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Wen-Zhao Zhong



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    FP01 - Early Stage/Localized Disease (ID 111)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP01.03 - Genetic Predisposition for Pre-Invasive Lung Adenocarcinoma Manifesting as Ground-Glass Nodules with Family History of Lung Cancer (ID 1512)

      00:00 - 00:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Introduction

      Lung cancer with family history have been increasing gradually of late years in East Asian, especially those presenting as pulmonary ground-glass nodules (GGNs). The predisposition of GGN with lung cancer family history remains baffling.

      Methods

      This prospective study (NCT04220268) enrolled patients with pulmonary pre-invasive or invasive adenocarcinoma, which presenting as GGN in computer tomography (CT) scans. We used extreme phenotype approach to select 50 GGN patients with a family history of lung cancer (FHLC) in one or more first-degree relatives. Blood samples were collected and sequenced by whole exome sequencing (WES) to investigate rare but potential pathogenic germline mutations with a stepwise filtering strategy including: variant quality and classification, minor allele frequency (MAF) < 0.01 in public and local database, functional prediction and family segregation.

      Results

      In total, 2325 single nucleotide variants (SNVs) and 238 frameshift mutations with MAF <0.01 were finally identified through the filter. The number of these rare, damaging germline mutations in non-smoking patients were significantly higher than those in smoking patients (Spearman’s ρ= -0.33, p=0.02). Fifty-nine SNVs and 10 frameshifts were not only rare and deleterious but also presented in more than two families. Importantly, twenty of them had been reported to be associated with higher risk or carcinogenesis of lung cancer. Two of them were validated in 126 nonoverlapping susceptibility loci for lung carcinogenesis identified by genome-wide association studies (GWAS).

      Conclusion

      Patients with GGNs and FHLC may have inheritable carcinogenesis mutations. These variants may potentially contribute to the risk of pulmonary pre-invasive adenocarcinoma susceptibility in Chinese population. Non-smoking patients with GGN probably had higher genetic predisposition than the smoking patients.

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    MA13 - Tumor Biology: Focus on EGFR Mutation, DNA Repair and Tumor Microenvironment (ID 214)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
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      MA13.09 - Heterogeneous Genomic Evolution and Immune Microenvironments in Metastatic Lung Cancer (ID 1155)

      16:45 - 17:45  |  Author(s): Wen-Zhao Zhong

      • Abstract

      Introduction

      The comprehensive insights into the genomic evolution and immune microenvironments of lung cancer metastasis remain unknown. Furthermore, whether non-stochastic patterns of lung cancer metastases to different sites exist is elusive.

      Methods

      We investigated the genomic evolution and immune microenvironments of paired primary-metastatic (P-M) tumors by employing multi-region whole-exome sequencing and immunohistochemistry in 179 samples from 51 lung cancer patients with metastases to the pleura, bone, adrenal gland, brain and additional lymph nodes.

      Results

      Our data revealed differences in genomic landscapes, molecular determinants, seeding patterns, and lymphocyte infiltration among different metastatic sites. Metastatic lymph nodes showed the highest P-M genomic divergence, followed by pleura, brain, bone, and adrenal gland. We identified MYC amplification as a selected event driving metastasis and associated with worse overall survival (P = 0.013). Interestingly, EGFR amplification and TP53 mutations were preferably selected in distant metastases whereas RICTOR amplification was selected in regional metastases (pleura and lymph nodes). Based on spatial tumor growth model, we demonstrated commonly late arising of metastatic seeding (61.1%) of lung cancer with quantitative evidence. However, mutation rate and timing of dissemination varied among different metastatic sites. Metastases at regional tissues were more frequently infiltrated with CD8+ tumor-infiltrating lymphocytes (TILs) than those at distant organs, among which bone metastases were merely infiltrated with CD8+ TILs. Furthermore, monoclonal and polyclonal seeding were associated with rapid and attenuated progression (P = 0.013), respectively, which supports the potential value as a prognostic predictor. Immune-heterogeneity and -homogeneity were primarily driven by arm-level and focal copy number events in primary tumors, respectively, indicating distinct mechanisms of tumor immune escape during metastasis.figure 1.jpgfigure 2.jpg

      Conclusion

      These findings implied the combinatorial role of multiple factors in shaping patterns of dissemination and advanced the clinical evaluation and intervention of lung cancer metastasis.

