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Wen-Zhao Zhong



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    JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)

    • Event: WCLC 2018
    • Type: Joint IASLC/CSCO/CAALC Session
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
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      JCSE01.22 - Differential Molecular Mechanisms Associated with Dramatic and Gradual Progression in NSCLC Patients with Intrathoracic Dissemination (ID 14713)

      11:15 - 11:15  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background
      Lung cancer is a highly heterogeneous disease with diverse clinical outcomes. The pleural cavity is a frequent metastasis site of proximal lung cancer. Better understanding of its underlining molecular mechanisms associated with dramatic and gradual progression of pleural metastasis in patients with non-small cell lung cancer (NSCLC) is essential for prognosis, intervention and new therapy development.We performed whole-exome sequencing (WES) of matched primary lung adenocarcinoma and pleural metastatic tumors from 26 lung cancer patients with dramatic progression (DP, n=13) or gradual progression (GP, n=13). Somatic alterations at both genome-wide level and gene level were detected. Kaplan-Meier survival analysis and multivariate Cox regression models were applied to analyze the association between different somatic alterations and clinical parameters.We first analyzed the differences in somatic alterations between AP and RP group in the primary tumors, and identified higher somatic copy number alteration (SCNA) level in DP group compared to GP group, which is significantly (p=0.016) associated with poorer progression-free survival (PFS). More specifically, patients with chromosome 18q loss in the primary tumor showed a trend (p=0.107) towards poorer PFS. PTEN (p=0.002) and GNAS (p=0.002) mutations are enriched in the primary tumors of DP group, and are associated with poorer PFS. Furthermore, pleural metastatic tumors harbor a relatively higher level of mutation burden (p=0.105) and significantly increased SCNA (p=0.035) compared to the primary tumors.NSCLC patients in the attenuated progression group have more stable genomes. High level of genomic instability, GNAS and PTENmutations, as well as chromosome 18q loss are associated with rapid progression.

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    MA24 - Genomic Evolution, KEAP 3 and More Non-Coding RNA (ID 928)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD
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      MA24.01 - Genomic Evolution Trajectory Depicts Invasiveness Acquisition from Pre-invasive to Invasive Adenocarcinoma (Now Available) (ID 11840)

      10:30 - 10:35  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Presentation
      • Slides

      Background

      Accumulation of molecular abnormalities may depict evolution trajectories of tumor initiation and development. However, the genomic profile of early stage adenocarcinoma and molecular mechanism of invasiveness acquisition from pre-invasive to invasive adenocarcinoma remains barely explored.

      Method

      We simultaneously collected 20 patients with adenocarcinoma in situ (AIS) (n=5), minimally invasive adenocarcinoma (MIA) (n=5) and stage IA adenocarcinoma (lepidic/acinar predominant) (n=10). Whole exon sequencing (WES) was performed in pre-invasive adenocarcinoma with multi-region specimens and stage IA adenocarcinoma. Analysis of genomic alteration among different pathological status was performed and tumor mutation burden (TMB) was calculated as well as six mutation types individually. Enriched pathways of each pathology were measured through KEGG analysis.

      Result

      Baseline characteristics was generated through heatmap with smokers (2/20, 10%) and EGFR mutation (13/20, 65%) among whole population. AIS/MIA indicated much lower number of mutations than invasive adenocarcinoma (IAC) while TMB revealed the same trend without statistical significance. Multi-region sequencing showed high heterogeneity of single nucleotide variation (SNV) in AIS and MIA. Unique SNV presented dominant proportion in initial status. Cluster analysis showed higher copy number variation in AIS/MIA than IAC with cell adhesion molecules (CAMs) enriched in AIS/MIA while variety pathway enrichment in IAC through KEGG analysis. C>A transversions held major proportion in early stage adenocarcinoma and a significant increase in the proportion of C>T and C>G mutation was exhibited when evolving into IAC.

