Survival Of Small Cell Lung Cancer Patients Research Articles

DLL3 is regulated by LIN28B and miR-518d-5p and regulates cell proliferation, migration and chemotherapy response in advanced small cell lung cancer

Delta-like protein 3 (DLL3) has been reported as a biomarker in various human tumors. However, the biological function and mechanism of it in advanced small cell lung cancer (SCLC) is rarely reported. This study was devised innovatively to explore the role of DLL3 in the progression of SCLC. Immunohistochemistry (IHC) analysis was used to examine DLL3 expression in paraffin-embedded SCLC tumor samples. Upregulation of DLL3 reduced chemotherapy sensitivity. Kaplan-Meier analysis was used to analyze the progression-free survival or overall survival of SCLC patients with high or low level of DLL3. The negative association between DLL3 expression and the PFS or OS rate of SCLC patients was identified. Relative high level of DLL3 was determined in SCLC cell lines by using qRT-PCR analysis. Loss-of function assays were performed to detect the biological functions of the silencing of DLL3 in SCLC. As a result, silencing of DLL3 led to the proliferative and migratory inhibition of SCLC cells and reversed EMT process. Mechanistically, DLL3 mRNA was stabilized by the RNA-binding protein lin-28 homolog B (LIN28B). Further mechanism investigation revealed that LIN28B and DLL3 are two downstream targets of miR-518d-5p. Finally, rescue assays demonstrated that LIN28B and miR-518d-5p could regulate DLL3-mediated cell proliferation and migration. Collectively, our present study revealed a novel molecular pathway in SCLC, which providing a new insight in exploring the therapeutic strategy for SCLC.

Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702).

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. 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. We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. 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 was more prevalent in patients with advanced clinical disease. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. This article examines the relationship between delta-like protein 3 (DLL3) and achaete-scute homolog-1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early-stage SCLC, including with Rova-T.

SBF2-AS1: An oncogenic lncRNA in small-cell lung cancer.

The long noncoding RNAs (lncRNAs) SBF2 antisense RNA 1 (SBF2-AS1) was found to act as an oncogenic lncRNA in non-small-cell lung cancer (NSCLC), but the role of SBF2-AS1 in small-cell lung cancer (SCLC) was still unclear. The purpose of this study was to provide the clinical significance and biological function of SBF2-AS1 in SCLC. In our results, SBF2-AS1 was found to be upregulated in SCLC tissues compared with NSCLC tissues or adjacent normal lung tissues. Besides, SBF2-AS1 expression was also elevated in SCLC cell lines compared with the normal bronchial epithelial cell line or NSCLC lines. Moreover, high expression of SBF2-AS1 was associated with clinical stage, tumor size, lymph node metastasis and distant metastasis in SCLC patients. Survival analysis showed SCLC patients with high expression of SBF2-AS1 had shorter overall survival than patients with low expression of SBF2-AS1, and high expression of SBF2-AS1 acted as an independent poor prognostic factor for overall survival in SCLC patients. The study in vitro suggested inhibition of SBF2-AS1 obviously depressed cell proliferation, migration, and invasion in SCLC. In conclusion, SBF2-AS1 acts as a novel oncogenic lncRNA in SCLC.

Prognostic significance of serum soluble DR5 levels in small-cell lung cancer.

The death receptor 5 (DR5) is a member of the tumor necrosis factor receptor superfamily that can transduce the apoptosis signal in cells. This study assessed serum levels of soluble death receptor 5 (sDR5) in small-cell lung cancer (SCLC) patients compared with those in healthy controls. Clinicopathological features of patients, treatment responses, and overall survival of patients were also recorded and analyzed. The sDR5 levels were analyzed using ELISA in 50 healthy controls and 82 SCLC patients before and after first-line chemotherapy. The statistical data showed that pre-treatment levels of serum sDR5 in SCLC patients were higher than those of healthy controls (P<0.001). Pre-treatment levels of serum sDR5 were significantly associated with smoking history of patients, Veterans Administration Lung Study Group (VALSG) stage, tumor size, and lymph node (N) metastasis (P=0.028, 0.001, 0.028, and 0.01, respectively). After treatment with the first-line chemotherapy, the post-treatment levels of serum sDR5 were obviously decreased (P<0.001), and correlated with treatment responses (P<0.001), although there was no significant difference in their pretreatment sDR5 levels (P=0.62). Cox proportional hazard analysis demonstrated that the post-treatment levels of serum sDR5, VALSG stage, and PS status were all independent predictors for overall survival of patients. The results from the current study indicate that serum level of sDR5 could be further confirmed as a biomarker to predict treatment responses and survival of SCLC patients.

