Primary Lung Cancer Patients Research Articles

EP1.03-34 Single Center Epidemiological Prevalence Study of Molecular Mutation in Bangladeshi Patients with Advanced Stage Non-Small Cell Lung Cancer

In a private tertiary hospital of Bangladesh about 2953 patients have been diagnosed as primary cancer patient of which 17% (510) patients were primary lung cancer patients, 77% of which were in advanced (stage III and IV). The study was performed to investigate the molecular mutations and prevalence of EGRF, T-790M, ROS-1, and ALK mutations in Bangladeshi patients with advanced stage non-small cell lung cancer (NSCLC), as per available local molecular lab facilities. This study was retrospective and single center, conducted in 35 patients representing the 77% advanced stage lung cancer patients aged 20 years or above with NSCLC in the outpatient department The Bangladesh Specialized Hospital Ltd. (BSHL) within the timeframe of March 2016 – March 2019 recommended for molecular mutation study. Data were collected from the electronic prescription from hospital imformation system. EGFR, T-790M, ROS-1, and ALK frequency were calculated. The tests were done by tissue sample or Liquid biopsy when tissue sample was unavailable. The tests were carried out by Real Time PCR. The frequency of molecular mutation diagnosis was compared between the number of patients advised for molecular mutation study and number of patients who performed the investigation. Of 35 patients 63% (22) were male and 37% (13) were female, median age 61 (range 45-86) and 65% (23) test carried out with Liquid Biopsy. 25.7% (9) patients were found to be EGFR positive, and 74.3% (26) were EGFR negative; also, out of 16 patients recommended for T790M study only 6.3% (1) was positive. ROS positive was found in 40% (14), and 48.6% (17) were negative. ALK screening showed to be positive in 37.1% (13) and negative in 45.7% (16). Among the 392 patients, only 9% performed the study, due to low availability of moleculer diagnosis which was started in Bangladesh since the early July 2017. The frequency of molecular testing may not reflect the international studies due to methods applied for the testing and also with the gender frequency as high predominance of male patients. With this limited data we have seen that the prevalence of ROS-1 (40%) mutation was higher than ALK (37.1%) and EGFR (25.7 %). Due to financial constrain and limited access to tests only 9% patients performed the study, though, molecular tests are recommended most oftenly. Due to time being a limiting factor for the sample size further studies can be performed on a larger scale.

Development and validation of a novel diagnostic model for assessing lung cancer metastasis in a Chinese population based on multicenter real-world data.

BackgroundAccurate disease staging plays an important role in lung cancer's clinical management. However, due to the limitation of the CT scan, it is still an unmet medical need in practice. In the present study, we attempted to develop diagnostic models based on biomarkers and clinical parameters for assessing lung cancer metastasis.MethodsThis study consisted of 799 patients with pulmonary lesions from three regional centers in China. It included 274 benign lesions patients, 326 primary lung cancer patients without metastasis, and 199 advanced lung cancer patients with lymph node or organ metastasis. The patients were divided into nodules group and masses group according to tumor size.ResultsFour nomogram models based on patient characteristics and tumor biomarkers were developed and evaluated for patients with nodules and masses, respectively. In patients with pulmonary nodules, the AUC to identify metastatic lung cancer from unidentified nodules (including benign nodules and lung cancer, model 1) reached 0.859 (0.827–0.887, 95% CI). Model 2 was used to predict metastasis in patients with lung cancer with AUC of 0.838 (0.795–0.876, 95% CI). In patients with pulmonary masses, the AUC to identify metastatic lung cancer from unidentified masses (model 3) reached 0.773 (0.717–0.823, 95% CI). Model 4 was used to predict metastasis in patients with lung cancer and AUC reached 0.731 (0.771–0.793, 95% CI). Decision curve analysis corroborated good clinical applicability of the nomograms in predicting metastasis.ConclusionAll new models demonstrated promising discrimination, allowing for estimating the risk of lymph node or organ metastasis of lung cancer. Such integration of blood biomarker testing with CT imaging results will be an efficient and effective approach to benefit the accurate staging and treatment of lung cancer.

