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Immune checkpoint inhibitors (ICIs) have successfully treated a number of different types of cancer, which is of great significance for cancer treatment. With the widespread use of ICIs in clinical practice, the increasing checkpoint inhibitor pneumonia (CIP) will be a challenge to clinicians. To guide the diagnosis and treatment of CIP, we conducted in-depth discussions based on the latest evidence, forming a consensus among Chinese experts on the multidisciplinary management of CIP.

The selection of patients for immunotherapy remains challenging given the lack of highly specific and highly sensitive biomarkers. Kirsten rat sarcoma (Clinical data were extracted from medical records of patients with advanced NSCLC at the First Affiliated Hospital of Guangzhou Medical University in China between January 2019 and March 2020. Overall survival (OS) and progression-free survival (PFS) rates were compared via log-rank tests, and independent prognostic factors were identified via Cox regression.Patients with advanced NSCLC without driver alterations who were treated with ICI and platinum-based chemotherapy (N=80) were identified, including 28.7% withThis work provides evidence that

Background ROS1-rearranged lung cancers benefit from first-line crizotinib therapy; however, clinical and molecular factors that could affect crizotinib efficacy in ROS1-rearranged lung cancers are not yet well-elucidated. Our retrospective study aimed to compare the efficacy of chemotherapy and crizotinib in the first-line treatment of ROS1-rearranged advanced lung cancer and evaluate various clinical and molecular factors that might impact crizotinib efficacy in real-world practice. Methods Treatment responses, survival outcomes, and patterns of disease progression were analyzed for 235 patients with locally advanced to advanced disease who received first-line chemotherapy (n = 67) or crizotinib (n = 168). Results The overall response rate was 85.7% (144/168) for first-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with first-line crizotinib (n = 168) had significantly longer median progression-free survival (PFS) than chemotherapy (n = 67) (18.0 months vs. 7.0 months, p CD74-ROS1 (n = 90) had significantly shorter median PFS with crizotinib than those harboring non-CD74 ROS1 fusions (n = 69) (17.0 months vs. 21.0 months; p = 0.008). Patients with baseline brain metastasis (n = 45) had a significantly shorter PFS on first-line crizotinib than those without brain metastasis (n = 123) (16.0 months vs. 22.0 months; p = 0.03). At progression, intracranial-only progression (n = 40), with or without baseline CNS metastasis, was associated with longer median PFS than those with extracranial-only progression (n = 64) (19.0 months vs. 13.0 months, p TP53 mutations were the most common concomitant mutation, detected in 13.1% (7/54) of patients with CD74-ROS1 fusions, and 18.8% (6/32) with non-CD74 ROS1 fusions. Patients with concomitant TP53 mutations (n=13) had significantly shorter PFS than those who had wild-type TP53 (n = 81) (6.5 months vs. 21.0 months; p n = 9) (11.0 months vs 24.0 months; p = 0.0167) or concomitant tumor suppressor genes (i.e., TP53, RB1, or PTEN) (n = 25) (9.5 months vs 24.0 months; p n = 58). Conclusion Our results demonstrate that baseline brain metastatic status and various molecular factors could contribute to distinct clinical outcomes from first-line crizotinib therapy of patients with ROS1-rearranged lung cancer. Clinical trials registration CORE, NCT03646994

Immunotherapy has provided a novel therapeutic option for lung cancer but studies involving patients with advanced non-small cell lung cancer (NSCLC) coupled with various degrees of comorbid chronic obstructive pulmonary disease (COPD) are limited. Thus, we performed a retrospective cohort study to optimize the use of immunotherapy in this special population.We enrolled a total of 99 patients with advanced (stage IIIB/C-IV) NSCLC with comorbid COPD who had received immune checkpoint inhibitors (ICIs) according to the inclusion and exclusion criteria. They were divided into four groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline criteria as follows: no COPD group (nThere were statistically significant differences in the incidence of irAEs among the four groups (P=0.003). The incidence of irAEs in patients with no COPD (nImmunotherapy should be selected with caution for advanced NSCLC patients with comorbid severe COPD, considering the limited efficacy and the increased risk of immune-related adverse events related to the immune-checkpoint inhibitors administration in this special population.

Purpose: Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non–small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641). Patients and Methods: Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1,021 genes. Clonal dominance analysis was performed on the basis of PyClone. Results: Overall, 300 treatment-naïve patients with stage IIIB–IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose EGFR was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24–0.88; P = 0.02]. The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n = 43) versus those not (n = 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04–0.50; P = 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). Conclusions: Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.

Objective The study aimed to analyze the efficacy and safety of combination regimen of anlotinib and S-1 for Chinese patients with EGFR mutation-negative advanced squamous cell lung cancer (SqCLC) with poor performance status (PS,2-3) after progression of second-line or later-line chemotherapy. Methods Clinical data of 70 SqCLC patients with PS scores of 2-3 treated in the First Affiliated Hospital of Guangzhou Medical University between January 1, 2018 to September 31, 2019 who failed second- or more-line treatment were analysed retrospectively. The patients were divided into two treatment groups: anlotinib (12mg) plus S-1 (25mg) combination group and anlotinib (12mg) monotherapy group. The efficacy and adverse reactions of the two groups were compared. Results In terms of the short-term efficacy, there were no significant differences in objective response rate (ORR) (20.0% vs 10.0%, p = 0.464) and disease control rate (DCR) (75.0% vs 60.0%, p = 0.181) between the two groups. As for the long-term efficacy, there was no significant difference in progression-free survival (PFS) between the two groups (3.87±0.29 months vs 3.00±0.24 months, p=0. 11). The overall survival (OS) of patients in the combination group was longer than S1 group (8.07±0.56 months vs 6.17±0.42 months, p=0.022). Conclusion Advanced SqCLC patients with higher PS scores still benefit from anlotinib and S-1 combination regimen, even after they failed second-line or later-line systemic treatment.

The tumor microenvironment (TME) constitutes a complex milieu of cells and cytokines that maintain equilibrium between tumor progression and prognosis. However, comprehensive analysis of the TME and its clinical significance in head and neck squamous cell carcinoma (HNSCC) remains to be unreported. In this study, based on large-scale RNA sequencing data pertaining to single nucleotide variants (SNVs) and copy number variations (CNVs) in HNSCC patients from The Cancer Genome Atlas database, we analysed subpopulations of infiltrating immune cells and evaluated the role of TME infiltration pattern (TME score) in assessing immunotherapy outcome. TME signature genes involved in several inflammation and immunity signalling pathways were observed in the TME score subtype, which were considered immunosuppressive and potentially responsible for significantly worse prognosis. In comparison with SNV- and CNV-mediated tumor mutation burden, TME score can significantly differentiate between high- and low-risk HNSCC and predict immunotherapy outcome. Our data provide clarity on the comprehensive landscape of interactions between clinical characteristics of HNSCC and tumor-infiltrating immune cells. TME score seems to be a useful biomarker that can predict immunotherapy outcome in HNSCC patients.