Additional radiation boost to whole brain radiation therapy may improve the survival of patients with brain metastases in small cell lung cancer

BackgroundThe role of the dose escalation strategy in brain radiotherapy for small cell lung cancer (SCLC) patients with brain metastases (BMs) has not been identified. This study aims to determine whether an additional radiation boost to whole brain radiation therapy (WBRT) has beneficial effects on overall survival (OS) compared with WBRT-alone.MethodsA total of 82 SCLC patients who were found to have BMs treated with WBRT plus a radiation boost (n = 33) or WBRT-alone (n = 49) from January 2008 to December 2015 were retrospectively analyzed. All patients were limited-stage (LS) SCLC at the time of the initial diagnosis, and none of them had extracranial metastases prior to detection of BMs. The primary end point was OS.ResultsThe median OS for all of the patients was 9.6 months and the 6-, 12- and 24-months OS rates were 69.1, 42.2 and 12.8%, respectively. At baseline, the proportion of more than 3 BMs was significantly higher in the WBRT group than in the WBRT plus boost group (p = 0.0001). WBRT plus a radiation boost was significantly associated with improved OS in these patients when compared with WBRT-alone (13.4 vs. 8.5 months; p = 0.004). Further, the survival benefit still remained significant in WBRT plus boost group among patients with 1 to 3 BMs (13.4 vs. 9.6 months; p = 0.022).ConclusionCompared with WBRT-alone, the use of WBRT plus a radiation boost may prolong survival in SCLC patients with BMs. The dose escalation strategy in brain radiotherapy for selected BMs patients with SCLC should be considered.

Genetic profiling-based prognostic prediction of patients with advanced small-cell lung cancer in large scale analysis

ObjectivesComprehensive genomic analysis of small-cell lung cancer (SCLC) revealed various genetic alterations. However, obtaining suitable samples for genetic analysis is difficult in advanced SCLC. Thus, the prognostic effect of genetic alterations on the outcome of SCLC patients has not been well investigated. Therefore, this study evaluated the effect of genetic alterations on the survival of SCLC patients. Materials and methodsWe collected samples obtained from 220 patients with advanced SCLC before cancer treatment. Genomic DNA extracted from the samples was subjected to a 1.499 Mb-sized custom panel that captured all exons of 244 cancer-related genes, and the captured DNA was analyzed through next-generation sequencing. The associations between genetic alterations and overall survival were evaluated. ResultsGenetic analysis was successful in 204 samples (93%). Genetic alterations in the PI3K/AKT/mTOR pathway and inactivating mutations inTP53 and RB1 were detected in 14 (7%), 150 (74%), and 85 (42%) of the tumors. In extensive disease (ED, N = 126) patients, multivariate analysis revealed that the presence of genetic alterations in the PI3K/AKT/mTOR pathway was significantly associated with unfavorable survival [hazard ratio (HR), 2.14; 95% CI 1.02–4.06; P = 0.04]. In limited disease (LD, N = 78) patients, the presence of TP53 mutation and the absence of RB1 mutation were significantly associated with unfavorable survival (HR, 2.41; 95% CI 1.21–5.34; P = 0.01, and HR, 0.45; 95% CI 0.25–0.79; P < 0.01, respectively). ConclusionsSequencing-based genetic profiling is feasible and useful to predict the prognosis in advanced SCLC. Genetic alterations in the PI3K/AKT/mTOR pathway, TP53 mutations and RB1 mutations were associated with prognosis in SCLC patients. The genetic alterations associated with the prognosis were different between ED-SCLC and LD-SCLC.

