Survival Of Small Cell Lung Cancer Patients Research Articles

Correlation of Systemic Inflammation Parameters and Serum SLFN11 in Small Cell Lung Cancer-A Prospective Pilot Study.

The objective of this research was to analyze the correlation of the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), soluble programmed cell death ligand 1 (sPD-L1), and Schlafen 11 (SLFN11) with the response to first-line chemotherapy in a cohort of small cell lung cancer (SCLC) patients, and to determine their potential as predictive serum biomarkers. A total of 60 SCLC patients were included. Blood samples were taken to determine CRP, sPD-L1, and SLFN11 levels. The first sampling was performed before the start of chemotherapy, the second after two cycles, and the third after four cycles of chemotherapy. The patients who died earlier during the study had NLR and SLFN11 concentrations significantly higher compared to the survivor group. In the group of survivors, after two cycles of chemotherapy, the NLR ratio decreased significantly (p < 0.01), but after four cycles, the NLR ratio increased (p < 0.05). Their serum SLFN11 concentration increased significantly (p < 0.001) after two cycles of chemotherapy, but after four cycles, the level of SLFN11 fell significantly (p < 0.01). CRP, NLR, and SLFN11 were significant predictors of patient survival according to Kaplan-Meier analysis. The combination of inflammatory parameters and SLFN11 with a cutoff value above the 75th percentile of the predicted probability was associated with significantly lower overall survival in SCLC patients (average survival of 3.6 months vs. 4.8 months). The combination of inflammatory markers and the levels of two specific proteins (sPD-L1, SLFN11) could potentially serve as a non-invasive biomarker for predicting responses to DNA-damaging therapeutic agents in SCLC.

FAK-LINC01089 negative regulatory loop controls chemoresistance and progression of small cell lung cancer.

The focal adhesion kinase (FAK) tyrosine kinase is activated and upregulated in multiple cancer types including small cell lung cancer (SCLC). However, FAK inhibitors have shown limited efficacy in clinical trials for cancer treatment. With the aim of identifying potential therapeutic strategies to inhibit FAK for cancer treatment, we investigated long non-coding RNAs (lncRNAs) that potentially regulate FAK in SCLC. In this study, we identified a long non-coding RNA LINC01089 that binds and inhibits FAK phosphorylation (activation). Expression analysis revealed that LINC01089 was downregulated in SCLC tissues and negatively correlated with chemoresistance and survival in SCLC patients. Functionally, LINC01089 inhibited chemoresistance and progression of SCLC in vitro and in vivo. Mechanistically, LINC01089 inhibits FAK activation by blocking binding with Src and talin kinases, while FAK negatively regulates LINC01089 transcription by activating the ERK signaling pathway to recruit the REST transcription factor. Furthermore, LINC01089-FAK axis mediates the expression of drug resist-related genes by modulating YBX1 phosphorylation, leading to drug resistance in SCLC. Intriguingly, the FAK-LINC01089 interaction depends on the co-occurrence of the novel FAK variant and the non-conserved region of LINC01089 in primates. In Conclusion, our results indicated that LINC01089 may serve as a novel high-efficiency FAK inhibitor and the FAK-LINC01089 axis represents a valuable prognostic biomarker and potential therapeutic target in SCLC.

Comorbidity in Small Cell Lung Cancer: Prognostic Impacts of Hypertension/Coronary Artery Disease, Diabetes Mellitus, and Chronic Obstructive Pulmonary Disease

Comorbidity, the most important components of which are hypertension/coronary artery disease (HTN/CAD), diabetes mellitus (DM), and chronic obstructive pulmonary disease (COPD), is frequently encountered in small cell lung cancer (SCLC) patients. We aimed to assess the possible impacts of these major comorbidities on the prognoses of SCLC patients. A total of 378 SCLC patients were analyzed retrospectively. We did not ascertain the effect of comorbidity on survival in SCLC patients in general; and similarly, the presence of HTN/CAD and COPD did not adversely affect the outcome. However, lower survival rates were observed in patients with SCLC coexisting with DM.

Prognostic value of pretreatment modified Glasgow Prognostic Score in small cell lung cancer: A meta-analysis.