      图片1.png

      Conclusion

      Intratumor heterogeneity may occur in the very beginning of adenocarcinoma. High copy number variation was dominant event for AIS/MIA while higher tumor mutation burden was seen in IAC. Tobacco signature encompassing C>A transversions dominates the early development of adenocarcinoma and APOBEC signature may play a potential role in acquisition of cancer invasiveness.

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    MA25 - Oligometastasis: Defining, Treating, and Evaluating (ID 929)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 203 BD
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      MA25.06 - RPA Analysis for Oligometastatic Non-Small Cell Lung Cancer: Smoking Combine T3/4 Patients May Not Be Benefit from Local Consolidative Treatment (Now Available) (ID 11994)

      14:05 - 14:10  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Presentation
      • Slides

      Background

      In the literature on oligometastasis, the relative importance of local consolidative treatment (LCT) has been gradually accepted. This study set out to investigate the prognosis heterogeneity and the effect of LCT for oligometastatic non-small cell lung cancer patients.

      Method

      We identified 436 patients in Guangdong General Hospital (GGH) from 2009 to 2016 with oligometastatic disease, and the factors predictive of overall survival (OS) were evaluated using Cox regression. Risk stratifications were defined using recursive partitioning analysis (RPA) on training set (2009~2014), which were further confirmed on validation set (2015-2016). And the effect of LCT for different risk groups was further examined by Kaplan-Meier method.

      Result

      Factors predictive of OS were: T stage (p=0.001), N stage (p=0.008), metastatic sites (p=0.031) and EGFR status (p=0.043). Prognostic risk RPA model was established, 4 risk groups were identified: Group I, never smokers and N0 disease (3-year OS: 55.6%, median survival time (MST)=42.8m); Group II, never smokers and N+ disease (3-year OS: 32.8%, MST=26.5m); Group III, smokers and T1/T2 disease (3-year OS: 23.3%, MST=19.4m); and Group IV, smokers and T3/T4 disease (3-year OS: 12.5%, MST=11.1m). Among four groups, OS significant differences were observed according to LCT except group IV (p=0.45).

      Conclusion

      This retrospective study identified the poor prognostic population (smoking combine T3/4 disease) of oligometastatic non-small cell lung cancer patients, and this population may not be benefit from local consolidative therapy.

      fig.png

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-55 - Unique Genetic Profiles from Cerebrospinal Fluid Could Predict Survival of EGFR-Mutant NSCLC with Leptomeningeal Metastases (ID 12369)

      16:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Leptomeningeal metastases (LM) are more frequent in NSCLC with EGFR mutations;and cerebrospinal fluid (CSF) could reveal the unique genetic profiles of LM in our previous studies, but whether they could predict the overall survival (OS) of LM remains unknown.

      Method

      EGFR-mutant NSCLC patients with LM were enrolled,and clinical data and genetic profiles detected by Next-generation sequencing were collected. We further drew nomogram with endpoint of OS after LM, then performed index of concordance (C-index) and survival analysis to evaluate predictive role.

      Result

      In total, 61 patients were enrolled and all with genetic profiles from CSF. Patents with high copy number variations (CNVs) or harboring CDK6, TP53 exon5 or FGF19 in CSF demonstrated significant poorer OS than those without (Fig. 1). Cox regression analysis indicated CNVs, CDK6,CDKN2A,TP53,MET and NTRK1 as prognostic factors and further selected for nomogram (Fig. 2). C-index of nomogram was 0.743, indicating the moderate predictive effect. In the calibration curves, we scored the patients based on the model, using bisection and trisection methods to divide into low and high points groups; and low, medium and high points groups (Fig. 3), and significant difference were found in both the survival analyses (NA versus 7.47months, P<0.01) and (NA, 10.33 versus 4.43 months, P<0.01) respectively. Patients who received Osimertinib after LM seemed to have longer OS than those who did not (14.5 months versus 7.7 months) but without significant difference(P=0.10); however interestingly, in those with EGFR T790M negative who took Osimertinib after LM by themselves obtained survival benefit than those who did not(NA versus 7.7 months, P=0.04), and the results needed to be validated.

      figure.jpg

      Conclusion

      Unique genetic profiles from CSF could well predict OS of LM. High CNVs, CDK6, TP53 exon5 or FGF19 in CSF in CSF may be related to poor prognosis of LM.

