferation, migration, invasion, apoptosis, and cycle progression of NSCLC cells with CARD9 knockdown or CARD9 overexpression. Co-immunoprecipitation was used to identify the interaction between CARD9 and B-cell lymphoma 10 (BCL10). SB203580 was used to inhibit p38 activation.ResultsCARD9 was decreased in NSCLC tissues compared with normal tissues; low CARD9 expression was associated with poor survival. CARD9 was expressed both in tumor cells and macrophages. Downregulation of CARD9 in NSCLC cells enhanced the abilities of proliferation, invasion and migration via activated MAPK/p38 signaling, while overexpression of CARD9 presented antitumor effects. BCL10 was identified to interact with CARD9.ConclusionWe demonstrate that CARD9 is an independent prognostic factor in NSCLC patients and inhibits proliferation, migration, and invasion by suppressing MAPK/p38 pathway in NSCLC cells.

Overexpression of miR-425-5p is associated with poor prognosis and tumor progression in non-small cell lung cancer.

MicroRNA-425-5p (miR-425-5p) has been investigated in some human cancers, but the understanding of its clinical and functional roles in non-small cell lung cancer (NSCLC) remains poor. This study sought to measure the expression of miR-425-5p in NSCLC samples, assess its prognostic significance in cancer patients, and explore its functional role during tumor progression. Expression of miR-425-5p was examined using quantitative Real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis and Cox analysis were conducted to evaluate the prognostic value of miR-425-5p. The effects of miR-425-5p on NSCLC cell proliferation, migration and invasion were assessed using cell experiments. Expression of miR-425-5p was upregulated in NSCLC tissues and cells compared with the normal controls (all P< 0.05). The increased miR-425-5p expression was associated with positive lymph node metastasis and TNM advanced stage of the patients (all P< 0.05). The survival curves and Cox analysis indicated that high miR-425-5p was correlated with poor overall survival and acted as an independent prognostic factor in NSCLC patients. Cell experiments suggested that miR-425-5p overexpression could enhance, whereas its reduction could suppress NSCLC cell proliferation, migration and invasion (all P< 0.05). Forhead box J3 (FOXJ3) was proved to be a direct target of miR-425-5p in NSCLC. Overexpression of miR-425-5p predicts poor prognosis of NSCLC and promotes cancer cell proliferation, migration and invasion by targeting FOXJ3.

Overexpression of p-Akt, p-mTOR and p-eIF4E proteins associates with metastasis and unfavorable prognosis in non-small cell lung cancer.

The Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway, which is dysregulated in various cancers, controls the assembly of eukaryotic translation initiation factor 4F (eIF4E) complex. However, whether aberrant expression of phosphorylated Akt (p-Akt), phosphorylated mTOR (p-mTOR) and phosphorylated eIF4E (p-eIF4E) is associated with clinicopathological characteristics in surgically resected non-small cell lung cancer (NSCLC) has been rarely reported. Here, we investigated expression of p-Akt, p-mTOR and p-eIF4E proteins in NSCLC by immunohistochemistry and evaluated their correlation with clinicopathological characteristics and prognostic significance. The results showed that the positive percentage of p-Akt, p-mTOR and p-eIF4E was higher in NSCLC. Additionally, p-mTOR and p-eIF4E was dramatically higher in lung adenocarcinoma (both P<0.05). Most importantly, NSCLC patients with lymph node metastasis had significantly elevated expression of p-Akt, p-mTOR and p-eIF4E (all P<0.05). Positive expression of p-Akt, and any positive expression of p-Akt, p-mTOR and p-eIF4E proteins were positively correlated with clinical stages (both P<0.05). Spearman’s rank correlation test revealed that expression of p-Akt was correlated with p-eIF4E and p-mTOR (r = 0.107, P = 0.047; r = 0.287, P<0.001, respectively). Also, p-eIF4E had positive correlation with p-mTOR (r = 0.265, P<0.001). Furthermore, NSCLC patients with increased expression of p-Akt, p-mTOR and p-eIF4E, and any positive expression of above three proteins had lower overall survival rates (all P<0.05). Multivariate Cox regression analysis further indicated thatp-eIF4E was an independent prognostic factor for NSCLC patients (P = 0.046). Taken together, overexpression of p-Akt, p-mTOR and p-eIF4E proteins is associated with metastasis and poor prognosis of NSCLC patients after surgical resection, and positive expression of p-eIF4E protein may act as an independent unfavorable prognostic biomarker for overall survival of NSCLC patients.