Transmembrane domain (TMD) mutations of ERBB2 have previously been reported in lung cancer patients in addition to well‐studied kinase domain (KD) mutations, which may stabilize ERBB2 heterodimerization with other EGFR family members and favor a kinase active conformation. However, the frequency and clinical significance of ERBB2 TMD mutations in Chinese population is unknown. We prospectively analyzed the next‐generation sequencing data of 34 368 Chinese lung cancer patients with different sample types, including tumor tissue, plasma, cerebrospinal fluid, and pleural effusion. Patients' clinical characteristics and treatment history were retrieved from the database for further evaluation. Our findings show that ERBB2 V659/G660 mutations were detected at a frequency of 0.13% (45/34 368), of which the most frequent was V659D/E (88.9%), with a trend in nonsmokers and male. Moreover, 18% of patients (8/45) showed EGFR and/or ERBB2 amplification, whereas nine patients presented EGFR L858R or exon19 deletion. Interestingly, novel ERBB3 TMD mutation I646R was found coexisting in three patients with ERBB2 V659D and one patient with ERBB2 G660D, which might influence its heterodimerization with ERBB2 and further activate ERBB2. Four ERBB2 TMD mutation‐positive patients received afatinib monotherapy or combination therapy, but showed variable responses. One patient with V659E responded well to ERBB2 inhibitor lapatinib plus capecitabine as well as subsequent afatinib treatment upon progression. Our study provides valuable insights into the distribution of ERBB2 TMD mutations by employing the largest Asian lung cancer cohort thus far. Patients with ERBB2 TMD mutations who received afatinib, a pan‐ERBB inhibitor, demonstrated mixed responses, posing the urgent need to develop more effective therapeutic strategy for patients who carry ERBB2 TMD mutations., Transmembrane domain (TMD) mutations of ERBB2 were identified in 0.13% of a large Chinese lung cancer cohort with a ratio of 0.17% in lung adenocarcinomas. Novel ERBB3 TMD mutation I646R was found co‐existing in four ERBB2 TMD mutation carriers, which might affect ERBB2‐ERBB3 heterodimerization. ERBB2 TMD carriers demonstrated mixed response to afatinib, posing the need for more effective therapeutic strategy.

The characterization of immunological and genomic differences in small-cell lung cancer (SCLC) between East Asian (EA) and Caucasian patients can reveal important clinical therapies for EA patients with SCLC. By sequencing and analyzing a molecular and immunological dataset of 98-SCLC patients of EA ancestry, immunogenicity, including DNA damage repair alterations and tumor mutation burden (TMB), was found to be significantly higher in the EA cohort than in the Caucasian cohort. The epithelial-mesenchymal transition (EMT) was the signaling signature with the predominant frequency of mutations across all patients in the EA cohort. Analysis of tumor-infiltrated immune cells revealed that resting lymphocytes were significantly enriched in the EA cohort. Compound-targeting analysis showed that topoisomerase inhibitors might be capable of targeting TP53 and RB1 comutations in EA SCLC patients. EA SCLC patients who harbored COL6A6 mutations had poor survival, while Caucasian SCLC patients with OTOF, ANKRD30B, and TECPR2 mutations were identified to have a shorter survival.

Background Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare subtype of non-small cell lung cancer associated with Epstein-bar virus (EBV) infection. Epithelioid granuloma (EG) has been more scarcely reported and frequently misdiagnosed. Methods Data were collected from January 2013 to October 2019. Of 227 patients diagnosed as having PLELC, 22 patients had EG. We analyzed their clinical features, pathological characteristics and treatment and a comparison between PLELC patients complicated with or without EG was made. Results Twenty-two patients had complicated with EG (9.6%). The median age was 50 years (38–67 years). There were more females than males (1.4:1). Most patients were at early stage (68.2%) with nonspecific manifestations and lack of Rich-Lewis phenomenon. Compared with the 205 patients complicated without EG, there were no significant difference among age (t=0.938, P=0.349), gender (χ2=0.898, P=0.343), initial symptoms (χ2=2.684, P=0.443), smoking status (χ2=0.210, P=0.647), diameter of tumor(t=0.993, P=0.332) and performance status (H=0.971, P=0.615). EG was often located inside or adjacent to the tumor (71.4%). Specific staining was negative, whereas in situ hybridization staining of EBV-encoded RNA was consistently positive. Most patients complicated with EG received multimodality therapy including surgery, neo-adjuvant/adjuvant chemotherapy or palliative chemotherapy and none of them received anti-TB therapy. Compared with the 205 patients complicated without EG, there were no significant difference among tumor stage, DFS (median, not reached, P=0.914), PFS (median, 12.3 months, P=0.848), OS (median, not reached, P=0.737) and treatment including anti-tumor therapy and anti-TB therapy. During follow-up duration for 14.6 months (range, 2.1–94.7 months), none of the patients had occurrence, progression or relapse of tuberculosis, regardless whether anti-tuberculosis therapy was initiated. Conclusions PLELC complicated with EG was lack of Rich-Lewis phenomenon and specific clinical characteristics compared with those without EG. EG might be caused by immunological hypersensitivity to tumor cells or EBV infection but not pulmonary tuberculosis. PLELC complicated with EG could be treated with chemotherapy and surgery. However, anti-tuberculosis therapy was unnecessary.

Background Medulloblastoma is an aggressive brain tumor mostly found in children, few studies on pathogenic germline mutations predisposing this disease was reported. Case presentation We present an 11-year-old male with medulloblastoma, who harbors a de novo PHOX2B germline mutation as detected by whole exome sequencing (WES). Family history was negative. Sanger sequencing confirmed this mutation in peripheral blood, hair bulbs, urine and saliva. Identification of novel germline mutations is beneficial for childhood cancer screening. Conclusions This case revealed a de novo PHOX2B germline mutation as a potential cause of medulloblastoma in a child and suggests familial germline variant screening is useful when an affected family is considering having a second child.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) complicated with chronic obstructive pulmonary disease (COPD) with poor performance status (PS) are common in clinical practice with few related studies. Present studies have found that weekly low-dose docetaxel or gemcitabine combined with platinum is suitable for elderly or poor PS patients with advanced NSCLC. METHODS: Untreated advanced driver mutation-negative NSCLC patients with COPD and PS ≥2 were enrolled in this double-blind randomized trial. Both groups controlled their COPD symptoms according to the GOLD guidelines. The anti-tumor regimens included docetaxel (37.5 mg/m(2), D1, D8)/carboplatin (AUC 5.0) (DC group) and gemcitabine (1,000 mg/m(2), D1, D8)/carboplatin (AUC 5.0) (GC group) were used every 3 weeks with continuous chemotherapy for 4–6 cycles or until disease progression. The primary endpoints were progression-free survival (PFS), and overall survival (OS). RESULTS: Among the 52 patients (DC, n=25; GC, n=27), the median follow-up time was 12.3 months. There was no significant difference in tumor overall response rate (ORR; DC, 20.0% vs. GC, 22.2%, P=0.845) and disease control rate (DCR; DC, 72.0% vs. GC, 74.1%, P=0.064) between the 2 groups. The median PFS (GC, 6.5 vs. DC, 5.5 months; P=0.296) and the median OS (GC, 14.9 vs. DC, 12.3 months; P=0.548) of the GC group was slightly longer than the DC group. The main adverse reactions were myelosuppression and there were few adverse reactions of grade 3–4. Compared with the anti-tumor therapy only group in previous literature, the median PFS in this study was longer (6.2 months, 95% CI: 3.533–6.733 vs. 3.5 months, 95% CI: 2.432–4.568; P=0.589). There was also no significant difference in median OS and median PFS between the 2 groups (14.0 vs. 15.0 months, P=0.718). Chemotherapy cycle (P

