Virtual Library

  • +

    Poster Session (ID 8)

    • Event: ACLC 2018
    • Type: Poster Session
    • Track:
    • Presentations: 90
    • Moderators:
    • Coordinates: 11/07/2018, 00:00 - 00:00, Poster Hall
    • +

      P001 - Discrepancy of Oncogenic Mutations in Bone Metastasis Derived from Lung Adenocarcinoma (ID 104)

      00:00 - 00:00  |  Author(s): L. Huang, A. Liu

      • Abstract

      Background:
      The objective of this study is to assess the different of cancer driver gene mutations in lung adenocarcinoma patients with bone metastasis using tilling PCR amplification sequencing (tPAS), a next-generation sequencing (NGS) method, and screen for the driver genes which are associated with bone metastasis of lung cancer.


      Method:
      Fifteen clinicopathologic samples from of lung adenocarcinoma combined with bone metastasis patients were collected. Exome sequencing was conducted within 398 tumor-associated genes using CN500 NGS platform.


      Results:
      Two hundred and twenty somatic gene mutations were detected, including point mutation, insertion, and deletion. Among all cancer driver genes, the top five gene mutations of EGFR (7/15), TP53 (7/15), ROS1 (3/15), IDH2 (2/15), and SYNE1 (2/15) were found to be mutated in lung adenocarcinoma patients; EGFR (7/15), TP53 (5/15), ADGRL3 (2/15), APC (2/15), and KMT2C (2/15) were found to be mutated in bone metastasis patients. Notably, KMT2C gene alternation was only observed in bone metastasis comparing to lung adenocarcinoma patients. In the lung adenocarcinoma mutation-negative cases, tPAS assay identified mutation frequency of EGFR (53.67%), CTNNB1 (16.01%), CASC5 (11.14%), MTOR (5.88%), FH (5.65%), and PIK3C2B (5.56%) in bone metastatic lesions. Moreover, according to over 50% mutation frequencies, the top three genes were EGFR (79.03%), ADGRL3 (75.25%), and FANCD2 (57.81%) in lung adenocarcinoma patients; the top four genes in bone metastasis patients were ADGRL3 (91.28%), EGFR (72.14%), KEAP1 (62.99%), and STK11 (55.18%). In addition, gene mutation frequencies of bone metastasis patients were higher than lung adenocarcinoma patients in EGFR (32.73%, 21.67%, 38.64%, 21.83% VS. 21.80%, 13.14%, 22.69%, 15.11%), KEAP1 (62.99% VS. 20.26%), PBRM1 (25.51% VS. 22.38), PIK3CG (44.74% VS 31.14%), TCF3 (15.00% VS. 12.38%), and TP53 (23.24% VS. 20.72), respectively. There were no significant differences (p>0.05) in correlation of tumor mutation burden (TMB) and lung cancer bone metastasis. TMB may not play a crucial role in bone metastasis.


      Conclusion:
      The results indicated that discrepancy of oncogenic mutations between lung adenocarcinoma and bone metastasis may be the biomarkers to predict cancer spreading. The patients with gene mutations found in bone metastases of lung adenocarcinoma suggested new potential molecular targets for diagnostics disease progression monitoring.

    • +

      P002 - Surgical Resection Improves the Survival of (ID 134)

      00:00 - 00:00  |  Author(s): B. Zhang, Q. Xiao

      • Abstract

      Background:
      Introduction: Due to the advent of molecular targeted therapy, the therapeutic landscape of advanced NSCLC with certain driver mutations has been changed substantially. Local consolidation therapy with surgery or radiotherapy in combination with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is believed to achieve longer progression-free survival (PFS) for stage IV NSCLC patients with oligometastases. We investigated whether primary tumor resection in non-small cell lung cancer (NSCLC) patients with ipsilateral pleural dissemination could achieve more clinical benefit during first-line targeted therapy.


      Method:
      Methods: Patients with an initial diagnosis of stage IVa NSCLC who had ipsilateral pleural dissemination and received first-line EGFR-TKIs were included. Overall survival (OS) and progression-free survival (PFS) were analyzed. Median (m)PFS was the primary endpoint.


      Results:
      Results: Patients were divided into three groups: 17 cases in the palliative resection (PR) group, 15 in the video-assisted thoracoscopic surgery (VATS) biopsy (VB) group, and 56 in the pneumocentesis (P) group. Median (m)PFS and mOS for the entire cohort were 15.7 and 37.5 months, respectively. MPFS for PR group was 27.4 months, significantly longer than that for the VB and P groups (15.1 months and 13.3 months, respectively (p<0.05)). The mPFS for patients with primary tumors ? 3.5 cm was 21.4 months, compared with 13.3 months for tumors >3.5 cm (p=0.017). In PFS multivariate analysis, primary tumor length (HR 1.682) and treatment modality (HR 0.795) were possible independent prognostic factors. The mOS and 5-year OS rate for the PR group was 48.0 months and 44.8%, respectively, compared with 37.5 months and 11.3%, respectively, for patients whose tumors were not resected (p=0.130). For patients who received subsequent targeted therapy (n=30) after first progression, mOS and 5-year OS rate were 52.9 months and 48.8%, respectively, compared with 29.6 months and 2.9%, respectively, for patients who received chemotherapy (n=45) (p=0.000). In further OS multivariate analysis, subsequent treatment was the only independent prognostic factor (HR 5.873, 95% CI, 2.694

    • +

      P003 - Prognosis of Advanced Lung Cancer by Age Groups : A SEER Database Analysis (ID 71)

      00:00 - 00:00  |  Author(s): B. Wang, J. Liu

      • Abstract

      Background:
      Lung cancer is very common in malignancies, it is the main cause of cancer death. Lung cancer usually occurs in the elderly, and it is late for diagnosis. However, there are few studies on the prognosis of advanced lung cancer by age groups. The purpose of this study is to investigate the effect of age on the prognosis of advanced lung cancer.


      Method:
      We extracted the data of lung cancer patients diagnosed stage IV between 2010 and 2014 from the Surveillance, Epidemiology and End Results (SEER) database in which data of patients with unknown age were excluded. We divided the patients into three groups: younger group (age <50 years old), middle-aged group (age between 50-69 years old) and elder group (age >69 years old). Pearson

    • +

      P006 - Evaluation of Efficacy and Safety of Uniportal Segmentectomy in the Treatment of Small Lung Nodule (ID 125)

      00:00 - 00:00  |  Author(s): C. Zhang, G. Wang, Z. Yu, H. Liu, H. Liu

      • Abstract

      Background:
      Uniportal segmentectomy is a therapeutic option for small lung nodule, but the debate over uniportal segmentectomy still remains. The aim of this study is to evaluate of efficacy and safety of uniportal segmentectomy in the treatment of small lung nodule.


      Method:
      A total of 85 patients who underwent uniportal segmentectomy or subsegmentectomy between January 2017 and September 2018 in Liaoning Cancer Hospital. The clinical data of these patients were retrospectively analyzed, including operation time, number of lymph nodes dissected and postoperative mortality, postoperative complications, postoperative intubation time, and postoperative hospital stay.


      Results:
      The surgery procedure was anatomical pulmonary segmentectomy or subsegmentectomy. Uniportal segmentectomy was in 81 cases, and subsegmentectomy was in 4 cases. The median operation time was 243 minutes (range, 60-405 minutes), median number of lymph nodes dissected was 14 (range, 0-31), median postoperative intubation time was 5 days (range, 1-9 days), median postoperative hospital stay was 8 days (range, 3-19 days). The postoperative complications were pneumonia 1 case (1.2%), fever 9 cases (10.6%), hemoptysis 1 case (1.2%), air leak 1 case (1.2%), atrial fibrillation 1 case (1.2%), and subcutaneous hydrops 2 cases (2.4%). There was no severe postoperative complications, including death, bleeding, reoperation, and bronchopleural fistula.


      Conclusion:
      Uniportal segmentectomy is a safe and feasible technique for treating small pulmonary lesions, with acceptable postoperative complications and mortality.

    • +

      P008 - Correlation Between Genetic Mutation State and Cancer-Associated Thrombosis in Advanced Cancer Patients (ID 33)

      00:00 - 00:00  |  Author(s): X. Zhang, Z. Wang, D. Jiang

      • Abstract

      Background:
      To investigate the correlation between genetic mutation state and cancer-associated thrombosis in advanced cancer patients.


      Method:
      133 cases of advanced cancer patients were divided into mutation group and non-mutation group according to their genetic states. Venous Doppler ultrasound examination was performed to determine the incidence of thrombosis. Incidence of thrombosis was compared between 2 groups. Genetic mutation rate was calculated in thrombosis patients. Risk factors for thrombosis were analyzed in 2 groups. Sensitivity and specificity were compared using Khorana risk assessment model. Low-risk subgroups/middle-risk subgroups/high-risk subgroups were determined by Khorana risk assessment model in mutation/non-mutation group. Incidence of thrombosis were compared between corresponding subgroups (low-risk to low-risk, middle-risk to middle-risk, high-risk to high-risk).


      Results:
      1. Genetic mutation rate was 75.2% in all patients. Thrombosis rate was 13.53% in all patients. Genetic mutation rate in thrombosis patients was 88.89%. 2. Thrombosis rates in mutation/non-mutation group were 16.0% and 6.1%, respectively (P=0.2490). 3. The thrombosis rates in EGFR?ALK?TP53?Her-2?KRAS?PIK3CA?T790M gene mutation were 27.8%?5.6%?33.3%?5.6%?11.1%?0?5.6%, respectively (P=0.248,0.873,0.804,1.000,0.959,0.469,1.000). 4. Sensitivity and specificity in mutation group were 16.8% and 60.0% in Khorana risk assessment model. In non-mutation group those were 6.9% and 100.0%, respectively. AUC for 2 groups ROC were 0.571 and 0419, respectively (P>0.05). 5. Thrombosis rates for each corresponding subgroups were 33.3% vs 0% (mutation low-risk subgroup vs non-mutation low-risk subgroup), 10.7% vs 7.1% (mutation middle-risk subgroup vs non-mutation middle-risk subgroup) and 57.1% vs 0% (mutation high-risk subgroup vs non-mutation high-risk subgroup). P values were 0.497, 0.940, 1, separately.


      Conclusion:
      There is no correlation between genetic mutation state and cancer-associated thrombosis in advanced cancer patients.

    • +

      P011 - Concurrent ALK/EGFR Alterations in Chinese Lung Cancers: Frequency, Clinical Features, and Differential Response to Therapy (ID 152)

      00:00 - 00:00  |  Author(s): D. Wu, J. Liu, Z. Mu, L. Liu, K. Li, R. Jiang, P. Chen, Q. Zhou, M. Jin, Y. Ma, Y. Xie, J. Xiang, T. Zhang, B. Li, B. Yu

      • Abstract

      Background:
      ALK rearrangement and EGFR alterations are oncogenic driver mutations in lung cancers. Generally considered mutually exclusive, some studies suggested that these two mutations might occur concomitantly. Limited studies have reported the underlying association of molecular features and drug response to EGFR-TKIs in lung cancers with such co-alterations. Here, we performed next-generation sequencing (NGS) analysis in Chinese lung cancer patients, and evaluated distinct features of EML4- vs. non-EML4-ALK fusions in EGFR-mutated cases.


      Method:
      A retrospective review was performed on genomic profiling data from either tissue or plasma of 419 ALK-rearranged lung cancer patients, sequenced in a CLIA-certified laboratory from 2015 to 2017. Patient characteristics (n=21) and clinical outcomes of patients harboring concurrent EGFR and ALK alterations were collected.


      Results:
      Among the 419 ALK-rearranged lung cancers, a total of 21 patients (5.01%) were detected harboring concurrent ALK and EGFR (exon 18-20) genomic alterations. The concomitant rate of EGFR in patients harboring EML4-ALK (3.06%, 11/359) was dramatically lower than in non-EML4-ALK patients (16.67%, 10/60, p<0.001). Four EML4-ALK and 1 non-EML4-ALK patients were found to have de novo ALK/EGFR co-mutations whereas 1 EML4-ALK and 3 non-EML4-ALK patients acquired their ALK alterations after EGFR TKI treatment. For dual-positive patients who received past EGFR-TKI with unknown ALK status before the treatment, EML4-ALK/EGFR patients (n=6) commonly had shorter PFS to EGFR-TKI as well as higher relative ALK/EGFR allele frequency compared to non-EML4-ALK/EGFR (n=6; mPFS, 5.45 vs 15 months, p=0.11; mRAF, 1.52 vs 0.41, p=0.01), suggesting that EML4-ALK was more likely to be de novo whereas non-EML4-ALK acquired after EGFR-TKI. In addition, we found that for 9 dual-positive patients who had prior first-generation EGFR-TKI treatment, the clinical efficacy of single TKI use varied greatly, and patients might benefit from combination therapy of ALK+EGFR TKIs.


      Conclusion:
      This study revealed that EML4-ALK/EGFR and non-EML4-ALK/EGFR co-alterations displayed distinct prevalence in Chinese lung cancer patients. Our analyses suggested that non-EML4-ALK might be an acquired gene alteration and function as a resistance mechanism to EGFR-TKI, which might explain the observed discrepancy in prevalence as our sequencing cohort consisted of both previously treated or untreated patients. In addition, we observed that patients with dual ALK/EGFR alterations may benefit from combinatorial TKIs therapy.

    • +

      P012 - Pooled Safety Analysis for Two Generations ALK Inhibitors: A Meta Analysis (ID 31)

      00:00 - 00:00  |  Author(s): D. Sun, H. Hou, X. Zhang

      • Abstract

      Background:
      2% - 7% NSCLC patients were detected to have ALK mutation. At present, two or more generations ALK inhibitors have been used for ALK positive NSCLC treatment which including crizotinib, alectinib, ceritinib, brigatinib and so on. Although, most of the adverse events(AEs) of ALK inhibitors are grade 1 to grade 2 and can be generally well tolerated, the serious adverse events(SAEs) of ALK inhibitors are lack of huge data analysis as we know and the lung toxicity of ALK inhibitors is needed to be payed attention to. Thus, we performed meta analysis to evaluate the safety of ALK inhibitors and especially the SAEs.


      Method:
      16 studies from 4 database (Pubmad, Science Direct, ClinicalTrials.gov and Cochrane Library) were included in this meta analysis. All statistical analyses in this meta analysis were performed by STATA 14.0 software. We analyzed the incidence of pooled AEs, the incidence of pooled SAEs and the incidences of common types of SAEs of ALK inhibitors.


      Results:
      ??2.pngThe pooled AEs of ALK inhibitors almost occurred in all participates and the pooled SAEs occurred in over 20% participates. Especially ceritinib and brigatinib, of which the SAEs occurred in over 40% participates. It is likely that alectinib is safest ALK inhibitors of the two generations ALK inhibitors. Generally, ALK inhibitors shows significant lung toxicity.


      Conclusion:
      In conclusion, the ALK related SAEs should draw our attention especially the lung toxicity. According to this meta analysis, alectinib seems to be the safest ALK inhibitor. Physicians should focus on the related SAEs when using ALK inhibitors.

    • +

      P013 - Anti-PD-1 Combination (ID 85)

      00:00 - 00:00  |  Author(s): F. Zhang, D. Huang, L. Li, J. Ma, J. Wang, S. Jiao, Y. Hu

      • Abstract

      Background:
      Effective treatment options are limited for advanced non-small cell lung cancer (NSCLC) patients who progressed after first-line therapy. Pronounced efficacy of anti-programmed cell death protein 1 (anti-PD-1) combination strategy was observed in first-line setting, therefore we assessed whether the addition of chemotherapy and/or bevacizumab to anti-PD-1 could improve clinical outcomes in second-line or later advanced NSCLC.


      Method:
      Advanced NSCLC patients treated with anti-PD-1 therapy from March 2015 to July 2017 were retrospectively screened for eligibility. First-line treatment or combined drugs beyond chemotherapy or bevacizumab were excluded. The primary objective was progression-free survival (PFS). Secondary objectives were overall response rate (ORR), disease control rate (DCR) and safety.


      Results:
      55 patients were included in the analysis (monotherapy, n=33; combination therapy, n=22). 90.0% of the patients have progressed after standard platinum-based chemotherapy in previous line therapies. Combination group exhibited longer PFS than monotherapy group (median, 7.5 vs 3.3 months, adjusted HR 0.32[0.16-0.65], P =0.001). 31.8% (7/22) patients in combination group achieved an objective response compared with 10.0% (3/30) in monotherapy group (P = 0.075). The DCR was 95.5% (21/22) in combination group compared with 46.7% (14/30) in monotherapy group (P<0.001). Adverse events of grade 3 or worse were occurred in 22.7% of the patients in the combination group and in 6.1% of those in monotherapy group. Most of the adverse events were manageable.


      Conclusion:
      Combination of anti-PD-1 plus chemotherapy and/or bevacizumab could be an effective and tolerable therapy as second-line or later treatment option for advanced NSCLC patients.

    • +

      P015 - Motion Management Without Fiducial Tracking Using Cyberknife SBRT (ID 10)

      00:00 - 00:00  |  Author(s): G. Lohith, S. Varun Kumar, S. Shwetha, P. Anuradha

      • Abstract

      Background:
      Cyber Knife robotic stereotactic radiosurgery is minimally invasive tumor treatment modality that can deliver high precision radiotherapy to any part of the body with minimal exposure to adjacent and surrounding vital organs and is used to treat oligometastasis of the lung from primary breast cancer patients.In the modern high precision treatment delivery,utmost care should be taken for motion management of tumor targets.The Objective of this study was to investigate the accuracy and efficacy of Cyber knife in the treatment of lung metastasis from breast cancer using fuducial free respiratory tracking system using cyberknife stereotactic radiosurgery.


      Method:
      We examined toxicity and local control rate with fiducial-free CyberKnife stereotactic body radiation therapy (SBRT) for lung metastases from 20 breast cancer patients. All patients had favorable performance status (ECOG 0

    • +

      P016 - The Optimal ALK inhibitor in Advanced ALK-Positive NSCLC Patients: An Indirect Comparison Between Brigatinib and Alectinib (ID 224)

      00:00 - 00:00  |  Author(s): H Zhou

      • Abstract

      Background:
      Recent randomized phase III trials (ALTA-1L and ALEX) reported the robust efficacy of next-generation anaplastic lymphoma kinase (ALK) inhibitors (brigatinib and alectinib) for the first-line treatment of patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). However, there is no head-to-head comparison of brigatinib vs. alectinib. In this study, we aimed to explore the optimal choice of ALK inhibitors treatment for advanced ALK-Positive NSCLC.


      Method:
      We performed an indirect comparison of ALTA-1L and ALEX to compared therapeutic efficacy and adverse event (AE) between brigatinib and alectinib as the first-line treatment of advanced ALK-Positive NSCLC. The clinical outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and AE. Hazard ratio (HR, for PFS and OS) / risk ratio (RR, for ORR and AE) and its 95% confidence interval (CI) were extracted.


      Results:
      Brigatinib and alectinib had similar PFS (hazard ratio (HR) with 95% confidence interval, 1.14, 0.69-1.88; P=0.61) and OS (HR, 1.29, 0.58-2.85; P=0.53), while they had similar ORR, all cause AE and grade 3-5 AE. For patients with/without baseline CNS metastases, Brigatinib and alectinib still showed similar PFS.


      Conclusion:
      Our study revealed that brigatinib and alectinib may be similar in terms of efficacy and safety for the first-line treatment of patients with ALK-positive NSCLC.

    • +

      P017 - Investigation of Mediastinal Lymph Node Metastasis in Non-Small Cell Lung Cancer (ID 72)

      00:00 - 00:00  |  Author(s): G. Wang, C. Zhang, H. Liu, Z. Yu, H. Liu

      • Abstract

      Background:
      To investigate the distribution of mediastinal lymph node metastasis in non-small cell lung cancer(NSCLC) and provide evidence for the range of mediastinal lymph node dissection.


      Method:
      Retrospectively analyze NSCLC patients underwent systematic lymph node dissection and confirmed mediastinal lymph nodes metastasis postoperatively.