EP1.18-15 Surgical Results of Primary Mucoepidermoid Carcinoma of Lungs: A 9 Years' Experience

Pulmonary mucoepidermoid carcinoma is a rare salivary-gland type lung cancer and accounts for 0.1%–0.2% of all primary lung malignancies. The optimal treatment of pulmonary mucoepidermoid carcinoma is not well determined. The aim of this study was to examine the surgical outcomes for the pulmonary mucoepidermoid carcinoma in our institution. From January 2010 to December 2018, we performed a retrospective review including all patients with primary pulmonary mucoepidermoid carcinoma of lung who underwent pulmonary resections in our institutions. The patients’demographic, clinical, and survival data were analyzed. A total of 3124 primary lung cancer patients underwent surgical resections by the same surgical team during the 8-year study period. 8 cases (0.25%) patients who were diagnosed with primary mucoepidermoid carcinoma of the lung were analyzed in this study. The patients’ characteristics are shown in Table 1. The median age of all patients was 57 year-old (range: 22-75 year-old). Cough is the most common symptom (5 cases, 62.5%). 7 cases had a low-grade tumor, and all the cases were completely resected thoracoscopically. Two cases were resected by wedge resection because peripherally located, and two cases required bronchial reconstruction. There was no adverse effect after the operation. One case recived adjuvent chemotherapy due to nodal invasion. However, this case had disease progression with patella bone metastasis 5 months after opeartion. The other cases were free of malignancy with a median follow-up of 27.2 months. Complete surgical resection of a mucoepidermoid carcinoma of lungs can be atributed to a long-term survival in patients. For an elederly patient with a peripherally located tumor, wedge rsection with mediastinal lymphnode dissection could be an alternative treatment.

Stereotactic body radiotherapy for primary non-small cell lung cancer patients with clinical T3-4N0M0 (UICC 8th edition): outcomes and patterns of failure.

The evidence for stereotactic body radiotherapy (SBRT) is meagre for patients with clinical T3-4N0M0 non-small cell lung cancer (8th Edition of the Union for International Cancer Control (UICC)). This study retrospectively investigated clinical outcomes following SBRT for such patients. Among consecutive patients treated with SBRT, patients staged as cT3-4N0M0 by all criteria were examined, most of whom were unsuitable to chemoradiotherapy due to their fragile characters. Clinical outcomes were evaluated and factors associated with outcomes were investigated. Between 2005 and 2017, 70 eligible patients (T3: 58, T4: 12; median age 81 (63–93) years) were identified. Median follow-up duration was 28.6 (1.0–142.5) months. No adjuvant chemotherapy was administered. The 3-year local recurrence rates were 15.8% and 16.7% in T3 and T4 patients, respectively, and they were significantly lower in the high-dose group (3.1% vs 28.6%, P < 0.01). Multivariate analyses showed that the dose-volumetric factor was the significant factor for local recurrence. The 3-year regional and distant metastasis rates, cancer-specific mortality, and overall survival in T3 and T4 patients were 22.7% and 25.0%, 26.5% and 33.3%, 32.2% and 41.7%, and 39.5% and 41.7%, respectively. Only age was correlated with overall survival. Radiation pneumonitis ≥grade 3 and fatal hemoptysis occurred in 3 and 1 patients, respectively. SBRT for cT3-4N0M0 lung cancer patients achieved good local control. Survival was rather good considering that patients were usually frail, staged with clinical staging, and were not given adjuvant chemotherapy, and it may be comparable to surgery. To validate these outcomes following SBRT, a prospective study is warranted.

Abstract LB-238: Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients

Abstract Early detection and intervention are crucial for long-term survival of either primary or recurrent lung cancer patients. Circulating tumor cells (CTCs) could be powerful biomarkers for the diagnosis, prognosis, and treatment planning of cancer. In this work we applied our FAST cytometer, a fiber-optic array scanning technology (FAST) to develop a sensitive diagnostic blood tests (“liquid biopsies”) for NSCLC. This technology is based on the ultra-rapid, sensitive and accurate detection of rare circulating cells expressing the biomarker(s) of interest. By applying the FAST cytometer with a unique NSCLC specific cocktail, we were able to detect CTC in NSCLC setting with higher sensitivity as compared with traditional cytokeratin-based detection. In a pilot cohort of 51 NSCLS patients, we have detected CTC in 74.2% using our unique panel for NSCLC CTC, this has raised our sensitivity from 48.8% using traditional cytokeratin-based detection. In addition, we have also interrogated circulating cancer associated fibroblasts (cCAF) as an additional liquid biopsy marker for NSCLC. We detected cCAF in 67% NSCLC patients. When combined with our enhanced CTC detection method, addition of cCAF further increased our sensitivity to 88.5%. Moreover, using clinically validated PD-L1 antibody (Ventana SP263) as reference, we have demonstrated our capacity to analyze PD-L1 expression on CTC at protein level, we have shown detection of PD-L1+ CTC in 80% of the patients. To summarize, we have developed an unique panel to detect CTC with higher sensitivity using combinational detection and we have demonstrated that by combining CTC detection with cCAF detection, liquid biopsy sensitivity for cancer detection can be further increased without significant increase in false positive rates. Lastly, we developed a method to analyze the PD-L1 expression on CTC using clinically validated Ventana PD-L1 (SP263) rabbit monoclonal antibody as reference which can potentially serve as a companion diagnostics tool for NSCLC immunotherapy Citation Format: Xiaohe Liu, Zheng Ao, Jordan S. Preiss, Joel Neal, Lisa Ya Zhou, Lidia Sambucetti, Heather A. Wakelee. Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients [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 LB-238.