Preliminary Study of Clinical Role of Circulating Tumor Cells in Patients with Small-Cell Lung Cancer Treated By Prophylactic Cranial Irradiation

Prophylactic cranial irradiation (PCI) decreases the rate of brain metastases, and improves the overall survival (OS) of small-cell lung cancer (SCLC). However, the improvement of OS is uncertain under the era of MRI. The circulating tumor cells (CTCs) play a vital role in recurrence, prognosis, efficacy evaluation, and individualized therapy of cancer patients. Our aims to investigate the preliminary clinical value of CTCs in SCLC patients treated by PCI. In this prospective study comparing two different thoracic radiotherapy regimens, SCLC patients received chemo-radiotherapy and subsequent PCI after brain metastases were excluded by MRI screening. The blood samples for CTCs analysis were obtained from 20 SCLC patients before and after PCI. Instead of the CellSearch system, CTCs were assessed with a new detection method based on telomerase-specific, replication-selective oncolytic herpes simplex virus-1 that targets telomerase reverse transcriptase-positive cancer cells and expresses a green fluorescent protein that identifies CTCs (oHSV1-hTERT-GFP), with high sensitivity and specificity in lung cancer patients. The endpoints were progression-free survival (PFS) and OS. Eleven patients were limited-stage SCLC, and 9 were extensive-stage SCLC. The CTCs detection rate was 100%. The follow-up time was 39.2 months for the whole group. Seven patients failed with distant metastases. The median CTCs count were 12 (range, 1-43) before PCI, and 4 (range, 0-34) after PCI. Logistic regression showed the CTCs count was not associated with the clinical parameters. Patients with ≥12 CTCs before PCI tended to show worse PFS and OS than those with <12 CTCs (31.8 months vs not reached, p = 0.084; not reached vs not reached, p = 0.457). Six in 12 patients with ≥12 CTCs failed, but only 1 relapsed in 8 patients with <12 CTCs before PCI. PFS and OS were significantly different in patients with ≥4 CTCs after PCI and those with <4 CTCs (28.1 months vs not reached, p = 0.001; not reached vs not reached, p = 0.029). All 10 patients were alive without disease in the group with <4 CTCs, however, 7 relapsed in 10 patients with ≥4 CTCs after PCI. Significantly better PFS and OS were found in 10 patients with the reduction rate of more than 58% than other 10 patients with less than 58% (not reached vs 26.4 months, p = 0.006; not reached vs not reached, p = 0.029). CTCs counts after PCI and CTCs reduction rate are valuable prognostic markers of better survival of SCLC patients. Patients with the high CTCs reduction rate could benefit from PCI. However, the prognostic significance of CTCs needs to be evaluated in large-scale clinical trials.

Clinical value of carcinoembryonic antigen for predicting the incidence of brain metastases and survival in small cell lung cancer patients treated with prophylactic cranial irradiation.

BackgroundAlthough the role of prophylactic cranial irradiation (PCI) in the treatment of small cell lung cancer (SCLC) has been confirmed, the occurrence of brain metastases (BM) in patients remains a major problem. We designed this study to evaluate the clinical value of carcinoembryonic antigen (CEA) for predicting the incidence of BM and survival in SCLC patients who received PCI.Materials and methodsThe records of 128 consecutive SCLC patients, who underwent PCI in our institute between 2005 and 2015, were analyzed. The collected data included clinicopathological features and the levels of CEA, neuron-specific enolase (NSE), cytokeratin 19 fragments (CYFRA21-1), and albumin. Kaplan–Meier and Cox regression analyses were used to determine the factors that affect BM and survival in SCLC patients after PCI.ResultsIn total, 128 patients were identified, with a median (range) age of 62 (30–83) years. Thirty-two patients developed BM at some time during follow-up. The median levels of CEA, NSE, CYFRA21-1, and albumin were 7.6 ng/mL, 44 ng/mL, 4.6 ng/mL, and 42.1 g/L, respectively. In the multivariate analysis, CEA level (HR: 2.479, 95% CI: 1.101–5.581; P=0.028), advanced clinical stage (HR: 2.929, 95% CI: 1.338–6.413; P=0.007), and NSE level (HR: 3.021, 95% CI: 1.226–7.442; P=0.016) were significantly correlated with BM. CEA (HR: 1.903, 95% CI: 1.133–3.195; P=0.015) and advanced clinical stage (HR: 2.002, 95% CI: 1.227–3.267; P=0.005) were independently associated with worse overall survival in SCLC patients.ConclusionCEA is an independent predictive factor for the incidence of BM after PCI in SCLC and can be used as a predictor of BM in SCLC. In addition, a high level of CEA indicates a poor prognosis in SCLC patients after PCI. Prospective randomized clinical studies are required to confirm these findings.

