RNA editing is a widespread post-transcriptional mechanism that confers specific and reproducible nucleotide changes in selected RNA transcripts and plays a critical role in many human cancers. However, little is known about how RNA editing operates in non-small-cell lung cancers. Here, we measured the sequence and expression level of genes of antizyme inhibitor 1 and adenosine deaminase acting on RNA family in 30 non-small-cell lung cancer patient samples and 13 cell lines and revealed RNA editing S367G in antizyme inhibitor 1 is a high-frequent molecular events. We determined overexpression of antizyme inhibitor 1 with RNA editing, implying the oncogenic function of this alteration. We also detected the association of adenosine deaminase acting on RNA overexpression with RNA editing occurred in antizyme inhibitor 1. Furthermore, the RNA editing could cause a cytoplasmic-to-nuclear translocation of antizyme inhibitor 1 protein and conferred the malignant phenotype of non-small-cell lung cancer cells. The in vivo experiment confirmed that this RNA editing confers higher capacity of tumor migration as well. In conclusion, antizyme inhibitor 1 RNA editing and its involvement in tumorigenesis of non-small-cell lung cancer pave a new way for potential clinical management of non-small-cell lung cancer.

Background: Small cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. In this study, we aimed to build a nomogram to predict the survival of individual with SCLC by incorporating significant clinical parameters. Methods:The patients with SCLC were enrolled from the First Affiliated Hospital of Guangzhou Medical University (GMUFAH) between 2009 and 2013. We identified and incorporated the independent prognostic factors to build a nomogram to predict the survival of SCLC patients. The predictive accuracy and discriminative ability of the nomogram were evaluated by concordance index (C-index) and calibration curve.We also compared the accuracy of the built model with the 7 th AJCC TNM and VALSG staging system. The nomogram was further validated in an independent cohort of 80 patients with SCLC from Cancer Center of Guangzhou Medical University (GMUCC) between 2009 and 2013.Results: A total of 275 patients with SCLC were included in the primary cohort, and seven independent prognostic factors were identified including age, N stage, metastasis status, histology, platelets to lymphocyte ratio (PLR), neuron specific enolase (NSE) and CYFRA21-1 as independent prognostic factors after using Cox regression model. A nomogram incorporating these prognostic factors was subsequently built. The calibration curves for possibilities of 1-, 2-year overall survival (OS) revealed optimal agreement between nomogram prediction and actual observation. The C-index of this nomogram was higher than that of TNM Conclusions:In this study, we established and validated a novel nomogram for the prediction of OS for the patients with SCLC. This model could provide more accurate individual prediction of survival probability of SCLC than the existing staging systems.

Background. Anlotinib has been shown to prolong progression-free survival (PFS) and overall survival (OS) for non-small cell lung cancer (NSCLC). Herein we sought to analyze the effect of anlotinib in managing brain metastases (BM) and its brain-associated toxicities. Methods. The PFS and OS of anlotinib versus placebo in those with and without BM recorded at baseline were calculated and compared respectively. Time to brain progression (TTBP), a direct indicator of intracranial control, was also compared between anlotinib and placebo. All calculations were adjusted for confounding factors, including stage, histology, driver mutation type, and therapy history. Results. A total of 437 patients were included; 97 cases were recorded with BM at baseline.

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Epidermal growth factor receptor (EGFR) mutations in cerebrospinal fluid (CSF) might be useful predictive markers for EGFR tyrosine kinase inhibitor treatment of intracranial metastatic tumors. In this retrospective study, amplification refractory mutation system (ARMS)-PCR assays were used to investigate the EGFR gene status in 30 lung adenocarcinoma patients with brain metastases. A total of 16 patients tested positive for EGFR-activating mutations in CSF or tumor tissues. These included L858R mutation in exon 21 in six CSF samples and exon 19 deletions in seven CSF samples. EGFR mutations were detected between CSF and primary tumor samples with a 75% positive predictive value (95% CI, 0.45-1.00), 75% negative predictive value (95% CI, 0.51-0.99), 67% sensitivity (95% CI, 0.36-0.97), and 82% specificity (95% CI, 0.59-1.00). Most of the patients who had EGFR mutations in CSF achieved good responses with EGFR-tyrosine kinase inhibitor treatment. In conclusion, ARMS-PCR could be a sensitive method of detecting EGFR mutations in the CSF of patients with lung adenocarcinoma with brain metastases. As such, ARMS-PCR could play an important role in guiding EGFR-tyrosine kinase inhibitor treatments of intracranial tumors and for diagnosing brain metastases in patients with lung adenocarcinoma.