Analysis of the clinical characteristics of 8 081 primary lung cancer

Objective: To characterize the clinical epidemiological features of primary lung cancer patients based on massive clinical data. Methods: The demographic and histological information of 8 081 primary lung cancer patients who were initially identified from 1 January 2012 to 31 December 2013 in 16 hospitals from 6 provinces were retrospectively analyzed to determine the characteristics of different histological subtypes among different gender, age-group and birth cohort. Results: Among the 8 081 lung cancer patients, 5 422 (67.10%) were male and 2 659 (32.90%) were female, the average age was (60.96±10.14) years. The most common histological subtypes of lung cancer successively were adenocarcinoma (ADC), squamous cell carcinoma (SCC), small cell carcinoma and large cell carcinoma, and the proportions of these subtypes were 53.13%, 24.51%, 14.59% and 0.66%, respectively, which collectively accounted for 92.89%. The current highest smoking rate was observed in SCC patients, which was 62.45%, while lowest in ADC, which was 29.68%. The incidence of lung cancer in male was significantly higher that that of female, with a sex ratio of 2.04∶1. The highest sex ratio was observed in SCC, which was 9.14∶1, while lowest in ADC, which was 1.14∶1. The distribution of histological subtypes in male lung cancer patients was consistent with the general situation.While among the female lung cancer patients, the proportion of ADC was the highest (75.42%), followed by SCC (10.08%), squamous cell carcinoma (7.34%) and large cell carcinoma (0.39%). Analyzed by the birth cohort, the proportion of ADC gradually increased with the age, while the reduced tendency was observed in SCC (P<0.000 1). Conclusion: Adenocarcinoma is the most important histological subtype of lung cancer, and the distribution characteristics of histological subtypes of lung cancer differs among genders, age and birth cohort.

Genome-wide DNA methylation and RNA expression profiles identified RIPK3 as a differentially methylated gene in Chlamydia pneumoniae infection lung carcinoma patients in China.

Aim: To explore the relationship between Chlamydia pneumonia (Cpn) infection and lung cancer using integrative methylome and transcriptome analyses.Methods: Twelve primary lung cancer patients who were positive for Cpn and twelve patients who were negative were selected for demographic, clinicopathological, and lifestyle matching. Genomic DNA and RNA were extracted and DNA methylation and mRNA levels were detected using the Infinium Human Methylation 450 Beadchip array and mRNA + lncRNA Human Gene Expression Microarray. We identified differentially expressed methylation and genes profiles.Results: Integrative analysis revealed an inverse correlation between differentially expressed genes and DNA methylation. Cpn-related lung cancer methylated genes (target genes) were introduced into the gene ontology and KEGG, PID, BioCarta, Reactome, BioCyc and PANTHER enrichment analyses using a q-value cutoff of 0.05 to identify potentially functional methylation of abnormal genes associated with Cpn infection. Gene sets enrichment analysis was evaluated according to MsigDB. Levels of differentially expressed methylated sites were quantitatively verified. The promoter methylation sites of 62 genes were inversely related to expression levels. According to the quantitative analysis of DNA methylation, the methylation level of the RIPK3 promoter region was significantly different between Cpn-positive cancerous and adjacent tissues, but not between Cpn-negative cancerous and adjacent tissues.Conclusion: Hypomethylation of the RIPK3 promoter region increases RIPK3 expression, leading to regulated programmed necrosis and activation of NF-κB transcription factors, which may contribute to the development and progression of Cpn-related lung cancer.

Mortality of lung cancer as a second primary malignancy: A population-based cohort study.