      Results:
      78 cases were enrolled in this research. 11 in left upper lobe (14.1%), 27 in left lower lobe (34.6%), 16 in right upper lobe (20.5%), 4 in right middle lobe (5.1%), 20 in right lower lobe (25.6%). Among all left upper lobe cancers, 10 had upper mediastinal lymph node metastasis (66.7%); 5 subcarinal metastasis (33.3%), and no lower metastasis cases; in left lower cancers, 5 had upper mediastinal lymph node metastasis (13.5%), 17 subcarinal metastasis (45.9%), and 15 lower mediastinal metastasis (40.5%). For right upper lobe, 16 had upper mediastinal metastasis (64%), 6 subcarinal metastasis (24%), and 3 lower mediastinal metastasis (12%); for right middle lobe, 2 had upper mediastinal metastasis (33.3%), 3 subcarinal metastasis (50%), and 1 lower mediastinal metastasis (16.7%); for right lower lobe, 12 had upper mediastinal lymph node metastasis (34.3%), 11 subcarinal metastasis (31.4%), and 12 lower mediastinal metastasis (34.3%).


      Conclusion:
      In all mediastinal lymph node metastasis cases , metastasis could emerge in the other locations except for left upper cancers with no lower mediastinal metastasis. It might be acceptable to perform mediastinal lymph node dissection of NSCLC, except for lower mediastinal lymph node in left upper lung cancer. However, further researches with larger amount of cases are required.

    • +

      P018 - Afatinib Named Patient Use Program in Advanced NSCLC with Progression on Prior Therapy: Experience from Asian Centers (ID 93)

      00:00 - 00:00  |  Author(s): G. Chang, D.C. Lam, C. Tsai, Y. Chen, J. Shih, S. Aggarwal, S. Wang, S. Kim, Y. Kim, I. Wahid, R. Li, W. Lim, V. Sriuranpong, T.T. Chan, J.C. Yang, C. Yu, W. Liao, C. Ho, R.M. Lorence, P. Carriere, C. Raabe, A. Cseh, K. Park

      • Abstract

      Background:
      A global named patient use (NPU) program for afatinib in patients with advanced/metastatic NSCLC who had progressed during prior therapy was conducted between May 2010 and January 2016 (Cappuzzo et al (2018). Here we describe outcomes for patients at Asian centers, including 840 patients treated at centers in Taiwan.


      Method:
      Eligible patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had an activating EGFR/HER2 mutation, had exhausted all other treatments, and were ineligible for afatinib trials. Patients received afatinib (starting dose: 30

    • +

      P020 - Characterization of Met Exon 14 Skipping and Association with Clinical Outcomes of Crizotinib in Chinese Lung Cancers (ID 192)

      00:00 - 00:00  |  Author(s): H. Yang, C. Zhou, Y. Su, Z. Zhou, P. Chen, M. Yang, C. Li, W. Guo, W. Zhao, K. Lu, J. Yin, J. Chen, Z. Li, X. Yu, X. Xu, J. Xiang, T. Zhang, B. Li, L. Zhang, H. Liu, N. Yang

      • Abstract

      Background:
      Mesenchymal-to-epithelia transition (MET) exon 14 skipping (METex14) has been recognized as a potential driver alteration in lung cancers, and represents an emerging molecular target for lung cancer treatment. However, most studies about patient characterization and clinical outcomes of METex14-positive lung cancer were conducted in Caucasians, relevant data in Chinese patients were lacking. Here, we retrospectively characterized the clinical and molecular features of patients harboring MET mutations causing exon 14 skipping in a large cohort of Chinese lung cancers, and interrogated relevant clinical parameters associated with clinical outcomes of crizotinib treatment.


      Method:
      Genomic profiling data obtained from either plasma or tissue of 7,507 lung cancer patients with various histological types were screened to identify patients harboring METex14.


      Results:
      A total of 68 patients (0.91%), different from the frequency of Western population (3%), were identified to carry DNA alterations predicted to cause METex14 with a median age of 67.5, which is statistically significantly older than the whole cohort (p<0.001, t-test). In addition, METex14 has a female predominance (p=0.036, Fisher

    • +

      P021 - The Impact of TP53 Mutation and Tumor Mutation Number on Outcomes in Patients with Stage I Non (ID 168)

      00:00 - 00:00  |  Author(s): S. Zheng, J. Xia, F. Zeng, L. Huang, F. Li, H. Zhu, G. Liao, Z. Lin, H. Zhou

      • Abstract

      Background:
      Mutations of the Tumor protein p53 (TP53) gene and Tumor Mutation Number (TMN) have been associated with the formation of tumor especially in non- small lung cancer (NSCLC). However, their prognostic roles in early stage NSCLC were not well defined. In this study we sought to identify the pure prognostic role of TP53 mutation and TMN in patients with completely resected stage I NSCLC.


      Method:
      244 patients of stage I (T1a-cN0) NSCLC who had been completely resected (1991-2014)with TP53 Mutation status and TMB data were collected from TCGA Database . TMB data was analyzed in 119 patients. Disease free survival (DFS) and overall survival (OS) were compared between TP53 mutation and wild-type mutation, higher TMN (?223.5) and lower TMN (<223.5).DFS and OS were estimated using Kaplan Meier methods and Cox regression models .


      Results:
      244 patients were included in this study with 122 (50%) TP53 mutations. Multivariate analysis identified TP53 mutation tumors were associated significantly shorter OS(HR 2.31, 95%-CI 1.34 to 3.87;p?0.002) and DFS(HR 1.80, 95%-CI 1.12 to 2.71;p?0.005) compared to wild-type tumors. The TMN between TP53 mutation and wild-type mutation was significant?mean 332.1 vs 164.1?p?0.001?,TMN?223.5was associated with worse OS (HR 2.72, 95% CI 1.25-5.93, p=0.012) and DFS(HR 1.79, 95% CI 1.01-3.15, p=0.045). TMN?223.5 were identified as independent prognostic markers. survival analysis of TP53 mutation and TMN.png


      Conclusion:
      TP53 and TMN?223.5 are two independent prognostic factors in resected stage I lung adenocarcinoma. TP53 mutation might increase TMN which impact on the prognosis.

    • +

      P022 - Association Between Oral Leukoplakia and Lung Cancer: A 28-Year Follow-Up Study in the Linxian General Population Trial (ID 145)

      00:00 - 00:00  |  Author(s): H. Liang, J. Wang, J. Fan, Y. Qiao

      • Abstract

      Background:
      Oral leukoplakia is a precancerous disorder that is also common among individuals in Linxian. However, the link between oral leukoplakia and risk of lung cancer mortality has not been reported. Therefore we investigated the relationships between oral leukoplakia and lung cancer in the Linxian General Population Trial cohort.


      Method:
      The Linxian General Population Trial cohort, with 29,584 healthy adults enrolled in 1985 and followed through the end of 2012. With collected baseline data, hazard ratios (HR) and 95% confidence intervals (95% CI) for developing lung cancer were estimated using Cox proportional hazard models.


      Results:
      Overall, a total of 29449 were included in the final analysis. During 28 years of follow up, we confirmed a total of 277 incident lung cancer cases. Overall, participants with oral leukoplakia had little risk for developing lung cancer (HR=1.01, 95%CI: 0.67, 1.16). No significant associations were observed for lung cancer in either all subjects or subgroups.


      Conclusion:
      Our results suggest that oral leukoplakia is not associated with increased risk of lung cancer mortality. Future studies are needed to confirm these findings.

    • +

      P023 - Factors associated with administration of subsequent cytotoxic chemotherapy after nivolumab in patients with advanced NSCLC (ID 164)

      00:00 - 00:00  |  Author(s): H. Jo, H. Horinouchi, R. Higashiyama, N. Tamura, S. Yagishita, Y. Matsumoto, S. Murakami, Y. Goto, S. Kanda, Y. Fujiwara, N. Yamamoto, Y. Ohe

      • Abstract

      Background:
      Immune checkpoint inhibitors, including nivolumab, have shown a promising clinical efficacy in patients with advanced non-small cell lung cancer (NSCLC). Based on the characteristic pattern of response and progression, however, there is substantial clinical concern about the timing of switching treatment after progressive disease in patients receiving nivolumab treatment.


      Method:
      We conducted a consecutive retrospective analysis of patients with advanced NSCLC treated with nivolumab as a second-line treatment at the National Cancer Center Hospital from December 2015 to November 2017. Clinical information including age, sex, performance status (PS), histology, and progressive disease (PD) situation at the point of the last dose of nivolumab were evaluated. We defined the PD situation as follows: continuation of nivolumab after worsening of imaging findings (beyond PD); PD after ?2 cycles of nivolumab without beyond PD (Early PD), and PD after 3? cycles of nivolumab without beyond PD as (Late PD).


      Results:
      A total of 213 patients received nivolumab; 109 of these patients received nivolumab as a second-line treatment. Finally, 105 patients (78 men, 27 women) without EGFR or ALK driver oncogene mutations were included in this analysis. The patients' characteristics were as follows: male/female, 78/27 patients; median age (range), 63 (34-83) years; PS 0/1/2/3/4, 19/57/18/6/5 patients; and non-squamous/squamous histology, 77/28 patients. Four patients were treated beyond PD. The median number of nivolumab treatment cycles was 6, the objective response rate was 16%, and the median progression-free survival was 3.9 months (95% confidence interval: 2.5-6.0 months ). Among the 90 patients with disease progression, 42 patients (47%) received chemotherapy after nivolumab treatment. Among the patients with disease progression who did not receive chemotherapy after nivolumab treatment (48 patients, 53%), the main reasons for non-administration were a worsening of the patient

    • +

      P024 - Sleeve Lobectomy for Centrally Located Non-Small Cell Lung Cancer: Experience of a Single Institute (ID 111)

      00:00 - 00:00  |  Author(s): H. Liu, Y. Ma, Z. Yu, Y. Ren, C. Zhang, G. Wang, H. Liu

      • Abstract

      Background:
      To evaluate the feasibility and safety of sleeve lobectomy for centrally located non-small cell lung cancer and summarize our surgical experience.


      Method:
      Clinical data of 45 patients who underwent sleeve lobectomy at Department of Thoracic Surgery of Liaoning Cancer Hospital & Institute from November 2016 to June 2018 including 6 cases had neoadjuvant chemotherapy were collected retrospectively, and operative strategies, time of postoperative drainage, postoperative hospital stay and postoperative complications were also recorded.


      Results:
      All patients received sleeve lobectomy successfully. Of all the patients, 8 patients underwent bronchial and arterial sleeve lobectomy, 4 underwent bronchial sleeve resection and partial side wall of arterial resection, 2 underwent arterial sleeve resection and partial side wall of bronchial resection, 31 underwent bronchial sleeve resection only. There was no perioperative death in all patients. Margin status was R0 in 39 patients (86.7%), R1 in 5 patients (11.1%), R2 in 1 patient (2.2%). The median time of postoperative drainage was 7 days (3-26 days), median time of postoperative hospital stay was 11 days (6-28 days). Major complications occurred in 11 patients (24.4%), including 1 chylothorax, 6 pneumonia, 3 pleural effusion, 1 air leak. Endotracheal endoscopic sputum aspiration was performed in 11 patients postoperatively. Pathologic diagnosis showed squamous cell carcinoma in 35 patients, adenocarcinoma in 6 patients, adenosquamous carcinoma in 2 patients, and large cell carcinoma in 1 patient. 2 patients were in stage ?A3, 7 patients were in stage ?B, 2 patients were in stage ?A, 24 patients were in stage ?B, 5 patients were in stage ?A?and 4 patients were in stage ?B. All patients recovered well and were discharged uneventfully.


      Conclusion:
      Sleeve lobectomy is a safe and feasible procedure for treatment of centrally located non-small-cell lung cancer. It is an accepted procedure to expand operation indications and avoid pneumonectomy, improve postoperative quality of life.

    • +

      P025 - Which Is the Optimal Immunotherapy for Advanced Non-Squamous Non-Small-Cell Lung Cancer in Combination with Chemotherapy? (ID 222)

      00:00 - 00:00  |  Author(s): H Zhou

      • Abstract

      Background:
      Two phase III randomized clinical trials (KEYNOTE-189 and IMpower132) reported that the addition of anti-programmed death (ligand) 1 (anti-PD-(L)1) antibodies to first-line platinum-based chemotherapy improve the therapeutic efficacy for advanced non-squamous non-small-cell lung cancer (NSCLC). However, there is no head-to-head comparison of pembrolizumab (anti-PD-1) plus chemotherapy vs. atezolizumab (anti-PD-L1) plus chemotherapy.


      Method:
      In terms of chemotherapy as the bridge, we performed an indirect comparison of KEYNOTE-189 and IMpower132 to compared therapeutic efficacy and adverse event (AE) between pembrolizumab (N=410) and atezolizumab (N=292) in combination with chemotherapy as the first-line treatment of advanced squamous NSCLC. Data of overall survival (OS) and progression-free survival (PFS) were extracted as hazard ratio (HR) and its 95% confidence interval (CI), while data of objective response rate (ORR) and AE were extracted as risk ratio (RR) and its 95% CI.


      Results:
      For overall patients, pembrolizumab had significantly superior OS (HR, 0.60, 0.43-0.86; P<0.01) and a significant increase of ORR (RR, 2.09, 1.24-3.52; P<0.01) than atezolizumab in combination with chemotherapy, while they had similar PFS (HR, 0.87, 0.66-1.14; P=0.31), all cause AE and grade 3-5 AE. For PD-L1 low/high patients, pembrolizumab and atezolizumab showed similar PFS. However, for PD-L1 negative patients, atezolizumab had significantly superior PFS (HR, 1.67, 1.01-2.74; P=0.04) than pembrolizumab. Table 1. Indirect comparison of pembrolizumab plus chemotherapy vs. atezolizumab plus chemotherapy for advanced non-squamous non-small-cell lung cancer. Item Statistical analysis HR / RRa (95%CI) P-value Overall OS 0.60 0.43 0.86 < 0.01 PFS 0.87 0.66 1.14 0.31 Overall ORR 2.09 1.24 3.52 < 0.01 All cause AE 2.35 0.16 33.64 0.53 Grade 3-5 AE 0.67 0.41 1.10 0.11 Subgroup (PFS) PD-L1 Highb,c 0.78 0.34 1.78 0.56 PD-L1 Lowd 0.69 0.40 1.17 0.17 PD-L1 Negativee 1.67 1.01 2.74 0.04 < 65 y 0.68 0.47 0.99 0.04 ?65 y 1.36 0.90 2.06 0.14 Male 1.03 0.72 1.47 0.86 Female 0.78 0.49 1.24 0.30 ECOG PS 0 0.88 0.56 1.37 0.56 ECOG PS 1 0.89 0.63 1.26 0.51 Smoker 0.89 0.66 1.18 0.41 Never smoker 0.88 0.38 2.05 0.76 Carboplatin 1.02 0.73 1.42 0.91 Cisplatin 0.68 0.41 1.11 0.12 Abbreviations: CI = confidence interval; HR = Hazard ratio; RR = Risk ratio; OS = overall survival; PFS = progression-free survival; ORR = objective response rate; AE = adverse event; PD-L1= programmed death ligand 1. ECOG PS = Eastern Cooperative Oncology Group (ECOG) Performance Status aHR is used for OS and PFS evaluation, RR is used for ORR and AE evaluation. bPD-L1 status available in 60% (344/578) and 93.8 % (578/616) of patients in IMpower 132 and KEYNOTE-189 respectively. cPD-L1 High is defined as TC3 or IC3 in IMpower132, TPS ?50% in KEYNOTE-189. dPD-L1 Low is defined as TC1/2 or IC1/2 in IMpower132, TPS ?1% and <50% in KEYNOTE-189. ePD-L1 Negative is defined as TC0 and IC0 in IMpower132, TPS <1% in KEYNOTE-189.


      Conclusion:
      Our results revealed that anti-PD-1 antibody may have superior efficacy compared to anti-PD-L1 antibody for advanced non-squamous NSCLC patients in combination with chemotherapy as first-line treatment. But anti-PD-L1 antibody might be better for PD-L1 negative patients. Further studies are warranted to confirm this.

    • +

      P026 - Impact of Prior Cancer History on the Overall Survival of Younger Patients with Lung Cancer (ID 202)

      00:00 - 00:00  |  Author(s): H. Zhou, Y. Zhang, J. Liu, G. Chen, Z. Zhang, L. Zhang

      • Abstract

      Background:
      Patients with a history of prior cancer are frequently excluded from cancer trials. Previous studies indicated that prior cancer does not adversely impact clinical outcomes for lung cancer patients older than 65 years. However, whether these research results are applicable to lung cancer patients aged younger than 65 years old remains unknown.


      Method:
      We identified younger lung cancer patients (<65 years) diagnosed between 2004 and 2009 in the SEER database. Propensity score matching were performed to balance differences in baseline characteristics between groups. Kaplan-Meier method and Cox proportional hazards model were used to evaluate the impact of prior cancer on overall survival (OS).


      Results:
      Among 103,370 eligible lung cancer patients, 15.18% (15696) had a history of prior cancer. Lung (25.83%), breast (14.13%), and prostate (8.85%) were the most common prior cancer. Localized and regional stages were accounting for 61.56% of prior cancers. More than 67.98% of prior cancer were diagnosed within 5 years. The median times of diagnosis for prior cancers were 38 months. The Kaplan-Meier curve (Figure 1 A) show an adverse effect of prior cancer on OS, compared to patients without an prior cancer (p=0.029). In COX regression analysis, patients with prior cancer had the similar OS as that of patients without a prior cancer (hazard ratio = 1.01, 95% confidence interval= 0.99 to 1.04, p=0.324). Subgroup analyses stratified by timing of prior cancer displayed almost the same tendency (p>0.05) (Figure 1 B). Early stage patients with prior cancer had adverse survival curves (p<0.05). Advanced stage patients with prior cancer had non-inferior survival (p>0.05). figure 1_aclc.jpg


      Conclusion:
      Prior cancer does not convey an adverse effect on clinical outcomes among advanced lung cancer patients age ? 65 years , regardless of timing of prior cancer. Broader inclusion trial criteria could be adopted in younger advanced lung cancer patients with a history of prior cancer.

    • +

      P028 - A Novel Method for Detecting Surface PD-L1 on Circulating Tumor Cells in Peripheral Blood of Patients with SCLC (ID 135)

      00:00 - 00:00  |  Author(s): D. Zhao, H. Li, Y. Liu, Y. Liu, J. Liu, Y. Cheng

      • Abstract

      Background:
      Previous studies have demonstrated that circulating tumor cell (CTC) might work as an alternative to biopsy tissues in the diagnoses of small cell lung cancer (SCLC). Programmed death ligand 1 (PD-L1) is one of the most commonly used biomarkers in immune targeted therapies. However, the expression of PD-L1 in CTC is still unknown. This study aimed to establish an approach to measure PD-L1 in peripheral CTCs from SCLC patients.


      Method:
      Control cells were screened by monoclonal culture and confirmed by immunohistochemistry (IHC) staining and flow cytometry. PD-L1 expression in CTCs and tumor tissue samples from SCLC patients was measured by CellSearch system while the usage of PD-L1 antibody was optimized.


      Results:
      The purity of PD-L1 positive H446 cells had been improved from 70% to 95% by clonal selection, and PD-L1 negative PC3 cells showed lower than 5% purity. In CellSearch system, positive control cells had 98% PD-L1 expression while negative control had less than 3% expression. In two SCLC patients with CTC positive expression, PD-L1 expression was found with 100% (1/1) and 40% (2/5) positive rate.


      Conclusion:
      CellSearch system was used to establish a novel approach for measuring surface PD-L1 expression on CTC, and showed supporting evidences in SCLC patients, thus providing novel insights for automatic assay of PD-L1 in peripheral samples.

    • +

      P029 - Circulating MDSCs Derived from Small Cell Lung Cancer Patients Secrete TGF - Beta 1 and Play Roles in Angiogenesis (ID 151)

      00:00 - 00:00  |  Author(s): S. Lan, H. Li, Y. Liu, D. Zhao, S. Yan, T. Tian, Y. Cheng

      • Abstract

      Background:
      Studies showed that small cell lung cancer (SCLC) induced CD33+cells production in vitro and the CD33+ cells present typical features of myeloid-derived suppressor cells (MDSCs). We previously reported CD33+CD11b+HLA-DR-MDSCs level was elevated in peripheral blood of SCLC patients and has a prognostic value for SCLC patients. In this study we further explored the mechanisms of SCLC-derived MDSCs involved in angiogenesis.