MiR-486 as an unfavorable prognostic biomarker for patients with non-small cell lung cancer.

BackgroundNon-small cell lung cancer (NSCLC) is the most common malignant tumor in China. miR-486 was found to be associated with many tumors. In previous study, we aimed to investigate the expression and prognostic value of miR-486 in patients with NSCLC.MethodsIn order to measure the expression of miR-486 in 140 NSCLC patients, in situ hybridization (ISH) was made. The staining of miR-486 was scored by two independent investigators. Then, the prognostic value of miR-486 was evaluated by plotting Kaplan-Meier survival curves and making multivariate analysis.ResultsmiR-486 was mainly expressed in the cytoplasm of tumor cells. miR-486 expression was corrected with tumor differentiation (P=0.011) but not with any other clinicopathological characteristics. However, high expression of miR-486 was significantly correlated with shortened overall survival (OS) in NSCLC patients (P=0.001), especially in stage I patients (P=0.005). Multivariate analysis revealed that miR-486 was an independent prognostic factor in NSCLC patients (P=0.002).ConclusionsmiR-486 high expression predicts poor survival in patients with NSCLC. miR-486 could be used as an unfavorable prognostic biomarker for NSCLC patients.

The TGFβ-Induced Long Non-coding RNA TBULC Promotes the Invasion and Migration of Non-small Cell Lung Cancer Cells and Indicates Poor Prognosis.

Objective: To investigate the biological function and clinicopathological significance of the TGFβ-induced long non-coding RNA (lncRNA) TBULC in non-small cell lung cancer (NSCLC) and to analyze its potential value in clinical diagnosis and treatment.Methods: RT-qPCR was used to detect the expression level of TBULC in NSCLC cells and tissues, and the correlation between the TBULC expression level and clinicopathological characteristics was analyzed. A cytoplasmic/nuclear fractionation assay was performed to define the cellular localization of the TBULC. A rapid amplification of cDNA ends (RACE) assay was performed to acquire the full-length sequence of the TBULC. Stable TBULC overexpression and TBULC knockdown cell clones were constructed by lentiviral infection, and Transwell assays were used to explore the effect of the TBULC on cell invasion and migration.Results: Stimulation with TGFβ in NSCLC cell lines significantly upregulated the expression level of the nuclear-localized lncRNA TBULC. The RACE assay indicated that the full-length TBULC sequence was 1,020 nucleotides, and the sequence was located on chromosome 15. Cell function experiments showed that the TBULC played a crucial role in promoting NSCLC metastasis. Knockdown of TBULC significantly suppressed the invasion and migration of NSCLC cells, and overexpression of TBULC had the opposite effects. The expression level of TBULC in 106 NSCLC tumor tissues was significantly higher than that in adjacent normal tissues, and TBULC was proven to be an independent prognostic factor in NSCLC patients [p = 0.030, OR = 0.513 (0.281–0.936)].Conclusion: The TGFβ-induced lncRNA TBULC was upregulated in NSCLC and promoted the invasion and migration of NSCLC cells. TBULC was an independent prognostic factor and might be a potential biomarker for predicting the prognosis of NSCLC patients.

Expression of DR5 and c‑FLIP proteins as novel prognostic biomarkers for non‑small cell lung cancer patients treated with surgical resection and chemotherapy.

TRAIL-R2 (DR5), one of the death receptors, can activate the extrinsic apoptosis pathway, while cellular FLICE-inhibitory protein (c-FLIP) can inhibit this pathway. Both of them play important roles in the occurrence and development of most tumors. To date, there is no relevant report concerning the relationship between expression of DR5 and c-FLIP protein and clinicopathological/prognostic implications in patients with non-small cell lung cancer (NSCLC) treated with surgical resection and chemotherapy. Thus, the aim of the present study was to investigate the potential prognostic significance of DR5 and c-FLIP in NSCLC patients and their predictive roles in the chemotherapeutic response. In the present study, DR5 and c-FLIP were detected by immunohistochemistry (IHC) in tissue microarrays of NSCLC. The results showed that the expression levels of DR5 and c-FLIP were significantly higher in lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC) tissues compared with levels noted in the non-cancerous control lung tissues (all P<0.05). In addition, DR5 expression was significantly increased in lung ADC (P<0.001), whereas, c-FLIP was higher in lung SCC (P<0.001) and smoker patients with clinical stage III (P=0.019, P=0.016, respectively). In addition, NSCLC patients with overexpression of DR5 and loss of c-FLIP expression exhibited a higher overall survival (OS) rate as determined by Kaplan-Meier analysis (P=0.029, P=0.038, respectively). Multivariate analysis confirmed that high expression of DR5 and loss of c-FLIP expression were independent favorable prognostic factors for NSCLC patients (P=0.016, P=0.035, respectively). In conclusion, overexpression of DR5 and loss of c-FLIP expression may serve as novel favorable prognostic biomarkers for NSCLC patients treated with chemotherapy after radical resection and used as predictors for tumor response to chemotherapy drugs.