Lung cancer as a second primary malignancy (lung‐2) is increasingly common, but its prognosis is poorly understood. This study aims to examine the overall and cancer‐specific survival of patients diagnosed with lung‐2 compared to lung‐1. Primary lung cancer patients diagnosed from 1988 to 2014 in the Surveillance, Epidemiology, and End Results (SEER) program were included. Lung‐2 was identified in patients with a previous diagnosis of nonlung primary malignancy in SEER. Hazard ratios (HRs) of overall and lung cancer‐specific mortality were estimated among patients with lung‐2 compared to lung‐1, adjusting for age and calendar period at diagnosis, sex, race, socioeconomic status, tumor stage, histology, tumor grade, and treatment. A total of 679 541 and 85 758 patients were identified as lung‐1 and lung‐2, respectively. Compared to lung‐1, patients with lung‐2 were more likely to be diagnosed at localized stage, with smaller primary tumor, and treated with surgery. Lung‐2 patients were at lower risk of lung cancer‐specific mortality in the first 5 years (HR, 0.77; 95% CI, 0.76‐0.78 at <1 year; HR, 0.87; 95% CI, 0.86‐0.89 from 1 to <5 years) but at higher risk thereafter (HR, 1.32; 95% CI, 1.27‐1.37 from 5 to 10 years), independent of tumor characteristics and cancer treatment. Similar pattern was found for overall mortality, although the survival benefit was restricted to the first year after diagnosis. Patients diagnosed with lung‐2 face a favorable lung cancer‐specific survival within the early period after diagnosis. A conservative approach to manage lung‐2 solely based on malignancy history is not supported.

Maximum standardized uptake value at pre-treatment PET in estimating lung cancer progression after stereotactic body radiotherapy.

PurposeThis study aimed to identify the feasibility of the maximum standardized uptake value (SUVmax) on baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) as a predictive factor for prognosis in early stage primary lung cancer treated with stereotactic body radiotherapy (SBRT).Materials and MethodsTwenty-seven T1-3N0M0 primary lung cancer patients treated with curative SBRT between 2010 and 2018 were retrospectively evaluated. Four patients (14.8%) treated with SBRT to address residual tumor after wedge resection and one patient (3.7%) with local recurrence after resection were included. The SUVmax at baseline PET/CT was assessed to determine its relationship with prognosis after SBRT. Patients were divided into two groups based on maximum SUVmax on pre-treatment FDG PET/CT, estimated by receiver operating characteristic curve.ResultsThe median follow-up period was 17.7 months (range, 2.3 to 60.0 months). The actuarial 2-year local control, progressionfree survival (PFS), and overall survival were 80.4%, 66.0%, and 78.2%, respectively. With regard to failure patterns, 5 patients exhibited local failure (in-field failure, 18.5%), 1 (3.7%) experienced regional nodal relapse, and other 2 (7.4%) developed distant failure. SUVmax was significantly correlated with progression (p = 0.08, optimal cut-off point SUVmax > 5.1). PFS was significantly influenced by pretreatment SUVmax (SUVmax > 5.1 vs. SUVmax ≤ 5.1; p = 0.012) and T stage (T1 vs. T2-3; p = 0.012).ConclusionSUVmax at pre-treatment FDG PET/CT demonstrated a predictive value for PFS after SBRT for lung cancer.

Second Primary Non–Small-Cell Lung Cancer After Head and Neck Cancer: A Population-Based Study of Clinical and Pathologic Characteristics and Survival Outcomes in 3597 Patients

IntroductionRetrospective studies have shown an increased risk of second primary lung cancer in patients with a history of head and neck cancer (HNC). No population-based study has examined the overall survival (OS) outcomes of patients with second primary non–small-cell lung cancer (NSCLC) after HNC comparison with patients with first primary NSCLC. Patients and MethodsIndividuals with histologically confirmed NSCLC diagnosed after nonmetastatic squamous-cell carcinoma of the head and neck (HNC-NSCLC; n = 3597) were identified in Surveillance, Epidemiology, and End Results 18 registries (1988-2013). OS and baseline characteristics were compared in patients with first primary NSCLC (NSCLC-1; n = 365,551) in the same registries. ResultsSquamous NSCLC was more common in HNC-NSCLC (n = 745 [64.1%] localized, n = 833 [71.9%] regional, and n = 811 [63.5%] distant) than in the NSCLC-1 (n = 30,901 [38.3%] localized, n = 50,557 [48.2%] regional, and n = 53,720 [29.8%] distant; P < .001). The leading cause of death in HNC-NSCLC was NSCLC (n = 2183; 60.6%), and median OS after localized, regional, and distant NSCLC diagnosis was 2.50 years, 1.17 years, and 5 months, respectively. For NSCLC-1, median OS was 4.58 years, 1.58 years, and 6 months, respectively. These differences were significant (P < .001). In multivariable analysis, a history of HNC remained associated with worse OS for localized (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.29-1.51; P < .001), regional (HR, 1.26; 95% CI, 1.19-1.35; P < .001) and distant (HR, 1.11; 95% CI, 1.04-1.18; P < .01) stage NSCLC. ConclusionA history of HNC adversely affects OS in patients who subsequently develop NSCLC. This OS decrement might have implications for NSCLC surveillance and NSCLC therapy selection in this population.