      Method:
      Peripheral blood specimens from SCLC patients and healthy volunteer were collected and CD11b+/CD33+cells were separated using magnetic bead. Giemsa stain was used in morphological identification of the cells. CD11b+/CD33+cells were cultured in vitro for 72 hrs, then TGF-?1 in cell pellets and supernatant was detected using RT-PCR and western blot, or ELISA respectively. Endothelial tube formation was performed through culturing HUVEC cells on Matrigel using the supernatant as medium. The supernatant was added into HUVEC cells cultured on Matrigel to test angiogenesis effects.


      Results:
      RT-PCR data showed that CD33+ and CD11b+MDSCs from SCLC expressed higher level of TGF-?1 than those from healthy control, 0.349 vs 0.174 (P=0.000632) and 0.191 vs 0.105 (P=0.000867), respectively, and the expression of TGF-?1 in CD33+MDSCs was higher than that in CD11b+cells (P=0.0382). In addition, the western blot results showed that CD33+MDSCs from SCLC expressed higher TGF-?1 than that in control (0.391 vs 0.164?P=0.000491), however, the similar effects were not seen in CD11b+ cells. TGF-?1 expression in supernatant was higher in SCLC-derived CD33+ or CD11b+MDSCs than those in healthy control, 0.620 vs 0.324 (P=0.0155) and 0.482 vs 0.307 (P=0.0413), respectively), and the TGF-?1 level was higher in CD33+MDSCs than that in CD11b+MDSCs (P=0.00668). A significant decrease in tube formation and TGF-?1 level was found in SCLC patients after treatment compared to those before treatment.


      Conclusion:
      The TGF-?1 was highly expressed in both CD11b+ or CD33+MDSCs from SCLC in both transcription and translation levels, along with level change after treatment implying TGF-? signaling pathway may participate in MDSC-mediated angiogenesis in SCLC. Moreover, the expression level of TGF-?1 was discrepant in different phenotypes of MDSCs demonstrating the plastic phenotype of MDSCs in SCLC.

    • +

      P030 - Prognostic Factors for Advanced Lung Adenocarcinoma Patients Who Received Tyrosine Kinase Inhibitor and Radiotherapy (ID 94)

      00:00 - 00:00  |  Author(s): H. Yang, B. Chen, Y. Wang, Y. Gong, Y. Xu, L. Zhou, Y. Liu, Y. Lu

      • Abstract

      Background:
      We sought to identify the independent prognostic factors for survival of the patients with advanced lung adenocarcinoma who respond to first-line tyrosine kinase inhibitor (TKI) and receive radiotherapy


      Method:
      Patients with stage III and IV lung adenocarcinoma who responded to first-line TKI and received radiotherapy in West China Hospital from Dec 1, 2007 to Jan, 1, 2018 were retrospectively enrolled. Univariate and multivariate analysis for prognostic factors including gender, age, stage, brain metastasis status, EGFR mutation type, radiotherapy type, duration between TKI and the staring of radiotherapy, biological equivalent dose (BED) of radiotherapy, and progression status before radiotherapy were analyzed by Cox regression model. Radiation-associated PFS (rPFS) was defined as the date of beginning of radiotherapy to the date of newly disease progression.


      Results:
      Forty-five patients were enrolled in this study and 8 of them received radiotherapy combined with TKI before progression. Among the patients with progression disease, 17 of them received radiotherapy with continuation of TKI, 20 patients were treated with radiochemotherapy and ceased the use of TKI after progression. The median follow-up for all patients was 58.3 month. The median rPFS was 5.4 month (95%CI: 4.4-6.4). The results of univariate analysis showed that higher BED (HR=0.460, 95%CI: 0.239-0.886, P =0.020) and radiotherapy prescribed before disease progression (HR=0.354, 95%CI: 0.135 -0.927, P =0.034) was relevant to longer rPFS. Multivariate analysis revealed that BED (HR=0.464, 95%CI: 0.240-0.899, P =0.023) and progression status before radiotherapy (HR=0.357, 95%CI: 0.135-0.940, P =0.037) were independent predicators for rPFS. No difference of rPFS was found between the patients with conventional radiotherapy or stereotactic body radiation therapy (SBRT) (P=0.450). The median overall survival (OS) was 43.3 month (95%CI: 29.7-56.9). Patients with advanced stage (HR=3.749, 95%CI: 0.883 -15.919, P =0.073) and shorter duration between TKI and the staring of radiotherapy (HR=1.962, 95%CI: 0.892-4.317, P =0.094) tend to have a shorter OS but without statistical significance.


      Conclusion:
      BED of radiotherapy and progression status were independent prognostic factor for rPFS. These results suggested the potential benefit of aggressive radiotherapy for patients with TKI treatment.

    • +

      P032 - Integrin Subunit Alpha 5: Potential Prognostic Biomarker in Lung Adenocarcinoma (ID 103)

      00:00 - 00:00  |  Author(s): J.H. Hong

      • Abstract

      Background:
      Identifying patients at high risk for recurrence in resected non-small cell lung cancer (NSCLC) is the key to choose patients who can benefit from postoperative adjuvant therapy. However, the criteria to stratify patients to receive postoperative adjuvant therapy is still clinicopathologic factor-oriented such as differentiation, tumor size, the presence of pleural involvement and vascular invasion and so on. Even using adjuvant treatment under these criteria, 5 - year survival rate is around 60% even in early-stage disease. Here, we extracted potential candidate genes for stratifying resected NSCLC patients according to correlation with their survival using public big data and validated the prognostic role of the extracted candidate gene in tumor samples of patients

    • +

      P033 - A Fusion-Protein Approach Enabling Mammalian Cell Production of Tumor Targeting Protein Domains for Therapeutic Development (ID 171)

      00:00 - 00:00  |  Author(s): J. Hu, Q. Zhou

      • Abstract

      Background:
      Background: Single chain Fv fragment (scFv) is kind of fusion protein of the variable regions of heavy (VH) and light chains (VL) of immunoglobulins, and it is an important element of chimeric antigen receptors (CARs) for cancer therapy.


      Method:
      Methods: We sought to produce a panel of 16 extracellular protein domains of tumor markers for use in scFv yeast library screenings. We developed a series of vectors comprising various combinations of expression elements and made GC content optimization of the signal peptide.


      Results:
      Results: Overall, expression was unpredictable and more than half of the protein domains could not be produced using any of the constructs. Here we described a novel fusion expression system based on mouse TEM7 (tumor endothelial marker 7), which could facilitate protein expression. With this approach we could produce all but one of the tumor marker domains that could not otherwise be expressed. In addition, we demonstrated that the tumor associated antigen hFZD10 produced as a fusion protein with mTEM7 could be used to enrich scFv antibodies from a yeast display library.


      Conclusion:
      Conclusion: Collectively our study demonstrates the potential of specific fusion proteins enabling mammalian cell production of tumor targeting protein domains for therapeutic development.

    • +

      P034 - A Case of Stage IIIA Thymoma Underwent Thymectomy with the Subxiphoid Approach (ID 34)

      00:00 - 00:00  |  Author(s): B. Aramini, J. Gening, J. Fan

      • Abstract

      Background:
      Thymectomy is recommended for the treatment of thymoma. The current literature suggests that minimally invasive surgery may be as effective or better than open thymectomy for treating small, early-stage thymic malignancies, possibly with no infiltration of the posterior structures. We show the potential benefits in an advanced thymoma undergoing thymectomy with subxiphoid approach.


      Method:
      A 55-year-old male came to our attention in May 2018 for blepharoptosis starting 3 months prior and worsening in the preceding month. Chest X-ray, CT scan, and RMI (Fig. 1A-1B) with enhancement showing a mass of 2 cm x 1.5 cm x 1 cm in the anterior mediastinum and infiltrating the joint position of the vena cava and the venae innominate and the anterior segment of the right upper lobe of the lung (Fig.2A-2B). The level of anti-acetylcholine antibodies in the blood was in the normal range, with no neurologic signs for myasthenia gravis. After clinical stabilization, the patient underwent thymectomy plus wedge resection of the right upper lobe of the lung using a subxiphoid approach. A hemostatic patch was used for pericardial repair.


      Results:
      Four hours operation with no intraoperative complications. Patient was extubated in the intensive care unit on the third postoperative day. Intravenous immunoglobulin was given immediately after surgery and pyridostigmine orally three days after surgery to prevent myasthenic crisis. Histology was positive for B3 thymoma Masaoka-Koga, stage IIIA. Patient was discharged after seven days,no morbidities and little pain.


      Conclusion:
      We believe think that the elevation of the sternum creates enough space through the anterior mediastinum to conduct more complicated procedures even if the thymoma is in an advanced stage, although a quality surgical experience, a high-volume surgical center, and careful selection of the patients are mandatory for improving postoperative outcomes. Fig.1A-B. RMI shows a thymoma infiltrating the vena cava and the right upper lobe of the lung. Fig.1C. Resection of the tumor at the joint position between the innominate vein and vena cava. Fig.1D. Thymus is completely removed. fig. 1 a-b-c-d.jpg

    • +

      P036 - Rechallenge Pemetrexed-Based Chemotherapy Provides an (ID 86)

      00:00 - 00:00  |  Author(s): J. Wang, X. Hu, Q. Qiao, Y. Liu, Z. Wang, J. Duan, Y. Feng, J. Wang

      • Abstract

      Background:
      In clinical practice, various treatments for advanced non-small-cell lung cancer (NSCLC) have been developed, aiming to alleviate the symptoms, prolong the survival and improve the life quality.Due to the absence of a standard multi-line treatment in advanced NSCLC, we hypothesized efficacy from rechallenge with pemetrexed alone or in combination with platinum or taxane for patients previously treated with pemetrexed. This article mainly observed the clinical efficacy and safety of rechallenge pemetrexed-based chemotherapy in locally advanced or metastatic NSCLC patients who had achieved first-line pemetrexed related benefitial response.


      Method:
      This retrospective study captured clinical data from 34 eligible pemetrexed rechallenge patients with advanced NSCLC who received benefitial response with first-line pemetrexed-platinum chemotherapy between January 2012 and December 2017.The progress time and safety of the disease were mainly observed.


      Results:
      With a median follow-up of 30.8 months,the DCR rate were 82.4%,with PR in 4 (11.8%) and SD in 24 (70.6%).Median rechallenge progression free survival(PFS) was 9.35 months, range from 0.9 to 44.2 months. Median overall survival (OS) was 42.2 months, range from 15.3 to 87.1 months.Patients with initial PFS (PFS1) of ?10 months had a longer rechallenge PFS compared to those with a PFS1 of <10 months (median PFS: 9.23 vs. 3.40 months;P=0.047).The significant prognostic factors for prolonging PFS after pemetrexed rechallenge are PFS1 (?10 vs <10 months,HR,0.383;95% CI,0.153-0.960;P=0.041) and line of rechallenge (2nd/3rd vs ?4th,HR,0.358;95% CI,0.145-0.880;P=0.025).It is noteworthy that maintenance treatment(HR,5.553;95% CI,1.266-24.361;P=0.023),and treatment-free survival(TFS)(?15 vs <15 months, HR,0.266; 95% CI,0.074-0.953 ; P=0.042) were indicated significant beneficial prognostic factors for overall survival(OS).Overall,pemetrexed-based rechallenge treatment was well tolerated. 0001.jpg


      Conclusion:
      Our results revealed that pemetrexed rechallenge strategy may be an option for advanced NSCLC patients who had shown beneficial response to previous pemetrexed-platinum chemotherapy.Therefore, patients with a PFS1 of ?10 months,TFS ?15 months,? 3rd line and rechallenge maintainance may be selected as benefit subgroups for pemetrexed rechallenge.

    • +

      P037 - QSOX1/2 Regulates (ID 197)

      00:00 - 00:00  |  Author(s): Y. Li, C. Shi, J. Xiong

      • Abstract

      Background:
      Elevated plasma concentration of Lipoprotein [a] (Lp(a)) is considered to be one of the important risk factors for coronary heart disease (CHD) and calcific aortic valve stenosis (CAVS), In recent years, the concentration of Lp(a) has been found to be elevated in plasma in some cancer patients without cardiovascular disease, However, the involvement of Lp(a) in the development of oncology and its regulatory mechanism is not fully understood. Previous studies have suggested that QSOX (Quiescin/sulfhydryl oxidase) may be involved in the synthesis of Lp(a) in vitro, but whether the process has an abnormal activation in the tumour is unclear.


      Method:
      Serum samples from 75 patients with lung, stomach, colorectal and ovarian cancer without cardiovascular disease and 50 normal subjects were collected at random. Lp(a) concentration was measured by Immunoturbidimetric assay (ITA). The expression levels of QSOX1/2 in 32 patients with lung, gastric, colorectal and ovarian cancer were measured by Enzyme-linked immunosorbent assay (ELISA) and westernblot. The difference expression of QSOX1/2 between tumor and para-cancerous tissues in TCGA-Pancancer database was analyzed by bioinformatics method. The difference gene analysis and pathway analysis of QSOX1/2 high and low expression groups were performed by Bayesian method, and the correlation between QSOX1/2 expression level and survival and clinical stage was further analyzed. In vitro, the ability to synthesize Lp(a) of HepG2 cells after QSOX1/2 deletion was verified by Immunoturbidimetric assay (ITA), and cell proliferation was analyzed by EdU and flow cytometry.


      Results:
      We found that serum Lp(a) concentrations in 27.5% of patients in the study cohort were higher than the mean value in the normal medical cohort. Serum Lp(a) concentrations in cancer patients were positively correlated with QSOX1/2 serum concentrations (R=0.34?P<0.005). In the TCGA-Pancancer database, the expression level of QSOX1/2 in tumor tissues were higher than that in para-cancerous tissues, and the over expression of QSOX1/2 may be related to abnormal regulation of tumor cell cycle. In vitro, experiments showed that the expression of QSOX1/2 regulated the extracellular synthesis ability of Lp(a). Silencing QSOX1/2 genes significantly inhibited the proliferation of tumor cells.


      Conclusion:
      The abnormal expression of QSOX1/2-Lp(a) can be used as a potential bio-marker for the poor prognosis of cancers. And targeted QSOX1/2 treatment may inhibit tumor growth with this molecular subtype.

    • +

      P038 - Docosapentaenoic Acid and Lung Cancer Risk: A Mendelian Randomisation Study (ID 54)

      00:00 - 00:00  |  Author(s): J. Liu, H. Zhou, Y. Zhang, Y. Huang, W. Fang, Y. Yang, S. Hong, G. Chen, S. Zhao, X. Chen, Z. Zhang, J. Shen, W. Xian, J. Zhan, Y. Zhao, X. Hou, Y. Ma, T. Zhou, H. Zhao, L. Zhang

      • Abstract

      Background:
      Docosahexaenoic acid and eicosapentaenoic acid have been reported to be associated with lung cancer risk; however, it remains unknown whether docosapentaenoic acid (DPA), another kind of n-3 PUFA, is related to lung cancer risk. The aim of this study is to investigate the causal effect of DPA on lung cancer with Mendelian randomization (MR) method.


      Method:
      With a two-sample MR approach, we analyzed the summary data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, 8,866 individuals of European ancestry) Consortium and International Lung Cancer Consortium (ILCCO, 11348 lung cancer cases and 15861 controls; European ancestry). Three single nucleotide polymorphisms (SNPs) that were genome-wide significant (p<5*10-8; linkage disequilibrium r2 < 0.1) for plasma DPA levels in CHARGE were explored for their associations with lung cancer risk in the ILCCO. Analysis for two different histologic subtypes of lung cancer (adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC)) was performed to investigate whether the effect of DPA is associated with the histology of lung cancer. To investigate whether lung cancer might be a causal factor for DPA, we performed an MR analysis in the opposite direction using 3 SNPs linked to lung cancer. Evidence of directional pleiotropy averaged across all variants was sought using MR

    • +

      P039 - Clinical Characteristics and Survival of Patients with Lymphoepithelioma-Like Carcinoma in Lung and Bronchus and Other Sites (ID 159)

      00:00 - 00:00  |  Author(s): J. Liu, X. Zhai, Y. Liu, L. Long, Q. Zhou, D. Lu

      • Abstract

      Background:
      Lymphoepithelioma-like carcinoma (LELC), an unusual histological type of malignancy, occurs in almost all anatomic sites of body including lung and bronchus. Although with strong ties to Epstein-Barr virus infection, LELC at different sites has distinct clinical characteristics. Because of the rarity, it is however largely unclear whether LELC at different sites would lead to different prognosis, independent of clinical characteristics.


      Method:
      Based on the population-based cancer cohort from the Surveillance, Epidemiology, and End Results database (SEER), we identified all LELC patients from year 1973 to 2015. According to tumor sites, we classified LELC patients into lung and bronchus, nasopharynx, and another eight most common sites. We studied overall survival as the primary outcome, while tumor characteristics as the secondary outcome.


      Results:
      In total, we identified 2079 LELC patients, of which 86 (4%) were positioned at lung and bronchus and 1208 (58%) at nasopharynx (Figure 1A). Patients with lung and bronchus LELC were older at diagnosis and with more advanced stage, as compared to nasopharyngeal LELC. The 5-year overall survival rates of LELC of lung and bronchus as well as nasopharynx were 35.8% and 59.5% in patients with localized stage (Figure 1B), while 35.1% and 55.5% in patients with regional stage (Figure 1C), respectively. After controlling for tumor characteristics and treatment modes, patients with lung and bronchus LELC were associated with increased risk of overall mortality as compared with LELC of nasopharynx (HR 1.72, 95% CI 1.03 to 2.88).????_20180914010827.jpg


      Conclusion:
      The demographics and clinical features of LELC greatly differ by organ of origin. Site may be an important predictor for survival in patients of LELC. Compared with LELC of nasopharynx, pulmonary LELC is associated with worse prognosis, independent of common prognostic factors.

    • +

      P040 - Highly Sensitivity and Fast Genetic Diagnosis by Mean of a Novel NGS-Based Resequencing Gene Panel Underlying SCLC Patients (ID 105)

      00:00 - 00:00  |  Author(s): J. Wang, L. Zhao, X. Sun, F. Zhou, Y. Zhang, S. Zhao, S. Liu, L. Chin, L. Wang, T. Guo, Z. Sun, F. Li, C. Gu

      • Abstract

      Background:
      Lung cancer is the leading cause of cancer death worldwide. Small cell lung cancer (SCLC) is a malignancy with multiplex toxin-associated mutations, which accounts for about 15% of all the types of lung cancers. Overall, it remains a clinical challenge with extremely aggressive behavior of early systemic spreading. No effective target therapies and protein biomarkers are available in the treatment of SCLC and the association between gene mutations and SCLC still remains unclear. It makes an urgent need for detection of novel biomarkers in this highly lethal neuroendocrine type of cancer.


      Method:
      We assessed the four protein biomarkers and performed 303 cancer driver genes to investigate the mutation profiles of 32 FFPE tissues derived from Chinese SCLC patients using next generation sequencing.


      Results:
      Amongst the 32 FFPE samples, mutant genes were observed in all the patients of SCLC (32/32, 100%). TP53 mutations were the most prevalent (19/32; 59.38%), followed by RB1 (11/32; 34.38%), KMT2D (8/32; 25%), BRCA1 (6/32; 18.75%), LRRK2 (6/32; 18.75%), and ARID2 (6/32; 18.75%). Notably, there was relatively high mutation hotspot (6.25%, 2/32) of the p.P278S and p.W516X mutations in TP53 and RB1, respectively. Overall, the six of the most frequent mutations were identified in patients with SCLC including three well-known mutant genes (TP53, RB1 and KMT2D) and three rare genes (BRCA1, LRRK2 and ARID2) not previously reported in Chinese patients with SCLC.


      Conclusion:
      Based on our findings, we propose that these oncogenic mutations might serve as potential biomarkers and provide clinicians with candidate therapeutic targets for Chinese SCLC patients.

    • +

      P041 - Different Recurrence Models in Lung Cancer Patients Between (ID 199)

      00:00 - 00:00  |  Author(s): J. Xia, S. Zheng, Q. Nie, S. Dong, W. Zhong

      • Abstract

      Background:
      As concluded recently, compared with

    • +

      P042 - LincRNA00494 Suppresses Non-Small Cell Lung Cancer Cell Proliferation by Regulating SRCIN1 Expression in A ceRNA Manner (ID 182)

      00:00 - 00:00  |  Author(s): J. Dong, F. Xu, Q. Zhou

      • Abstract

      Background:
      Lung cancer has been recognized as the leading cause of cancer-related deaths throughout the world . Due to failing early diagnosis and severe chemotherapy response, the 5-year survival rate of lung cancer has been staggering at about 15% . Therefore, searching for new biomarkers for metastatic progression of non-small cell lung cancer (NSCLC) is urgent. Recent studies have demonstrated the association between long non-coding RNA (LncRNA) and multiple cancer types. LincRNA00494, a novel long intergenic non-protein coding gene, its function has not been fully expounded. In the present study, we found that LincRNA00494 was down-regulated in non-small cell lung cancer tissue compared with the corresponding adjacent non-tumor tissue. Our findings might reveal the underlying mechanism by which LincRNA00494 aberrant expression conferred NSCLC tumorigenesis.