The prognostic role of pretreatment modified Glasgow Prognostic Score (mGPS) in small cell lung cancer (SCLC) patients remains unclear now. The PubMed, EMBASE, Web of Science, and CNKI electronic databases were searched up to December 14, 2022. The primary and secondary outcomes were overall survival and progression-free survival, respectively. The hazard ratios (HRs) and 95% confidence intervals (CIs) were combined to assess the association between pretreatment mGPS and survival of SCLC patients. Subgroup analysis based on the country, tumor stage, treatment and comparison of mGPS were further conducted and all statistical analyses were performed by STATA 15.0 software. A total of ten retrospective studies involving 2831 SCLC patients were included. The pooled results demonstrated that elevated pretreatment mGPS was significantly related to poorer overall survival (HR = 1.90, 95% CI: 1.36-2.63, P < .001) and progression-free survival (HR = 1.40, 95% CI: 1.13-1.74, P = .002). Subgroup analysis stratified by the country, tumor stage, treatment and comparison of mGPS also showed similar results. Pretreatment mGPS was significantly associated with prognosis in SCLC and patients with elevated mGPS experienced obviously worse survival. Thus, pretreatment mGPS could serve as a novel and reliable prognostic indicator in SCLC patients.

A 15-Gene-Based Risk Signature for Predicting Overall Survival in SCLC Patients Who Have Undergone Surgical Resection.

Small cell lung cancer (SCLC) is a malignancy with a poor prognosis whose treatment has not progressed for decades. The survival benefit of surgery and the selection of surgical candidates are still controversial in SCLC. This study is the first report to identify transcriptomic alterations associated with prognosis and propose a gene expression-based risk signature that can be used to predict overall survival (OS) in SCLC patients who have undergone potentially curative surgery. An integrative transcriptome analysis of three gene expression datasets (GSE30219, GSE43346, and GSE149507) revealed 1734 up-regulated and 2907 down-regulated genes. Cox-Mantel test, Cox regression, and Lasso regression analyses were used to identify genes to be included in the risk signature. EGAD00001001244 and GSE60052-cohorts were used for internal and external validation, respectively. Overall survival was significantly poorer in patients with high-risk scores compared to the low-risk group. The discriminatory performance of the risk signature was superior to other parameters. Multivariate analysis showed that the risk signature has the potential to be an independent predictor of prognosis. The prognostic genes were enriched in pathways including regulation of transcription, cell cycle, cell metabolism, and angiogenesis. Determining the roles of the identified prognostic genes in the pathogenesis of SCLC may contribute to the development of new treatment strategies. The risk signature needs to be validated in a larger cohort of patients to test its usefulness in clinical decision-making.

Construction, validation, and visualization of a web-based nomogram to predict overall survival in small-cell lung cancer patients with brain metastasis.

Brain metastasis (BM) is an aggressive complication with an extremely poor prognosis in patients with small-cell lung cancer (SCLC). A well-constructed prognostic model could help in providing timely survival consultation or optimizing treatments. We analyzed clinical data from SCLC patients between 2000 and 2018 based on the Surveillance, Epidemiology, and End Results (SEER) database. We identified significant prognostic factors and integrated them using a multivariable Cox regression approach. Internal validation of the model was performed through a bootstrap resampling procedure. Model performance was evaluated based on the area under the curve (AUC) and calibration curve. A total of 2,454 SCLC patients' clinical data was collected from the database. It was determined that seven clinical parameters were associated with prognosis in SCLC patients with BM. A satisfactory level of discrimination was achieved by the predictive model, with 6-, 12-, and 18-month AUC values of 0.726, 0.707, and 0.737 in the training cohort; and 0.759, 0.742, and 0.744 in the validation cohort. As measured by survival rate probabilities, the calibration curve agreed well with actual observations. Furthermore, prognostic scores were found to significantly alter the survival curves of different risk groups. We then deployed the prognostic model onto a website server so that users can access it easily. In this study, a nomogram and a web-based predictor were developed to predict overall survival in SCLC patients with BM. It may assist physicians in making informed clinical decisions and determining the best treatment plan for each patient.