Antioxidant Protection System in the Saliva of Patients with Non-Small Cell Lung Cancer

The purpose of the study was to study parameters of the antioxidant protection system in saliva for non-small cell lung cancer. In the case-control study, included 683 volunteers, which were divided into 3 groups: primary (lung cancer patients, n = 290), comparison group (patients with nonmalignant pulmonary pathologies, n = 178) and control (conditionally healthy individuals, n = 215). Biochemical examination of saliva, histological verification of the diagnosis were carried out for all participants. The parameters of the antioxidant defense was determined spectrophotometrically. Intergroup differences were estimated by a nonparametric criterion. Saliva of lung cancer patients was characterized by imbalance in the antioxidant defense. It is shown that the activity of the enzymes of the first link of antioxidant protection (catalase, SOD) was significantly reduced (p ˂ 0.0001), whereas activity of salivary peroxidases increase (p = 0.0037). The parameters of non-enzymatic protection varied in opposite directions: the level of uric acid in lung pathologies decreases (p = 0.0399), whereas albumin concentration increased, under these conditions, it begins to exhibit prooxidant properties. Differences between adenocarcinoma and squamous cell lung cancer have been found in terms of the mode of the dynamics of antioxidant protection parameters. Probably, against the background of squamous cell lung cancer, an enzymatic link (catalase, SOD) contributes to the antioxidant protection system, whereas against adenocarcinoma - nonenzymatic (uric acid, albumin).

Bronchial Artery Embolization for Hemoptysis in Primary Lung Cancer: A Retrospective Review of 84 Patients

PurposeTo evaluate the safety and efficacy of bronchial artery embolization (BAE) in patients with primary lung cancer-related hemoptysis and to identify factors associated with hemoptysis-free survival. MethodsData from 84 patients with primary lung cancer (non-small cell [n = 74] and small cell [n = 10]) who underwent BAE from 1997 to 2018 for the management of hemoptysis were retrospectively reviewed. Of these, 53 patients had stage IV lung cancer. The hemoptysis volume prior to initial BAE was trivial (blood-tinged sputum) in 21 patients, moderate (< 300 mL per 24 hours) in 34 patients, and massive (> 300 mL per 24 hours) in 29 patients. ResultsTechnical success, defined as the ability to selectively embolize the abnormal vessel, was achieved in 83 patients (98.8%), and clinical success was achieved in 69 (82.1%) patients. Polyvinyl alcohol particles were used to embolize in 51 patients, gelfoam in 15 patients, and gelfoam plus microcoils in 17 patients. Hemoptysis recurred in 20 patients (23.8%) during follow-up. The median hemoptysis-free survival and overall survival periods were both 61 days. In the clinical-success and clinical-failure groups, the median overall survival period was 99 and 9 days, respectively (P < .001). In multivariable analysis, massive hemoptysis (P = .012) and cavitary lung mass (P = .019) were predictive factors for shortened hemoptysis-free survival. ConclusionsBAE is a safe and effective approach to control hemoptysis, although the prognosis in primary lung cancer patients presenting with hemoptysis is generally poor. Massive hemoptysis and cavitary lung mass are significant predictors of shortened hemoptysis-free survival.

Diagnosis status and pathological diagnosis derived treatment of elderly lung cancer patients over 75 years old

Background: The number of lung cancer in the elderly is increasing. However, a disturbing number of elderly patients failed to get pathological diagnosis and therapeutic outcomes are worse than the young. This study is conducted to explore the diagnosis and treatment status of lung cancer in patients over 75 years old. Methods: Patients diagnosed with lung cancer between September 1, 2010 and October 30, 2017 were continuously screened. The pathological diagnosis must be based on the cytology or histology diagnosis. The clinical diagnosis must be built on both typical imaging features and increased tumor markers. Clinical features and survival information were obtained and analyzed. Results: A total of 338 primary lung cancer inpatients were finally included with an age of 78.02±2.94 years. The most frequent comorbidities were hypertension, chronic obstructive pulmonary disease (COPD) and cardiovascular disease; 290 of all these patients were pathologically diagnosed while the other 48 patients only got a clinical diagnosis. Among the pathological diagnosis, adenocarcinoma, squamous carcinoma and small cell lung cancer counted for 91.72%. Epidermal growth factor receptor (EGFR) detection was performed in 126 patients and 41 of them were sensitive mutated. Among all included patients, 150 were treated by the best supportive treatment (BST). Anti-cancer treatment is significantly associated with better survival than BST (P Conclusions: Pathological diagnosis of lung cancer in elderly patients is relatively deficient. Pathologic and molecular pathological diagnosis derived anti-cancer treatment is effective in improving survival.