Circulating endothelial cells and microparticles as diagnostic and prognostic biomarkers in small-cell lung cancer

ObjectivesIt has been proposed that circulating endothelial cells (CECs) and microparticles (MPs) may be useful for the assessment of patients with non-small-cell lung cancer (NSCLC). However, little is known about the potential clinical relevance of these biomarkers in small-cell lung cancer (SCLC). Therefore, we investigated the utility of baseline levels of CECs and MPs in SCLC patients. Materials and methodsAn immunomagnetic separation (IMS) technique was used to isolate and quantify CECs in the peripheral blood, while plasma samples were analyzed using flow cytometry for the measurement of circulating MPs. ResultsWe prospectively collected data from 56 patients and 41 healthy individuals. Forty-three patients presented at initial diagnosis and 13 patients presented at relapse. Baseline levels of CECs and MPs were significantly higher in SCLC patients either at initial diagnosis or at relapse than in healthy subjects (p < 0.0002 and p < 0.007, respectively). However, estimated tumor volume (ETV) was significantly correlated with basal MP values (p < 0.0001) but not with pretreatment CECs (p = 0.57). The amount of baseline CECs and MPs was significantly lower in patients with an objective response (OR, n = 23) than in those with progressive disease (PD, n = 15) after treatment (p = 0.016 and 0.05, respectively). With cut-off values of 110 cells/mL for CECs and 1257 events/μL for MPs according to receiver operating characteristics (ROC) analysis, baseline levels of these biomarkers were not significantly correlated with either progression-free survival (PFS) or overall survival (OS). However, patients with 6-month PFS displayed significantly decreased pretreatment CEC counts (p = 0.042), whereas basal MP values significantly increased in 1-year survivors compared with those in non-survivors (p = 0.05). ConclusionOur results suggest that baseline CECs and MPs may be predictive biomarkers of tumor response and long-term survival in SCLC patients.

Functional role of CyclinD1 polymorphism (G870A) in modifying susceptibility and overall survival of North Indian lung cancer patients.

The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

Functional Role of CyclinD1 Polymorphism (G870A) in Modifying Susceptibility and Overall Survival of North Indian Lung Cancer Patients.

Purpose The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. Methods The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. Results The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). Conclusions Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

Usage of Prophylactic Cranial Irradiation in Elderly Patients With Small-cell Lung Cancer

BackgroundProphylactic cranial irradiation (PCI) reduces the risk of overt brain metastases in patients with small-cell lung cancer (SCLC) and is currently recommended in guidelines for both limited and extensive disease. Given the concerns about the greater frequency of neurologic side effects in elderly patients, we studied the association among age, PCI usage, and survival for SCLC patients in the Netherlands. Patients and MethodsData from the Netherlands Cancer Registry for patients diagnosed with SCLC from 2009 to 2013 were queried. Separate analyses were performed for patients with stage I to III, treated with chemoradiotherapy (n = 1684) and patients with stage IV, treated with chemotherapy or chemoradiotherapy (n = 3481). Patients with brain metastasis at diagnosis were excluded. ResultsFor patients with stage I to III, the overall PCI usage rate was 74%, and the rate decreased with age, from 78% for patients aged 18 to 59 years to 66% for patients aged ≥ 80 years. For patients with stage IV, the overall PCI usage rate was 41% and decreased with age, from 46% for patients aged 18 to 59 years to 23% for patients aged ≥ 80 years. Gender and socioeconomic status did not affect the PCI rates. For patients aged < 70 years and treated with PCI, the median survival was 45, 24, and 12 months for stage I and II, III, and IV, respectively. For patients aged ≥ 70 years treated with PCI, the corresponding survival duration was 33, 17, and 10 months. ConclusionIn the Dutch population, PCI usage rates were fairly high but were significantly lower for elderly patients.

Neuron-specific enolase and response to initial therapy are important prognostic factors in patients with small cell lung cancer.