Prolonged exposure of environmental concentration benzo[a]pyrene promoted cancer stemness through AhR/PKA/SOX2 dependent pathway in small cell lung cancer

Benzo[a]pyrene (BaP) is commonly found in the environment as a result of incomplete combustion of organic materials and cigarette smoke. Epidemiological studies have consistently suggested that elderly smokers are at higher risk for small cell lung cancer (SCLC), with risks and clinical stages increasing with the intensity and duration of smoking. However, the underlying mechanism remains insufficiently investigated. Here, we established a positive correlation between smoking and BaP metabolite 3-hydroxybenzo[a]pyrene (3OH-BaP) in urine. The pooled standardized mean difference of urinary 3OH-BaP concentration for smokers versus nonsmokers was 5.18 (95 % CI 2.86–7.50). Clinical data suggested that smoking led to more lymph node metastasis, higher pathological N-stage, and worse overall survival in SCLC patients. We identified 75 genes that participate in BaP-associated cancer stemness of SCLC from Comparative Toxicogenomics Database and validated the expression of these candidate genes in SCLC patient samples. Protein kinase cAMP-activated catalytic subunit alpha (PRKACA) was found to be most upregulated in SCLC patients and in vitro experiments indicated that long-term exposure of SCLC cells to BaP, at the concentration equivalent to those detected in blood, increased PKA protein level. Further investigation revealed that PKA could directly interact with SOX2 and protect SOX2 from COP1-mediated ubiquitination and degradation. Upregulated SOX2 then contributed to the stemness and metastasis of SCLC cells while inhibition of aryl hydrocarbon receptor (AhR) signaling pathway abolished BaP induced PKA expression and downstream PKA/SOX2 axis. Our findings firstly pinpoint BaP exposure as a high-risk factor for SCLC and worse outcomes in patients, with the underlying mechanism being the activation of cancer stemness of SCLC via the AhR/PKA/SOX2 axis.

Longitudinal detection of subcategorized CD44v6+ CTCs and circulating tumor endothelial cells (CTECs) enables novel clinical stratification and improves prognostic prediction of small cell lung cancer: A prospective, multi-center study

Current management of small cell lung cancer (SCLC) remains challenging. Effective biomarkers are needed to subdivide patients presenting distinct treatment response and clinical outcomes. An understanding of heterogeneous phenotypes of aneuploid CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells (CTECs) may provide novel insights in the clinical management of SCLC. In the present translational and prospective study, increased cancer metastasis-related cell proliferation and motility, accompanied with up-regulated mesenchymal marker vimentin but down-regulated epithelial marker E-cadherin, were observed in both lentivirus infected SCLC and NSCLC cells overexpressing the stemness marker CD44v6. Aneuploid CTCs and CTECs expressing CD44v6 were longitudinally detected by SE-iFISH in 120 SCLC patients. Positive detection of baseline CD44v6+ CTCs and CD44v6+ CTECs was significantly associated with enhanced hepatic metastasis. Karyotype analysis revealed that chromosome 8 (Chr8) in CD44v6+ CTCs shifted from trisomy 8 towards multiploidy in post-therapeutic patients compared to pre-treatment subjects. Furthermore, the burden of baseline CD44v6+ CTCs (t0) or amid the therapy (t1-2), the ratio of baseline CD31+ CTEC/CD31- CTC (t0), and CTC-WBC clusters (t0) were correlated with treatment response and distant metastases, particularly brain metastasis, in subjects with limited disease (LD-SCLC) but not in those with extensive disease (ED-SCLC). Multivariate survival analysis validated that longitudinally detected CD44v6+/CD31- CTCs was an independent prognostic factor for inferior survival in SCLC patients. Our study provides evidence for the first time that comprehensive analyses of CTCs, CTECs, and their respective CD44v6+ subtypes enable clinical stratification and improve prognostic prediction of SCLC, particularly for potentially curable LD-SCLC.

Prognostic significance of Memorial Sloan-Kettering prognostic score in small-cell lung cancer patients.

Aim: To assess the potential factors with predictive value for survival in small-cell lung cancer (SCLC) patients and to develop a nomogram prediction model. Patients & methods: We retrospectively screened and analyzed patients with pathologically confirmed SCLC from April 2015 to December 2021. Results: A total of 167 patients with SCLC were included. According to the Memorial Sloan-Kettering prognostic score (MPS), patients were divided into three groups: group 0 (n=65), group 1 (n=69) and group 2 (n=33). The multivariate analysis showed that MPS was an independent prognostic factor for progression-free and overall survival in SCLC patients (p<0.05). The nomogram showed that MPS was the most influential factor for overall survival. Conclusion: MPS is an independent prognostic factor for overall and progression-free survival in SCLC patients and performed better than other indicators used in this study.