Nonbacterial thrombotic endocarditis (NBTE) is a rare disease that most often found post mortem. Malignant neoplasms, particularly adenocarcinomas, are the common underlying diseases associated with NBTE. In recent years, remarkable advances in targeted therapy have been made, but the effectiveness in treating NBTE in patients with severe lung cancer is poorly reported. Here we present two cases of severe NBTE in patients with stage IV lung adenocarcinoma harboring driver gene mutations, one with EGFR mutation, the other with positive ALK fusion oncogene. Both patients scored 4 according to the Cooperative Oncology Group performance status (ECOG PS) before the initiation of targeted therapies and anticoagulation therapies. Both patients showed significant improvement: the vegetations in their hearts vanished, their ECOG PS score changed from 4 to 3. We also discuss the current understanding of NBTE, including its epidemiology, pathogenesis, clinical presentation, evaluation, diagnosis, and treatment. Our report highlights the necessity of early and timely diagnosis of NBTE and gene classification for NSCLC patients (ECOG PS score ≥3), the importance of concurrent therapy for the cancer and its complications, and further stresses the effectiveness of targeted therapy for NBTE in patients with severe lung cancer harboring driver gene mutations.

Objective NUT midline carcinoma (NMC), a rare type of squamous cell carcinoma, is genetically characterised by NUT midline carcinoma family member 1 (NUTM1) gene rearrangement. NMC can arise from the lungs; however, there is no standard for the management of primary pulmonary NMC. This study aimed to confirm the clinical features and report the treatments, especially with immune checkpoint inhibitors (ICIs), and outcomes of patients with primary pulmonary NMC. Methods A retrospective review of patients with primary pulmonary NMC was performed in the First Affiliated Hospital of Guangzhou Medical University between January 2015 and December 2018. Clinical manifestations as well as radiographic and pathological findings were recorded. Whole-exome sequencing (WES), a predictor for ICI response, was used to determine the tumour mutational burden (TMB). Treatments, especially by immune checkpoint blockade, and patient survival were analysed. Results Seven patients with primary pulmonary mass (four men and three women) with a mean age of 42 years (range, 23–74) who were diagnosed with NMC according to NUT immunohistochemistry staining were included for analysis. One patient had a rare fusion of CHRM5-NUTM1 by tumour sequencing. A wide range of TMB (1.75–73.81 mutations/Mbp) was observed. The initial treatments included chemotherapy (5/7, 71.4%), surgery (1/7, 14.3%), and radiotherapy (1/7, 14.3%). Five patients (5/7, 71.4%) received ICIs (programmed cell death protein 1 [PD1]/programmed cell death ligand 1 [PDL1] monoclonal antibody) as second- or higher-line treatments. The median overall survival (OS) was 4.1 months (range, 1.5–26.7 months). Conclusions Patients with primary pulmonary NMC have a poor prognosis and chemotherapy is often preferred. Checkpoint immunotherapy is a good option as the second- or higher-line treatment. TMB seems to be not associated with OS.

To date, immunotherapy has opened a new chapter in the treatment of lung cancer. Precise biomarkers can help to screen subpopulations of lung cancer to provide the best treatment. Multiple studies suggest that specific gene mutations may be predictive markers in guiding non-small cell lung cancer (NSCLC) immune checkpoint inhibitor (ICI) treatment. A published immunotherapy cohort with mutational and survival data for 350 NSCLC patients was used. First, the mutational data of the immunotherapy cohort were used to identify gene mutations related to the prognosis of ICI therapy. The immunotherapy cohort and TCGA-NSCLC cohort were further studied to elucidate the relationships between specific gene mutations and tumor immunogenicity, antitumor immune response capabilities, and immune cell and mutation counts in the DNA damage response (DDR) pathway. In the immunotherapy cohort (N = 350), ZFHX3 mutations were an independent predictive biomarker for NSCLC patients receiving ICI treatment. Significant differences were observed between ZFHX3-mutant (ZFHX3-MT) and ZFHX3-wild type (ZFHX3-WT) patients regarding the overall survival (OS) time (P

Xiaoshun Shi,1,2,* Haoming Tan,3 Xiaobing Le,4,5,* Haibing Xian,6,* Xiaoxiang Li,1 Kailing Huang,4,5 Viola Yingjun Luo,4,5 Yanhui Liu,4,5 Zhuolin Wu,7 Haiyun Mo,8 Allen M Chen,4,5,* Ying Liang,9 Jiexia Zhang1 1National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Department of Medicine, Guangzhou Institute of Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, China; 2Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; 3Department of Thoracic Surgery, Shunde Lecong Affiliated Hospital of Guangzhou Medical University, Guangdong 528315, China; 4Mendel Genes Inc, Guangzhou 510515, China; 5Mendel Genes Inc, Manhattan Beach, CA 90266, USA; 6Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of Foshan, Guangdong 528000, China; 7Department of Biomedical Engineering, University of Minnesota, Twin Cities, MN, USA; 8Department of Public Health, Guangzhou Medical University, Guangzhou 510000, China; 9Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China *These authors contributed equally to this work Background: The current TNM staging system plays a central role in lung adenocarcinoma (LUAD) prognosis. However, it may not adequately stratify the risk of tumor recurrence. With the aid of gene expression profiling, we identified 31 lncRNAs whose expressions in tumor tissues could be used as a risk indicator for the guidance of lung cancer therapy. This exploratory analysis may shed new light on identification of potential prognostic factors. Materials and methods: A survival prediction scoring model was developed from the data that are publicly available in The Cancer Genome Atlas (TCGA) LUAD RNA Sequencing dataset. Multivariate Cox regression analysis and Kaplan–Meier analysis were performed on a cohort of 254 stage I lung carcinoma patients with survival records. Results: Our model indicates that the panels comprising 31 lncRNAs are highly associated with overall survival (OS): 18.9% (95% CI: 10.4%–34.5%) and 89.5% (95% CI: 80.7%–99.2%) for the high- and low-risk group, respectively. The specificity and sensitivity of the model are verified, which show that the area under receiver operating characteristic curve yields 0.881, meaning our model has good accuracy and it is feasible for further applications. Conclusion: The 31-lncRNA model might be able to predict OS in patients with LUAD with high accuracy. Its further applications in biomolecular experiments using clinical samples with independent cohorts of patients are needed to verify the results. Keywords: lung adenocarcinoma, lncRNA, signature, survival analysis, prognosis, RNA-seq

Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a histologically distinctive subtype of NSCLC and an Epstein-Barr virus (EBV)-associated epithelial neoplasm. We investigated the clinical significance of plasma concentrations of EBV DNA in patients with pulmonary LELC.Two independent sets of plasma samples from a total of 429 patients with patients with pulmonary LELC (287 initial and 142 confirmatory) were available for EBV DNA determination. Plasma samples from the patients were subjected to a real-time quantitative polymerase chain reaction before treatment and 3 months after radical resection. Cutoff points were determined for pretreatment plasma EBV DNA concentration (low4000 copies/mL versus high ≥4000 copies/mL) on the basis of a measure of heterogeneity with the log-rank test statistic with respect to overall survival (OS). The Kaplan-Meier method and Cox regression were used to evaluate the relationship between plasma EBV DNA concentrations and clinical outcome. Among patients with advanced-stage pulmonary LELC who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in EBV DNA concentrations by using nonparametric tests.High EBV DNA concentration was associated with shorter OS in the initial, confirmatory, and combined data sets (combined data set hazard ratio = 3.67, 95% confidence interval: 2.72-4.38, p0.001). These findings persisted after multivariable adjustment. Compared with low EBV DNA concentration, high EBV DNA concentration was associated with shorter OS in patients with any stage of disease. High EBV DNA concentration was also associated with shorter disease-free survival (DFS) in patients with stage I/II disease. Patients with persistently detectable plasma EBV DNA had significantly poorer OS (p0.001) and DFS (p0.001) than did patients with undetectable EBV DNA 3 months after radical resection. In patients who underwent sequential evaluation of EBV DNA, an association was identified between an increase in EBV DNA concentration and a poor response to treatment and disease progression of pulmonary LELC.High baseline EBV DNA concentration is an independent poor prognostic marker in patients with pulmonary LELC. These results should be confirmed in larger prospective trials.

Lung cancer (LC) is a common lethal malignancy with rapid progression and metastasis, and Ring1 and YY1 binding protein (RYBP) has been shown to suppress cell growth in human cancers. This study aimed to investigate the role of RYBP in LC progression and metastasis. In this study, a total of 149 LC patients were recruited, and the clinical stage of their tumors, metastasis status, survival time, presence of epidermal growth factor receptor (EGFR) mutation, and RYBP expression levels were measured. RYBP silencing and overexpression were experimentally performed in LC cell lines and in nude mice, and the expressions of genes in EGFR-related signaling pathways and epithelial-mesenchymal transition (EMT) were detected. The results showed that RYBP was downregulated in LC compared with adjacent normal tissues, and low RYBP expression was associated with a more severe clinical stage, high mortality, high metastasis risk, and poor survival. Cell proliferation and xenograft growth were inhibited by RYBP overexpression, whereas proliferation and xenograft growth were accelerated by RYBP silencing. EGFR and phosphorylated-EGFR levels were upregulated when RYBP was silenced, whereas EGFR, p-EGFR, p-AKT, and p-ERK were downregulated when RYBP was overexpressed. Low RYBP expression was related to a high metastasis risk, and metastasized tumors showed low RYBP levels. Cell migration and invasion were promoted by silencing RYBP but were inhibited by overexpressed RYBP. In addition, the EMT marker vimentin showed diminished expression, and E-cadherin was promoted by the overexpression of RYBP. In conclusion, our data suggest that RYBP suppresses cell proliferation and LC progression by impeding the EGFR-ERK and EGFR-AKT signaling pathways and thereby inhibiting cell migration and invasion and LC metastasis through the suppression of EMT.

Background: Lung tumors harboring genomic rearrangements involving ROS1 clinically benefits from crizotinib therapy. Our retrospective study aims to compare the efficacy of chemotherapy and crizotinib in the first-line setting and evaluate other clinical and molecular factors that might impact crizotinib efficacy in real-world practice. Methods: ROS1 rearrangements were retrospectively analyzed from NGS data of 21,747 treatment-naive patients diagnosed with lung cancer at various hospitals from 4 provinces of China. Treatment response and survival outcomes were analyzed in 235 patients with locally advanced to advanced disease who received first-line chemotherapy (n=67) or crizotinib (n=168). Findings: A total of 233 different ROS1 fusion partners were detected from 264 patients, with CD74 as the most common partner. The overall response rate was 85.7% (144/168) for front-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with front-line crizotinib had significantly longer median progression-free survival (mPFS) than chemotherapy (18.0 months vs. 7.0 months, p

Background: Although EGFR mutations in lung cancer are identified most often as trunk mutations in the early stage, cancer evolution often follows a branched trajectory. Whether EGFR would always be the dominant clone in the advanced stage is unknown. Methods: This prospective multicenter clinical trial recruited treatment naive patients with stage IIIB-IV non–small cell lung cancer from 14 centers in China. Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1021 genes. Clonal dominance analysis was performed on the basis of PyClone. Findings: Overall, 300 patients were recruited and 132 patients treated with first line targeted therapy were followed. The median follow-up time was 10 months (IQR 6–13). Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The mPFS was longer for these patients than for the 22 patients who had EGFR non-dominant clone (11 months vs 10 months, hazard ratio [HR] 0.46, 95% CI 0.24–0.88, p = 0.02). The difference was more significant if patients who were defined as having EGFR dominant clone by both tumor tissue and plasma (n = 43) versus those not (n = 8) (11 vs 6 months, HR = 0.13, 95% CI 0.04–0.50, p = 0.003). Moreover, multivariate cox proportional hazard ratio analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors. Interpretation: In advanced NSCLC,EGFR mutations do not always make up a dominant clone. Clonal architecture of EGFR in the pretreatment ctDNA is associated with the efficacy of EGFR-TKIs in NSCLC. Trial Registration: The trial has been registered with the number NCT03059641. Funding Statement: Geneplus-Beijing Co. Ltd. Declaration of Interests: RC, PL, LC and XY were employees of Geneplus-Beijing Co. Ltd. All other authors declare no conflict of interests. Ethics Approval Statement: This study was performed under a protocol (KS1707) approved by the Institutional Review Board of Shanghai Chest hospital (Shanghai, China).