The prognostic factors for the survival of small cell lung cancer (SCLC) patients are still widely debated. The aim of this study was to identify the clinical features and prognostic factors in SCLC patients. A retrospective study was conducted on SCLC patients who were treated in our hospital between July 2010 and July 2015. Comparison of overall survival (OS) was performed using the Kaplan-Meier method. Prognostic factors for OS were identified by multivariate Cox regression models. A total of 523 patients with complete data and ECOG 0-2 were enrolled in our study. A total of 383 patients (73.2%) were diagnosed with ES-SCLC (extensive-stage SCLC) and 140 patients (26.8%) were diagnosed with LS-SCLC (limited-stage SCLC). In all patients, early disease stage, good ECOG, normal neuron-specific enolase (NSE), thoracic radiotherapy, ≥4 cycles of chemotherapy, prophylactic cranial irradiation, good response to initial therapy were independent favorable prognostic factors for OS, along with gender, age, CEA and CA125. In LS-SCLC patients, normal NSE, normal CEA, good response to initial therapy and surgery were independent favorable prognostic factors for OS. In ES-SCLC patients, good ECOG, normal NSE, thoracic radiotherapy, ≥4 cycles of chemotherapy, prophylactic cranial irradiation and good response to initial therapy were independent favorable prognostic factors for OS. Remarkably, NSE and response to initial therapy were independent prognostic factors for OS in all SCLC patients, LS-SCLC patients and ES-SCLC patients. The normal NSE and good response to initial therapy predicted a better survival for SCLC patients, regardless of disease stage.

P1.07-040 Prognostic Factors in Extensive Disease (ED) Small Cell Lung Cancer (SCLC): An ELCWP Phase III Randomized Trial

Main prognostic factors for survival in SCLC patients are performance status, disease extent, age or gender, as previously reported by the European Lung Cancer Working Party (ELCWP) (Paesmans et al, Eur Respir J 2011). Based on a previous meta-analysis (Mascaux et al, Lung Cancer 2000) showing a survival advantage for regimens including cisplatin (CDDP) or etoposide (VP16), the ELCWP designed a phase III trial to determine if addition of CDDP to VP16 would improve survival in comparison with VP16 combination without CDDP in a population of ED SCLC. The aim of this work was to search for prognostic factors for survival. Untreated patients with ED (limited (LD) not amenable to radiotherapy or stage IV disease) SCLC, Karnofsky performance status (PS) ≥60, adequate hematological, hepatic, renal and cardiac functions, were centrally randomized to receive either CDDP-VP16 (CE) or ifosfamide-VP16-epirubicin (IVE). According to statistical considerations, 315 deaths had to occur before analysis. Univariate and multivariate tests were performed for prognostic factors analyses. 346 eligible patients were randomized (176 in CE and 170 in IVE arms) between 2000 and 2013. At the time of analysis, 329 deaths occurred. No statistically significant imbalance was observed regarding age, gender, PS, disease extent (LD vs stage IV), neutrophil count and weight loss. No statistically significant difference was observed between CE and IVE groups according to main evaluation criteria: best response rate (60% vs 59%, p=0.88), progression-free survival (median 5.1 vs 5.3 months; p=1) and overall survival times with medians of 9.6 months and 10 months and 2-year rates of 5 % and 9 % (p=0.16), respectively. The following variables were statistically significantly associated with survival in univariate analysis: age (continuous evaluation) (HR=1.02, p=0.002), gender (male as reference) (HR=0.69, p=0.008), PS (PS ≤ 70 as reference) (HR=0.60, p=0.0001), weight loss (≤5% as reference) (HR=1.28, p=0.05) and neutrophil count (≤7500/mm3 as reference) (HR=1.46, p=0.003). In addition, variables with a p-value < 0.2 in univariate analysis were also included in the multivariate analysis: disease extent (LD as reference) (HR=1.38, p=0.10), WBC count (≤10000/mm3 as reference) (HR=1.23, p=0.08) and treatment arm (CE as reference) (HR=0.84, p=0.16). Two variables retained their statistical significance in multivariate analysis: gender (HR=0.69, 95% CI 049-0.97; p=0.03) and PS (HR=0.53, 95% CI 0.49-0.97; p<0.0001). Adding CDDP to VP16 failed improving survival in ED SCLC. In this population, gender and performance status confirmed their prognostic value for survival.

RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR.

Small cell lung cancer (SCLC) is an aggressive cancer that represents ~15% of all lung cancers. Currently there are no targeted therapies to treat SCLC. Our genomic analysis of a metastatic SCLC cohort identified recurrent RICTOR amplification. Here, we examine the translational potential of this observation. RICTOR was the most frequently amplified gene observed (~14% patients), and co-amplified with FGF10 and IL7R on chromosome 5p13. RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells. In parallel, cells with RICTOR copy number (CN) gain showed increased sensitivity to three mTOR inhibitors, AZD8055, AZD2014 and INK128 in cell growth assays, with AZD2014 demonstrating the best inhibition of downstream signaling. SCLC cells with RICTOR CN gain also migrated more rapidly in chemotaxis and scratch wound assays and were again more sensitive to mTOR inhibitors. The overall survival in SCLC patients with RICTOR amplification was significantly decreased (p = 0.021). Taken together, our results suggest that SCLC patients with RICTOR amplification may constitute a clinically important subgroup because of their potential response to mTORC1/2 inhibitors.