STEM-03. NOVEL METASTATIC BRAIN TUMOR TARGETS ISOLATED THROUGH PHAGE DISPLAY BIOPANNING AGAINST BRAIN METASTASIS-INITIATING CELLS

Despite treatment advances for primary cancers that may result in brain metastases, the treatment for brain metastases has lagged behind, partly due to the unique environment created by the central nervous system. Recent work has highlighted that metastatic brain tumors demonstrate significant genotypic deviation from their parental tumors, which highlights the need to focus on metastatic brain tumors for the development of more effective targeted therapeutics. The epithelial-mesenchymal transition suggests the existence of brain metastasis-initiating cells (BMICs), which may possess stem cell-like phenotypes that play a pivotal role in metastasis. To properly isolate this subpopulation of tumor cells, we compared patient derived metastatic brain tumor cells against brain metastasis cell lines. We found that both types of cells demonstrated similar morphology when grown in standard serum media conditions, but when grown in serum-free media, both demonstrated a tumor sphere morphology. Gene expression analysis showed increased expression of stem cell markers CD133 and EYA1 when grown in serum-free media. To isolate therapeutic targets specific to BMICs, we performed in vitro and in vivo phage display biopanning against BMICs. Analysis of the recovered peptides derived several potential targets. Among them were angiomotin (AMOT) and bromodomain testis-specific factor (BRDT). Gene expression analysis confirmed significant upregulation of these gene in metastatic brain tumors cells when compared to non-tumor neural cells and primary lung cancer cell lines. Tissue microarray analysis of eleven matched brain metastasis and primary lung cancer patient tissue from Moffitt Cancer Center demonstrated an increased expression in brain metastasis over primary lung tissue. Analysis through NIH GEO database demonstrated decreased survival with increased gene expression. Our results show that we can use phage display biopanning to isolate novel targets that may be specific to metastatic brain tumors by isolating the proper growth conditions that support the BMIC phenotype.

MA01.10 Toxicity and Local Control in “Ultra-Central” Lung Tumors Treated With SBRT or High-Dose Hypofractionated RT

Stereotactic body radiation therapy (SBRT) for , NYcentral lung tumors has been associated with higher rates of severe toxicity. Data suggests that tumors with specific high-risk features, namely GTV abutting proximal bronchial tree (PBT), trachea or PTV intersecting esophagus (“ultra-central” tumors), are at risk of severe complications. We sought to evaluate toxicity and efficacy for high-risk lung tumors treated with SBRT in our institution. All patients treated with SBRT for central lung tumors during 2008 to 2017 were reviewed to identify ultra-central tumors. Patients who received more than 4 Gy per fraction and BED10≥84 were included in the analysis. The primary endpoint was grade 3+ adverse events potentially attributable to RT, based on CTCAE 4.0. Secondary endpoints were local control (LC) and overall survival (OS) for primary lung cancer patients, Kaplan-Meier analysis was used to estimate LC and OS. We identified 88 patients who met the inclusion criteria (76 with abutment of PBT, 8 with abutment of trachea, 22 with overlap of esophagus, and 17 with multiple structures at risk). The median follow-up was 21.5 (95%CI, 12.5 to 30.5) months. Forty-six patients had primary NSCLC, 7 had locally recurrent NSCLC and 35 had lung metastases. The prescription doses were 400cGy x 15 (n=21), 750cGy x 8 (n=13), 1000cGy x 5 (n=29) and 900cGy x 5 (n=25). Eight patients (9.1%), all abutting the PBT, experienced fatal complications potentially related to RT. Four patients developed fatal pulmonary hemorrhage. Maximum point doses to PBT were 54.9Gy, 51.4Gy, 49.4Gy (in 5 fractions) and 63.8Gy (8 fractions) and 2 of them had received bevacizumab in close proximity to RT. Four patients developed fatal pneumonia/radiation pneumonitis (all had pre-existing COPD). No Grade 4 toxicity was identified. Grade 3 overall toxicity rate was 12.5%. Only 3 of 22 (13.6%) patients whose PTV overlapped with esophagus had Grade 3 toxicity. The 1-year and 2-year LC for the whole cohort were 87.5% and 79.1%, respectively. The 1, 2-year OS for primary NSCLC patients were 77.8% and 62.6%, respectively. To our knowledge, this is the largest reported series of patients who received SBRT for ultra-central tumors. RT achieves high rates of local control in these patients, but the rate of severe or fatal toxicity is substantial. Further studies are needed to establish the relationship between SBRT and toxicity in these patients.