Biomarqueurs des carcinomes pulmonaires à petites cellules en 2022

AbstractConversely of non-small cell lung cancer, the small cell lung cancer (SCLC) made little profit since last twenty years from discoveries of molecules based notably of genomic alteration, in order to develop new therapeutic targets. Recent data, based on the expression of dominant transcriptional signatures, then on methylome studies, permitted classification of SCLCs into four biologically distinct subtypes, namely, SCLC-A, SCLC-N, SCLC-P, and SCLC-I. This molecular characterization led to new classification of these cancers. The different subtypes can be identified on variable immunohistochemical profiles thanks to the use of anti-ASCL1, NEUROD1, POU2F3 and YAP1 antibodies. These histo-molecular subtypes are associated with a predictive potential for emerging and promising therapies, including PARP inhibitors, immune checkpoint inhibitors, and DLL3 therapies. In this context, an immunohistochemistry analysis combining the four antibodies cited above, plus anti-DLL3 and anti-SLFN11 antibodies might be soon necessary in clinical practice. The new findings offer a glimmer of hope for patients and open room for increasing the quality of life as well as the over all survival of SCLC patients in the near future.

Clinical impact of number of lymph nodes dissected on postoperative survival in node-negative small cell lung cancer.

Small cell lung cancer (SCLC) is a lethal histologic subtype of lung cancer. Although the Commission on Cancer recommends pathological examination of at least 10 lymph nodes dissected (LNDs) for resected early-stage non-small cell lung cancer, its survival benefit of LNDs in patients with early-stage SCLC is unknown. The National Cancer Database was queried for SCLC patients with clinical stage I-II and clinical N0, NX disease per AJCC 7th edition who had undergone lobectomy between 2004 and 2017. Overall survival of SCLC patients by the number of LNDs was compared using Log-rank tests. Univariate and multivariable Cox proportional hazards analyses were performed. In total, 688 (42%), 311 (20%), 247 (16%), 196 (12%), 126 (8%), and 36 (2%) of 1,584 patients with early-stage SCLC had ≥10, 7-9, 5-6, 3-4, 1-2, and 0 LNDs, respectively. The sequential improvement in the HRs was no longer evident if the number of LNDs exceeds 4. Patients with ≥3 LNDs (n = 1,422) had a significantly longer overall survival than those with <3 LNDs (n = 162) (hazard ratio for death: 0.76, 95% confidence interval: 0.62-0.94, P = 0.0087). Multivariate analysis revealed that ≥3 LNDs was an independent factor for predicting overall survival (hazard ratio for death: 0.76, 95% confidence interval: 0.61-0.93, P = 0.0083). Although we are reluctant to recommend a definitive "optimal number" of LNDs, our findings suggest the prognostic and therapeutic roles for performing ≥3 LNDs in patients with early-stage SCLC who undergo lobectomy.

Neither the presence nor the severity of hyponatremia affected the outcome of the patients with small cell lung cancer.

Hyponatremia is the most common electrolyte disorder in lung cancer, and it particularly occurs in small cell lung cancer (SCLC) patients. The prognostic significance of hyponatremia has been reported in several studies with controversial results. We aimed in this study to investigate hyponatremia and evaluate its prognostic value in SCLC patients. The data of 373 SCLC patients were analyzed retrospectively. Serum sodium concentrations were measured from blood samples taken from all patients before treatment. Hyponatremia was defined as a serum sodium concentration below 135mmol/L and then assigned into two groups: mild (130 to 134mmol/L) and severe (below ≤ 129mmol/L) hyponatremia. Hyponatremia was detected in 85 (22.8%) patients (mild hyponatremia in 51 (13.7%) and severe hyponatremia in 34 (9.1%) patients). Furthermore, 26% (63 of 242) of ED-SCLC patients and 16.8% (22 of 131) of LD-SCLC patients had hyponatremia. While no clinical parameter was statistically associated with serum sodium concentrations in LD-SCLC patients, hyponatremic ED-SCLC patients were more frequently associated with weight loss (p = 0.04) and liver metastasis (p = 0.04). In LD-SCLC, the overall survival (OS) rates of patients with hyponatremia were similar to those with normonatremia (p = 0.6). Likewise, hyponatremic and normonatremic ED-SCLC patients had similar life expectancies (p = 0.1). Moreover, the severity of hyponatremia did not affect OS in either LD-SCLC (p = 0.3) or ED-SCLC (p = 0.1). Serum sodium concentration did not have an impact on survival in SCLC patients; thus, we concluded that neither the presence nor the severity of hyponatremia affected the outcome of these patients.