EPHA3 regulates the multidrug resistance of small cell lung cancer via the PI3K/BMX/STAT3 signaling pathway.

Multidrug resistance (MDR) is a major obstacle to the treatment of small cell lung cancer (SCLC). EPHA3 has been revealed to be the most frequently mutated Eph receptor gene in lung cancer with abnormal expression. Growing evidence indicates that the signaling proteins of EPHA3 downstream, including PI3K, BMX and STAT3, play crucial roles in tumorigenesis and cancer progression. To explore the possible role of EPHA3 in MDR, we assessed the influence of EPHA3 on chemoresistance, cell cycle, apoptosis, and tumor growth, as well as the relationship between EPHA3 and the expression of PI3K, BMX, and STAT3 in SCLC. We observed that overexpression of EPHA3 in SCLC cells decreased chemoresistance by increasing apoptosis and inducing G0/G1 arrest, accompanied by reduced phosphorylation of PI3K/BMX/STAT3 signaling pathway. Knockdown of EPHA3 expression generated a resistant phenotype of SCLC, as a result of decreased apoptosis and induced G2/M phase arrest. And re-expression of EPHA3 in these cells reversed the resistant phenotype. Meanwhile, increased phosphorylation of PI3K/BMX/STAT3 signaling pathway was observed in these cells with EPHA3 deficiency. Notably, both PI3K inhibitor (LY294002) and BMX inhibitor (LFM-A13) impaired the chemoresistance enhanced by EPHA3 deficiency in SCLC cell lines. Furthermore, EPHA3 inhibited growth of SCLC cells in vivo and was correlated with longer overall survival of SCLC patients. Thus, we first provide the evidences that EPHA3 is involved in regulating the MDR of SCLC via PI3K/BMX/STAT3 signaling and may be a new therapeutic target in SCLC.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-016-5048-4) contains supplementary material, which is available to authorized users.

Prophylactic cranial irradiation for patients with small-cell lung cancer: a systematic review of the literature with meta-analysis.

BackgroundSmall cell lung cancer (SCLC) accounts for about 13% of all lung cancer cases. Small cell lung cancer (SCLC) accounts for about 13% of all lung cancer cases. The purpose of the present article is to assess the role of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) by performing a systematic review of the randomized trials published in the literature.MethodsRandomized controlled trials were identified that compared brain metastases incidence and overall survival between PCI and No PCI in patients with SCLC. Search strategies were limited to the English language and to articles published since 1997, and included: databases searched from 1997 to March 2013 –CINAHL, Embase, Medline, Web of Science, and CENTRAL. Methodological quality was assessed with the Jadad scale. The main end points were brain metastasis and survival.ResultsThe review identified 5 trials, although few were of high quality. Two trials reported the one-year incidence of brain metastasis. PCI reduced the incidence of brain metastasis in one year, with a pooled relative risk of 0.45 (95% CI, 0.35 to 0.58; P < 0.00001). Four trials described the one year survival rate. The combined result revealed a significant (P = 0.01) survival benefit in the group assigned to PCI as compared with the control group, with a pooled relative risk of 0.87 (95% CI, 0.79 to 0.97). Three trials reported the three-year survival rate. The combined result revealed a great significant (P < 0.00001) survival benefit in the PCI group as compared with the No PCI group, with a pooled relative risk of 0.87 (95% CI, 0.83 to 0.91). the Five-year survival rate was compared in four trials Compared with the No PCI group, the PCI group had a significant (P < 0.00001) survival benefit with a pooled relative risk of 0.92 (95% CI, 0.88 to 0.95).ConclusionsThe present systematic review indicates that PCI decreases brain metastases incidence and that PCI improves survival in SCLC patients. Prophylactic cranial irradiation should be part of standard care for all patients with small-cell lung cancer who have a response to initial chemotherapy, and it should be part of the standard treatment in future studies involving these patients.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-793) contains supplementary material, which is available to authorized users.