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    P56 - Tumor Biology and Systems Biology - Basic and Translational Science - CT DNA (ID 193)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P56.01 - Postoperative ctDNA Positive Presents the High-risk of Recurrence in Resectable Non-Small Cell Lung Cancers (ID 1436)

      00:00 - 00:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Introduction

      Effective biomarkers to predict the prognosis for non-small cell lung cancer (NSCLC) patients after radical resection are needed. As a potential novel maker, ctDNA help to determine which patients harbor residual disease after surgery. Here, we analyze the significance of postoperative ctDNA in this prospective cohort.

      Methods

      Twenty-six NSCLC surgical patients were enrolled. The paired surgical tissues and postoperative peripheral blood samples were collected. Using hybridization capture-based NGS ER-seq method, 1021-gene panel for 26 tissues and 293-gene panel for 30 ctDNA samples, which enables simultaneously assess snv/indel, cnv and rearrangement variation.

      Results

      Median age was 61 years (range 33-78), 9 had smoking history, and 17 were males. There were 16 lung adenocarcinoma, 6 lung squamous carcinoma, 2 sarcomatoid carcinoma, 1 adenosquamous carcinoma and 1 lymphoepithelioma-like carcinoma. Four were stage Ⅰ, 10 stage Ⅱ and 12 stage Ⅲ. Thirteen patients received adjuvant therapy.

      In tissue samples, TP53 was the most common driver gene (65.4%). Followed by EGFR (30.8%), APC (19.2%), KRAS (11.5%), et. The median mutation number was 8.5 (from 3-50), and median TMB was 6.9muts/Mb (range 1-48). The mutation number had no relationship with ctDNA status. Postoperative ctDNA positive was found in 5 of 26 patients (19.2%), 3 stage Ⅲ and 2 stage Ⅱ, with a total of 10 mutations, range from 1 to 6 per-sample. The median highest mutant allele frequency (hMAF) per-sample was 0.1% (range 0.07%-6.6%). Two (7.7%) patients had actionable mutation in ctDNA.

      The median follow-up time was 10 months (range 3.5-18). Only 5 (5/21, 23.8%) patients in ctDNA negative group had disease recrruence, but patients in ctDNA positive group were all relapsed (P=0.004). The disease-free survival (DFS) was significantly shorter in ctDNA positive group than ctDNA negative (mDFS 7.4 vs 16.9 mos, P﹤0.0001; HR, 9.455; 95% CI, 1.149 to 77.78). Among 12 stage Ⅲ patents, shorter DFS was also observed in ctDNA positive patients than negative (P=0.0017; HR, 7.032).

      There were three patients had ctDNA monitoring results. Two persistently ctDNA negative cases did not relapse. But the patient with ctDNA changed from negative to positive relapsed within one month after transformation.

      Conclusion

      Postoperative ctDNA could be a promising biomarker to indicate the recurrence risk for NSCLC patients after radical surgery.

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    P59 - Tumor Biology and Systems Biology - Basic and Translational Science - Genomics (ID 197)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P59.03 - Intratumoral Heterogeneity and Clonal Evolution in Large Non-Small Cell Lung Cancer (>7cm) Delineated by Multiregion Sequencing (ID 1305)

      00:00 - 00:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Introduction

      T4N0M0 (size > 7cm) non-small cell lung cancer (NSCLC) represent relatively favorable prognosis in stage IIIA category, probably due to the limited metastatic potential. The intratumor genomic profile of these oversize tumors have not been well studied.

      Methods

      T4N0M0 surgical NSCLC patients were enrolled. Whole-exome sequencing on three regions of each surgical tumor was performed. Single nucleotide variation (SNV), small insertion and deletions (Indels), and copy number variation were called and used for the analysis of intratumoral heterogeneity (ITH). Driver genes were identified by a gene list from the research of Matthew H. Bailey 2018. Tumor mutation burden (TMB) was calculated using all somatic nonsynonymous mutations (variant allele frequency > 0.03). Phylogenetic trees were constructed by regionally shared and private alterations.

      Results

      Five NSCLC were enrolled, including three adenocarcinoma and two squamous cell carcinoma. 15 tumor regions were sequenced successfully, with a median coverage of 452×. Interestingly, two distant ITH/TMB phenotypes were found, ITHlow/TMBhi (P1,P4,P5) andITHhi/TMBlow (P2,P3). The average heterogeneous somatic mutations in these two categories were 36% vs 98%, while the TMB was 154 vs 19. The ITHlow/TMBhi type had higher proportion of trunk SNV and Indels (62.2%, 53.2, and 65.5%, respectively), while ITHhi/TMBlow had lower of trunk (0% and 3.2%). In total, 11 driver mutations were identified and 72.73% of the driver mutations located on the trunks of tumor phylogenetic trees, including KEAP1, TP53, FAT1, CDKN2A, SMARCA4, and FAT1.