Elevated expression of G3BP1 associates with YB1 and p-AKT and predicts poor prognosis in nonsmall cell lung cancer patients after surgical resection.

PurposeG3BP1 is an RNA‐binding protein and plays roles in regulating signaling pathway. YB‐1 is a DNA/RNA binding protein encoded by YBX1 gene. Phosphorylated AKT (p‐AKT) acts as a pivotal molecule in PI3K/AKT pathway. YB‐1 drives stress granules (SGs) formation by activating G3BP1 translation under diverse conditions. SGs are involved in many different metabolic and signaling pathways which may include PI3K/AKT/mTOR. So far, there has been no report on the relationship between expression of G3BP1, p‐AKT, and YB1 and clinicopathological features/prognosis in surgically resected nonsmall cell lung cancer (NSCLC) patients.MethodsIn this study, data from TCGA (The Cancer Genome Atlas) were downloaded to investigate the mRNA expression of G3BP1 and YB1 (YBX1) and their correlation in NSCLC. Also, expression of G3BP1, YB1, and p‐AKT proteins was studied using immunohistochemistry in tissue microarrays of NSCLC and in noncancerous lung tissues.ResultsWe found that the mRNA expression of G3BP1 and YB1 was higher in NSCLC tissues (both P < .05), and G3BP1 was positively correlated with YB1 in mRNA level (r = .399, P < .001). Also, expression of G3BP1, YB1, and p‐AKT proteins was higher in NSCLC tissues (all P < .05). And higher expression of G3BP1 and YB1 proteins was seen in patients with clinical stage II and III compared with stage I (both P < .05). Besides, expression of G3BP1 protein had a positive correlation with YB1 and p‐AKT (both P < .05). Moreover, overall survival was shorter in patients with overexpression of G3BP1, YB1, and p‐AKT proteins (all P < .05). Multivariate analysis confirmed that overexpression of G3BP1 protein was an independent poorer prognostic factor for NSCLC patients (P = .039).ConclusionG3BP1 may play a crucial role in activating PI3K/AKT/mTOR pathway. G3BP1 might be served as a novel prognostic biomarker for surgically resected NSCLC patients, which afforded new insights into the study on the mechanism and therapy of NSCLC.

Correlation of body composition by computerized tomography and metabolic parameters with survival of nivolumab-treated lung cancer patients.

PurposeWeight loss is a well-recognized prognostic parameter for survival of lung cancer patients. Computerized-tomography (CT)-based analysis of body composition and blood-based metabolic evaluation are promising prognostic tools. We aimed to assess the correlation between albumin, body mass index (BMI), skeletal muscle mass index (SMI), fat-free mass index (FFMI), fat mass index (FMI) and weight change, as well as their correlation with survival of lung cancer patients on nivolumab treatment.MethodsData were retrospectively collected. Weight was measured at a diagnosis of stage 4 disease and before start of nivolumab. Albumin levels were measured before starting nivolumab. BMI, SMI, FFMI, and FMI were evaluated from CT scans performed at start of nivolumab. Overall survival (OS) was from starting of nivolumab to death or censured at last follow-up. Statistical analysis was done to identify correlation between the various factors and between those factors and survival.ResultsForty-six patients with advanced non-small cell lung cancer (NSCLC) were included. Median follow-up was 22 months. Pathology was Adenocarcinoma/Squamous/non-other specified in 25/15/6 respectively. All patients received nivolumab as an advanced-line treatment for stage IV NSCLC. We observed a significant correlation of weight loss (P=0.01, HR=2.85) and albumin (P=0.043, HR=0.34) with OS in multivariate analysis. A significant correlation was found between BMI to SMI, FFMI, FMI, and weight change.ConclusionWeight loss and low albumin levels are significant negative prognostic factors for NSCLC patients on immunotherapy. CT-based parameters of body composition remain to be proven as more reliable than standard clinical parameters.