      Method:
      We compared the expression level of LINCRNA00494 by RT-PCR in 163 patients with non-small cell lung cancer with the tumor tissue and the normal tissue of distant cancer. We compared the association between LINCRNA00494 and SRCIN1 mRNA in tumor tissues by RT-PCR. Plasmid knockdown and overexpression of LINCRNA00494 were used to compare the effects of changes in LINCRNA00494 expression on SRCIN1 mRNA. To verify the role of miR-150-3p in NSCLC cells, we cloned the 3

    • +

      P043 - Cost-Effectiveness Analysis of Different Sequences of Osimertinib Administration for EGFR-Mutated Non-Small-Cell Lung Cancer (ID 35)

      00:00 - 00:00  |  Author(s): W. Li, L. Qian, W. Li, X. Chen, H. He, H. Tian, Y. Zhao, X. Wang, J. Cui

      • Abstract

      Background:
      Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is clinically effective as a first-line and second-line therapy in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Use of this treatment is limited by high costs. Here, we conducted a cost-effectiveness analysis of different sequences of osimertinib administration in China and the United States.


      Method:
      We established Markov models based on data from the FLAURA and AURA3 trials, which included patients with EGFR mutation-positive advanced NSCLC. The cost-effectiveness analysis compared first-line osimertinib to first-generation EGFR-TKIs or second-line osimertinib after the failure of first-generation EGFR-TKIs. The analysis also considered different payment modalities available in China. Additionally, we performed 1-way sensitivity and probability sensitivity analyses with a willingness-to-pay threshold (WTP) of 3

    • +

      P044 - Cost-Effectiveness Analysis of Icotinib vs Whole-Brain Irradiation in NSCLC Patients with Brain Metastases (ID 122)

      00:00 - 00:00  |  Author(s): W. Li, R. Bai, L. Qian, N. Chen, Y. Zhao, F. Han, L. Bai, J. Li, Y. Yu, J. Cui

      • Abstract

      Background:
      Non-small-cell lung cancer (NSCLC) patients with brain metastases had a poor prognosis and quality of life. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) might benefit patients on survival and quality of life. We investigated the cost-effectiveness of icotinib compared with WBI with or without chemotherapy for NSCLC patients with brain metastases.


      Method:
      A markov model was conducted based on the data of BRAIN trial. We compared the economic benefit among icotinib, whole-brain irradiation (WBI) alone group, WBI plus chemotherapy group, and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness-to-pay (WTP) was set as 3

    • +

      P045 - Prognostic Value of MHC-I, PD-L1 and CD8+ TILs Expressions in Patients with Surgically Resected Non-Small Cell Lung Cancer (ID 138)

      00:00 - 00:00  |  Author(s): X. Ding, J. Cui

      • Abstract

      Background:
      Lung cancer is the most commonly diagnosed cancer and also the leading cause of cancer death globally. Chemotherapy showed limited improvement in the survival of surgically resected non-small cell lung cancer (NSCLC) patients. There was no effective prognostic indicators in surgically resected NSCLC. The expression levels of tumor surface molecules, such as major histocompatibility complex class I (MHC-I), programmed cell death-ligand 1 (PD-L1) and CD8+ tumor infiltrating lymphocytes (TILs) were detected in this study to investigate the potential prognostic markers in the patients with surgically resected NSCLC.


      Method:
      Tissue of 125 patients with surgically resected NSCLC were obtained from the First Hospital of Jilin Universtiy. MHC-I, PD-L1 and CD8+ TILs expressions were detected with immunohistochemistry. The association between their expression levels and patients

    • +

      P047 - Clinical Characteristics of the Surviving Lung Cancer Patients at Shanghai Chest Hospital During 2007- 2017 (ID 200)

      00:00 - 00:00  |  Author(s): Y. Zhao, Y. Yao, Z. Cheng

      • Abstract

      Background:
      Using retrospective studies to observe and analyze the clinical characteristics of local surviving primary bronchogenic carcinoma patients hospitalized at Shanghai Chest Hospital during 2007- 2017.


      Method:
      This research categorized local lung cancer patients into various pathology or cancer stage groups based on their diagnostic codes; compared their survival rates; and identified the factors with significant impact on overall survival. Statistical methods used in this study include Kaplan-Meier method, Cox risk regression model, Student's t test, Chi-square test and Fisher exact test.


      Results:
      From 2007 till the end of 2017, 15,396 patients with primary bronchogenic carcinoma from Shanghai Chest Hospital were followed up. The clinical characteristics of the surviving patients were observed at three time points: December 31, 2011, December 31, 2014, and December 31, 2017. 2,609, 6,994 and 10,638 cases were observed at these three time points respectively, with average age of 61

    • +

      P049 - Neurocognitive Functions Before Radiotherapy for Brain Metastasis from Lung Cancer: An Analysis of 74 Cases (ID 97)

      00:00 - 00:00  |  Author(s): J. Zhen, Z. Peng, S. Li, M. Lai, L. Cai

      • Abstract

      Background:
      To assess the baseline neurocognitive functions in patients with brain metastasis from lung cancer before receiving radiotherapy, and determine the risk factors for neurocognitive function impairment.


      Method:
      The clinical data of patients suffering from brain metastasis from lung cancer who were admitted to Guangdong Sanjiu Brain Hospital from January 2017 to December 2017 were retrospectively analyzed. At 1-2 weeks before radiotherapy for brain metastasis, several scales were used to assess the neurocognitive functions in the 74 patients. Psychometricians assessed and divided the the neurocognitive functions into 4 levels, namely normal, mild impairment, moderate impairment and severe impairment. All analyses were performed using the statistical package R, to analyze the relationships between cognitive assessment results and clinical characteristics, and Kappa test was used to analyze the consistency of physical examination and cognitive scales for assessing the neurocognitive functions in patients. Finally, the related factors were analyzed with univariate and multivariate analysis.


      Results:
      Clinical physical examination showed that there were 21 cases of cognitive decline (28.4%) and 53 cases of normal cognition (71.6%), while the results of cognitive scales revealed that there were 6 cases of normal cognition (8.1%), 26 cases of mild impairment (35.1%), 2 cases of moderate impairment (2.7%) and 40 cases of severe impairment (54.1%). The result of Kappa test showed Kappa<0.4, indicating that the differences between cognitive scale results and physical examination were significant. The univariate analysis on the factors related to neurocognitive function impairment revealed that the risk factors that may affect the degree of neurocognitive function impairment included age, KPS score, GPA score, RPA class and the number of metastatic tumors; and the multivariate analysis showed that age and RPA class>2 were the independent risk factors for neurocognitive function impairment.


      Conclusion:
      Patients with brain metastasis from lung cancer have various degrees of neurocognitive function impairment before receiving radiotherapy. Compared with clinical physical examination, the cognitive scales can greatly improve the detection rate of neurocognitive function impairment. Age and RPA class>2 are considered as independent risk factors for neurocognitive function impairment.

    • +

      P050 - Long-Term Survival of Stage IIIA-N2 NSCLC Patients with Interstitial Lung Diseases (ID 210)

      00:00 - 00:00  |  Author(s): J. Watanabe, H. Horinouchi, Y. Shinno, S. Murakami, Y. Goto, S. Kanda, Y. Fujiwara, N. Yamamoto, Y. Nakamura, S. Watanabe, Y. Ohe

      • Abstract

      Background:
      Interstitial lung diseases (ILD) frequently occur in patients with lung cancer. The optimal treatment strategy for non-small-cell lung cancer (NSCLC) patients with ILD remains unclear. We reviewed the efficacy and safety of surgery, chemotherapy, and radiotherapy.


      Method:
      We analyzed the medical records of patients with clinical stage IIIA-N2 NSCLC with ILD who were treated at our hospital between 2001 and 2016.


      Results:
      505 patients with clinical stage IIIA-N2 NSCLC were included. Of these patients with ILD, treatments included surgical resection (S) in 14 patients, chemoradiotherapy (CRT) in 7 patients, palliative chemotherapy (C) in 7 patients and palliative radiotherapy in one patient.The median follow-up period was 38 months. The patients' characteristics were as follows S/CRT/C: male, 26/6/7 patients; median age (range), 69 (58-82)/69 (60-75)/69 (35-82) years. Of the S, pathological stage IA/IIA/IIB/IIIA/IIIB, 1/1/2/9/1 patients. The median progression-free survival times were 9.5 months (95% CI: 5.3-45.3 months) in S, 45.9 months (95% CI: 7.2 months- not reached [NR]) in CRT, and 5.0 months (95% CI: 0.5-10.5 months) in C. The median overall survival time were 33.3 months (95% CI: 9.8 months-NR) in S, 45.9 months (95% CI: 8.3 months-NR) in CRT, and 9.9 months (95% CI: 1.6-42.4 months) in C. One patient died within 1 month of surgical resection. Acute exacerbations of ILD (AE-ILD) were noted in 14 % of the patients; 3 patients after surgery and 1 patient after chemoradiotherapy.


      Conclusion:
      The surgery and chemoradiotherapy can be considered as a treatment option for selected patients with IIIA-N2 NSCLC with ILD, with careful management after sufficient evaluation of the risks and the benefits.

    • +

      P051 - A Novel (ID 176)

      00:00 - 00:00  |  Author(s): K. Yin, Y. Li, M. Zheng, B. Jiang, W. Li, J. Yang, H. Tu, Q. Zhou, W. Zhong, X. Yang, H. Yan, L. Li, Y. Wu, X. Zhang

      • Abstract

      Background:
      Leptomeningeal metastasis (LM) occurs in 3%-5% of patients with advanced non-small-cell lung cancer (NSCLC). However, its incidence has increased in patients with driver gene mutations owing to their prolonged survival from target therapies. The prognosis of NSCLC patients with LM has improved to 3-11months in the era of precision medicine. Understanding how prognosis varies across this heterogeneous patient population is essential to individualize care and design future clinical trials.


      Method:
      We retrospectively reviewed the medical records of 301 lung cancer patients, who were diagnosed as LM by brain MRI or cytology or next-generation sequencing of cerebrospinal fluid between January 2011 and April 2018. Their clinicopathological characteristics and prognostic data were analyzed. All prognostic factors were weighted for significance by hazard ratios (HR).


      Results:
      Among the 301 patients, the median age was 55 years (26-86). Most of them were adenocarcinoma (96.3%?290/301). There were 149 males and 152 females. The median overall survival of the 301 patients was 7.1 months from LM diagnosis. Multivariate analysis revealed that KPS score <60 (HR, 4.30, 3.15-5.87), presence of extracranial metastases (ECM) (HR, 1.79, 1.27-2.52), EGFR negative or unknown and ALK negative or unknown (HR, 1.83, 1.27-2.62) were the independent prognostic factors for poor overall survival. Based on the HR, we made a novel molGPA scoring criteria for LM modified from the molGPA for brain metastasis (BM) and developed a novel molGPA model stratified patients into three categories. The median overall survival for patients with the novel molGPA scores of 0, 0.5-1.0, and1.5-2.0 was 0.3, 4.2, and 12.8 months, respectively (p < 0.001). The C-index of this model was 0.69 (95%CI: 0.65-0.72).


      Conclusion:
      We developed a novel molGPA model, which could help clinicians to stratify lung cancer patients with LM in the era of precision medicine. Further research is needed to validate and improve this model.

    • +

      P052 - A Biomarker Study of Advanced Non-Small Cell Lung Cancer Using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry (ID 177)

      00:00 - 00:00  |  Author(s): K. Zhang, Y. Liu, Q. Yang, Y. Liu, Y. Zeng, X. Hong, Y. Hu, J. Liang, L. Liu

      • Abstract

      Background:
      This study is to explore changes of serum metabolites in patients with advanced non-small cell lung cancer (NSCLC) and healthy controls, so as to provide new diagnostic strategies for NSCLC.


      Method:
      A total of 151 samples were obtained, including 86 NSCLC patients and 65 healthy controls. After serum was extracted, metabolic assays based on a wide range of targeted metabolome technologies and the Ultra-High-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS /MS) detection platform were applied to detect metabolites in it. A self-built database and the multivariate statistical analysis were utilized to explore the difference in metabolome between the two arms.


      Results:
      A total of 296 metabolites were detected in all samples. Eighty-three genes were found differentially expressed, of which 20 were down-regulated and 63 were up-regulated in NSCLC patients. There were no significant differences in the serum metabolite between adenocarcinoma and squamous cell carcinoma. KEGG functional annotation analysis was made on the 81 metabolites to elucidate their biological functions. Signaling pathways which might cause changes in metabolites were summarized.


      Conclusion:
      Based on our novel UPLC-MS / MS platform, more metabolites can be detected, which might provide new potential tumor biomarkers. Our study can accelerate development of new diagnostic strategies in NSCLC.

    • +

      P053 - The Potential of Assessing Blood Tumor Mutation Burden (bTMB) Using a Large Panel (ID 70)

      00:00 - 00:00  |  Author(s): K. Zhang, Y. Tang, X. Xu, S. Zhang, W. Tao, Z. Rao, F. Wu, S. An, J. Liu, J. Yang, T. Hou, L. Zhang, Y. Zhang, L. Liu

      • Abstract

      Background:
      TMB, measuring the number of non-synonymous mutation per megabase of DNA, has shown to associate with response to checkpoint inhibitors in a number of cancers, including lung cancer. Whole exome sequencing (WES), the gold standard for evaluating TMB, is less cost-effective. Multiple studies have shown large panels can yield comparable results in tissue samples. However, the feasibility of assessing bTMB using a large panel has not been extensively evaluated. In this study, we evaluated TMB of 30 treatment-na

    • +

      P054 - Applicability of the Lung-molGPA Index in NSCLC (ID 28)

      00:00 - 00:00  |  Author(s): K. Chen, X. Yu, Y. Fan

      • Abstract

      Background:
      The Lung-molGPA index is based on the original diagnosis-specific graded prognostic assessment (DS-GPA) and incorporates recently reported gene alteration data for non-small cell lung cancer (NSCLC) patients with brain metastases (BM). However, the prognostic value of the DS-GPA and Lung-molGPA models remains undetermined, especially for patients with different molecular types.


      Method:
      A total of 1,184 NSCLC patients with BM were analyzed for clinical factors and outcomes at Zhejiang Cancer Hospital, China. All prognostic factors were weighted for significance by hazard ratios. The applicability of DS-GPA and Lung-molGPA were reappraised in NSCLC patients with BM and various genetic profiles. Additionally, a modified Lung-molGPA was newly developed for NSCLC patients with gene variations.


      Results:
      NSCLC patients in the present study had a median survival time of 14.0 months from BM diagnosis. Both the DS-GPA and Lung-molGPA models predicted the patients

    • +

      P057 - Pembrolizumab + (ID 16)

      00:00 - 00:00  |  Author(s): K.F. Ang, R.J. Villafuerte, E. Regala

      • Abstract

      Background:
      It remains uncertain if there is an improvement of efficacy with the addition of a third agent in platinum-doublet chemotherapy as first line treatment of PD-L1 positive advanced non-small cell lung cancer. Pembrolizumab, an anti-PD-1 monoclonal antibody, has been effective as monotherapy in patients with advanced NSCLC. But there is still limited evidence on its combination with chemotherapy as first line treatment in the metastatic setting. Hence, we performed a meta-analysis of randomized controlled trials that compared the efficacy and safety of combining pembrolizumab with chemotherapy versus chemotherapy alone as first line therapy for advanced non-small cell lung cancer.


      Method:
      Extensive search of PubMed, Medline and Cochrane was done for articles published after 2015. Studies were limited to RCTs comparing combined pembrolizumab and chemotherapy VS chemotherapy alone as first line treatment in advanced NSCLC. Outcomes measured included overall survival and progression-free survival in 5 yrs and 10 yrs. Statistical analysis was done using Review manager V5.3.


      Results:
      For pembrolizumab plus chemotherapy VS chemotherapy alone, pooled odds ratio of overall survival in 5 yrs and 10 yrs were 0.62 (95% CI: 0.21-1.85) and 0.67 (95% CI 0.50-0.91) respectively. slide2.jpg Pooled odds ratio of progression-free survival in 5 yrs and 10 yrs were 0.39 (95% CI 0.29-0.54) and 0.51 (95% CI 0.34-0.76) respectively. slide1.jpg Results demonstrate a significant survival benefit in giving pembrolizumab with chemo


      Conclusion:
      Pembrolizumab plus chemotherapy improved overall survival and progression-free survival in patients with PD-L1 positive advanced NSCLC. We encourage using this regimen as first line treatment.

    • +

      P058 - Effects of Neoadjuvant Chemotherapy on the Expression (ID 82)

      00:00 - 00:00  |  Author(s): W. Sun

      • Abstract

      Background:
      Immune checkpoints PD-1 and its ligand PD-L1, PD-L2 pathways can mediate negative synergistic stimulation signals. Immunotherapy combined with chemotherapy can increase the objective response rate of cancer patients. This study aims to analyze the changes of PD-L1, PD-L2 in lung cancer tissues and the changes of TILs surrounding the tumor before and after neoadjuvant chemotherapy, in order to provide a theoretical basis for relevant clinical studies.


      Method:
      Tumor samples were obtained from 26 patients who confirmed primary lung cancer before and after NAC in the First Hospital of Jilin University. The expression of PD-L1, PD-L2 in lung cancer specimens and the TILs around the tumor were assessed by IHC. 5%, 10%, 20%, 30%, 50% expression thresholds were used to define PD-L1, PD-L2 positive status, respectively. We analyze the changes of PD-L1 and PD-L2 in lung cancer tissues before and after NAC, the correlation between the changes of PD-L1 in lung cancer tissues and tumor shrink rate, the interval from the end of NAC to operation, pathological type, gender and smoking status. Of 16 patients, the changes of TILs around the tumor before and after NAC were also evaluated. P<0.05 was considered statistically significant.


      Results:
      1. When using 5%, 10%, and 20% as expression threshold, 65.4%, 53.8%, and 42.3% were found to be PD-L1 positive prior to NAC, and 92.3%, 80.8%, 69.2% expressed positively after NAC, PD-L1 was up-regulated after NAC (P=0.008, P=0.016, P=0.016 ), however, there were no obviously statistical significance about the expression of PD-L1 when using 30%, 50% expression threshold (P?0.05 ). 2. The expression of PD-L2 were not show any statistical significance before and after NAC?P?0.05 ) . 3. Of 16 patients, the expression of CD4+, CD8+, and CD28+ lymphocytes increased after NAC compared with that before NAC (P=0.014, P=0.038, P=0.021), whereas the change of CD56+ lymphocytes was not statistical significant (P> 0.05). 4. There were no significant difference between the changes of PD-L1 and tumor shrink rate, interval from the end of NAC to operation, pathological type, gender and smoking status (P?0.05 ) .


      Conclusion:
      1. The expression of PD-L1 in lung cancer tissues were increased after NAC when the expression thresholds were 5%, 10%, and 20%. 2. The expression of CD4+, CD8+ and CD28+ lymphocytes were increased after NAC. 3. No correlation exists between the variation of PD-L1 and tumor shrink rate, interval from the end of NAC to operation, pathological type, gender and smoking status.

    • +

      P061 - Real Clinical Practice of Using Immunotherapy In NSCLC Patients With EGFR Mutation (ID 201)

      00:00 - 00:00  |  Author(s): L. Shen, S. Lu

      • Abstract

      Background:
      Immunotherapy (PD-1/PD-L1 inhibitors) has been shown to be less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. However, little is known regarding its performance in real-world. The efficacy of immunotherapy might be different in patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Herein, we carried out a retrospective study to describe real clinical outcomes when using PD-1/PD-L1 inhibitors to treat NSCLC patients with EGFR mutation.


      Method:
      We retrospectively identified 27 patients with EGFR mutation-positive NSCLC who were treated with PD-1/PD-L1 inhibitors between January 2017 and April 2018.