Diagnostic role of circulating extracellular matrix-related proteins in non-small cell lung cancer

BackgroundInteractions between cancer cells and the surrounding microenvironment are crucial determinants of cancer progression. During this process, bi-directional communication among tumor cells and cancer associated fibroblasts (CAF) regulate extracellular matrix (ECM) deposition and remodeling. As a result of this dynamic process, soluble ECM proteins can be released into the bloodstream and may represent novel circulating biomarkers useful for cancer diagnosis. The aim of the present study was to measure the levels of three circulating ECM related proteins (COL11A1, COL10A1 and SPARC) in plasma samples of lung cancer patients and in healthy heavy-smokers controls and test whether such measurements have diagnostic or prognostic value.MethodsGene expression profiling of lung fibroblasts isolated from paired normal and cancer tissue of NSCLC patients was performed by gene expression microarrays. The prioritization of the candidates for the study of circulating proteins in plasma was based on the most differentially expressed genes in cancer associated fibroblasts. Soluble ECM proteins were assessed by western blot in the conditioned medium of lung fibroblasts and by ELISA assays in plasma samples.ResultsPlasma samples from lung cancer patients and healthy heavy-smokers controls were tested for levels of COL11A1 and COL10A1 (n = 57 each) and SPARC (n = 90 each). Higher plasma levels of COL10A1 were detected in patients (p ≤ 0.001), a difference that was driven specifically by females (p < 0.001). No difference in COL11A1 levels between patients and controls was found. SPARC levels were also higher in plasma patients than controls (p < 0.001) with good performance in discriminating the two groups (AUC = 0.744). No significant association was observed between plasma proteins levels and clinicopathological features or survival.ConclusionSoluble factors related to proficient tumor-stroma cross-talk are detectable in plasma of primary lung cancer patients and may represent a valuable complementary diagnostic tool to discriminate lung cancer patients from healthy heavy-smokers individuals as shown for the SPARC protein.

HOTAIR lncRNA SNPs rs920778 and rs1899663 are associated with smoking, male gender, and squamous cell carcinoma in a Chinese lung cancer population.

The abnormal expression of the long noncoding RNA (lncRNA) HOX transcript intergenic antisense RNA (HOTAIR) plays an important role in the development of various cancers; however, single nucleotide polymorphisms (SNPs) in HOTAIR and their association with primary lung cancer susceptibility have not yet been reported. Here, we performed a case-control study including 262 primary lung cancer patients and 451 cancer-free control individuals to investigate the association between four haplotype-tagging SNPs (rs920778, rs12826786, rs4759314, and rs1899663) in the HOTAIR lncRNA and the risk of developing primary lung cancer. We found a significant association between the SNPs rs920778 and rs1899663 in the HOTAIR and primary lung cancer susceptibility (P < 0.05). Moreover, homozygous C/T (C/T + TT) for rs920778 (C > T) sites was significantly associated with gender, smoking history, and pathological type. In addition, linkage disequilibrium and haplotype analysis of HOTAIR gene polymorphisms for susceptibility to lung cancer revealed a high degree of linkage disequilibrium between the rs920778 and rs1899663 loci (D' = 0.86, r2 = 0.52). The population of rs920778, rs1899663, and rs4759314 had a significantly increased risk of lung cancer (P < 0.001). In summary, the present study provides persuasive evidence that SNP rs920778 is closely correlated with susceptibility to primary lung cancer. Future studies are warranted to validate and expand these findings, and to further dissect the importance of these SNPs in the development of primary lung cancer.

Interaction Between Environmental Risk Factors and Catechol-O-Methyltransferase (COMT) and X-Ray Repair Cross-Complementing Protein 1 (XRCC1) Gene Polymorphisms in Risk of Lung Cancer Among Non-Smoking Chinese Women: A Case-Control Study.

BackgrpoundVarious studies have highlighted the link between polymorphisms in the XRCC1 gene (encoding X-ray repair cross-complementing group 1) with the incidence of decreased DNA repair capacity and an increased predisposition to cancer. Catechol-O-methyltransferase (COMT) plays a crucial role in estrogen-induced cancers. In the present study was analyzed the potential influence of XRCC1 and COMT gene polymorphisms as predisposing factors from a lung cancer perspective, in addition to conducting an investigation into their interaction with environmental risk factors in relation to lung cancer among non-smoking Chinese women.Material/MethodsThe XRCC1 gene T-77C, Arg194Trp, Arg280His, Arg399Gln, COMT gene 186C>T, and Val158Met mutations were evaluated in peripheral blood collected from 261 non-smoking female patients diagnosed with primary lung cancer and 265 female patients with benign lung disease.ResultThe results obtained from this study demonstrated that XRCC1–77TC + CC, XRCC1 399Gln/Gln, COMT 186CT + TT, COMT 158Val/Met genotypes, type of occupation, cooking-oil fumes, and soot exposures were all independent risk factors involved with the occurrence of lung cancer among non-smoking women. Moreover, interactions between environmental exposure factors as well as XRCC1 and COMT gene polymorphisms were determined to play significant contributory roles regarding susceptibility of non-smoking females to lung cancer.ConclusionsTaken together, T-77C and Arg399Gln polymorphisms of the XRCC1 gene, as well as the 186C>T and Val158Met polymorphisms of the COMT gene, increased the risk of lung cancer in non-smoking women, with the factors of occupation type, cooking-oil fumes, and soot exposures representing key contributing factors.