Prognostic Value of Neutrophil-to-Lymphocyte Ratio before Cranial Radiotherapy in Non-Small Cell Lung Cancer Patients with Limited Brain Metastases: A Propensity-Score Matched Pair Comparison of Whole-Brain Radiotherapy and Stereotactic Irradiation Alone

Stereotactic irradiation (STI) alone as initial management has emerged as a widely practiced treatment modality for selected non-small cell lung cancer (NSCLC) patients with 1 to 10 small brain metastases. However, no randomized study comparing whole brain radiotherapy (WBRT) versus STI alone has been reported. To better assess the prognosis and guidance for optimal treatment selection of patients with brain metastases, we introduced the neutrophil to lymphocyte ratio (NLR) recognized as a poor prognostic factor in various cancers before cranial radiotherapy. A total of 193 consecutive NSCLC patients with 1 to 10 brain metastases with diameters less than 3cm in our institution were retrospectively analyzed. Patients with leptomeningeal metastasis, those who underwent craniotomy before RT and poor performance status were excluded. The evaluated prognostic factors for OS included gender, neurological deficit, histology, epidermal growth factor receptor (EGFR) mutation status, the number of target, target volume, previous EGFR-tyrosine kinase inhibitor treatment, recursive partitioning analysis (RPA) class and NLR. All factors with a p < 0.05 in univariate analysis were entered into multivariate analysis using Cox regression and matched on a 1:1 basis for these prognostic variables. One hundred seven patients received STI and 86 received WBRT. The median follow-up for the entire cohort was 8.3 months (range, 0.8 - 154 months), 9.3 months for STI group and 7.7 months for WBRT group. Patient characteristics of the entire cohort were balanced in terms of gender, histology, EGFR status, and previous treatment. However, the rates of neurological deficit, the number of target, target volume, poor RPA class, and NLR were significantly larger in the WBRT group. Median overall survival (OS) in STI group and WBRT group was 10.1 months (range, 1.7 - 154 months) and 6.3 months (range, 0.8 - 112 months), respectively (p = 0.047). Univariate analysis showed that factors affecting OS were EGFR status, RPA class, solitary intracranial metastasis and NLR (p <0.05). Multivariate analysis found that NLR less than the cutoff value 3.6 (p = 0.0001) and solitary intracranial metastasis (p = 0.03) were independent favorable prognostic factors affecting OS. Propensity-score matching created a matched cohort of 92 patients (STI: n = 46 and WBRT: n = 46) with similar baseline characteristics. The survival benefit was not found in the STI group compared with the WBRT group (p = 0.56), whereas WBRT group reduced intracranial failure than STI group (p = 0.043). Adjusting for prognostic factors, treatment with either STI or WBRT did not result in any statistically significant difference in OS. NLR prior to cranial radiotherapy could be one of the strongest prognostic factors for NSCLC patients with limited brain metastases, and future prospective clinical investigation to validate its prognostic value is warranted.

Abstract 4019: High TERT expression in NSCLC is associated with poor prognosis

Abstract Background: Activation of human telomerase reverse transcriptase (TERT) has been linked to tumorigenesis and aggressive tumor behavior. This study was undertaken to evaluate if TERT expression was correlated with clinicopathological parameters and survival in patients with non-small cell lung cancer (NSCLC). Methods: TMA slides made from 254 NSCLC patients (cohort 1 and cohort 2), including 127 adenocarcinoma (LUAD), 78 squamous carcinomas (LUSC) and 46 other types, were included. TMA Formalin-fixed and paraffin-embedded (FFPE) tissue sections were stained using the immunohistochemistry stain (IHC). The percentage of positive nuclei was determined for each case and the cut-off value was set as 5%, 20% and 50% positive tumor cells. TERT expression levels were analyzed for associations with patient survival rates and clinicopathological parameters (such as age, gender, tumor grade, tumor stage, metastasis). Survival analysis was performed using the Kaplan-Meier method. Results: TERT was positive in 199/254 (78%) of the samples. High TERT expression was seen in tumor specimens compared with normal adjunct tissues (p &amp;lt; 0.001). Kaplan-Meier curves indicated that high TERT expression was significantly associated with poor overall survival in NSCLC patients (p &amp;lt; 0.001 and p &amp;lt; 0.0001, 20% and 50% cut-off, respectively). Multivariate analysis of survival demonstrated that TERT expression at 50% cutoff was an independent prognostic factor for NSCLC patients (HR = 0.1461, 95% CI: 0.0862-0.2475, p &amp;lt; 0.0001). High TERT expression was also associated with short survival of LUSC and LUAD patients at 50% cutoff (p &amp;lt; 0.0001). No significant association with OS was observed at 5% cutoff. There was also significant correlation between TERT expression with metastasis but no correlation with clinical stage, histological type and tumor differentiation. Conclusion: Our study showed that high TERT expression is present in 78% of NSCLC tumors and is associated with poor prognosis. TERT may serve as a prognostic biomarker and novel drug target for NSCLC. Citation Format: Tianhong Li, Weijie Ma, Qianping Li, Sixi Wei, Tao Wang, Jingyi Xiang, Cheng Liu. High TERT expression in NSCLC is associated with poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4019.