      Results:
      Of 27 patients included in our study, 40.7% (n=11) harbored EGFR ex19del, 51.9% (n=14) harbored EGFR L858R, 3.7% (n=1) harbored EGFR G719X and 3.7 % (n=1) harbored EGFR ex20S768I. A total of 26 patients were treated with PD-1/PD-L1 inhibitors after disease progression during treatment with at least one EGFR-TKI and only one patient was EGFR-TKI na

    • +

      P063 - STE029 Overcomes EGFR-TKI Resistance in Human Lung Adenocarcinoma (ID 121)

      00:00 - 00:00  |  Author(s): L. Huang, Q. Zhou

      • Abstract

      Background:
      STE029 is a novel anticancer drug which consists of 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor and novel cancer cell membrane targeting molecular. This study aimed to investigate the effect and mechanism of STE029 on overcoming the EGFR-TKI resistance in NSCLC.


      Method:
      CCK8 test was used to test the cell viability and survival rate of EGFR mutated PC9 cell (Gefitinib sensitive), PC9/BB4 cell (acquired Gefitinib resistant), and EGFR wild type A549 cell after treatment of STE029, Gefitinib or combination of both. Edu test was applied to detect changes in cell cycle and Hoechst 33258 was applied to detect apoptosis rate in treatment groups. We examined the activity of EGFR/PI3K/Akt, cell cycle and apoptosis signal pathways. In vivo, nude mice were exposed to STE029, Gefitinib and STE029+Gefitinib for 5 weeks, tumor volume was measured, tumor weight was obtained on the last day. P value less than 0.05 would be considered statistically significant.


      Results:
      PC9 Cells was highly sensitive to Gefitinib , while PC9/BB4 and A549 cell showed significant resistance to Gefitinib treatment, the IC50 of Gefitinib in PC9, PC9/BB4 and A549 cell was 0.12

    • +

      P066 - A Phase I Study of Apatinib Combined with Pemetrexed and Carboplatin in Untreated EGFR-Negative Stage IV Non-Squamous NSCLC (ID 81)

      00:00 - 00:00  |  Author(s): M. Huang, Y. Gong, J. Zhu, Y. Qin, F. Peng, L. Ren, Z. Ding, Y. Liu, Y. Wang, Y. Lu

      • Abstract

      Background:
      This phase I study aimed to establish the feasible dose of Apatinib in combination with pemetrexed plus carboplatin as first-line therapy for EGFR-negative stage IV non-squamous non-small-cell lung cancer (NSCLC).


      Method:
      Using a 3+3 dose-reduction design, patients received oral Apatinib at four dose levels: 750 mg qd, 500 mg qd, 500 mg/day 2 weeks on/1 week off schedule (schedule 2/1) or 250mg qd. Pemetrexed (500 mg/m2) plus carboplatin (AUG=5) was administered every 3 weeks. The feasible dose was determined based on cycle 1 dose-limiting toxicities (DLT); other assessments included safety and antitumor activity according to response evaluation criteria in solid tumors.


      Results:
      A total of 12 patients were enrolled and cycle 1 DLTs were observed in two patients at 750 mg qd treatment (both Grade 3 hypertension), two patients at 500 mg qd (Grade 3 hypertension and Grade 3 hand-foot syndrome), and only one of six patients at 500 mg/day schedule 2/1 (Grade 3 hypertension). The most frequently drug-related adverse events were hematological toxicity, hypertension, hand-foot syndrome and hepatic transaminases elevation. Partial response was observed in 4 patients of 11 evaluable patients (ORR 36.4%), and 6 patients exhibited stable disease (DCR 90.9%).


      Conclusion:
      In patients with advanced non-squamous NSCLC, the feasible dose of Apatinib given with standard-dose pemetrexed and carboplatin was 500 mg/day schedule 2/1. The schedule was generally well tolerated and demonstrated promising clinical benefit in NSCLC.

    • +

      P068 - The Geriatric Nutritional Risk Index Predicts the Overall Survival in Geriatric Patients with Metastatic Lung Adenocarcinoma (ID 131)

      00:00 - 00:00  |  Author(s): M. Tang, L. Li

      • Abstract

      Background:
      Metastatic lung adenocarcinoma patients have poor prognosis. Many factors are associated with the prognosis of lung cancer patients, including nutrition status. Geriatric nutrition risk index (GNRI) is a simplified, objective screening parameter for nutrition risk in geriatric patients. The aim of this study was to assess the prognostic value of pretreatment GNRI in geriatric patients with metastatic lung adenocarcinoma, which has not been reported before.


      Method:
      The clinical and pathological data of 144 consecutive geriatric patients with metastatic lung adenocarcinoma between January 2011 and May 2017 were retrospectively analyzed. The pretreatment GNRI was calculated as follows: GNRI=1.489

    • +

      P069 - HOTAIR, A Long Non-Coding RNA, Is a Marker of Abnormal Cell Cycle Regulation in Lung Cancer (ID 68)

      00:00 - 00:00  |  Author(s): M. Liu, F. Ren, X. Li, H. Zhang, J. Chen

      • Abstract

      Background:
      The dis-regulation of cell cycle is an obvious marker of tumors including lung cancer. Recently, the study of cell cycle inhibitor has made great progress in lung cancer. While a question, what kinds of patients could use cell cycle inhibitor, has plagued us. So seeking an accurate and convenient marker for the abnormal cell cycle in lung cancer is very important.


      Method:
      MTT, EdU, Transwell, ChIRP, Western-blot, luciferase reporter assay, Orthotopic nude mouse model, Immunohistochemistry


      Results:
      In the present research we had showed lnc-RNA HOTAIR is an optimal indicator of cell cycle dis-regulation in lung cancer. HOTAIR specific expression in lung primary tumor sample by the analysis of TCGA public database and 67 pairs of patients

    • +

      P070 - Pembrolizumab for Non-Small Cell Lung Cancer with Untreated Central Nervous System Metastases: A Case Report (ID 101)

      00:00 - 00:00  |  Author(s): M. Di, L. Zhang

      • Abstract

      Background:
      Non?small cell lung cancer (NSCLC) accounts for up to 85% of lung cancers. Central nervous system(CNS) metastasis is a common complication of NSCLC with a poor prognosis and dismal survival rate. Treatment is limited and has poor outcomes and affects the quality of the life of patients. Pembrolizumab is a Programmed cell death-1 (PD-1) antibody, has shown good results in management of NSCLC. However, it has not been well studied for CNS penetration, and patients with untreated brain metastases are excluded from most clinical trials.


      Method:
      We hereby report 2 cases of NSCLC patients with brain metastases who successfully treated with pembrolizumab, to discuss the efficacy and safety of pembrolizumab in NSCLC patients with brain metastases.


      Results:
      In the present cases, patients with untreated/progressing brain metastases can be well controlled with pembrolizumab and have a long PFS with a high quality of life by using pembrolizumab. Neither of the patients have treatment-related serious and grade 3

    • +

      P071 - Variants Distribution and Heterogeneity of Outcomes to Crizotinib in ALK-Rearranged Chinese Non-Small Cell Lung Cancers (ID 179)

      00:00 - 00:00  |  Author(s): N. Liang, P. Xing, Y. Su, X. Long, Y. Gao, P. Chen, Z. Zhang, J. Liu, B. Li, T. Zhang, X. Mao, L. Zhang, H. Liu

      • Abstract

      Background:
      ALK-rearranged NSCLC is a unique molecular subgroup with high sensitivity to ALK inhibitors. Crizotinib, a FDA-approved tyrosine kinase inhibitor for ALK-rearranged NSCLCs, showed remarkable response in ALK-positive NSCLC. However, the magnitude and duration of clinical responses to crizotinib among different ALK variants are found to be heterogeneous, and studies about the clinical outcomes showed contradict conclusions.


      Method:
      We collected sequencing information from 110 ALK-positive Chinese NSCLC patients, whose tissue or plasma biopsies were sequenced in a CLIA-certified genomic profiling laboratory. Sequencing results were reviewed with the intent of studying ALK rearrangement distribution and clinical outcomes to crizotinib.


      Results:
      A total of 134 (5.6%) ALK rearrangements were identified in a cohort of 1971 NSCLCs, with 39 unique rearrangement partners. EML4 was the most common ALK rearrangement partner, with variant 3 (v3) as the most frequent variants (42.7%) of EML4-ALK fusion, accounting for 71.6% (96/134) of all the rearrangements in 87.3% (96/110) patients. For EML4-ALK positive patients after crizotinib treatment (n=96), survival analysis revealed that patients with EML4-ALK only displayed favorable PFS (10.0 vs 7.2 months, p=0.037) and OS (36.0 vs 20.0 months, p=0.037) than those combined with other fusions. In vitro data reported that variant v3 and v5 was structurally stable and less sensitive to ALK inhibitors due to the lack of TAPE domain. In this study, patients harboring v3 and v5 displayed significantly inferior OS than those with other variants (31 vs 37.6 months, p=0.010). For all the ALK-rearranged patients (n=110), no significant difference was observed between the survival of EML4-ALK and non-EML4-ALK (PFS, 9.4 vs 14.5 months, p=0.61; OS, 35.1 vs 35.5 months, p=0.58), below and above 40-years (PFS, 7.3 vs 11.3 months, p=0.23; OS, 25.4 vs 35.5 months, p=0.69).


      Conclusion:
      This study demonstrated the distribution pattern of ALK rearrangements in Chinese NSCLCs, and illustrated the clinical outcomes of ALK-positive patients in different sub-groups. We hope this study could improve basic knowledge of ALK rearrangement and might be helpful for clinicians in choosing patients for appropriate medical treatment. Moreover, these findings advocate for more comprehensive ALK genomic profiling and validation of current results of clinical outcomes in large populations.

    • +

      P072 - Low Detection Rate of EGFR Driver and T790M Mutation in Plasma by (ID 110)

      00:00 - 00:00  |  Author(s): O. Yuko, T. Yoshida, K. Asada, T. Oguri, N. Inui, S. Morikawa, K. Ito, T. Kimura, E. Kunii, T. Matsui, A. Kubo, T. Kato, J. Shindo, T. Tsuda, M. Okuno, T. Hida

      • Abstract

      Background:
      Cell free DNA (cfDNA) genotyping in plasma by cobas EGFR Mutation Test v2 (cobas test) is the first liquid biopsy approved as companion diagnostic systemtest to identify patients with EGFR T790M (T790M) mutation after first-generation EGFR-TKIs (G: gefitinib and erlotinib: E)and second-generation EGFR-TKIs (afatinib) failure. However, it remains unclear whether cobas testin plasma is sufficient method for detecting T790M mutation after afatinib failure. This study aimed atinvestigating the efficacy and sensitivity of cfDNA genotyping in plasma by cobas test for detecting T790M after the resistance to afatinib.


      Method:
      We collected plasma in patients who acquired resistance to afatinib between November 2016 and April 2018 as multi-institutional prospective observational study (UMIN000025112). All plasma samples were assessed by cobas test. Additionally, we retrospectively reviewed patients who had underwent cobas test in plasma after resistance to G/E as control arm. In all patients, patient characteristics, efficacy of EGFR-TKIs, and T790M status in plasma and tissue were reviewed.


      Results:
      Fifty-one patients with resistance to afatinib were enrolled in the prospective observation study. Of these patients, 35 patients were treated with afatinib as first-line setting. Fourteen patients (40%) had EGFR driver mutation in plasma, and only 3 patients (7.3%) had T790M in plasma.To compare the detection rate of EGFR driver and T790M mutation in plasma between patients treated with G/E than with afatinib, we selected 38 patients who were treated G/E as first-line setting and underwent plasma assay after resistance to G/E. There was no difference in the detection of EGFR driver mutation and T790M mutation in patients treated with G/E than afatinib ([EGFR driver mutation]: 52.6% vs 40.0%, p=0.28 and [T790M]: 23.7% vs. 8.6%, p=0.08). However, on patients with EGFR driver mutation positive in plasma (N=34), the T790M detection in plasma was significantly higher in patients treated with G/E than those with afatinib (45.0% vs. 14.3%, p=0.05). On the other hands, in 42 patients who underwent tissue analysis for T790M mutation, there was no significant difference in the frequency of T790M mutation in tissue by rebiopsy between two groups (G/E vs afatinib: 20.7% vs 23.7%, p=0.77).


      Conclusion:
      CfDNA analysis for T790M mutation by cobas test in patients treated with afatinib could be insufficient compared with those with first-generation EGFR-TKIs (G and E).

    • +

      P073 - Cbl-b Predicts Prognosis of NSCLC Patients and Affects PD-L1 Expression in A549 (ID 23)

      00:00 - 00:00  |  Author(s): P. Li, X. Yan, G. Zhang, M. Zhang, X. Zhang, J. Yang, Y. Chang, H. Wang, J. Ma, Z. Ma

      • Abstract

      Background:
      Casitas B-lineage lymphoma (Cbl-b) is an important gene for T cell immunity regulation. We sought to understand the involvement of PD-L1 and Cbl-b expressions in NSCLC.


      Method:
      With immunohistochemistry (IHC), we investigated the expression of PD-L1 and Cbl-b in 165 patients with stage I

    • +

      P075 - Hippo-YAP Pathway Mediated Resistance to Crizotinib in ROS1-Positive Lung Cancer (ID 113)

      00:00 - 00:00  |  Author(s): P. Sun, H. Gao

      • Abstract

      Background:
      At present, limited data exist on the spectrum of resistance mechanisms in ROS1-positive lung cancer. The Hippo-YAP pathway has been recently implicated in the acquisition of drug resistance in anti-cancer therapy, Yes-associated protein (YAP) is a main mediator of the Hippo pathway, but no data are available about Hippo-YAP pathway in ROS1-positive lung cancer. In this study, we evaluated the expression of YAP in non-small-cell lung carcinoma (NSCLC) tissues, we also investigated the role of YAP in primary and crizotinib-resistant cell lines.


      Method:
      Immunohistochemical (IHC) staining of YAP and epithelial-to-mesenchymal transition (EMT) proteins was performed on tissue sections from 200 NSCLCs. Correlations between the expression of the above proteins and clinicopathologic features and prognostic significance were analyzed. Crizotinib -resistant cells (HCC78CR) were established using crizotinib -na

    • +

      P076 - A Lung Adenocarcinoma with Concomitant EGFR And De Novo MET Amplification Response Well to Combination of TKI And Bevacizumab (ID 193)

      00:00 - 00:00  |  Author(s): Q. Chu, J. Jiang, S. Huang, P. Zhang, Y. Chen, T. Zhang

      • Abstract

      Background:
      Patients with NSCLC who are carrying concomitant de novo EGFR and MET amplification were commonly reported to have poor response to therapy. Here, we presented a case of a patient harboring concomitant de novo MET and EGFR, who obtained favorable response to combinatorial therapy of TKI and bevacizumab.


      Method:
      We presented a lung adenocarcinoma patient harboring dual EGFR-MET alterations, and evaluated his response to combinatorial therapy of TKI and bevacizumab. In vitro experiments were performed in HCC827(EGFR-19del) and HCC827-GR (EGFR-19del+MET amplification) cells to validate the effect of bevacizumab on MET pathway.


      Results:
      A 44-year-old male stage IV lung adenocarcinoma with left lung tumor was detected harboring of EGFR-19del and MET amplification using PCR and FISH. The patient was treated with erlotinib+bevacizumab and achieved partial response (PR) with a PFS with 13 months. After PD, NGS performed on both tissue and plasma biopsies revealed that the patients obtained first-generation resistant mutation EGFR-T790M, concomitant with EGFR-19del. The patient was treated with osimertinib+bevacizumab and achieved PR. He developed PD again with a PFS of 10.2 months, and repeated biopsies sequencing identified concomitant EGFR-19del and MET amplification. Then, the patient was treated with crizotinib+bevacizumab and the best curative effect was stable disease. Four months later, he developed PD and the third biopsy still revealed positive EGFR-19del and MET amplification. The patient received osimertinib+crizotinib+bevacizumab and he achieved PR one month after treatment initiation. He is still under the treatment and the PFS is more than eight months. In vitro data revealed that, under gefitinib treatment, cell viability was higher in HCC827(EGFR-19del) than HCC827-GR (EGFR-19del+METamp). However, the patient harboring dual EGFR-MET alterations in this study obtained a PFS of 13 months to erlotinib, similar with patients with EGFR-19del only (mPFS was 13 months to erlotinib as reported), suggesting the efficacious treatment of EGFR-TKI and bevacizumab than TKI alone. We observed that VEGFR-2 was expressed at relatively high levels in HCC827-GR than other cell line without METamp, and VEGF pathway inhibition by bevacizumab resulted in decreased phospho-c-Met in HCC827-GR cell lines. This result provided in vitro evidence that bevacizumab can reduce MET pathway activation.


      Conclusion:
      This study provided basic knowledge and evidence for patients harboring concomitant EGFR and de novo MET amplification who may obtain favorable response to combinatorial treatment of TKI and bevacizumab. Encouraging antitumor activity of TKI+bevacizumab support further development of this combination for patients with advanced NSCLC and other solid tumors.

    • +

      P077 - miR-338-3p Promotes the Resistance of Non-Small Cell Lung Cancers To EGFR-TKI By Targeting PTPN12 (ID 186)

      00:00 - 00:00  |  Author(s): Q. Wu, F. Guo, Y. Li, W. Li, G. Ma, Y. Deng, W. Luo, Y. Zhao, F. Xu, Q. Zhou

      • Abstract

      Background:
      Most of patients harboring EGFR activating mutations will inevitably acquire resistance to EGFR-TKI after 6-12 months of treatment. The T790M mutation in exon 20 of EGFR gene is the main cause of drug resistance, accounting for about 50%. The third-generation TKI targeting T790M mutation has been marketed and used in clinical practice, such as Osimertinib (AZD9291), but there are still nearly 50% of TKI resistance mechanisms unknown or currently lack of clinical approaches for reversing drug resistance. Therefore, exploring the molecular mechanism of T790M-negative EGFR-TKI secondary drug resistance has become a hot spot in lung cancer research. A growing number of studies found that microRNA (miRNA) plays an important role in the regulation of acquired drug resistance of EGFR-TKI, and it is expected to reverse acquired resistance of EGFR TKIs.


      Method:
      Cell viabilities of PC9 and PC9/BB4 cells was detected by CCK-8 method, the EdU method was used to detect cell proliferation, cell apoptosis was detected by FACS, and plate colony assay was used to detect colony formation ability. Western blot detected to difference of EGFR downstream signaling pathways in PC9 and PC9/BB4 cells.


      Results:
      The results of in vitro experiments indicated that miR-338-3p was down-regulated in Gefitinib-sensitive PC9 cell and highly expressed in PC9/BB4 resistant cells. Up-regulation or down-regulation of miR-338-3p, respectively, can alter the effect of Gefitinib on the survival, proliferation, apoptosis and clonality of PC9 and PC9/BB4 cells, and can regulate the activity of p-Akt and p-Erk1/2 protein, indicating miR -338-3p promotes EGFR-TKI resistance in non-small cell lung cancer by activating EGFR downstream signaling pathway. Using bioinformatics software to predict and confirm by dual luciferase reporter system, PTPN12 is a downstream target gene of miR-338-3p. PTPN12 protein is highly expressed in PC9 cells, low in PC9/BB4 cells, and can interfere with Gefitinib sensitivity after interfering with PTPN12 expression level in PC9 and PC9/BB4 cells, respectively. In vitro experiments demonstrated that miR-338-3p activates EGFR downstream PI3K/Akt and Ras/Raf/Erk signaling pathways by targeting PTPN12, and promote Gefitinib resistance in non-small cell lung cancer. Further study showed that down-regulation of miR-338-3p by miR-338-3p antagomir reversed the resistance of PC9/BB4 xenografts to Gefitinib by activating PTPN12.


      Conclusion:
      We conclude that alteration of miR-338-3p/PTPN12 expression as a novel mechanism for EGFR-TKI resistance in NSCLC. miR-338-3p/PTPN12 could serve as a therapeutic target for overcoming EGFR-TKI resistance in NSCLC.

    • +

      P080 - Efficacy and Safety of Docetaxel Plus Ramucirumab: A Consecutive Analysis of 68 Patients with Advanced NSCLC (ID 214)

      00:00 - 00:00  |  Author(s): S. Yokota, H. Horinouchi, S. Kanda, Y. Fujiwara, S. Murakami, Y. Goto, Y. Matsumoto, R. Morita

      • Abstract

      Background:
      Docetaxel plus ramucirumab (DTX+RAM) prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. We assessed the efficacy and safety, especially the incidence of febrile neutropenia (FN), in patients who received DTX+RAM.