CCL5 as a Prognostic Marker for Survival and an Indicator for Immune Checkpoint Therapies in Small Cell Lung Cancer.

The standard treatment for small cell lung cancer (SCLC) has not changed in decades. Recently, important advances have been made in immunotherapy. However, analysis of these trials suggests that only a small proportion of patients benefit from immune checkpoint blockade (ICB). Identifying these patients is a clinical challenge. In this study, we applied the ESTIMATE calculation to calculate immune scores in 159 cases of SCLC from two published cohorts. COX regression analysis was used to analyze the differentially expressed genes (DEGs) with high and low immune score. We found that CCL5 expression was positively correlated with survival in SCLC patients. In addition, we verified the effect of CCL5 on survival and response to treatment in another cohort that received immunotherapy. Meanwhile, Gene set enrichment analysis (GSEA) showed that genes with high expression of CCL5 were mainly enriched in immune-related activities. The result of Tumor Immune Dysfunction and Exclusion (TIDE) demonstrated that CCL5 was a potential biomarker to predict response to ICB for SCLC, which is correspondent with the result in verified cohort. These results suggest that CCL5 may be the reason for TME to maintain its immune dominance, making it a favorable factor for ICB. Therefore, CCL5 levels may help to outline the prognosis of patients with SCLC.

A new nomogram and risk classification system for predicting survival in small cell lung cancer patients diagnosed with brain metastasis: a large population-based study

BackgroundThe prognosis of patients with small cell lung cancer (SCLC) is poor, most of them are in the extensive stage at the time of diagnosis, and are prone to brain metastasis. In this study, we established a nomogram combined with some clinical parameters to predict the survival of SCLC patients with brain metastasis.MethodsThe 3522 eligible patients selected from the SEER database between 2010 and 2015 were randomly divided into training cohort and validation cohort. Univariate and multivariate Cox regression analysis were used to evaluate the ability of each parameter to predict OS. The regression coefficients obtained in multivariate analysis were visualized in the form of nomogram, thus a new nomogram and risk classification system were established. The calibration curves were used to verify the model. And ROC curves were used to evaluate the discrimination ability of the newly constructed nomogram. Survival curves were made by Kaplan-Meier method and compared by Log rank test.ResultsUnivariate and multivariate analysis showed that age, race, sex, T stage, N stage and marital status were independent prognostic factors and were included in the predictive model. The calibration curves showed that the predicted value of the 1- and 3-year survival rate by the nomogram was in good agreement with the actual observed value of the 1- and 3-year survival rate. And, the ROC curves implied the good discrimination ability of the predictive model. In addition, the results showed that in the total cohort, training cohort, and validation cohort, the prognosis of the low-risk group was better than that of the high-risk group.ConclusionsWe established a nomogram and a corresponding risk classification system to predict OS in SCLC patients with brain metastasis. This model could help clinicians make clinical decisions and stratify treatment for patients.

Small cell lung cancer: Real-world data from two institutions in Lebanon for patients receiving carboplatin etoposide or atezolizumab in first line of treatment.