Abstract 4840: Characterization of URST1 as a biomarker and therapeutic target for precision medicine of lung cancer

Abstract This study aims to identify novel biomarkers and therapeutic targets for lung cancer. We initially screened genes that overexpressed in the majority of lung cancers by using our original gene expression profile database. During this process, we identified up-regulated in solid tumor 1 (URST1) as a candidate. Immunohistochemical staining showed that URST1 was expressed in 231 (64.5%) of 358 non-small cell lung cancer (NSCLC) that had undergone curative surgery. Strong URST1 expression was associated with poor prognosis for NSCLC patients (P = 0.0003 by log-rank test). In addition, multivariate analysis showed that strong URST1 expression was an independent prognostic factor for NSCLC patients. Reduction of URST1 expression by siRNA or treatment with selective URST1 inhibitor significantly suppressed cancer cell growth partly through cell cycle arrest at G2/M phase and mitotic cell death as detected by flow cytometric analysis and live cell imaging. Our findings suggest that URST1 could be a potential biomarker and therapeutic target for developing precision medicine of lung cancer. Note: This abstract was not presented at the meeting. Citation Format: Atsushi Takano, Yohei Miyagi, Yataro Daigo. Characterization of URST1 as a biomarker and therapeutic target for precision medicine of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4840.

The prognostic value of the preoperative albumin to alkaline phosphatase ratio in patients with non-small cell lung cancer after surgery.

BackgroundTo assess the potential prognostic value of the albumin to alkaline phosphatase ratio (AAPR) in patients with non‐small cell lung cancer (NSCLC) after surgery.MethodsThe log‐rank and Kaplan‐Meier analyses were performed to detect differences in survival levels between different groups. A model of Cox proportional hazards was used to perform univariate and multivariate survival analyses. Comparisons of receiver operating characteristic (ROC) curves and the likelihood ratio test (LRT) were also utilized to compare the prognostic abilities of different systems for overall survival (OS) prediction.ResultsThe optimal cut‐off value of the preoperative AAPR was 0.64. A decreased AAPR was associated with several clinicopathological and clinicolaboratory variables related to cancer progression. The preoperative AAPR of patients was positively correlated with the poor prognosis of NSCLC. In multivariate analyses, the preoperative AAPR was identified as an independent prognostic factor for disease‐free survival (DFS; P = 0.001) and overall survival (OS; P = 0.003). The LRT showed that the AAPR tumor‐node‐metastasis (TNM) system presented a significantly larger χ2 value (112.4 vs. 89.2, respectively, P < 0.01) and a relatively smaller Akaike information criterion (AIC) value (2955 vs. 2977, respectively, P < 0.01) than the TNM staging system.ConclusionPreoperative AAPR was a potentially valuable prognostic factor in NSCLC patients who underwent surgery. Our results further showed that the AAPR‐TNM system was superior to the current TNM staging system.

High developmental pluripotency‑associated 4 expression promotes cell proliferation and glycolysis, and predicts poor prognosis in non‑small‑cell lung cancer.