      Method:
      Consecutive patients who received DTX+RAM between August 2016 and May 2018 were reviewed retrospectively.


      Results:
      A total 68 patients received DTX+RAM. The patients

    • +

      P081 - Clinical Characteristics and Molecular Patterns Of RET-Rearranged Lung Cancer in Chinese Patients (ID 191)

      00:00 - 00:00  |  Author(s): S. Fei, K. Zhang, H. Chen, Y. Wang, L. Yang, C. Zhou, W. Yin, G. Wang, B. Li, T. Zhang, J. Xiang, X. Mao

      • Abstract

      Background:
      Rearrangement of RET is identified as an oncogenic alteration in lung cancer. However, studies about characteristics of RET rearrangement in lung cancers are still limited, and several reports were conflicting. Our aim was to demonstrate the clinical and molecular features of RET rearrangement in Chinese lung cancers.


      Method:
      We reviewed genomic profiling data of biopsies (including either tissue or plasma) from 6125 lung cancer patients sequenced in a CLIA-certified laboratory from 2015 to 2017. Patient characteristics, including age, gender and histology classification were collected.


      Results:
      A total of 106 RET rearrangements in 84 patients (1.37%, 84/6125) were identified. RET rearrangement had a tendency to occur in female, adenocarcinoma, with a median age of 58 years. KIF5B-RET fusion was the most frequently occurred subtypes, identified in 53.8% (57/106) RET rearrangements and 67.9% (57/84) of patients, followed by CCDC6-RET and NCOA4-RET. Besides, several rare and novel RET fusion partners were identified, to the best of our knowledge, including TSSK4, SORBS1, SIRT1, PTPRK, ADD3-AS1, PRKG1, IL2RA, CCNYL2, CCDC186 and ANKS1B. We further investigated the concurrent and exclusive genomic alterations in RET-rearranged patients. TP53 was the most commonly seen concurrent mutation, occurring in 42.5% (20/47) of patients, which was followed by EGFR (14.9%, 7/47). KIF5B-RET subtype was fully mutual exclusive with EGFR mutation, suggesting that KIF5B-RET was a strong oncogenic driver mutation. RET fusion partners of the 7 patients harboring concurrent EGFR and RET rearrangement were all non-KIF5B. In addition, we observed that allelic fraction of first-generation EGFR-TKI sensitizing mutation was higher than non-KIF5B-RET in each individual patient, indicating that non-KIF5B-RET fusion might function as a potential acquired resistance mechanism to EGFR tyrosine kinase inhibitors. Clinical outcomes of cabozantinib, a RET kinase inhibitor, were available in six patients with RET-rearrangement, and the median treatment period of cabozantinib for these patients was 5 months. A stage IV adenocarcinoma patient developed resistance to osimertinib and followed NGS revealed that he harbored concurrent CCNYL2-RET fusion and EGFR mutation. After the combinatorial treatment of osimertinib and cabozantinib, he achieved stable disease (SD) with a PFS of 5 months before disease progression.


      Conclusion:
      Lung cancer patients with RET-rearrangement displayed identifiable clinical characteristics and heterogeneous molecular distribution. The investigation of clinical and molecular pattern of RET-rearrangements might be helpful to provide basic knowledge for personalized diagnosis and clinical considerations. Further investigations are needed in the fields of potential sensitivities among different fusion variants and resistance mechanism to RET inhibition.

    • +

      P082 - DNA Methylation: A More Sensitive Marker for Treatment Monitoring? (ID 78)

      00:00 - 00:00  |  Author(s): S. Xia, S. Chuai, Y. Chen, L. Huang, W. Deng, H. Han-Zhang, Y. Zhang, F. Xu, X. Ren, Y. Chen

      • Abstract

      Background:
      Detection of genomic aberrations in cell-free DNA (cfDNA), requiring ultra-deep sequencing due to the low allelic frequencies (AF) of mutation, has been utilized to monitor treatment response. However, 20%-30% of patients yield no mutation from plasma genotyping despite deep sequencing depth, thus necessitating alternative monitoring method. The role of aberrant DNA methylation in the process of tumorigenesis both at individual genes and a genome-wide scale has been well elucidated. We investigated the potential of DNA methylation as a biomarker for treatment monitoring.


      Method:
      We investigated the performance of mutation and DNA methylation as biomarkers to evaluate response to osimertinib using a DNA methylation panel consisting of 100,000 CpG sites and a targeted panel for mutation detection consisting of 168 lung cancer related genes with an average sequencing depth of 1,000x and 10,000x, respectively. Longitudinal plasma samples from 6 patients undergoing osimertinib were collected prior to treatment and at regular interval until disease progression, ranged from 6 to 9 times. Methylation level of a given sample was reflected by the percentage of significantly methylated blocks, which were significantly hypermethylated blocks comparing to healthy individuals.


      Results:
      All patients had EGFR sensitizing mutation and T790M at baseline. Four patients had additional concurrent mutations, including TP53, RB1, OR6F1 and BRCA2. At PD, all patients had detectable mutations except for one and 3 developed EFGR C797S. Four patients had at least two times of no detectable mutation during treatment. Among them, P05 and P06 had 5 and 6 times of no detectable mutation, respectively. In contrast, all patients had significantly methylated blocks detected at every point. In general, the trend of changes in mutation AF corresponds to the changes in the percentage of significantly methylated blocks in all patients except for one, who only had mutations detected at baseline and had consistently detectable DNA methylation at every point. Collectively, DNA methylation reached nadir at best response and gradually increased thereafter. An elevation of mutation AF or the emergence of new mutation(s) (molecular PD) was observed in 4 patients prior to PD assessed by imaging. In all patients, an elevation of DNA methylation was observed prior to PD assessed by imaging; among them, 3 had changes in DNA methylation prior to molecular PD, suggesting DNA methylation may be a more sensitive biomarker.


      Conclusion:
      Collectively, our study demonstrates DNA methylation, continuously increasing from the nadir (best response), can be utilized as a biomarker for treatment monitoring.

    • +

      P083 - Efficacy of EGFR-TKIs in Patients Harboring EGFR Mutations with Non-Adenocartinoma Histology (ID 223)

      00:00 - 00:00  |  Author(s): O Yuko

      • Abstract

      Background:
      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have substantial anti-tumor activity for NSCLC harboring EGFR sensitizing mutations. Adenocarcinoma (ADC) is the most common histological subtypes in patients with NSCLC harboring EGFR mutations. Whereas, EGFR mutations are occasionally observed in other histological subtypes of NSCLC. However, little is known about the efficacy of EGFR-TKIs in patients with non-adenocarcinoma harboring EGFR mutations.


      Method:
      We retrospectively analyzed 1467 patients with EGFR mutated NSCLC and treated with EGFR-TKIs between January 2008 and August 2017 from 11 institutions in Japan. We investigated the efficacy of EGFR-TKIs in patients with non-ADC NSCLC, compared with patients with EGFR mutated ADC. The protocol of this study was approved by institutional review board in each institution, and this study was registered in trial registration with preplanned statistical protocol (Clinical Trial information: UMIN000030121).


      Results:
      Finally, 1400 patients were analyzed, 68 patients with non-ADC, including 25 in squamous cell carcinoma, 4 in large cell carcinoma, 5 in pleomorphic carcinoma and 34 in others. Among 63 non-ADC patients, 57 patients received first generation TKIs and 10 patients received second generation TKI (there is some overlapping). The ORR of EGFR-TKIs was 60.0% in non-ADC and 64.2% in ADC, respectively. The median time to treatment failure were 7.4 months (95% CI, 4.7-10.2) in non-ADC and 11.1 months (95% CI, 10.3-12.0) in ADC (p=0.008). The median overall survival were 16.8 months (95% CI, 12.1-21.5) in non-ADC and 33.3 months (95% CI, 30.3-36.4) in ADC (p<0.001).


      Conclusion:
      EGFR-TKIs are less effective in EGFR mutated patients with non-ADC than ADC, nevertheless EGFR-TKIs has certain clinical benefit against EGFR mutated non-ADC.

    • +

      P084 - Musashi-2 Expression Is an (ID 148)

      00:00 - 00:00  |  Author(s): T. Wang, Q. Zhou, L. Luo

      • Abstract

      Background:
      Most patients with non-small cell lung cancer (NSCLC) would have local or distant metastases at the time of diagnosis and lose the chance of cure. Currently, there is no reliable biomarker to predict the lymph node metastasis and prognosis of NSCLC. As an RNA-binding protein, the Musashi-2 gene blocks translation by binding to mRNA non-translated region and plays an important role in regulating biological procedures of cell. Existing studies have suggested that Musashi-2 protein associates with the development and poor prognosis of various solid tumors and was reported overexpressed in lung cancer tissue compared with normal lung tissue. Our study aimed to assess the role of Musashi-2 expression in lymph node metastasis and postoperative survival.


      Method:
      In this present study, immunohistochemistry (IHC) was performed to characterize expression of Musashi-2 protein in NSCLC patients who underwent radical surgeries in our hospital between 2008 and 2013. The expression of Musashi-2 protein in human lung cancer tissues, paracancerous tissues, and metastatic lymph nodes was detected by IHC. The relationship between Musashi-2 protein expression and clinicopathological features, including gender, age, smoking history, pathological type, tumor size, TNM classification, lymph nodes metastasis, and postoperative survival, was analyzed. Kaplan-meier survival analysis and multivariate analysis were used to evaluate the significance of Musashi-2 overexpression as an independent adverse prognostic factor for NSCLC patients received surgery.


      Results:
      The results revealed that Musashi-2 protein expression was significantly lower in adjacent non-tumor tissues than that in primary lung cancer tissues (P?0.001). The Musashi-2 protein expression was lower in primary lung cancer tissues than that in metastatic lymph nodes (P?0.001). Chi-square test showed that Musashi-2 protein expression was correlated to tumor size (P?0.05), pathological type (P?0.05), tumor stage (P?0.001), and lymph node metastasis (P?0.001), but not to gender, age, smoking history or tumor grade. Kaplan-Meier survival analysis indicated an association of high Musashi-2 protein overexpression with worse postoperative survival in patients with NSCLC (P?0.001). Multivariate COX regression analysis furtherly confirmed that Musashi-2 protein overexpression is an independent predictor for postoperative survival (P?0.001).


      Conclusion:
      Therefore, Musashi-2 protein overexpression significantly correlates with lymph node metastasis and predicts poorer postoperative survival of NSCLC patients. It may serve as a novel prognostic marker in these patients.

    • +

      P086 - Toward the Standardization of Bioinformatics Methods for the Accurate Assessment of Tumor Mutational Burden (TMB) (ID 213)

      00:00 - 00:00  |  Author(s): H. Chang, S. Srinivasan, A. Sasson, R. Golhar, D. Greenawalt, S. Kirov, J. Szustakowski

      • Abstract

      Background:
      TMB has emerged as a predictive biomarker of response to immune checkpoint inhibitors. CheckMate 227 demonstrated that patients with non-small cell lung cancer (NSCLC) with TMB ?10 mutations/megabase derived enhanced benefit from first-line treatment with nivolumab + ipilimumab vs chemotherapy (Hellmann et al. NEJM 2018). Standardized approaches for the measurement and reporting of TMB are essential for the real-world implementation of TMB. This study aimed to refine a bioinformatic pipeline for mutation calling and annotation of whole exome sequencing (WES) data for TMB assessment.


      Method:
      In CheckMate 026, TMB was assessed by WES on formalin-fixed, paraffin-embedded tumor samples and matched blood from 312 patients with NSCLC (Carbone et al. NEJM 2017). Data from each sample were aligned to a reference human genome and somatic mutations were called by comparing matched tumor and blood samples using the TNsnv and Strelka algorithms. The somatic mutations were additionally filtered for germline variants in public databases. TMB scores were compared with data from 710 NSCLC samples in The Cancer Genome Atlas (TCGA) dataset. We examined the concordance of TMB estimates using several mutation filtering schemes, with and without matched germline controls.


      Results:
      TMB scores including synonymous, indel, frameshift, and nonsense mutations (all mutations) were ~3-fold higher than matched data filtered for missense mutations only, but values were highly correlated (Spearman's r=0.99). Scores including missense mutations only were similar to those generated from TCGA, but those including all mutations were on average higher. Using public databases for germline subtraction showed a trend for race-dependent increases in TMB scores.


      Conclusion:
      Standardization of bioinformatic analyses is critical to the clinical implementation of TMB assessment. TMB assessment is sensitive to variations in bioinformatic parameters (eg, which type of mutation to include), which may affect the identification of patients likely to respond to immunotherapy. These results show that data from different pipelines are highly correlated, suggesting that reliable assessment of TMB across different centers and platforms is achievable. Chang H et al., ESMO 2018, Annals of Oncology, Volume 29, 2018 Supplement 6.

    • +

      P087 - TNM Staging Inversely Correlates with Age in ALK-positive Lung Cancer (ID 63)

      00:00 - 00:00  |  Author(s): W. Tang, C. Zhang, Y. Lei, R. Fu, J. Kang, H. Yan, X. Yang, H. Tu, Y. Wu, W. Zhong

      • Abstract

      Background:
      The patients with lung cancer and anaplastic lymphoma kinase (ALK) rearrangement predominantly occur younger. However, few large-scale studies revealed the clear correlation between age, tumor nodes metastases (TNM) staging and morbidity in this rare population.


      Method:
      The age of ALK-positive lung cancer at initial diagnosis were compared between various TNM stages. Clinical characteristics, morbidity and prognosis were analyzed stratified by different age groups.


      Results:
      Of 411 patients, the younger group showed more frequent T3/4 stage (P = 0.014), more frequent lymph nodes metastasis (P = 0.011) and more frequent distant metastasis (P = 0.015). Across the entire patient cohort, the median age was 51 years, which decreased steadily with clinical stages (stage I/II vs. III vs. IV, 55 vs. 52 vs. 49 years). There was significant inverse correlation between age and clinical stages (P < 0.001). These laws also existed at various T, N, M categories. What was more, morbidity of ALK rearrangement manifested a steady downward trend with older age groups (?40 vs. 40-49 vs. 50-59 vs. ?60 years: 18.8% vs. 11.6% vs. 5.0% vs. 2.2%). Surprisingly, ALK-positive patients with stage IIIb-IV disease had much higher incidence than the patients with stage I-IIIa disease (6.1% vs. 3.4%, P < 0.001). Finally, the ALK-positive patients aged younger showed poorer outcomes compared with the older group.


      Conclusion:
      TNM staging exhibited a significant inverse correlation with age in ALK-positive lung cancer. More unique therapeutic and research strategies should be required in these patients of young age.

    • +

      P088 - Distribution of Different HER2 Mutations (ID 219)

      00:00 - 00:00  |  Author(s): W Wang

      • Abstract

      Background:
      Human epidermal growth factor receptor 2 (HER2)-targeted therapies in lung cancer exhibit limited and variable efficacies, suggesting the heterogeneity of HER2-mutant lung cancers. Here, we explored the genetic characteristics in different HER2 mutations and co-mutations and their impact on responses to afatinib in NSCLC patients.


      Method:
      Eighty-six HER2-mutant lung cancer patients who were referred to OrigiMed (Shanghai, China) for NGS-based genomic testing were identified (OrigiMed cohort). The frequency and distribution of genomic alterations were analyzed with a 37 or 450 gene panel with a mean coverage depth of >800X. Another 32 HER2-mutant adenocarcinoma patients who treated with afatinib were identified (Afatinib cohort). Clinical outcomes on afatinib were retrospectively evaluated according to types of HER2 mutations. The most common mutation A775_G776insYVMA were classified into Group 1; Group 2 contained other exon 20 insertions; Group 3 contained missense mutations.


      Results:
      The frequency of HER2 mutation was 4.23% (86/2035), which was higher than those observed in TCGA (15/546, 2.75%) and MSK-IMPACT (45/1275, 3.53%). Thirty-one different HER2 mutations were detected in OrigiMed cohort. The most frequent HER2 mutations in two cohort were A775_G776insYVMA (35/86; 14/32), G778_P780dup (6/86; 5/32), G776delinsVC (4/86; 5/32) and S310F/Y (7/86; 1/32). A775_G776insYVMA and G776delinsVC/G778_P780dup respectively correlated with the worst and the best clinical outcomes on afatinib in overall response rate (P=0.018), disease control rate (P=0.001) and progression-free survival (PFS) (Figure 1). In multivariable analysis, A775_G776insYVMA (HR[95%CI]: G2/G1, 0.009 [0.001-0.079], P<0.001; G3/G1, 0.184 [0.062-0.552], P=0.003), TP53 co-mutations (6.317 [2.180-18.302], P=0.001) and PI3K/AKT/mTOR pathway co-mutations (19.422 [4.098-92.039], P<0.001) correlated with significantly shorter PFS, while G776delinsVC and G778_P780dup correlated with the longest PFS (G2/G3, 0.050 [0.008-0.307], P=0.001). figure 1.jpg


      Conclusion:
      Different HER2 genotypes exhibit divergent drug sensitivities. G776delinsVC and G778_P780dup derive the greatest benefit from afatinib, while A775_G776insYVMA, co-mutations in TP53 and the PI3K/AKT/mTOR pathway confer primary resistance to afatinib.

    • +

      P089 - An EGFR KDD Data in the Chinese NSCLC Population and the Response to EGFR-TKIs: A Multicenter Study (ID 21)

      00:00 - 00:00  |  Author(s): W. Wang, C. Xu, Y. Zhu, M. Fang, W. Zhuang, Y. Chen, G. Chen, T. Lv, Y. Song

      • Abstract

      Background:
      Epidermal growth factor receptor (EGFR) mutations are major driver genes in non-small cell lung cancer (NSCLC), especially in lung adenocarcinomas. The most frequent EGFR mutations include deletions in exon 19 and point mutations in exon 21 (L858R). EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). With the development of detection techniques, uncommon genomic mutations are increasingly identified. EGFR exon 18-25 kinase domain duplication (EGFR-KDD), as a new EGFR gene molecular subtype in NSCLC, is rare. The efficacy of EGFR-TKIs for this subtype of mutant patients is uncertain.


      Method:
      A multicenter study in China was initiated from July 2013, and a total of 3279 NSCLC patients have been enrolled as of November 2016 from four medical centers in many different area. They were screened by using a next-generation sequencing (NGS)-based gene panel assay for detecting EGFR-KDD.


      Results:
      Of this entire cohort, just one (0.07% EGFR M+NSCLC ) patient was identified with an EGFR-KDD in Chinese population. Here is a 63-year-old Chinese female with a left lung tumor (NSCLC T1N0M1, stage IV) and pleural metastasis. Histologic examination of the surgical specimens from the left lung tumor and pleural nodes revealed lung adenocarcinoma. Using a next generation sequencing assay, we found that the tumor had EGFRKDD and the most common types of EGFR mutations were wild. The patient experienced a stable tumor response to icotinib. Considering this rare EGFR mutation and response to TKI treatment, we conclude that the incidence of rare EGFR gene mutations in NSCLC patients should be studied.


      Conclusion:
      The frequency of EGFR-KDD in Chinese population with NSCLC is more than Caucasus population (0.07% vs 0.02%). This case facilitates an increase in the detection of uncommon EGFR gene mutations and enhances the evidence of a clinical response to EGFR inhibitors. The landscape of EGFR-TKI-responsive EGFR genotypes demonstrates that comprehensive molecular types are necessary to realize the identification of patients who would benefit from targeted therapy, especially EGFR-wild NSCLC patients.

    • +

      P090 - Prevalence of Brain Metastases in Limited Stage Small Cell Lung Cancer Immediately Before Prophylactic Cranial Irradiation (ID 22)

      00:00 - 00:00  |  Author(s): X. Chu, X. Yang, Z. Zhu

      • Abstract

      Background:
      Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastasis (BM) and improves overall survival (OS) in limited-stage Small Cell Lung Cancer (LS-SCLC) patients with complete or partial remission after receiving chemoradiotherapy. However, cranial magnetic resonance imaging (CMRI) before scheduled PCI is not mandatory, and its necessity remains controversial. Therefore, we conducted this study to evaluate LS-SCLC patients

    • +

      P091 - Association Between BIM Polymorphism and Lung Cancer Outcomes: A Meta-analysis (ID 24)

      00:00 - 00:00  |  Author(s): X. Li, L. Wu, H. Chen, Y. Zhu, W. Wang, C. Xu, X. Lin, D. Xie, K. Du

      • Abstract

      Background:
      Accumulating evidences have indicated that BIM expression largely decides the development of lung cancer and outcome of EGFR-mutant lung cancers after TKI treatments. BIM polymorphism is a 2,903-bp deletion in the second exon. To clarify the relationship between this BIM polymorphism and clinical outcomes of lung cancers, we conducted this meta-analysis and observed the survival and responses to TKIs.