e20578 Background: Small-cell lung cancer (SCLC), accounts for approximately 15% to 17% of all diagnosed lung cancers. It is an aggressive high-grade neuroendocrine carcinoma, diagnosed during advanced stages in the majority of patients. Despite the fact that first line treatment provides response rates of up to 80%, the majority of patients relapse within 6 months after completion of initial treatment. Few advances have been made in the management of recurrent disease and treatments patterns are poor and limited in each line of the disease. The aim of this study is to present real world data regards survival outcomes such as progression free survival and overall survival in SCLC patients receiving carboplatine etoposide or tecentriq carboplatin etoposide regimens as first line of treatment. Methods: This is a retrospective (descriptive) study on 56 patients aged ≥ 18 years and with confirmed histological SCLC. Patients with extensive stage of SCLC were enrolled in this cohort study from 2 health institutions in Lebanon from July 2007 to December 2019 and followed up until progression or death. Primary end points were overall survival (time from randomization to death from any cause) and progression free survival at 6 and 12 months (time from randomization to disease progression). Secondary endpoints included objective response rate and the duration of response. Exploratory analyses included the assessment of survival outcomes of each type of treatment according to liver and brain metastasis. Results: Overall, 56 SCLC patients, diagnosed between 2003 and 2019, were observed (age &lt;65: (27.0%, 10 patients); ≥65 (73.0%, 41 patients)). Most often prescribed treatment were etoposide-carboplatyl (80.8%, 42 patients) and atezolizumab (19.2%10 patients). Regarding metastasis at diagnosis, liver and brain metastasis were respectively (26.8%, 11 patients) and (17.1%, 7 patients). 27patients (71.1%) were alive at 6 months without progressive disease and 13 patients (34.21 %) alive at 12 months without PD. Median progression free survival incidence since diagnosis was 8.8 months. Overall survival was 10.86 months. Objective response rate after first line was 84.2%. In a cox regression analysis, liver metastasis, brain metastasis, survival at 6 or 12 months without progressive disease did not decrease significantly PFS or OS since diagnosis. Conclusions: To our knowledge, this is the first real world clinical data on SCLC in Lebanon. This study showed limited treatment options and short survival outcomes with PFS= 8.8months and OS= 10.86 months respectively for carboplatin etoposide regimen and tecentriq carboplatin etoposide regimen. There is an essential needs for clinical comparative studies in real world practicing between treatments at each line, specially for novel treatment like atezolizumab that may present new hope and directions for SCLC.

Prognostic significance of serum osteopontin levels in small cell lung cancer

BackgroundOsteopontin (OPN) is closely related to tumor occurrence and metastasis. This study explored the clinical value of serum OPN levels in small cell lung cancer (SCLC) patients.MethodsThe ELISA method was used to determine the OPN level of 96 SCLC patients before and after first-line chemotherapy, and compared with 60 healthy controls.ResultsThe serum OPN level of SCLC patients before treatment was significantly higher than that of the healthy control (P < 0.001). Serum OPN levels were related to disease stage, tumor size, and lymph node metastasis (P = 0.012, 0.034, and 0.037, respectively). Serum OPN level decreased after first-line chemotherapy (P = 0.019), which was related to treatment response (P = 0.011). The serum OPN level was an independent predictor of overall survival.ConclusionsThe serum OPN level can be used as a biomarker to predict treatment response and survival of SCLC patients.

NOVA1 expression is associated with clinicopathological characteristics and prognosis in patients with small cell lung cancer.

BackgroundSmall cell lung cancer (SCLC) is a highly aggressive lung malignancy which is characteristic of rapid tumor proliferation, metastasis as well as paraneoplastic neurological syndromes (PNS). Recent studies have shown that neuro-oncological ventral antigen-1 (NOVA1) plays a crucial role in the progression of various tumors. However, its effect on SCLC is still exclusive. This study was aimed to explore NOVA1 expression in tumor tissues of SCLC patients as well as its correlation with clinicopathological characteristics and cancer-specific overall survivals.MethodsIn this study, the patients pathologically diagnosed with new primary SCLC were enrolled. Firstly, we compared NOVA1 expression in SCLC tissues and adjacent normal tissues by immunohistochemistry. We further investigated the association of NOVA1 expression with clinicopathological markers (especially the categories of PNS) and survival time in SCLC patients.ResultsOur finding exhibited that NOVA1 was remarkably expressed in SCLC tumorous tissues compared with adjacent normal lung tissues (P<0.001). Additionally, NOVA1 expression was closely associated with clinicopathological characteristics in SCLC patients in terms of tumor staging(χ2=15.833; P<0.001), lymph node metastasis (χ2=9.624; P=0.002), brain metastasis (χ2=9.624; P=0.002) and PNS (χ2=5.004; P=0.024). With the COX proportional hazard regression model, we detected that high expression of NOVA1 (HR =0.445; 95% CI: 0.213–0.934; P=0.032) was an independent factor for shorter survival time.ConclusionsHigh expression of NOVA1 is closely associated with aggressive clinicopathological characteristics including PNS as well as poor survival in SCLC patients. NOVA1 can be served as a promising predictive factor for prognosis in SCLC.