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    P1.11 - Screening and Early Detection (Not CME Accredited Session) (ID 943)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.11-18 - A Classification-Based Machine Learning Method Reveals Exosomal miRNA Biomarkers for Patients with Pulmonary Ground Glass Nodule (ID 12462)

      16:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract

      Background

      Non-invasive detection of lung cancer is of critical importance but has proven challenging due to the rate of false-negative diagnosis with current tests. Plasma exosomes have been implicated as a non-invasive diagnostic source. However, little high throughput screening has been done in the early-stage lung cancer and problems such as bias of enrollment, less rigorous identification exists. This study aimed to reveal the plasma exosome-derived miRNA biomarkers for early-stage lung cancer patients, especially those with ground glass nodule (GGN).

      Method

      Pre-operative and paired post-operative plasma samples from patients with solitary pulmonary nodule and healthy volunteers were prospectively collected. Finally 38 malignant nodules, 7 benign nodules and 5 healthy volunteers were enrolled. The malignant nodules included 9 pure GGNs, 11 mixed GGNs and 18 solid nodules. Exosomes were collected from 1mL plasma and were isolated with 3D Medicine EV isolation kit. Exosomal miRNA profiling was performed using miRNA-seq. And an exosomal miRNA diagnostic model for patients with malignant nodules was constructed by using support vector machine (SVM).

      Result

      In general, malignant nodules, benign nodules and healthy volunteers were indistinguishable based on overall clustering. Regarding to malignant nodules, pure GGNs and solid nodules could be separated under principal component analysis (PCA), and the mixed GGNs presented a transitional state between the pure GGNs and the solid nodules. Ultimately, a two-dimensional SVM diagnostic model for discriminating malignant and benign nodules was established. The optimal miRNA combination could reach an area under curve (AUC) of 0.96, with sensitivity and specificity of 94.7% and 91.7%, respectively.

      Conclusion

      This preliminary analysis highlights the potential of exosomal miRNA based liquid biopsy for non-invasive detection of early-stage lung cancer. The SVM model seems could effectively distinguish pulmonary nodules, but needs further verified.

      fig.png

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-18 - Differential Molecular Mechanisms Associated with Dramatic and Gradual Progression in NSCLC Patients with Intrathoracic Dissemination (ID 12979)

      16:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Lung cancer is a highly heterogeneous disease with diverse clinical outcomes. The pleural cavity is a frequent metastasis site of proximal lung cancer. Better understanding of its underlining molecular mechanisms associated with dramatic and gradual progression of pleural metastasis in patients with non-small cell lung cancer (NSCLC) is essential for prognosis, intervention and new therapy development.

      Method

      We performed whole-exome sequencing (WES) of matched primary lung adenocarcinoma and pleural metastatic tumors from 26 lung cancer patients with dramatic progression (DP, n=13) or gradual progression (GP, n=13). Somatic alterations at both genome-wide level and gene level were detected. Kaplan-Meier survival analysis and multivariate Cox regression models were applied to analyze the association between different somatic alterations and clinical parameters.

      Result

      We first analyzed the differences in somatic alterations between AP and RP group in the primary tumors, and identified higher somatic copy number alteration (SCNA) level in DP group compared to GP group, which is significantly (p=0.016) associated with poorer progression-free survival (PFS). More specifically, patients with chromosome 18q loss in the primary tumor showed a trend (p=0.107) towards poorer PFS. PTEN (p=0.002) and GNAS (p=0.002) mutations are enriched in the primary tumors of DP group, and are associated with poorer PFS. Furthermore, pleural metastatic tumors harbor a relatively higher level of mutation burden (p=0.105) and significantly increased SCNA (p=0.035) compared to the primary tumors.