The developmental pluripotency-associated 4 (Dppa4) gene serves critical roles in cell self-renewal, as well as in cancer development and progression. However, the regulatory role of Dppa4 in non-small-cell lung cancer (NSCLC) and its underlying mechanisms remain elusive. The aim of the present study was to investigate the biological function of Dppa4 in NSCLC and its underlying mechanism of action. Dppa4 expression was measured in NSCLC tissue samples and cell lines, and its effect on cell proliferation and the expression of glycolytic enzymes was determined. In addition, the underlying mechanisms of Dppa4-induced alterations in glycolysis were analyzed. Univariate and multivariate analyses were also performed to analyze the prognostic significance of clinicopathological characteristics. Dppa4 was found to be highly expressed in NSCLC tissues and cell lines. Furthermore, it was observed that Dppa4 was correlated with the degree of tumor differentiation and TNM stage. Univariate and multivariate analyses identified Dppa4 expression and clinical stage as prognostic factors for NSCLC patients. Kaplan-Meier analysis further revealed that patients with lower Dppa4 expression exhibited a better prognosis. In NSCLC cells, Dppa4 knockdown inhibited cell proliferation, while Dppa4 overexpression enhanced cell proliferation, which was likely mediated by glycolysis promotion. Dppa4 knockdown had no evident effect on the majority of enzymes examined; however, glucose transporter type 4 (GLUT-4) and pyruvate kinase isozyme M2 were significantly upregulated, and hexokinase II (HK-II) and lactate dehydrogenase B (LDHB) were downregulated following Dppa4 knockdown. By contrast, Dppa4 overexpression resulted in downregulation of GLUT-4, and upregulation of HK-II, enolase and LDHB, whereas it had no effect on other enzymes. Since the most evident effect was observed on LDHB, further functional experiments demonstrated that this enzyme reversed the promoting effects of Dppa4 in NSCLC. In conclusion, Dppa4 promotes NSCLC progression, partly through glycolysis by LDHB. Thus, the Dppa4-LDHB axis critically contributes to glycolysis in NSCLC cells, thereby promoting NSCLC development and progression.

Prognostic value of a novel scoring system using inflammatory response biomarkers in non-small cell lung cancer: A retrospective study.

BackgroundThe neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR) are reported to show a strong correlation with prognosis in patients with non‐small cell lung cancer (NSCLC). We aimed to describe a novel scoring system combining these ratios, termed the inflammatory response biomarker (IRB) score, and test its prognostic value in NSCLC.MethodsThe data of 261 NSCLC patients who underwent thoracoscopic radical resection in a single center were retrospectively reviewed. The IRB score was defined as follows: a high NLR (> 2.12), a high PLR (92.9), and a low LMR (< 4.57) were each scored as 1; the opposite values were scored as 0. The individual scores were added to produce the IRB score (range: 0–3).ResultsMultivariate analyses indicated that high tumor node metastasis (TNM) stage (hazard ratio [HR] 2.721, 95% confidence interval [CI] 1.597–4.989; P < 0.001) and an IRB score ≥ 2 (HR 2.696, 95% CI 1.506–4.826; P = 0.001) were independent prognostic factors for poor overall survival. Furthermore, smoking history (HR 2.953, 95% CI 1.086–8.026; P = 0.034), high TNM stage (HR 3.108, 95% CI 1.911–5.056; P < 0.001), and IRB score ≥ 2 (HR = 2.316, 95% CI: 1.389–3.861; P = 0.001) were demonstrated to be independent prognostic factors for poor disease‐free survival.ConclusionThe novel scoring system combining NLR, PLR, and LMR was an independent prognostic factor in NSCLC patients undergoing thoracoscopic radical resection and was superior to these ratios alone for predicting prognosis.

The clinical characteristic and prognostic factors of leptomeningeal metastasis in patients with non-small-cell lung cancer-a retrospective study from one single cancer institute.