Linc00173 promotes chemoresistance and progression of small cell lung cancer by sponging miR-218 to regulate Etk expression.

The functional effects of long noncoding RNAs (lncRNAs) in cancer have been widely recognized. However, there is little research on SCLC-related lncRNAs. Here, long intergenic nonprotein coding RNA 173 (Linc00173) was first shown to be involved in chemoresistance and progression of small-cell lung cancer (SCLC). We found that Linc00173 was highly expressed in SCLC chemoresistant cell lines, and promoted SCLC cells chemoresistance, proliferation, and migration-invasion. Animal studies validated that Linc00173 induced tumor chemoresistance and growth of SCLC in vivo. Moreover, Linc00173 upregulated Etk through functioning as a competitive endogenous RNA (ceRNA) by "sponging" miRNA-218 and led to the upregulation of GSKIP and NDRG1, resulting in the translocation of β-catenin. Importantly, expression analysis revealed that both Linc00173 and Etk were upregulated in SCLC patient samples and exhibiting positive Linc00173/Etk correlation. High expression of Linc00173 closely correlated with chemoresistance, extensive stage, and shorter survival in SCLC patients. Collectively, our study illustrated a Linc00173-mediated process that facilitated chemoresistance and progression in SCLC, which might provide treatment strategy against SCLC.

Abstract 4029: Analysis of DLL3 and ASCL1 in surgically resected small cell lung cancer (HOT1702)

Abstract Background:Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC and has shown improved clinical response in patients with high DLL3 expression. DLL3 is a transcriptional target of the achaete-scute homolog-1(ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. Materials and Methods:We collected 95 formalin-fixed and paraffin-embedded SCLC samples, which were surgically resected at 11 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Immunohistochemistrystaining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. Results:Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥ 1% of tumor cells), and DLL3-high expression (≥ 75%) was observed in 44 samples (47%). Sixty-one (64%) of 95 samples were positive for ASCL1 (expression in ≥ 5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 and ASCL1 were more prevalent in patients with advanced clinical disease and pure SCLC, respectively. Conclusion:DLL3 and ASCL1 were highly expressed in surgically resected SCLC patients. Citation Format: Megumi Furuta, Jun Sakakibara-Konishi, Hajime Kikuchi, Hiroshi Yokouchi, Hiroshi Nishihara, Hiroyuki Minemura, Masao Harada, Shigeo Yamazaki, Kenji Akie, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Masaharu Nishimura, Hirotoshi Dosaka-Akita, Hiroshi Isobe. Analysis of DLL3 and ASCL1 in surgically resected small cell lung cancer (HOT1702) [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 4029.

KRAS Exon 3 and PTEN Exon 7 Mutations in Small-cell Lung Cancer.

Small cell lung cancer (SCLC) is recognized as one of the most aggressive and fatal malignant tumors. No significant improvement has been made to prolong the survival of SCLC patients. This study aimed to examine the mutation status of K-Ras (KRAS) and phosphatase and tensin homolog (PTEN) in SCLC patients in order to identify potential therapeutic targets for SCLC. Nineteen primary SCLC tumor specimens were enrolled in the study. Direct sequencing was performed to detect the mutations of KRAS exon 3 and PTEN exon 7 in the specimens. Kaplan- Meier and Cox regression analysis was performed to determine the overall survival (OS) of these SCLC patients. KRAS exon 3 mutation was found in 4 (21%) SCLC patients, and PTEN exon 7 mutation in only 1 (5%) SCLC patient. Kaplan Meier analysis showed that clinical stage and brain metastasis were significantly associated with OS (both P<0.05), but neither KRAS exon 3 mutation nor PTEN exon 7 mutation was significantly associated with OS (P>0.05). Cox proportional hazards regression model indicated that extensive stage of disease was the only independent negative prognostic factor for OS in SCLC patients. In conclusion, KRAS exon 3 and PTEN exon 7 mutations had no significant impact on OS of SCLC patients. Further study is still necessary to validate the molecular profiles of SCLC.