Abstract 44: Characterization and targeting of a temporal micro-metastatic signature in human brain metastases

Abstract Metastases to the brain (BM) are the most common neoplasms to affect the adult central nervous system, arising in 40% of cancer patients and at a rate 10 times greater than primary brain tumors. Despite the prevalence and poor survival rates, therapeutic strategies for BM remain limited, and a substantial cause is the lack of proper preclinical models available to interrogate the intricacies of BM development. Previous work in our lab utilized BM samples from patient-derived lung-to-brain metastases to successfully establish clinically relevant in vivo models of BM. Here we further characterized the cells responsible for BM, termed brain metastasis initiation cells (BMIC). Patient-derived BMICs were injected via intracranial (BT), intracardiac (IC) and intrathoracic (IT) routes into NOD/SCID mice and re-isolated at different stages of metastatic progression. We isolated cells from primary lung tumors (LT), cells injected via intra-thoracic route that crossed the blood brain barrier to seed the brain forming micro-metastases (BMIT), and cells injected via intracardiac route that seeded large macro-metastases (BMIC). Through RNA sequencing we determined cells from BMIT (micro-metastasis stage) to retain a vastly different genetic profile compared to BMICs isolated at other stages of metastasis. Several of these genes belonged to pathways implicated in autonomic central nervous system neoplasms and neural development. Through connectivity mapping of BMIT profiles we discovered drugs that could inhibit the micro-metatsasis signature, and further in vitro validation revealed apomorphine to reduce BMIC sphere formation and proliferation. In vivo treatment with apomorphine blocked both micro- and macro-metastatic stages of our BMIC model. Of 5 BMIT genes identified to be specifically targeted by apomorphine, KIF16B, TESK2 and SEPW1 were shown to have significant value when applied as an independent prognostic signature in a cohort of lung adenocarcinoma patients. Future work will further validate the efficacy of apomorphine in targeting BMICs in primary lung cancer patient samples. With this work we present a possible new avenue for therapeutic targeting toward the prevention of BM development, where it is anticipated to transform a uniformly fatal disease into one that is eminently more treatable. Citation Format: Mohini Singh, Chitra Venugopal, Tomas Tokar, Nicole McFarlane, Minomi Subhapanditha, David Bakhshinyan, Maleeha Qazi, Parvez Vora, Neil Savage, Naresh K. Murty, Igor Jurisica, Sheila K. Singh. Characterization and targeting of a temporal micro-metastatic signature in human brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 44.

Effect of invasive mucinous adenocarcinoma on lung cancer-specific survival after surgical resection: a population-based study.

In 2015, the World Health Organization (WHO) announced a new classification of lung tumors. Mucinous bronchioloalveolar adenocarcinomas were reclassified as invasive mucinous adenocarcinomas (IMAs). Due to the rarity or this tumor type, conflicting clinical outcomes have been reported based on small patient numbers. Patients diagnosed as primary lung nonmucinous adenocarcinoma (NMA) or IMA from 2000 to 2014 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. General features of each IMA were explored and the effect of histological characteristics on lung cancer-specific survival was analyzed in matched samples using the TNM staging system. The incidence of IMA among all primary lung cancer patients was 0.2% (1,783/1,154,742), and the incidence of IMA among patients with a primary resected lung adenocarcinoma was 1.5% (531/35,406). IMAs tended to be located in the lower lobe (P<0.001), be well differentiated (P<0.001), and be N0 (91.7% vs. 72.3%, P<0.001), T1 or T2 (P<0.001), and stage I tumors (P<0.001) when compared with NMAs. After matching by stages, a stratified Cox PH analysis revealed that the tumor histologic type (P=0.2) did not increase the risk of lung cancer-specific death, while advanced age (HR 1.03, P<0.001), male sex, and the need for radiation, pneumonectomy or sublobar resections increased the risk of cancer-specific death. The histologic type of the tumor, whether IMA or not, did not affect lung cancer-specific survival times among patients with a primary M0 stage lung adenocarcinoma. When stratified by the TNM staging system, patents that required pneumonectomy, sublobar resection or radiation had shorter lung cancer-specific survival times.