BackgroundLeptomeningeal metastasis (LM) is a detrimental complication of advanced non‐small‐cell lung cancer (NSCLC), and the optimal therapeutic approach for LM patients is in shortage. This retrospective study aimed to investigate the clinical features and prognostic factors of NSCLC patients with LM.MethodsWe retrospectively reviewed the medical records of NSCLC patients with LM at the Shandong Cancer Hospital and Institute between July 2014 and March 2018. Identified cases had pathology‐proven NSCLC with either positive cerebrospinal fluid cytology or leptomeningeal enhancement by MRI.ResultsOne hundred and thirty‐six NSCLC patients (58 men, 78 women) with LM were enrolled in the retrospective study; median age was 55 years (range, 29‐89 years). Fifty‐one patients harbored EGFR mutations, ALK rearrangement was detected in 6 patients. Treatment for LM consisted of EGFR‐TKIs alone in 11 patients, whole brain radiotherapy (WBRT) alone in 19 patients, Chemotherapy (ChT) alone in 12 patients, EGFR‐TKIs plus WBRT in 30 patients, WBRT plus ChT in 25 patients, and EGFR‐TKIs plus ChT in 24 patients. The median progression‐free survival was 3.9 months (95% confidence interval [CI]: 3.178‐4.622), and the median overall survival (OSLM) was 9.8 months (95% CI:7.5‐12.1). Thirty patients who received WBRT plus EGFR‐TKIs achieved longer survival than those who only received WBRT (median 13.6 vs 8.8 months; P = 0.027), but did not add any survival benefit than those only received EGFR‐TKIs (median 13.6 vs 13.9 months; P = 0.352). A multivariate analysis indicated that KPS ≥ 80 (hazard ratio [HR] = 0.592, 95% CI:0.369‐0.95; P = 0.03) and EGFR‐TKIs (HR = 0.507, 95% CI:0.283‐0.908; P = 0.022) after LM diagnosis were independent favourable predictors of survival, whereas smoking (HR = 1.181, 95% CI:1.009‐3.246; P = 0.047) was an independent predictor of poor survival.ConclusionsOur results suggest that patients with good performance statuses, non‐smoking patients, and the administration of EGFR‐TKIs might improve clinical outcomes in NSCLC patients with LM.

Nociceptin Receptor Is Overexpressed in Non-small Cell Lung Cancer and Predicts Poor Prognosis.

Classic opioid receptors, mu (μ), delta (δ), and kappa (κ), have been reported to be expressed in non-small cell lung cancer (NSCLC) cell lines and tumor tissues and to play a role in tumor prognosis. However, the expression and role of the non-classic opioid receptor, nociceptin receptor (NOP) in cancer are unclear. Our hypothesis was that NOP was also highly expressed in NSCLC tumor tissues and this could be correlated with patients' prognostic characters. Expression of NOP was examined in archived cancer tissues from 129 enrolled NSCLC patients by immunohistochemistry and was further analyzed with the patients' outcomes. NOP expression in NSCLC cell lines was also detected. The dataset from Kaplan-Meier Plotter was used to explore the correlation between the levels of NOP mRNA in cancerous tissue and the prognosis of NSCLC patients. Cell functional assays were performed to detect the effect of NOP activation on tumor aggressive furthers. Results showed NOP expression was highly expressed in cancer tissues and human cancer cell lines. NOP expression was not associated with patients' opioid requirement but closely with some clinicopathological indicators which reflected the malignancy. Moreover, NOP staining level was the independent poor prognostic factor for NSCLC patients receiving lobectomy, which was further verified by determining the mRNA expression levels through the online dataset. In vitro experiments revealed that NOP activation promotes the proliferation and invasion of A549 cells via PI3K/Akt signaling pathway. We conclude that NOP is overexpressed in NSCLC and is inversely correlated with patient's postoperative survival.

CHAF1B promotes proliferation and reduces apoptosis in 95‑D lung cancer cells and predicts a poor prognosis in non‑small cell lung cancer.

Chromatin assembly factor 1 subunit B (CHAF1B) participates in DNA synthesis and repair. High CHAF1B expression has been associated with a poor prognosis in several types of cancers. However, no study has evaluated the clinical significance and biological function of CHAF1B in non‑small cell lung cancer (NSCLC). In the present study, we aimed to investigate CHAF1B expression and its role in NSCLC. In the present study, it was revealed that CHAF1B was highly expressed in NSCLC lung tissues and 95‑D cells. Kaplan‑Meier survival analysis indicated that high CHAF1B expression in tumour tissue was associated with poor clinical outcomes in NSCLC patients. Multivariate Cox analyses revealed that lymph node metastasis, tumour‑node‑metastasis (TNM) stage and CHAF1B expression were independent prognostic factors in NSCLC patients. Moreover, CHAF1B knockdown in 95‑D cells markedly inhibited tumour proliferation, reduced colony formation, induced cell cycle arrest and promoted apoptosis. In vivo studies demonstrated that CHAF1B knockdown inhibited the growth of transplanted tumours. Furthermore, our results revealed that the mechanism by which CHAF1B induced apoptosis was mediated by the activation of the p53‑dependent apoptotic signalling pathway (BAK/Bcl‑2/caspase‑3) in 95‑D cells. These data indicated that CHAF1B plays an important role in tumourigenesis and may be a therapeutic molecular target to counter NSCLC progression.