      Method:
      This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literatures were searched using the following key words:

    • +

      P093 - DNA Methylation in CTC And ctDNA is A Promising Marker for Early Detection of Lung Cancer Metastasis (ID 183)

      00:00 - 00:00  |  Author(s): X. Qiu, Q. Zhou

      • Abstract

      Background:
      Lung cancer is the leading cause of cancer-related death worldwide and metastatic dissemination of lung cancer cells represents a significant clinical obstacle to cure the the disease. Aberrant DNA methylation represses gene expression and correlates with cell proliferation, angiogenesis, invasion and metastasis. Many DNA methylation markers have already been used in the early detection of lung cancer. The role of DNA methylation in lung cancer metastasis remains poorly understood and no satisfied marker predicting metastasis were found up to date. We will try to screen out usable methylation markers to improve our diagnosis for metastasis in lung cancer.


      Method:
      Scientific literature databases were exhaustively searched to retrieve published studies relevant to DNA methylation and NSCLC metastasis. Retrieved studies published in English and Chinese languages were screened according to the stringent predefined inclusion and exclusion criteria, and high quality studies were selected for further analysis. Genes were screened and sorted for further validation.


      Results:
      A total of 45 published studies were selected in the present analysis. 23 genes or microRNAs were studied in the relationship between methylation and tumor metastasis. The genes include metastatic genes, metastasis suppressor genes , EMT-related genes, microRNAs and noncoding RNA. The methylation rate of these genes and tumor metastasis were studied. Genes with intensive research include P16, Rassf1, DAPK, HOXA5, SOX9, MALAT1 and microRNAs such as mir-182, mir-139. mir-224. No further studies were regarded in the prediction value of these markers in serum and CTC in lung cancer metastasis. These markers might be validated in metastasis prediction in further studies.


      Conclusion:
      Our analysis results reveal that methylation might be associated with tumor metastasis and poor prognosis in NSCLC patients, and might be good markers in liquid biopsy for early detection of lung cancer metastasis.

    • +

      P094 - Evaluation of the Efficacy of Salvage Surgery for Advanced NSCLC Patients After Neoadjuvant (ID 102)

      00:00 - 00:00  |  Author(s): X. Cao, Y. Liao

      • Abstract

      Background:
      The clinical effect of gefitinib on patients with EGFR mutational advanced non-small cell lung cancer (NSCLC) was remarkable, but was inevitably impaired by progressive drug resistance, and the median time to progression is about 1 year. When complete resection of residual disease is possible, the patients can then be considered disease free before drug-resistant. We have aggressively performed salvage lobectomy for patients with gefitinib responses and demonstrated down-staging to under ?A stage. The purpose of this study was to evaluate the perioperative safety and survival benefit of the combined treatment.


      Method:
      A total of 19 advanced NSCLC patients undergoing surgery after gefitinib treatment were collected from 2016.06 to 2018.06. Among them, 9 cases were ?B stage, 2 cases were ?C stage and 8 cases were ? stage, according to The 8th Edition UICC Lung Cancer TNM Staging Criteria. All of the 19 patients would make PET/CT scan and assess the clinical stage down-staging to under ?A stage after treating by gefitinib for from 2-6 months. Then all patients were undergoing video-assisted thoracoscopic (VATS) lobectomy and systemic lymph node dissection. Preioperative risk was evaluated and all patients were followed-up regularly.


      Results:
      All patients were successfully performed by VATS lobectomy and the pathologic stage was down-staging to under ?A stage. Of them, 2 patients were 0 stage, 11 patients were ?A stage, 4 patients were ?B stage and 2 patients were ?A stage. The average operative time is ?210

    • +

      P095 - MicroRNA-330-3p Promotes Brain Metastasis of Non-Small Cell Lung Cancer by Activating MAPK/MEK/ERK Signaling Through GRIA3 (ID 172)

      00:00 - 00:00  |  Author(s): C. Wei, Q. Cai, R. Zhang, F. Tong, X. Dong

      • Abstract

      Background:
      Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with NSCLC. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. MicroRNAs (miRNAs) play an essential role in the development of NSCLC. We investigated miRNAs that serve as biomarkers to differentiate NSCLC patients with and without BM, and explored the underlying mechanism.


      Method:
      Logistic regression was conducted in 122 NSCLC patients (60 without BM, 62 with BM) to examine the association between miRNAs and BM. Stable over-expression and knock-down of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR). The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330-3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay.


      Results:
      High serum miR-330-3p was an independent risk for BM. Tissue miR-330-3p was also higher in subjects with BM (P=0.003). Migration and invasiveness were increased by over-expressing miR-330-3p using a lentivirus, and decreased by miR-330-3p knockdown in both cell lines. In nude mice receiving NSCLC cells, either subcutaneously or into the brain, tumor growth was faster in mice receiving cells permanently expressing exogenous miR-330-3p, and slower in cells expressing the anti-miR-330-3p sequence. Bioinformatics analysis, followed by microarray analysis of A549 cells over-expressing miR-330-3p and luciferase reporter assay suggested the glutamate receptor GRIA3 as a target of miR-330-3p. Experiments using selective kinase inhibitors suggested that GRIA3 is regulated by miR-330-3p via MAPK/MEK/ERK signaling pathway.


      Conclusion:
      miR-330-3p promotes NSCLC brain metastasis possibly in part via the MAPK/MEK/ERK pathway and GRIA3, and might be a potential target for the further research of NSCLC brain metastasis.

    • +

      P096 - MLPH Activates CDC42/PAK1 Signaling to Promote Epithelial (ID 173)

      00:00 - 00:00  |  Author(s): C. Wei, L. Peng, F. Tong, X. Dong

      • Abstract

      Background:
      Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). Therefore, a better understanding of molecularmechanisms underlying NSCLC development and progression could provide helpful insights for NSCLC prevention and effective treatment. Melanophilin (MLPH) is a protein coding gene encoding a member of the exophilin subfamily of Rab effector proteins. Recently, MLPH was reported to be associated with cancers, however, to date, the role of MLPH in lung cancer has never been studied.


      Method:
      RNA-Sequencing was performed to identify differentially expressed genes- MLPH in lung tissues of NSCLC patients with and without BM, then the expression of MLPH was further examined in the serum of BM+ and BM- patients. To study the role of MLPH in the initiation and progression of NSCLC, we examined MLPH levels in NSCLC cells and tissues and analyzed the relationship between MLPH levels and patient survival. Then we knocked down MLPH in NSCLC cells. We used cell counting kit-8 assay, wound healing assay, transwell assay, flow cytometry analysis, Phalloidin staining, xenografted tumor model and brain metastasis model to determine the effects of MLPH on the proliferation, migration, invasion, EMT, tumorigenesis and brain metastasis of NSCLC. Western blot analysis was used to explore the underlying mechanism.


      Results:
      In this study, we found that MLPH was up-regulated in NSCLC tissues and cells. Patients with high levels of MLPH expression had significantly shorter survival than those with low MLPH expression. In NSCLC cell lines, shRNA-mediated depletion of MLPH inhibited the proliferation, lead to apoptosis, induced G0/G1 arrest and suppressed cell migration, invasion, EMT, tumorigenesis and brain metastasis. Mechanistically, we identified TGF-? as a key downstream effector of MLPH. More importantly, MLPH silencing attenuated CDC42/PAK1 signaling activation at least in part through the downregulation of TGF-?.


      Conclusion:
      Together, our findings demonstrated that MLPH positively modulated the CDC42/PAK1 signaling pathway via TGF-? to promote EMT and metastasis, suggesting MLPH as a potential oncogenic biomarker and a promising therapeutic target in the treatment of NSCLC and brain metastasis.

    • +

      P097 - ctDNA Changes and TCR Diversity Associated with Clinical Outcomes Following Brain Therapy in NSCLC (ID 174)

      00:00 - 00:00  |  Author(s): C. Wei, L. Chen, X. Dong

      • Abstract

      Background:
      Radiotherapy (RT) is a highly effective anti-cancer treatment forming the standard strategies for brain metastasis in non-small cell lung cancer (NSCLC) patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity and T cell receptor (TCR) repertoire diversity. however, the genomic evolution and mechanisms of RT induced immune responses are unknown.


      Method:
      Here, we perform targeted deep sequencing of circulating tumor DNA (ctDNA) on peripheral blood samples and cerebrospinal fluid (CSF) samples collected prior to and during brain radiotherapy from 13 NSCLC patients with brain metastasis. We used a panel to identify cancer-associated gene mutations and analyze tumor mutation burden. We applied next-generation sequencing (NGS) to investigate the T-cell receptor (TCR) repertoire.


      Results:
      In this study, we showed that patients with high blood TMB (high >10 mutations/Mb) tended to benefit from brain radiotherapy both in the terms of clinical outcomes of brain lesions and lung lesions. High TMB of CSF was correlated with a favorable clinical efficacy of brain. Response to therapy indicated according to the changes of ctDNA level between baseline and 28 days post-treatment was consistent with clinical outcomes of lung lesions measured by thoracic CT. Moreover, we showed that the low overlap of TCR repertoire in paired blood samples (base to T0) was detected in patients with partial relief (PR), and high overlap of TCR repertoire was in patients with disease stable (SD). Within 24h post-therapy, a high degree of TCR overlap in peripheral blood and CSF was observed from patients with PR in lung lesions, and a low degree of TCR overlap was from patients with SD in lung lesions.


      Conclusion:
      These data demonstrated the potential of ctDNA analysis to be a sensitive tool for predicting treatment responsivity, and the level of TCR repertoire overlap correlated with clinical outcomes.

    • +

      P100 - Stem Cell Factor Leads to Lung Cancer Escapes from Anti-Angiogenic Therapy by Increasing the ALDH1+ Lung Cancer Cell Number (ID 146)

      00:00 - 00:00  |  Author(s): Y. Liu, L. Wang, F. Luo

      • Abstract

      Background:
      Although the anti-angiogenic therapy becomes an important treatment for non-small-cell lung cancer, cancer cells can escape from this therapy through several different ways so as to keep growth. Our previous results showed that anti-angiogenic drugs increased the number of ALDH1+ lung cancer cells in mouse models. This study is to explore the significance and mechanism of this phenomenon.


      Method:
      The xenograft tumor murine models and molecular experiments in vitro were used in this study.


      Results:
      In our experiments with murine lung cancer xenografts, we found that the anti-angiogenic agent endostatin increased the number of ALDH1+ lung caner cells. In vitro results showed that SOX and OCT4 were highly expressed in ALDH1+ lung cancer cells. These cells had stronger ability in surviving in hypoxic environment, metastasis and invasion than ALDH1- lung cancer cells. We also found that the expressions of HIF-1a and stem cell factor (SCF) in the xenografts were increased after anti-angiogenic therapy. HIF-1? could up-regulate the expression of SCF in lung cancer cells. The over-expression of SCF can increase the proportion of ALDH1+ cells in lung cancer. The mechanism was related to the HIF-1?/SCF/c-Kit/PI3K/AKT pathway. Finally, when we combined anti-angiogenic therapy with decreasing SCF expression, it is found that the survival time of mice in the combination group was significantly longer than that in the single anti-angiogenic group.


      Conclusion:
      Anti-angiogenic therapy aggravated hypoxia which could induce the up-regulated expression of SCF in lung cancer. SCF promoted lung cancer to escape from anti-angiogenic therapy by increasing the number of ALDH1+ lung cancer cells.

    • +

      P101 - Intratumor Heterogeneity Comparison Among Different Subtypes of (ID 206)

      00:00 - 00:00  |  Author(s): Y. Zhang, Y. Yang, W. Fang, L. Chang, L. Zhang, L. Zhang

      • Abstract

      Background:
      Intratumor heterogeneity (ITH) can lead to therapeutic failure, drug resistance, and poor survival. Understanding of ITH among different non-small cell lung cancer (NSCLC) subtypes is necessary. Circulating tumor DNA (ctDNA) released by tumor cell into the blood, can originate from any subclonal population within the tumor and therefore has great potential for presenting ITH. Whether ctDNA profile could represent these ITH is still an open question.


      Method:
      We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. ITH is evaluated by ITH index (ITHi). The ITHi will be higher, if the tumor has less trunk mutations.


      Results:
      EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD (P=0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P=0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P=0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60% , P=0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. Additionally, for driver mutations, the proportions of oncogenes and tumor suppressor genes (TSGs) seemed to be similar both in the trunk (58% and 42%) and branch (49% and 51%) in general. However, oncogenes showed a higher proportion in EGFR-mutant LUAD, while TSG alterations had a strong enrichment in LUSC in trunk. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%;, P=4.53e-6) among all NSCLC subtypes. LUSC and EGFR&KRAS-wild-type LUAD had higher proportions for tumor-derived trunk mutations (81% and 53%) than those in EGFR-mutant LUAD (30%) and KRAS-mutant LUAD (22%), while the detections for tumor-derived branch mutations in ctDNA were extremely poor (from 13% to 25%) among all above NSCLC subtypes.


      Conclusion:
      EGFR-mutant LUAD has the highest ITHi than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA analysis shows unsatisfactory detections of tumor-derived mutations among all NSCLC subtypes, thus it maybe not an appropriate method to reflect ITH.

    • +

      P102 - The Correlations of Tumor Mutational Burden Among Single-region Tissue, Multi-region Tissues And Blood in NSCLC (ID 208)

      00:00 - 00:00  |  Author(s): Y. Zhang, W. Fang, Y. Yang, L. Chang, L. Zhang, L. Zhang

      • Abstract

      Background:
      Tumor mutational burden (TMB) is emerging as a practical biomarker for response to immune checkpoint inhibitors (ICIs). Non-small cell lung cancer (NSCLC) patients with high-level tissue TMB (tTMB) or blood TMB (bTMB) are associated with better efficacy of ICIs. However, the correlations of single-region tTMB, multi-region tTMB and bTMB remain to be determined. Moreover, whether intratumor heterogeneity (ITH) has impact on TMB should be clarified.


      Method:
      We collected multi-region tumor tissues with matched blood from 32 operative NSCLC and explored the correlations among one-region tTMB, multi-region tTMB and bTMB through a 1021-gene panel sequencing. One-region tTMB was defined as the number of somatic non-synonymous mutations from single region. multi-region tTMB was calculated with non-repetitive mutations from all regions. bTMB was analyzed with tumor-derived mutations from ctDNA. TMB of >9 mutations/Mb was classified as high, using the top quartile threshold of 2000 samples from database of Geneplus. Besides, we used TMB fold-change, computed by the mean tTMB of single, double, and triple regions through a random iterated algorithm, to evaluate the influence of the enrolled region numbers on tTMB and explored the impact of ITH on tTMB.


      Results:
      Both of single-region tTMB and bTMB showed strong correlations with multi-region tTMB, while the former correlated better (Pearson r=0.94, P=2E-84, Pearson r=0.47, P=0.0067). It showed extremely high specificity (100%) but relatively low sensitivity (43%) when using bTMB define TMB-high patients, while most false-negative predictions were in early-stage patients. The classification accuracy was higher in late-stage patients (83%) than in early-stage patients (70%).Compared to single region, we found significantly enhanced tTMB fold-change if taking multi-regions for consideration. However, it showed insignificant tTMB fold-change increase if the included regions' number more than three. Moreover, the tTMB fold-change increased more sharply in ITH-high group compared with the ITH-low group significantly (fold-change 2.32 vs. 1.02, P=8.879e-05). The conversion rate of tTMB level status (conversion of tTMB-low to tTMB-high) in the ITH-high group was numerically higher than that in the ITH-low group (16.67% vs. 3.84%).


      Conclusion:
      Single-region tTMB has stronger correlation with multi-region tTMB compared with bTMB, revealing the limitation of TMB analysis using ctDNA. ITH has an impact on tTMB, especially in high-level ITH patients, thus firstly demonstrating tTMB heterogeneity and providing an explanation for why some low-TMB patients evaluated by a single region biopsy still achieve benefit from ICIs.

    • +

      P104 - Anti-PD-1 Combination Therapy in Second or Later Lines in (ID 114)

      00:00 - 00:00  |  Author(s): F. Zhang, D. Huang, S. Cai, Y. Hu

      • Abstract

      Background:
      Recent studies have indicated that anti-PD-1/PD-L1 antibodies combined with chemotherapy and/or bevacizumab could be a tolerable and effective option for patients with non-squamous NSCLC in the first line treatment. However, in second-line setting, overall response rate (ORR) of PD-1/PD-L1 checkpoint blockades used as single agent for advanced NSCLC patients who experience progression on or after platinum-based chemotherapy is limited. Therefore, we retrospectively assessed the safety and efficacy of anti-PD-1 combined with chemotherapy and/or bevacizumab as second-line treatment or beyond in patients with advanced NSCLC patients.


      Method:
      92 Patients of stage IIIB or IV NSCLC treated with anti-PD-1 therapy in the Cancer Center of the PLA General Hospital from January 2015 to September 2017were screened for eligibility. First-line treatment were excluded. Regimens were anti-PD-1 antibody as monotherapy or in combination with chemotherapy and/or bevacizumab. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR) and safety profile.


      Results:
      A total of 55 patients were enrolled for the study, 33 patients were received anti-PD-1 antibody monotherapy, 22 patients were received anti-PD-1 antibody plus chemotherapy and/or bevacizumab. The PFS of anti-PD-1 combination therapy was longer than that of monotherapy group (median, 7.5 vs 3.3 months, HR, 0.349, 95% CI, 0.17-0.73, P <0.0001). 7 of 22 patients (31.8%) in the combination groups achieved an objective response compared with 3 of 30 patients (10.0%) in the PD-1 antibody monotherapy group (P=0.075). 21 of 22 (95.5%) patients in the combination therapy achieved a disease control compared with 14 of 30 patients (46.7%) in the monotherapy group (P=0.000). The incidence of grade 3/4 treatment-related adverse events were 2 of 33 patients (6.1%) in monotherapy group and 5 of 22 patients (22.7%) in combination group. No treatment-related mortality was observed.


      Conclusion:
      Preliminary data indicated that PD-1 based combination therapy as second line treatment and beyond exhibited a promising safety profile. More importantly, PD-1 antibody plus chemotherapy and/or bevacizumab could have a longer PFS and a higher ORR and DCR. Given the relative small sample size and limitations of retrospective observational study, the strategy needs further exploration.

    • +

      P105 - Computational Design of IgG-like Tetra-specific Antibody Targeting EGFR/VEGF/PD-1/CTLA-4 Against NSCLC (ID 133)

      00:00 - 00:00  |  Author(s): Y. Hu, F. Zhang, S. Chen, L. Li, L. Zhao

      • Abstract

      Background:
      Although monoclonal antibodies (mAbs) are widely used for the treatment of cancer, the acquired resistance is one of the prime obstacles for cancer treatment and development of novel antibodies with potent anti-tumor activities and specificities is urgently needed. Due to complex diseases are often multifactorial in nature, and involve redundant or synergistic action of disease mediators or upregulation of different receptors, multi-specific antibodies with the capacity to blockade of multiple targets or binding sites are showing improved therapeutic efficacy against cancer. Although

    • +

      P106 - The Efficacy and Safety of Bevacizumab Combined with Chemotherapy in the Treatment of Drug-Resistant SCLC (ID 153)

      00:00 - 00:00  |  Author(s): X. Liu, S. Wang

      • Abstract

      Background:
      To explore the efficacy and safety of bevacizumab combined with chemotherapy in the treatment of drug-resistant small cell lung cancer (SCLC).


      Method:



      Results:
      Of the 25 patients, 5 patients achieved partial response, 16 patients achieved stable disease, 4 patients achieved progressive disease, and no patients achieved complete response. The short-term effective rate was 20% (5/25) and the clinical benefit rate was 84% (21/25). PFS ranged from 2 months to 6.3 months, and the median PFS was 3.7 months. OS ranged from 5.0 to 12.0 months, with a median OS of 7.6 months. Five patients were still alive as of April 10, 2018. Common toxic and side effects are myelosuppression, alimentary tract reaction and alopecia.