      Conclusion

      NSCLC patients in the attenuated progression group have more stable genomes. High level of genomic instability, GNAS and PTEN mutations, as well as chromosome 18q loss are associated with rapid progression.
      scna&survival.jpg

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      P2.01-52 - Identification of Leptomeningeal Metastasis-Specific Exosomal miRNA Signatures in Cerebrospinal Fluids of NSCLC Patients (Now Available) (ID 13074)

      16:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Leptomeningeal metastasis (LM) is a devastating complication with poor prognosis in non-small-cell lung cancer (NSCLC) patients. The confirmed diagnosis of LM usually involves neurological evaluation, MRI imaging, and cytopathology analysis of limited tumor cells from cerebrospinal fluid (CSF). Exosomes are extracellular vesicles in body fluids enriched with microRNAs (miRNAs), which have been implicated to participate in brain metastasis. Here, we aimed to identify LM-specific exosomal miRNA signatures in NSCLC patients to elucidate their potential role in LM mechanism and to predict LM via liquid biopsy.

      Method

      Exosomes prepared from CSF and plasma samples of 39 advanced NSCLC patients with (LM+) or without (LM-) LM as well as 12 non-cancer individuals (NC) were underwent small RNA next-generation sequencing. For patients in the LM+ group, paired plasma samples were taken before (PLM+pre) and upon (PLM+post) LM diagnosis. Exosomal miRNA profiles were subjected for differential expression analysis, pathway enrichment analysis, and signature discovery.

      Result

      Unsupervised hierarchical clustering of the miRNA expression profiles clearly separated CSF samples into LM+ and LM free groups (LM- and NC). Interestingly, these samples were stratified based on their LM status only, regardless of their intraparenchymal metastasis status. In total, 247 (185 up and 62 down-regulated) miRNAs were identified differentially presented in the LM+ CSF exosome samples compared to the LM- and NC groups. Top altered miRNAs include dramatically up-regulated miR-200 family and down-regulated miR-144/451 cluster. Predicted gene targets of these top-regulated miRNAs were significantly enriched in Ras/MAPK/PI3K-AKT signaling, endocytosis pathways, and so on. Promisingly, a signature of five CSF exosomal miRNAs (let-7e-5p, miR-28-3p, miR-375, miR-200a-3p, and miR-486-5p) was identified for classification of LM+ patients with 100% sensitivity and 100% specificity. Due to the higher background complexity, we only identified one miRNA (miR-24-3p) was significantly up-regulated and one miRNA (miR-92b-5p) was significantly down-regulated in LM+ patients’ plasma-derived exosomes (PLM+pre and PLM+post) compared with the LM free group (PLM- and PNC). However, a combined signature of seven miRNAs (miR-24-3p, miR-223-3p, miR-340-5p, miR-27a-3p, miR-423-5p, miR-2110 and miR-342-5p) from PLM+pre samples was identified for the prediction of future LM with 81% sensitivity and 76% specificity.

      Conclusion

      NSCLC patients with LM present a remarkably distinct CSF exosomal miRNA signature, which may involve in the progression of LM, and can be used as diagnostic biomarkers for LM. Furthermore, the identification miRNA signature in the pre-LM plasma samples suggests the potential use of liquid biopsy to predict LM for better patient care.

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-30 - PD-1/PD-L1 Inhibition Might be an Option for the Treatment of Advanced Primary Pulmonary Lymphoepithelioma-Like Carcinoma (Now Available) (ID 12698)

      16:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of non-small-cell lung cancer mostly reported in Asian countries, which is frequently associated with Epstein-Barr virus (EBV) infection. There is no consensus on the choice for the treatment of advanced primary pulmonary LELC. The utility of PD-1/PD-L1 inhibitor to this cancer type remains poorly understood.