Background: The tumor microenvironment (TME) constitutes a complex milieu of cells and cytokines that maintain equilibrium between tumor progression and prognosis. However, comprehensive analysis of the TME and its clinical significance in head and neck squamous cell carcinoma (HNSCC) remains to be reported. Methods: Based on large-scale RNA sequencing data of HNSCC patients from The Cancer Genome Atlas database, we analysed subpopulations of infiltrating immune cells. An unsupervised clustering method was used to evaluate TME infiltration pattern (TME score); TME phenotypes were systematically correlated with genomic characteristics and clinicopathological features of HNSCC. Three TME phenotypes were defined, and TME score was obtained using principal component analysis algorithms. Mutational signatures were analysed based on single nucleotide variants (SNVs) and copy number variations (CNVs). Findings: TME signature genes were characterized by immunoglobulin complex and antigen receptor-mediated signalling pathway. Allograft rejection, inflammatory response, and reactive oxygen species pathway were observed in the low TME score subtype, which were considered immunosuppressive and potentially responsible for significantly worse prognosis. Tumor mutation burden based on SNVs and CNVs was involved in immune regulation. Interpretation: Our data provide clarity on the comprehensive landscape of interactions between clinical characteristics of HNSCC and tumor-infiltrating immune cells. We suggest that TME score is a novel biomarker that can predict immunotherapy response in HNSCC patients. Funding Statement: This study was supported by grants from the Science and Technology Program of Guangzhou (201803010024), Social Science and Technology Development Key Project of Dongguan (201750715046462), Guangzhou Key Medical Discipline Construction Project Fund (B195002004042), and Open Funds of State Key Laboratory of Oncology in South China (KY013711). Declaration of Interests: The authors stated: "None." Ethics Approval Statement: This study was approved by the Ethics Committees of Cancer Hospital & Institute of Guangzhou Medical University and performed in accordance with guidelines established by the Declaration of Helsinki.

Patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer can benefit significantly from EGFR tyrosine-kinase inhibitors (TKIs) treatment, but almost every patient will inevitably develop resistance. The transformation to small cell lung cancer (SCLC) has been described as an EGFR-TKI resistance often associated with aggressive clinical course and poor prognosis. In this study, we report an unexpected favorable response to etoposide and cisplatin (EP) from an EGFR-mutant patient who developed SCLC transformation at disease progression after the administration of erlotinib with a progression-free survivalof 7.7 months. At disease progression (PD) after erlotinib, rebiopsy showed typical SCLC histology accompanied by positive expressions of CD56, TTF-1, CK7, and synaptophysin. Subsequently, he was switched to standard SCLC treatment regimen EP in combination with erlotinib due to the retention of EGFR 19 del and achieved PR four cycles after the treatment. His disease progressed again 7.7 months after the initiation of EP treatment, with an enlargement of both primary and metastatic lesions. Collectively, this case illustrated the transformation from adenocarcinoma to SCLC and the subsequent durable benefit from standard treatment for SCLC.

Background: Emerging evidence indicates that chemotherapy for lung cancer may alter EGFR mutation status. However, whether chemotherapy as a firstline treatment may increase or reduce the frequency of EGFR mutations in NSCLC remains uncertain. Therefore, we conducted a meta-analysis to evaluate whether chemotherapy leads to altered EGFR mutation status. Methods: A systematic literature search was performed using the PubMed, OVID, Science Direct, Cochrane Library, and CNKI databases for studies on pre- and post-chemotherapy EGFR mutation status. Relevant studies documenting perichemotherapy EGFR mutation ratios were included. Analyses of pooled odds ratios (OR) were performed. Results: Six studies involving 656 patients were included in this meta-analysis. It was found that chemotherapy may alter EGFR status (OR = 1.93, 95% CI 1.05 - 3.56; p < 0.0001). No significant differences in EGFR mutation alterations were observed in terms of gender, smoking history, EGFR loci, or chemotherapy response in NSCLC patients. Conclusions: Chemotherapy may contribute to altered EGFR status. NSCLC patients with EGFR mutations might need to be considered for EGFR status redeterminations prior to second-line EGFR-TKI treatment or upon tumor recurrence after chemotherapy. Further randomized clinical trials should investigate the impact of neoadjuvant or first-line chemotherapy on EGFR mutation status in NSCLC patients.

e13520 Background: Approximately 2-3% of lung cancer (LC) was found in very young patients (≤ 45 years old) and they were reported to have different clinical characteristics and genetic profiles when compared to older patients. However, it is still lack of large-scale genomic studies that could provide deep insights into the tumorigenesis, precision treatment and prognosis for this particular population. Methods: Clinically annotated data of targeted next generation sequencing (NGS) on 7858 tumor tissue specimens from LC patients were analyzed. For all specimens, a total of 422 or 425 cancer-related genes were interrogated with a mean coverage depth greater than 500x. Results: Of 7858 LC cases, 814 of them were younger than 45 (age at diagnosis), which were compared to 7044 old LC cases ( > 45 years old). Clinical information showed that young LC are more prevalent in female, to be more advanced disease and to have more adenocarcinoma in histology. Somatic genomic data analysis revealed that compared to old LC, young LC has significantly higher ALK/ROS1/RET fusions, ERBB2 mutations and 5q amplification(FDR < 0.1), but lower mutational frequencies in KRAS, CDKN2A, ERBB4, FAT1, NF1, lower copy number gain (CNG) of PIK3CA, MDM2, FGFR1, and less 5q deletion(FDR < 0.1). Interestingly, in young LC, genetic differences between female and male are not significant, with TP53 and EGFR being most frequently mutated in both sexes. Similarly, the differences between young and old female LC are also limit, with young female LC having more ALK fusions (13.43% vs. 5.1%, FDR < 0.01), less EGFR mutations and MDM2 CNG than old female. On the contrary, male patients demonstrated much wide disparity between young and old LC: young LC was enriched with ALK/ROS1/RET/ERBB2 fusions and mutations in EGFR, ERBB2 and SMAD2, while old LC have more mutations in KRAS, TP53, CDKN2A, and CNG of PIK3CA (all FDR < 0.1). We also found that EGFR exon19 deletion (19del) was significantly enriched in young LC, especially in male, while p.L858R showed preference in old LC. Conclusions: The data suggest that the prevalence of different genetic alterations is both age and sex related. The high level of ALK/ROS1/RET fusions and less CNV in young LC could potentially lead to more effective treatment and better prognosis. We also noted that genomic alterations in young LC were not significantly different across sexes, but the disparity by sex was enormously enlarged in old LC, which might be correlated to their life-long exposures, such as smoking, life styles and sex-affected factors.