The prognostic significance of the circulating neuroendocrine markers chromogranin A, pro-gastrin-releasing peptide, and neuron-specific enolase in patients with small-cell lung cancer

Lung cancer is the most common cancer, and small-cell lung cancer (SCLC) accounts for around 20% of lung cancers. SCLC has a neuroendocrine cellular origin, and the tumor cells usually express neuroendocrine markers. There have been major recent advances in the management of SCLC, and multimodal approaches are now the norm. An improved knowledge of the prognostic variables would assist in defining which patients were better candidates to receive these newer intensive therapies. This single-center retrospective study of 97 previously untreated and histologically proven SCLC patients analysed the circulating neuroendocrine markers chromogranin A (CGA), pro-gastrin-releasing peptide (ProGRP), and neuron-specific enolase (NSE) in addition to the other more classical variables. Fifty patients had limited-stage disease and 47 had extensive disease. Sixty patients had an ECOG performance status (PS) of 0-1 and 37 had PS 2-4. Median survival for the whole study population was 13months. Univariate analysis and univariate Cox regression modeling found a statistically significant association between survival and PS, disease stage, and CGA, ProGRP, and NSE levels. Age and sex were not prognostic. A shorter survival time was found in patients with a PS equal to or >2, extensive stage disease, a serum CGA level >56ng/ml, a serum ProGRP level >58pg/ml, and a serum NSE level >19ng/ml. This study has found that there is a potential role for ProGRP, NSE, and CGA in both staging and prognosing survival in SCLC patients.

Prognostic value of chemotherapy-induced leukopenia in small-cell lung cancer.

ObjectiveChemotherapy is the standard treatment for small-cell lung cancer (SCLC), and leukopenia is a common side effect. This study assesses whether chemotherapy-induced leukopenia is a predictor of efficacy and whether it is associated with the survival of SCLC patients.MethodsA retrospective analysis was conducted on data from 445 patients with SCLC who received standard chemotherapy for 4 to 10 cycles. The World Health Organization grading system classifies leukopenia during chemotherapy as follows: absent (grade 0), mild (grades 1 and 2), or severe (grades 3 and 4). The primary endpoint is overall survival (OS).ResultsThe association between chemotherapy-induced leukopenia and OS was assessed. According to a multivariate Cox model with time-varying covariates, the hazard ratio of death was significantly lower among patients with mild leukopenia than among patients with severe leukopenia at 0.687 (0.506 to 0.943) and 1.414 (1.147 to 1.744), respectively. The median survival was 13 months (95% CI: 11 to 15 months) for patients who did not experience leukopenia, 17 months (95% CI: 14 to 18 months) for those with mild leukopenia, and 14 months (95% CI: 13 to 16 months) for those with severe leukopenia (absent vs. mild vs. severe leukopenia, P=0.047).ConclusionLeukopenia during chemotherapy is associated with the survival of SCLC patients. Mild leukopenia is strongly associated with longer survival time.

Abstract 3257: Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor, PF-4989216.

Abstract Aberrant PI3K/AKT signaling occurs commonly in cancer. Gene mutation, amplification, and copy number gains in the catalytic p110α of PI3K have been shown in a variety of human cancers. Tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates the 3-phosphoinositides and is frequently mutated, deleted, or down-regulated in many human cancers to constitutively activate the PI3K pathway. Small cell lung cancer (SCLC) patients have poor prognosis; response to second-line chemotherapy for patients with refractory disease is less than 10%, and survival is 3-4 months. Multiple phase III trials have been conducted, however the survival of SCLC patients has not significantly improved over the years. In this study, we characterized a selective PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway may be a potential therapy for SCLC. PF-4989216 inhibits phosphorylation of PI3K downstream molecules and subsequently leads to induction in apoptosis and cell cycle block, as well as inhibition of cell proliferation, transformation, and xenograft tumor growth in SCLCs harboring a PIK3CA mutation. Moreover, our results suggest that there may be different mechanisms of tumorigenesis between PIK3CA mutation and PTEN loss in SCLCs, and indicate that PF-4989216 is a potential cancer drug candidate for small-cell lung cancer patients harboring a PIK3CA mutation. Citation Format: Marlena Walls, Sangita M. Baxi, Pramod P. Mehta, Elizabeth Epps, Heather Estrella, Kevin KC Liu, JinJiang Zhu, Chunze Li, Tod Smeal, Min-Jean Yin. Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor, PF-4989216. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3257. doi:10.1158/1538-7445.AM2013-3257