      Method

      From January 2008 to April 2017, a total of 53 patients receiving surgical removal and diagnosed as primary pulmonary LELC in Guangdong Lung Cancer Institute (GLCI) were enrolled in this study. Sections formalin-fixed and paraffin-embedded (FFPE) tumor samples were stained with PD-L1 antibody (clone E1L3N, Cell Signaling Technology) by immunohistochemistry (IHC). PD-L1 expression more than 1% in tumor cells was considered as PD-L1 positive. Moreover, we reviewed the medical records of 13 primary pulmonary LELC patients who received the treatment of PD-1/PD-L1 inhibitors in GLCI. Their clinicopathological characteristics and relevant prognostic data were analyzed.

      Result

      Among the 53 patients with operable disease, the median age was 56 (36-78), there were 26 males and 27 females, 15 smokers and 38 nonsmokers. Positive rates of PD-L1 in the early pulmonary LELC were 78.8% (41/52,one specimen can't evaluate) and 73.1% (38/52) and 23.1% (12/52) respectively at the cutoff values of 1% and 5% and 50% positivity in tumor cells. ORR of PD-1/PD-L1 inhibition in the evaluable 12 patients with advanced LELC was 16.7% (2/12), and DCR was 75.0% (9/12). In the 6 patients with positive PD-L1 expression, ORR was 33.3% (2/6), DCR was 100.0% (6/6). The two responder patients got 55% and 64% shrinkage of the tumors respectively. All patients had no EGFR mutations.

      io in lelc1.tif

      Conclusion

      This preliminary study showed that pulmonary LELCs have remarkably high incidence of PD-L1 expression. PD-1/PD-L1 inhibitors might be an option for the treatment of advanced primary pulmonary LELC, which needs further investigation.

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    P2.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 965)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.16-47 - “Improved aBVA Method” and “Anterior VAB Method” Result in Analogous Survival Benefits During Right Upper Lobectomy (Now Available) (ID 14321)

      16:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      As concluded in recent research, compared with “Anterior VAB Method” (dissecting pulmonary vessels first, followed by the bronchus), “Improved aBVA Method” (dissecting the posterior ascending arterial branch first, followed by the bronchus and vessels) during RUL would promote surgical feasibility and postoperative recovery for lung cancer patients. This study compared their long-term survival benefits basing on propensity score matching (PSM).

      Method

      Consecutive lung cancer patients undergoing RUL were grouped into aBVA and VAB groups. PSM was conducted to reduce confounding bias between groups. After PSM, DFS and OS were estimated using the Kaplan–Meier method.

      Result

      1_副本.png

      397 patients were selected (167 in the aBVA group, and 230 in the VAB group). Before PSM, the histological subtypes, the mean number of dissected lymph node stations, operation time, amount of blood loss, number of used staplers, and the rate of conversion to thoracotomy during the operation, and the rate of pneumothorax and pneumonia, the mean duration of postoperative chest drainage after the operation were not balanced (P<0.05) between two groups. After PSM (caliper=0.02), 96 pairs of patients were successfully matched, and these 9 characters were all balanced (P>0.05) among the two groups. DFS and OS of the two groups were not significantly different (both P > 0.05). The median DFS and OS were comparable for all patients in the two groups (not arrived vs. 39 months, P > 0.05; both not arrived, P > 0.05). DFS and OS among patients with disease recurrence were not significantly different (both P > 0.05). The median DFS and OS were still similar in the two groups (16 vs. 11 months, P > 0.05; both not arrived, P > 0.05).

      Conclusion

      “aBVA Method” and “VAB Method” result in analogous survival benefits during RUL for lung cancer patients basing on PSM.