e21501 Background: Though EGFR mutations in lung cancer are identified most often on the trunks of tumor phylogenetic trees in early stage, whether EGFR would always be the dominant clone in the advanced stage is unknown, as cancer evolution often follows a branched trajectory, with divergent subclones evolving simultaneously. The impact of clonal dominance of EGFR on outcomes with targeted therapies has not been explored. Methods: Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve patients with advanced NSCLC in the clinical trial (NCT03059641). cfDNA and tumor DNA were sequenced by target-capture deep sequencing of 1021 genes related to solid tumors, with blood cells as the germline control. Clonal dominance analysis was performed on the basis of the CCF determined for SNVs and clustered in plasma or tumor sequencing data using a modified version of Pyclone. PFS was estimated using Kaplan-Meier method and compared using log-rank test. Results: From February 2017 to December 2019, 300 advanced NSCLC patients were enrolled prospectively from 14 centers cross China. One hundred and fourteen EGFR mutant patients treated with EGFR-TKI were followed until disease progression (PD). The medium follow-up time was 10 month (1-27 months) and 92 (80.7%) patients have reached PD, with the ORR of 74.6% (85/114), mPFS of 10.5 months. Clonal dominance analysis of EGFR showed 76 patients had EGFR as the dominant clone according to tissue NGS results, and 66 patients as the dominant clone according to plasma cfDNA NGS results (p = 0.04). The ORR was significantly higher for patients with EGFR as dominant clone according to plasma cfDNA NGS results (84.8% vs 60.9%, p = 0.016), and PFS was significantly longer (12 vs 8 months, HR = 2.58). There was no difference when using tissue NGS results to analyze EGFR clonal dominance. However, if comparing patients who were defined as EGFR dominant clone by both tissue and plasma (n = 44) with those defined as EGFR nondominant (n = 9), EGFR dominance was associated with higher ORR (84.1% vs 44.4%, p = 0.01), and longer PFS (11 vs 6 months, HR = 9.88) significantly. Moreover, multivariate Cox proportional hazard ratio analysis demonstrated it as an independent prognostic indicator of EGFR-TKIs. Conclusions: Clonal dominance of EGFR in the pretreatment plasma cfDNA is associated with the efficacy of EGFR-TKIs in NSCLC. This study indicated the importance of evaluating clonal dominance in the current clinical practice and future trial designs. Clinical trial information: NCT03059641.

e18576 Background: Tracheal adenoid cystic carcinoma (TACC) is the second type of cancer in bronchial tumors, has a high rate of postoperative recurrence and poor prognosis for which therapeutic targets are unavailable. Currently, studies were mostly about ACC of salivary gland. Our study is aim to elucidate genomic landscape and predict clinical biomarker of TACC. Methods: We performed whole-exome sequencing (WES), T cell repertoire sequencing (TCR) and immunohistochemistry (IHC) on tumor tissue samples and matched peripheral blood (PB) samples from TACC patients. All patients were followed up for their disease-free survival. Results: 13 cases were enrolled from 2010 to 2019. Median age of 13 TACCs was 35 yrs. 7 patients were female. 12 patients were stage I. In 8 WES samples, TCEB3CL (62%, 5/8), LPAR3 (50%, 4/8), ALPI (38%, 3/8), ARID1A (38%, 3/8) and BCOR (38%, 3/8) mutated most frequently. The median TMB was 3.67 (1.37-6.77) mutations/Mb. 1 patient showed microsatellite instability high (MSI-H). 2 patients with the highest TMB both had POLE mutations. We compared frequency of most mutated genes in our 8 samples with three different ACC types, including 935 ACC of salivary gland cancer, 76 ACC of the lung, and 38 ACC of breast cancer. 7 mutated frequently genes were found both in TACC and other types of ACCs, including ARID1A, BCOR, ARID1B, KMT2C, KMT2D, CREBBP and FAT3. 6 of them were more frequent in TACC. 7 FFPE tumors and 13 PB samples from 13 TACCs were used to investigate immune microenvironment. In 13 PB samples, TCR diversity (shannon index) and clonality was negatively associated with age (Pearson, r = -0.53, p = 0.06; r = 0.53, p = 0.06, respectively). There was no significant association between the other clinical characteristics (gender and smoking history) and any TCR parameter (clonality, clonotype, shannon index). Patients with lower clonotype number had longer DFS than those with higher clonotype number (15.0 vs 9.5 months, p < 0.001, 95% CI, 0.23-675.66, HR, 12.46), while shannon index and clonality was not significantly associated with DFS. Conclusions: The genetic mutations associated with TACC are different from those implicated in non-small cell lung cancer. TCR analysis as a useful of indicator of disease development and prognosis in TACC may be utilized to direct further immunotherapy.

e21665 Background: The study aimed to analyze the efficacy and safety of combination regimen of anlotinib and S-1 for Chinese patients with EGFR mutation-negative advanced squamous cell lung cancer (SqCLC) with poor performance status (PS, 2-3) after second-or-more-line treatment. Methods: Clinical data of 32 SqCLC patients with PS scores of 2-3 treated in the First Affiliated Hospital of Guangzhou Medical University between Jan.1, 2018 to Sep.31, 2019 who failed second-or-more-line treatment were analyzed retrospectively. The patients were divided into two treatment groups: anlotinib (12mg) plus S-1 (25mg) combination group and S1 (12mg) monotherapy group. The efficacy and adverse reactions of the two groups were compared. Results: In terms of the short-term efficacy, there was no significant difference in objective response rate (ORR) (16.7% vs 5.0%, p= 0.54), and disease control rate (DCR) (66.7% vs 55.0%, p= 0.713) between the two groups. As for the long-term efficacy, there was no significant difference in progression-free survival (PFS) between the two groups (5.19 ±1.13 months vs 3.17 ±0.42 months, p= 0.062). the overall survival (OS) of patients in the combination group was longer than S1 group (10.0 ±1.14 months vs 6.37 ±0.47 months, p= 0.042). Conclusions: SqCLC patients with higher PS scores still benefit from anlotinib and S-1 combination regimen, even after they failed second-line or above systemic treatment. [Table: see text]

e21668 Background: RB1 is one of the most vital cancer suppressor genes in various cancer types. RB1 mutation always occurs in treatment-naïve small cell lung cancer (SCLC) patients or in resistance to EGFR TKI therapy of non-small cell lung cancer (NSCLC) patients. However, we observed a group of clinical NSCLC patients, and found that RB1 mutations also occurred in treatment-naïve patients. Methods: RB1 is one of the most vital cancer suppressor genes in various cancer types. RB1 mutation always occurs in treatment-naïve small cell lung cancer (SCLC) patients or in resistance to EGFR TKI therapy of non-small cell lung cancer (NSCLC) patients. However, we observed a group of clinical NSCLC patients, and found that RB1 mutations also occurred in treatment-naïve patients. Results: Nonsense and frame-shift mutations were the major pathogenic mutations found in RB1 gene, which predicted RB1 protein-deficient in these mutational patients. Furthermore, we found these RB1 mutation patients had TP53 mutations at the same time. Patients with RB1 mutation had a higher smoking prevalence than patients who had wildtype RB1 genes (P < 0.0001). Gene testing showed RB1 mutations patients also developed EGFR driver mutations, while the mutation frequency was significantly lower than RB1 wildtype patients ( P = 0.0368). Eight RB1 mutated patients diagnosed with actionable EGFR mutations, including exon 19 del, L858R, L861Q, G719S and S768I, while no patients diagnosed with EGFR exon 20 insertion. 10 (62.5%, 10/16) patients in RB1 mutated group, and 25(32.1%, 25/78) patients with RB1 wildtype had bone metastases. The proportion of bone metastases in patients with RB1 mutation was significantly increased than others ( P = 0.0216). Conclusions: This study demonstrates that the function of tumor suppressor gene RB1 in advanced stage of NSCLC. From the results, we considered RB1 mutation had influence on bone metastases. Although loss-of-function mutations in tumor suppressor gene (TSG) RB1 always had no targets therapeutic drugs, it also suggested that some other clinically treatment can be performed as soon as possible.