      Conclusion:
      Bevacizumab combined with chemotherapy is effective in the treatment of drug-resistant small cell lung cancer, and its side effects are tolerable. However, due to the small number of cases observed, the results are biased to a certain extent, it is necessary to establish a large-scale, randomized, double-blind, controlled multi-center clinical study to further confirm its efficacy and safety.

    • +

      P107 - The Study of Relationship Between Tumor Burden (TMB) and Molecular Typing of Non-Small Cell Lung Cancer (NSCLC) (ID 127)

      00:00 - 00:00  |  Author(s): R. Zhong, H. Li, Y. Cheng

      • Abstract

      Background:
      Tumor mutation burden (TMB) is one of the strongest biomarker to stratify patients suitable for immunotherapy. However, the relationship between TMB and other typical genetic profile in lung adenocarcinoma is not clear. This study aimed to explore the genetic characteristics of non-small cell lung cancer (NSCLC) relationship between TMB and typical genetic profile in NSCLC patients.


      Method:
      Tumor tissue from 11 NSCLC patients in Jilin Cancer Hospital from July 2018 to August 2018 were tested by next generation sequencing (>500 target gene panel). 10 mutations/1 M basepairs as cut-off value, patients were divided into high tumor butden (TMB-High) and low tumor burden (TMB-Low). TMB relationship with lung cancer core genes (EGFR, ALK, ROS1, KRAS, BRAF, MET, RET and ERBB2), tumor suppressor genes, proto-oncogenes, and MSI was statistically analyzed.


      Results:
      Among the 11 NSCLC patients, 45% (5/11) of patients were TMB-low and 55% (6/11) of patients were TMB- high. 100% (11/11) of patients were microsatellite Stable (MSS) and there were no MSI patients. In TMB-low patients, there were 14 mutations in 9 tumor suppressor genes and 1 mutation in 1 proto-oncogene; 40% (2/5) of these patients had TP53 mutations; 60% (3/5) of these patients had 5 mutations in 4 lung cancer core genes (EGFR, MET, KRAS and ROS1). In TMB-high patients, there were 29 mutations in 17 tumor suppressor genes, 8 mutations in 4 proto-oncogenes; 100% (6/6) of these patients had TP53 mutations.; 83% (5/6) of these patients had 9 mutations in 4 lung cancer core genes.


      Conclusion:
      Compared with TMB-high, TMB-low patients have less number of tumor suppressor genes, proto-oncogene mutations, TP53 mutations and lung cancer core gene mutations In addition, TMB may not be associated with MSI. This study could further understand the genetic characteristics of NSCLC and provide new theoretical basis for immunotherapy for NSCLC.

    • +

      P109 - Combined Chemotherapy Versus Topotecan Monotherapy as Second-Line Treatment for Patients with Sensitive Relapsed SCLC (ID 160)

      00:00 - 00:00  |  Author(s): L. Zhang, X. Liu, Y. Cheng

      • Abstract

      Background:
      Cisplatin, etoposide and irinotecan are primary drugs in the treatment of small cell lung cancer. We did this retrospective study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was better than topotecan alone as second-line chemotherapy in patients with sensitive relapsed SCLC.


      Method:
      Between 1stSep, 2014 and 30thSep, 2017?We collected the patients information in Jilin Province Cancer Hospital. All patients with SCLC responded in first-line treatment and showed radiological evidence of disease relapse or progression at least 90 days after completion of the first-line treatment. 36 patients received combination chemotherapy with cisplatin plus etoposide plus irinotecan and 42 patients received topotecan alone. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m 2 on days 1 and 8, intravenous etoposide 60 mg/m 2 on days 1

    • +

      P111 - Circulating Tumor Cells Combined Myeloid Derived Suppressor Cells Predict Prognosis of Advanced Small Cell Lung Cancer (ID 126)

      00:00 - 00:00  |  Author(s): Y. Liu, H. Li, D. Zhao, Y. Cheng

      • Abstract

      Background:
      Small cell lung cancer (SCLC) is an aggressive malignancy, and circulating tumor cells (CTCs) can predict early dissemination of tumor cells, thus monitoring relapse and predicting prognosis of advanced SCLC. Myeloid derived Suppressor Cells (MDSCs) are heterogeneous cell population and involved in tumor microenvironment. Our previous study showed CD11b+CD33+HLA-DR? MDSCs are associated with response and prognosis in SCLC patient

    • +

      P112 - Significance of Low Expression of Tumor Associated Gene ki67 in Recurrence of Small Cell Lung Cancer (ID 165)

      00:00 - 00:00  |  Author(s): X. Zhang, L. Ma, Y. Hao, X. Zuo, Y. Cheng

      • Abstract

      Background:
      Small cell lung cancer (SCLC) has high malignancy and high metastasis rate. Ki67 as an antigen for cell proliferation, the higher the ratio, the more active the cancer cells proliferate.The aim of this study was to observe the effect of Ki67 expression on recurrence and prognosis of small cell lung cancer.


      Method:
      From July 2013 to July 2014, 91 patients with SCLC were selected. All cases were confirmed by histopathology, and Ki67 immunohistochemical staining showed positive expression. The short-term efficacy was evaluated according to RECIST 1.1. All data were processed by SPSS 19.0 statistical software. The data were expressed by mean standard deviation (x

    • +

      P113 - Icotinib Alone or with Radio Therapy Inpatients with EGFR Mutations Non-Small Cell Lung Cancer Who Develop Brain Metastases (ID 120)

      00:00 - 00:00  |  Author(s): Y. Xin

      • Abstract

      Background:
      To retrospectively analyze the efficacy and prognostic factors of ectinib hydrochloride alone or combined with brain radiotherapy in the treatment of brain metastases from NSCLC with EGFR mutation, so as to provide a reference for more accurate evaluation of prognosis and selection of the best treatment modality.


      Method:
      Total of 85 patients were enrolled from Oct/2014 to Oct/2017 in JLCH who pathologically diagnosed or cytology for NSCLC with EGFR mutations and had developed brain metastases. All the 85 patients were adenocarcinoma. 51 patients received with icotinib combined radiotherapy. 34 patients received with Icotinib alone, 15 patients took loca lesion radiotherapy, 11 patients took whole brain radiation therapy, 25 patients took whole brain radiation therapy and plus dose. SPSS22.0 was applied for survival analysis with Kaplan-Meier method and categorical data with chi-square test. COX model for multiple factors analysis. Logistic method for RR and DCR multi-factor analysis.


      Results:
      The total iORR is 64.6%, the iDCR is 95.3%. For the group of icotinib alone, iCR is 5 (14.7%), iPR is 14 (41.2%), iSD is 10 (29.4%), and iPD is (14.7%). iORR is 55.9%, iDCR is 85.2%. For the group of icotinib combined radiotherapy, iCR is 5 (9.8%), iPR is 29 (56.9%), iSD is 17 (33.3%). iORR is 66.7%, iDCR is 100%. There were statistical difference for iDCR between two groups (?2=7.698, P=0.022). Logistic model multi-factor analysis results: the surgery history of pulmonary lesion, Update-GPA grading scale and the number of metastasis organs were OS independent factors, the time to brain metastasis, mutation type and Update-GPA grading scale were PFS independ- ent factors, the time to brain metastasis, mutation type and Update-GPA grading scale were iPFS independent factors. The iDCR of the group of loca lesion radiotherapy, the whole brain radiation therapy and local acceleration were 100%, the iORR is 53.8%, 77.8%, 70.0%. The iDCR of the group of the early involvement of radiotherapy is 100%, the iORR is 77.8%, 46.7%, there were statistical difference between two groups (?2=4.200, P=0.040).


      Conclusion:
      1. The use of Icotinib to EGFR mutant NSCLC patients with brain metastases have a higher intracranial objective response rate, prolonged survival significantly. 2. The history of pulmonary lesion surgery, update-GPA grading scale and the number of metastasis organs were OS independent factors, the time to brain metastasis, mutation type and update-GPA grading scale were PFS and iPFS independent factors. 3. The participation of brain radiotherapy can increase iDCR. The early participation of brain radiotherapy can increase iORR.

    • +

      P114 - Whole-Exome Sequencing (ID 118)

      00:00 - 00:00  |  Author(s): Y. Xu, Y. Cai, K. Ma, X. Wang

      • Abstract

      Background:
      Lung adenocarcinoma is an evolutional disease, which includes different stages such as atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) , and invasive adenocarcinoma (IA) ,which all can occur independently with each other. However, whether these primary tumors exist synchronous or successively in just one individual. What is the major factor to drive a focus developing from AAH (benigh) to MIA or IA(malignant). In this study, we reported a case with AAH, MIA, and IA to understand and recognize this kind of disease, and to explore the gene heterogeneities among these focuses.


      Method:
      XXX, female, 50 years old?non-smoker,whose chest CT suggested two nodules in the right upper lobe, sized 1 cm and 0.5 cm, respectively .Surgical resection in the upper lobe of the right lung was performed for her. Postoperative pathology confirmed that these two nodules were IA and MIA, respectively. Besides those, a third more nodule, which was AAH was found in the deeper resectional lung tissue which had not been found in the chest CT scan. We then performed whole-exome sequencing (WES) to analyze the details of gene information.


      Results:
      Sequencing data showed that there was no obvious overlap among these three nodules, we listes the major gene information in Figure 1. We found that EGFR mutation was just observed in the nodule with IA, but not in MIA or AAH. figure 1.jpg


      Conclusion:
      AAH, MIA, and IA are different evolutional stages of lung adenocarcinoma. Different gene information existing in these different pathologies made them highly heterogenous. EGFR should be the major driver gene which could be observed just in IA, but not in the earlier evolutional stage. More sequencing data is needed to verify our findings.

    • +

      P115 - Clinical Outcome of Crizotinib in Diverse ALK Fusion Partners and Different Detection Methods Treatment Na (ID 129)

      00:00 - 00:00  |  Author(s): Y. Zhang, L. Zeng, N. Yang, Y. Li

      • Abstract

      Background:
      It

    • +

      P116 - Real World Data of 1st Line A+T in Advanced EGFR+ NSCLC: Clinical Outcome, PFS Influential Factors and Acquired Resistance (ID 132)

      00:00 - 00:00  |  Author(s): Y. Zhang, L. Zeng, N. Yang, Y. Li, D. Hu

      • Abstract

      Background:
      The PFS advantage of bevacizumab combined to EGFR-TKI (A+T) over EGFR-TKI monotherapy in 1st line treatment of advanced EGFR mutant NSCLC was firstly reported in phase 2 randomized trial JO255671 and newly demonstrated in phase 3 randomized trial NEJ0262. However, this combination had not been evaluated in the real world, the influential factor of PFS was not sure, and we knew little about the acquired resistance which is of great importance to the subsequent therapy, thus we conducted this study to address these medical needs.


      Method:
      A total of 30 advanced EGFR mutant(Del19/L858R) NSCLC patients who received Bevacizumab plus Erlotinib/Gefitinib from March 2014 to July 2017 in Hunan Cancer Hospital were enrolled in this analysis. Clinical information was fully collected. NGS (Burrning rock biotech, 168 genes panel) was applied to detect genetic aberration in both tissue and blood samples, in a dynamic pattern: tissue test before treatment and at progression; blood analysis before treatment, at first radiography evaluation, at the last radiography evaluation before progression and at progression.


      Results:
      All patients benefited from this combination. The overall response rate (ORR) was 77% and the median progression survival m(PFS) was 16 months. Neither baseline brain metastasis nor concomitant TP53 mutation shortened PFS (with vs without, 16 m vs 16 m, p=0.79; 17m vs 13m, p=0.34). Of EGFR mutation analysis by NGS, the concordant rate was well enough, 70% (21/30) between the paired initial tissue and blood samples. At progression, T790M was defined as the domain acquired resistance mechanism, contributing 43.8%, followed by MET amplification (12.5%), ERBB2 amplification (6.3%), high abundance of SMAD4 mutation (6.3%). Subgroup analysis showed patients with SMAD4 mutation have shorter PFS compared with those without SMAD4 mutation (10m vs 16m, p=0.035), while EGFR amplification did not impact PFS (17m vs 16m, p=0.60).


      Conclusion:
      The efficacy of A+T combination was encouraging in the clinical practice and the PFS data 16m in the overall population is consistent with what observed in clinical trials. Patients with baseline brain metastasis & concomitant TP53 and EGFR amplification at progression benefited similar in PFS compared to those without these characters. T790M and MET amplification are the domain acquired resistance mechanism. SMAD4 mutation was regarded as novel resistance mechanism, with PFS shorter than 1 year. We will do a continuous observation on A+T combination in the real world. Reference 1, KATO T, et al. 2014 ASCO Abstract 8005#. 2, Furuya N, et al. 2018 ASCO Abstract 9006#.

    • +

      P117 - MET 14 Skipping Mutation in Pulmonary Sarcomatoid Carcinoma Using Reverse Transcription Polymerase Chain Reaction Method (ID 20)

      00:00 - 00:00  |  Author(s): Y. Zhu, C. Xu, W. Wang, Y. Chen, M. Fang, Z. Gong, G. Chen

      • Abstract

      Background:
      Pulmonary sarcomatoid carcinoma (PSC) is a recognized category of highly aggressive and poorly differentiated non-small-cell lung carcinoma (NSCLC), with five different subtypes: pleomorphic, spindle, giant cell, carcinosarcoma, and pulmonary blastoma. Although uncommon (0.1% to 0.4% of all pulmonary malignancies), their clinical importance is underscored by poorer prognosis and higher rate of resistance to conventional
      chemotherapy than other NSCLCs. And the incidence of MET 14 skipping in PSC is controversial. The aim of this study was to reveal the reliable frequency and the clinical-pathologic characteristics of PSC with MET 14 skipping in Chinese population.


      Method:
      A total of 35 patients with PSC were recruited between September 2007 and December 2017. The status of MET 14 skipping was detected by reverse transcription polymerase chain reaction (RT-PCR).


      Results:
      Of this study, three patients were identified with MET 14 skipping in Chinese PSC population (2.86%, 1/35). The patient was a pulmonary pleomorphic carcinoma (PPC).


      Conclusion:
      The incidence rates of MET 14 skipping in PSC in the Chinese population are more than those of other subtypes of NSCLC. Crizotinib may serve as an effective treatment for MET 14 skipping PSC.

    • +

      P119 - Impact of Treatment Modality on Long-Term Survival of Small-Cell Lung Cancer with IA Stage: a Population-based Study (ID 39)

      00:00 - 00:00  |  Author(s): Y. Zheng, H. Liao, H. Zhou, X. Xue, C. Wu, J. Zhao

      • Abstract

      Background:
      The purpose of this study is to identify the optimal treatment modality for small-cell lung cancer (SCLC) patients with IA stage (T1N0M0 status).


      Method:
      The Surveilance, Epidemiology and End Results database was used to identify SCLC patients with IA stage who received surgical resection or chemo-radiotherapy (CRT) between January 2004 and December 2014. Surgery program include lobectomy / wedge resection / segmentectomy plus lymphadenectomy (examined lymph node [ELNs] ?1). Propensity score match analysis is utilized to balance the baseline characteristics.


      Results:
      A total of 686 SCLC with IA stage were included; 337 patients received surgery and 349 patients were treated by CRT alone. Patients received surgery presented better outcome than CRT alone, with the 5-year estimated overall survival (OS) of 50.0% and 24.7%, respectively (adjusted HR=0.495, 95%CI, 0.401-0.611). The median survival duration is longer in patients who received lobectomy or extended lymphadenectomy (lobectomy vs. sublobectomy, 67 months vs. 38 months in matched cohort, p=0.223; ELN>7 vs. ELN?7, 91 months vs. 54 months, p=0.105). Additional chemo/radiotherapy is associated with longer survival in patients who received lobectomy. For SCLC patients with IA stage, the best prognosis is observed in patients who received lobectomy plus chemotherapy and radiotherapy and the 5-year survival rate is 73.5% (Figure 1).figure 1.jpg


      Conclusion:
      Lobectomy plus CRT as a component of treatment is associated with significantly longer survival than other treatment modality and should be considered in the management of SCLC with IA stage.

    • +

      P120 - How to Become Exsomes As Messengers and Sentinels to Influence Lung Cancer Growing? (ID 44)

      00:00 - 00:00  |  Author(s): Z. Yu

      • Abstract

      Background:
      How to become Exsomes as messengers and sentinels to influence lung cancer growing? Zhang Yu1, Chen Chang2 1. The Thoracic Surgery Department in The First Hospital of Lanzhou University, Lanzhou city, China; 2. The Shanghai Pulmonary Hospital of Tongji University, Shanghai, China. Email: *Keenan2006@hotmail.com* Tel: +86-15095319196 Abstract: [Background] Exsomes are special capsules including proteins, DNA, RNA, etc. They have great important role in Cell Growth, Cell Invasion, Cell Differentiation. How to transfer the messages to tumor cells each other and influence tumor cells invasion is hard question.


      Method:
      [Methods] First, exosomes involved in the division and proliferation of cancer cells were detected in lung cancer cell lines. Second, the animal model of lung cancer was made, and tumor specimens were regularly cut to detect the quantitative and qualitative changes of exosomes in tumor cells, so as to analyze the changes of exosomes in tumor growth. Thirdly, specific exosomes were calibrated and tracked to inhibit the secretion of specific exosomes and observe the division and growth of tumor cells.


      Results:
      [Results] The secretion of exosomes significantly affected the pathological and physiological mechanism of lung cancer cell division, differentiation, growth and invasion.


      Conclusion:
      [Conclusion] Exosomes are important messengers that affect tumor cells, but how the messengers send signals, how they affect the mechanism of the tumor cells, and how to turn the "messenger" into a "sentinel" that monitors tumors is a long way off.

    • +

      P121 - Clinical Value of Local Therapy in Advanced Crizotinib-Treated ALK-Rearranged Lung Cancer: Pattern of Failure Analyses (ID 19)

      00:00 - 00:00  |  Author(s): J. Ni, G. Li, Z. Zhu

      • Abstract

      Background:
      The pattern of failure and clinical value of local therapy (LT) in metastatic crizotinib-treated ALK-rearranged lung cancer, with or without baseline brain metastases (BBM), are largely unknown.


      Method:
      Consecutive patients were retrospectively enrolled and serial imaging were intensively examined. Disease progression in original sites (primary/metastatic), new sites, or both, are classified as original failure (OF), distant failure (DF) and ODF, respectively. Progression free survival, from crizotinib initiation to the first disease progression, and from that to the second disease progression, were calculated as PFS1 and PFS2.


      Results:
      Ninety-three patients with adequate imaging and measurable disease were identified. Fifty-seven patients received crizotinib as first-line therapy, while the remaining 36 patients had 1-2 lines of prior chemotherapy, with or without LTs. With a median follow up of 22.0 (range, 2.0-72.0) months, 52 patients had crizotinib-treatment failure, with a median PFS1 of 11.5 (95%CI 9.8-13.2) months. The frequencies of OF, ODF, and DF, were 50.0%, 26.9%, and 23.1%, respectively. Histology, primary tumor size and presence of BBM, were independently associated with OF, using competing risks analyses. The brain was the most common site of initial disease progression. Patients with BBM had a significant higher possibility developing multiple-progressive lesions in the brain (p=0.002). Brain radiation before crizotinib could alter the disease failure patterns and improve PFS1 among patients with BBM (p=0.006). Of note, four (50.0%)of the eight patients who had baseline oligo-metastatic cranial disease but did not receive prior brain radiation, developed multiple-progressive disease in the brain, while none of the four patients who had baseline oligo-metastatic cranial disease and received prior brain stereotactic radiosurgery developed multiple-progressive disease in the brain. On the other hand, extra-cranial LT before crizotinib was not associated with PFS1 (p=0.223). Thirty-five (67.3%)of the 52 patients with disease failure to crizotinib were eligible for certain kind of radiotherapy. By the time of data cut-off, 28 patients had second disease progression, with a median PFS2 of 7.0 (95% CI 5.4-8.6) months. Patients who received LT after RECIST-defined disease progression to crizotinib had a significant longer PFS2 (p=0.003). In addition, patients received any LT during their treatment course had a significant longer overall survival (p=0.048).


      Conclusion:
      Among patients with BBM, brain radiotherapy before crizotinib provide considerable clinical benefits. Conversely, deferring extra-cranial local therapies until after initial crizotinib-treatment failure and adopting regular surveillance may be a better treatment strategy for metastatic lesions outside the brain.