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    P2.17 - Treatment of Locoregional Disease - NSCLC (Not CME Accredited Session) (ID 966)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.17-32 - Dynamic Monitoring Before and After Neo-Adjuvant Crizotinib in Non-Small Cell Lung Cancer: A Brief Report (Now Available) (ID 11829)

      16:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Neo-adjuvant therapy has been considered as an optional approach for locally advanced non-small-cell lung cancer (NSCLC) patients. While targeted therapy has been widely applied in advanced NSCLC, neo-adjuvant targeted therapy remains poorly explored.

      Method

      We describe four ALK-positive patients with pathological confirmed locally advanced NSCLC receiving neo-adjuvant Crizotinib. All patients received Crizotinib at a starting dose of 250mg twice daily for 1-3 months before surgical resection. One patients provided dynamic monitoring before and after neo-adjuvant therapy through next generation sequencing of plasma and tissue.

      Result

      Three patients were partial response without apparent adverse event before surgery while one received pathological complete response to neo-adjuvant Crizotinib but suffering from grade 4 hepatic damage. One of them had disease recurrence but achieved long duration of response (PFS=15m) through first-line Crizotinib. Dynamic monitoring with both plasma and tissue indicated simultaneously decrease of sensitive ALK-signaling in a patient with partial response (-51%) and no ALK-dependent resistant variants were captured.

      1.png

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      Conclusion

      Neo-adjuvant Crizotinib may be feasible and well-tolerated in locally advanced disease for complete resection. Crizotinib prior to surgery may provide thorough elimination of circulating molecular residual disease and it did not influence the response of reusing Crizotinib in first-line setting.

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-10 - Immunogenomic Characteristics of SCLC and LCNEC Redefined Molecular Subgroups (ID 12577)

      12:00 - 13:30  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      While small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are distinct classes of high-grade neuroendocrine carcinomas, the differential diagnosis between SCLC and LCNEC remains challenging. In fact SCLC and LCNEC overlap in clinical, histopathologic, cytologic, morphologic and genetic characteristics. Molecular profiling with microarray or next-generation sequencing has provided growing evidence suggesting that both SCLC and LCNEC are biologically heterogeneous and a great part of them are borderline neuroendocrine carcinomas falling between typical SCLC and LCNEC. On account of accumulated knowledge, we speculated that immunogenomically characterizing SCLC and LCNEC collectively as one group, or rather morphologically or cytologically separating SCLC from LCNEC has superior clinical value.

      Method

      We analyzed gene expression profiles of 44 SCLCs, 56 LCNECs and 25 normal lung samples obtained from Gene Expression Omnibus. Unsupervised and supervised analyses were performed to understand molecular characteristics of samples. Pathway and CIBERSORT analyses were employed to obtain immune landscape of SCLC and LCNEC.

      Result

      Unsupervised clustering with 1189 differentially expressed genes revealed 2 distinct molecular subgroups (G1 and G2) of SCLC and LCNEC, which is not associated with histopathology. Targeted pathway analysis found that G1 was marked by activated IL-17, MAPK and Hippo signaling pathways. In contrast, transcriptional factors, such as ASCL1, INSM1, SOX2, and NKX2-1 were significantly up-regulated in G2, but not in G1. Moreover, in silico analysis of cellular composition and expression of immune genes disclosed unique immunoprofiles for G1 and G2. G1 was characterized by enriched CD4 memory cells, M1 macrophages and activated dendritic cells. While G2 was composed of high fractions of memory B cells and naïve CD4 cells. Strikingly, expression of both immunoinhibitors (IL10, PDL1, IDO1) and immunomodulators (OX40L, BAFF, GITR, IL6), as well as MHC class I and II molecules was higher in G1 compared to that in G2.

      Conclusion

      We identified the common intrinsic features and molecular subgroups of SCLC and LCNEC, which are beyond conventional histopathology and better associated with immunogenomics of tumors. Further research is warranted to identify potential clinical implication of SCLC and LCNEC molecular subgroups.

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