BACKGROUND/AIMS: Lung cancer is the leading cause of cancer-associated mortality worldwide. Long noncoding RNAs (lncRNAs) have been found to be related to different cancers and play important roles in regulating the pathological and physiological processes of numerous cancers. The aim of the current study was to identify potential prognostic long non-coding RNA biomarkers for predicting survival in patients with lung adenocarcinoma (LUAD) using The Cancer Genome Atlas (TCGA) dataset. METHODS: The clinical pathology and gene expression profiles of lung cancer were downloaded from The Cancer Genome Atlas. The differentially expressed lncRNAs were identified and patient survival analysis performed. The prognostic signature was further evaluated by functional assessment and bioinformatics analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to predict the function of lncRNAs and to construct a gene co-expression network relationship to predict downstream target genes with the aid of the STRING database and Cytoscape software RESULTS: lncRNA RP11-434D9.1 and FENDRR had lower expression levels in lung cancer and were associated with poor prognoses. We found that the major functions of lncRNA RP1-434D9.1 and FENDRR were related to the cell cycle, and we further screened out the possible downstream target genes CDK1, CCNB1, CCNB2, CCNA1, AURKA, PLK1. CONCLUSIONS: LncRNA RP11-434D9.1 and FENDRR can be used as molecular biomarkers for the diagnosis and prognosis of lung adenocarcinoma. These dysregulated lncRNAs might negatively regulate cell cycle through the hub genes, which then affected cancer cell proliferation. These results may provide new ideas for further clinical research for markers used for lung cancer diagnosis and prognosis. FUNDING STATEMENT: This work was supported by National Natural Science Foundation of China (81672270); Key project of Guangzhou Science Technology and Innovation Committee (201707020042); Science and Technology Program of Guangzhou (201803010024); Science and Technology Planning Project of Guangdong Province, China (2017B020226005); Science and Technology Program of Guangzhou (201903010003). Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016PY013); Scientific Research Projects of Wu Jieping Medical Research Foundation (320.6750.17206). DECLARATION OF INTERESTS: The authors declare that no conflicts of interest exist. ETHICS APPROVAL STATEMENT: Every specimen was anonymously handled based on ethical standards. All participants provided signed informed consent and our study had full approval from the hospital’s Ethical Review Committee.

Emerging reports have revealed that several microRNAs (miRNAs) are abnormally expressed in non‑small cell lung cancer (NSCLC). miRNAs have been identified as oncogenes or tumor suppressors, and regulate various biological processes including oncogenesis and development. miR‑802 is dysregulated in multiple types of human cancer, and exerts tumor‑suppressive or promoting roles. However, the expression levels and functional roles of miR‑802 in NSCLC remain largely unknown. In the present study, miR‑802 expression was demonstrated to be decreased in NSCLC tissues and cell lines. A low miR‑802 expression was significantly correlated with the tumor stage, lymph node metastasis and brain metastasis in NSCLC patients. Restoring miR‑802 expression inhibited NSCLC cell proliferation and colony formation, induced cell apoptosis, decreased cell migration and invasion in vitro, and hindered in vivo tumor growth. Mechanistically, fibroblast growth factor receptor 1 (FGFR1) was confirmed as the target gene of miR‑802 in NSCLC cells. In addition, FGFR1 silencing mimicked the tumor‑suppressing roles of miR‑802 upregulation in NSCLC cells. Furthermore, rescue experiments revealed that FGFR1 reintroduction rescued the miR‑802‑induced inhibition of the malignant phenotypes in NSCLC cells. Notably, miR‑802 was able to deactivate the phosphoinositide 3‑kinase (PI3K)/AKT serine/threonine kinase (Akt)/mammalian target of rapamycin (mTOR) pathway in NSCLC cells in vitro and in vivo. Overall, these results demonstrated that miR‑802 could downregulate FGFR1 expression, thereby deactivating the PI3K/Akt/mTOR pathway and inhibiting the malignant development of NSCLC. Thus, miR‑802 may be a therapeutic candidate for patients with NSCLC.

e20588 Background: MET exon 14 ( METex14) skipping caused by certain mutations in splice sites of METex14 has been regarded as a promising target for non-small cell lung cancer (NSCLC) treatment with crizotinib, and was observed with lower responsiveness to immunotherapy (Joshua K. et al ASCO 2017). The molecular and immune characteristics, antitumor activity of crizotinib for Chinese NSCLC patients harboring METex14 skipping alterations remain to be elucidated. Methods: Tumor genomic profiling was performed by next-generation sequencing (NGS) assay (GeneCast Biotechnology Co., Beijing) on 9722 samples (FFPE and/or peripheral blood derived from 9289 Chinese NSCLC patients). PD-L1 expression was determined by qualitative immunohistochemical assay. Multiplex immunohistochemistry (mIHC) analysis was adopted to evaluate the immune microenvironment of selected samples. Retrospective analysis was performed to explore antitumor activity of crizotinib monotherapy in 10 patients harboring METex14 skipping alterations. Results: A total of 62 (0.67%) patients with somatic mutations occurred in METex14 splice sites (± 3bp) were identified. Median age of these patients is 64.5 years and 39% patients are female. Main histologic types are adenocarcinoma (81%, 50/62) and squamous carcinoma (13%, 8/62). 30 patients harbored high frequency METex14 mutations ranged from 1.34% to 79.49% nearly without co-existed known driver variants. Other 32 patients had low frequency mutations (below 1%) with some crucial oncogenic mutations such as EGFR 19del/L858R. In addition, very few CD8+ T cells were observed in tumor region and significantly less infiltrated than in stroma region ( P< 0.01). The overall response rate of crizotinib monotherapy on the ten patients with METex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. Conclusions: The occurrence rate of METex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( < 1%) METex14 mutations usually co-exist with other driver mutations while high frequency METex14 mutations do not. That little infiltration of CD8+ T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying METex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring METex14 skipping alterations.

e13011 Background: To summarise the prevalence of pathogenic germline variants in East Asian cancer genomes and to develop an online resource and reference for genetic analysis of cancer susceptible germline mutation hotspots. Methods: We performed the most extensive investigation of germline mutations in East Asian cancer population based on publicly available data collected from multiple institutions over 1,600 patients with 15 cancer types. The pathogenic cancer susceptibility gene mutations were called by analyzing whole exome sequencing data generated from the normal control samples from the cancer patients deposited on the SRA database. Results: Compared with 9,435 East Asian controls in the gnomAD dataset, we identified pathogenic recurrent germline mutations based on our MaGiC analysis pipeline including quality controlled, filtration and annotation. More than 150 variants were found, and the top 3 hotspot mutations are TP53 in 5 types of cancer, BRCA2 in 3 types of cancer and PIK3CA in 4 types of cancer. The hotspot variants(same cancer predisposition gene set, but different pathogenic mutations) were of population difference in comparison with Caucasian population. Conclusions: Our work is the first comprehensive analysis of East Asian cancer predisposition germline mutations. It provides informative references for cancer genetic consulting and early prevention in more than 20% of world population. The update of our database covering larger populations and more cancer types is needed and still ongoing.