Molecular analysis of potentially actionable mutations has become routine practice in oncological pathology. However, testing a wide range of oncogenes and mutations can be technically challenging because of limitations associated with tumor biopsy. Circulating tumor DNA (ctDNA) is a potential tool for the noninvasive profiling of tumors. In this study, we developed a next-generation sequencing (NGS)-based test for the detection of clinically relevant mutations in ctDNA and evaluated the feasibility of using this ctDNA NGS-based assay as an alternative to tissue genotyping. Tissue and matched blood samples were obtained from 72 patients with advanced nonsmall cell lung cancer (NSCLC). NGS-based testing was performed using plasma cell-free DNA (cfDNA) samples of all 72 patients as well as tumor DNA samples of 46 patients. Of the remaining 26 patients, tDNA was tested by amplification refractory mutation system PCR (ARMS-PCR) because of insufficient tissue sample or quality for NGS. Of the 46 patients who had tDNA and cfDNA NGS performed, we found 20 patients were concordant between tDNA and ctDNA alterations and 21 sample pairs were discordant because of additional alterations found in tDNA. Considering all clinically relevant alterations, the concordance rate between tDNA and ctDNA alterations was 54.9% with a sensitivity of 53.2% and a specificity of 75.0%. Our findings demonstrate that targeted NGS using cfDNA is a feasible approach for rapid and accurate identification of actionable mutations in patients with advanced NSCLC, and may provide a safe and robust alternative approach to tissue biopsy.

Limited treatment options are available for lung cancer with brain metastases. Recent reports indicated that erlotinib and pemetrexed had synergistic effects in lung adenocarcinoma. Thus, we speculated that erlotinib plus pemetrexed/cisplatin may be more effective for the treatment of refractory central nervous system metastases in patients after gefitinib failure. Six lung adenocarcinoma patients with leptomeningeal metastasis (LM) who showed initial good response to gefitinib and subsequent gefitinib resistance were enrolled in this retrospective study. Five of the six patients had an epidermal growth factor receptor (EGFR) mutation in the primary tumor tissues or plasma. One patient showed complete remission, two patients showed a partial response, and two patients had stable disease. Performance and symptoms improved in the six patients. The survival time after the combination therapy was from 8 to 15 months (median, 9 months). There was no significant difference in cerebrospinal fluid (CSF) penetration rates of erlotinib between the erlotinib-only and the combination groups (P = 0.44). Erlotinib combined with pemetrexed/cisplatin may be effective in the treatment of LM in EGFR mutation patients after gefitinib failure. Small but measurable penetration of erlotinib and pemetrexed into the CSF was observed.

e21618 Background: Immune checkpoint blocker (ICB) monotherapy showed a lack of response in advanced NSCLC patients with EGFR mutations. This Phase II study aimed to evaluate the efficacy and safety of toripalimab, a humanized PD-1 mAb plus platinum doublets chemotherapy in EGFR mutant advanced NSCLC patients, who developed resistance to 1st/2nd generation of EGFR TKIs and without T790M mutation. Methods: Patients received toripalimab (240 or 360 mg) intravenously combined with carboplatin (AUC = 5) and pemetrexed (500mg/m2) on day 1, Q3W, for up to 6 cycles, followed by toripalimab and pemetrexed maintenance until disease progression or unacceptable toxicity. Efficacy was evaluated every six weeks according to RECIST v1.1. PD-L1 expression (JS311 assay) and co-mutation status by whole exome sequencing were further analyzed. Results: From Apr 2018 to March 2019, 40 patients were enrolled from 8 centers in China. The median age was 57 years with 53% female, 57.5% EGFR exon19 deletion and 42.5% L858R mutation. By the cutoff date of Jan 2, 2020, 20 partial response and 15 stable disease were observed (ORR 50% and DCR 87.5%) with a median DOR of 7.0 months. The median PFS was 7.0 months and the median OS was still not reached. 52.6% (20/38) patients were PD-L1+ (TPS≥1%) and had numerically higher ORR (60% vs 39%, p= 0.33) and longer PFS (median 8.3 vs 5.7 months, p= 0.61) than PD-L1- patients. Co-mutations analysis revealed common genetic alternations including TP53 (79%), RB1 (18%), ERBB2 (15%), PIK2CA (12%), CDKN2A (12%), HDAC9 (12%) and MET (9%). Patients with TP53 co-mutation responded significantly better in ORR than TP53 wild type patients (62% vs 14%, p= 0.04) . Most frequent TRAE included leukopenia (78%), neutropenia (70%), anemia (70%), ALT elevation (48%), AST elevation (48%) and nausea (48%). Grade 3+ TRAE occurred in 55% patients, including neutropenia (43%), leukopenia (20%) and anemia (13%). Dose delay due to TRAE occurred in 40% patients while 10% patients discontinued treatment due to TRAE. Conclusions: Toripalimab in combination with chemotherapy showed promising anti-tumor activity with a manageable safety profile for advanced NSCLC patients with EGFR mutations refractory to TKI therapies. Patients with PD-L1+ tumor biopsy or TP53 co-mutation preferentially responded to the combination. A randomized phase III trial is ongoing to further validate the finding in this study (NCT03924050). Clinical trial information: NCT03513666.