1572 Background: PLELC, a rare and distinct type of primary lung cancer, is characterized by Epstein-Barr virus (EBV) infection. Histologically, it resembles undifferentiated nasopharyngeal carcinomas (NPC). Only a few hundred cases have been reported since its discovery. Due to the extreme rareness, its genomic landscape remains elusive. Methods: Tissue samples of 27 PLELC patients (13 males and 14 females) with various stages (Ib to IV) were subjected to targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. Results: Collectively, we identified 184 somatic mutations spanning 109 genes, including 107 SNVs, 12 insertions or deletions (INDELs) and 65 copy-number amplifications (CNAs). Approximately, 50% of patients had CNAs. One patient had no mutation detected from this panel. Except for 2 patients, 1 with HER2 amplification and another with KRAS mutation, no other classic NSCLC driver genes were detected. The most frequently mutated genes were CCND1, TP53, DAXX and NF kBIA, occurring in 30%, 26%, 22% and 22% of patients, respectively. Interestingly, 78% (21/27) patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in epigenetics-related genes. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of PLELC with lung adenocarcinoma and EBV positive NPC. The frequency of TP53 mutations was significantly higher in lung adenocarcinoma (68% vs 26%, p = 0.021). Comparing to NPC, PLELC had significantly more mutations in epigenetic regulators. TMB analysis revealed a median TMB of 1.6/Mb, significantly lowered than lung adenocarcinomas (p < 0.01). We also assessed PD-L1expression and revealed that 67% had an overexpression of PD-L1. Interestingly, TP53-mutant patients were more likely to associated low PD-L1 expression (p < 0.01). Conclusions: In this study, we elucidated a distinct genomic landscape associated with PLELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for PLELC.

The high frequency of epidermal growth factor receptor (EGFR) mutations in tyrosine kinase inhibitor-responsive non-small-cell lung cancer (NSCLC) cases is now well established, highlighting the predictive value of activating EGFR mutations in guiding the clinical use of EGFR-targeted therapies. However, specimen source and methods for EGFR mutation analysis are limited by tissue availability and technical feasibility in clinical application. Therefore, the current study is designed to establish a blood-based approach for the assessment of EGFR mutations in NSCLC patients, in particular the advanced stage, and to test its clinical application. Plasma samples were obtained from the enrolled 134 NSCLC patients. The detection rate of the EGFR exon19 deletions and exon21 L858R was 49.3% (66/134) by the blood-based, mutant-enriched polymerase chain reaction. In the paired tumor and plasma samples, the detected mutant types of each pair respectively by direct sequencing and mutant-enriched polymerase chain reaction were concordant in 17 of 18 (94.4%). In the patients treated with gefitinib as a second-line therapy, those with plasma EGFR mutation have a prolonged median progression-free survival compared with those with EGFR wild type (7.609 vs. 2.877 months, p = 0.002). On comparing the efficacy of gefitinib with that of docetaxel, it was found that the median progression-free survival was significantly longer for patients treated with gefitinib than those with docetaxel in those harboring plasma EGFR mutation (7.609 vs. 3.192 months, p = 0.006). These results suggest that the blood-based EGFR mutations test has the ability to provide a reliable guidance for clinical decision making for the treatment of the advanced NSCLC patients.

// Mian Xie 1 , Xiaojun Wu 2 , Chaosheng He 3 , Jiexia Zhang 1 , Jinjun Zhang 4 1 China State Key Laboratory of Respiratory Disease and Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 2 State Key Laboratory of Oncology in Southern China, Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China 3 Department of Internal Medicine, Guangdong General Hospital, Guangzhou, China 4 Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China Correspondence to: Mian Xie, e-mail: mianxie@gird.cn Keywords: lung cancer, Ski, DNA methylation, prognosis Received: July 20, 2015 Accepted: November 22, 2015 Published: December 12, 2015 ABSTRACT Epigenetic silencing of tumor suppressors contributes to the development and progression of lung cancer. We recently found that Ski was hypermethylated in lung cancer. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in lung cancer. Ski methylation was evaluated by methylation-specific PCR (MS-PCR) and bisulfite sequencing. mRNA level of Ski was measured by RT-PCR and compared with the methylation status. Ski methylation correlated with decreased mRNA expression in human lung cancer cell lines. Ski hypermethylation was detected in 56.0% of primary lung tumors and associated with poor differentiation and late tumor stage. Demethylation agent 5-aza-2′-deoxycytidine (5-aza-2′dC) restored Ski expression. Re-expression of Ski in lung cancer cells inhibited cell proliferation, clonogenicity, migration, invasion and tumor formation. Ski decreased transcriptional activities of Smads and TAZ. Multivariate analysis showed that patients with Ski positive expression had a better overall survival in resected non-small cell lung cancer (NSCLC) patients. Our results revealed that Ski acts as a tumor suppressor inactivated by DNA methylation and is an independent prognostic factor of lung cancer.

Purpose This study aimed to identify potential epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer that went undetected by amplification refractory mutation system-Scorpion real-time PCR (ARMS-PCR). Materials and Methods A total of 200 specimens were obtained from the First Affiliated Hospital of Guangzhou Medical University from August 2014 to August 2015. In total, 100 ARMS-negative and 100 ARMS-positive specimens were evaluated for EGFR gene mutations by Sanger sequencing. The methodology and sensitivity of each method and the outcomes of EGFR-tyrosine kinase inhibitor (TKI) therapy were analyzed. Results Among the 100 ARMS-PCR-positive samples, 90 were positive by Sanger sequencing, while 10 cases were considered negative, because the mutation abundance was less than 10%. Among the 100 negative cases, three were positive for a rare EGFR mutation by Sanger sequencing. In the curative effect analysis of EGFR-TKIs, the progression-free survival (PFS) analysis based on ARMS and Sanger sequencing results showed no difference. However, the PFS of patients with a high abundance of EGFR mutation was 12.4 months [95% confidence interval (CI), 11.6−12.4 months], which was significantly higher than that of patients with a low abundance of mutations detected by Sanger sequencing (95% CI, 10.7−11.3 months) (p

TPS10142Background: The peripheral neurotoxicity induced by cisplatin is a common adverse event in non-small cell lung cancer (NSCLC) patients. This phase III trial will evaluate the efficacy and s...