      Conclusion

      Our data implied two distant ITH/TMB phenotypes in the T4N0M0 NSCLC (>7cm). It may contribute to our need for further understanding of tumor indolent growth pattern.

      fig 1.jpg

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    P72 - Tumor Biology and Systems Biology - Basic and Translational Science - Tumor Microenvironment (ID 211)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P72.02 - Cellular Landscape of Tumor Immune Microenvironment and Genetic Signatures Identify Prognostic of LUAD (ID 736)

      00:00 - 00:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Introduction

      Tumour microenvironment (TME) has been recognized to support the initiation and progression of lung adenocarcinoma (LUAD). The innate and adaptive immune cells in the lung TME harbour both tumour-promoting and tumour-suppressing activities, which may also predict clinical outcome. Therefore we carried out a systematic analysis of cellular interactions in tumor immune microenvironment. And identify cell-intrinsic and cell-extrinsic pathways cell types and activation states that may serve as biomarkers of overall survival (OS).

      Methods

      Public gene-expression data and relevant clinical annotation were obtained from Gene-Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) database. Three TME infiltration patterns were comprehensively analyzed in 442 LUAD patients using CIBERSORT algorithm and the LM22 gene signature. Based on the TME patterns, we build a model to calculate TMEscore based on gene set variation analysis via ssGSEA algorithm. Functional enrichment analysis were performed by GO and KEGG.

      Results

      Four datasets with available outcome data and clinical information in GEO and TCGA-LUAD were enrolled in our study. GSE72094 was used as the training cohort, while GSE11969, GSE26939, GSE31210 and TCGA-LUAD was used as validation cohorts. TME cell network established based on GSE72094 depicted a comprehensive landscape of tumor-immune cell interactions, cell lineages, and their correlation with OS (Fig. 1A, 1B). Three subgroups with distinct TME signature gene sets were obtained/identified based on unsupervised hierarchical clustering in 442 LUAD cases. OS in TME gene subgroup B was significantly longer than which in TME gene subgroup A and subgroup C. TME gene group B was associated immune activation (Fig. 1C). TMEscore was further constructed using principal component analysis algorithms. Lower TMEscore is significantly associated with better prognosis. Functional annotation analysis showed TMEscore had a positive correlation with cell cycle, DNA replication, homologous recombination, mismatch repair, nucleotide excision repair and DNA damage repair (Fig. 1D). The enriched pathways in subtype with lowest/low TMEscore involved bile_acid_metabolism, fatty_acid_metabolism and myogenesis. While high TMEscore subtype was characterized by significant enrichment of interferon_alpha_response, myc_targets and unfolded_protein_response pathway (Fig. 1E). TMEscore model was then validated on 525 patients from GEO datasets and 585 patients from TCGA-LUAD project and proved to be a valuable method for prognostic stratification of LUAD except for TNM stage(Fig. 1F).

      fig-1.png

      Conclusion

      Variability in the composition of the tumor immune microenvironment contributes to heterogeneity in OS. Deeper validation is in need to define the positive association between lower TMEscore and longer OS.

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    P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P76.19 - Clinical Outcomes of Lung Cancer Patients Who Acquired EGFR T790M/in trans-C797S Mutations After Resistance to Osimertinib (ID 1260)

      00:00 - 00:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Introduction

      EGFR C797S is a well-established mechanism of resistance to osimertinib. Previous studies have documented whether C797S occurred in cis (on the same allele) or trans (on a different allele) with T790M affects the efficacy of subsequent therapies, and in trans C797S/T790M remain sensitive to a combination of first- and third-generation EGFR TKIs. To date, no standard treatment is available for patients with lung cancers harboring EGFRT790M/in trans-C797S mutations. We set out to characterize the clinical outcomes in this subset of patients.

      Methods

      Patients with a pathologically confirmed diagnosis of stage IV lung cancer harboring EGFR T790M/in trans-C797S mutations were analyzed. EGFR mutation was identified by DNA-based next-generation sequencing. A retrospective review of clinicopathologic and treatment information was performed. Response to subsequent therapy was determined (RECIST v1.1). Progression-free survival (PFS) in patients were determined using Kaplan-Meier estimates. Survival was measured from the date of the first subsequent treatment start.

      Results

      29 patients with EGFR T790M/in trans C797S-mutant lung cancers were identified. The median age was 55 (range 31-71 years), 69% were women. All had adenocarcinoma. Accurate information of previous and subsequent treatment were available for 16 patients. All patients had previous osimertinib administration, mostly at the 2nd line (n = 7) or 3rd line (n = 5). The majority (88%, 14/16) received subsequent therapy, of whom under half (n = 6) were treated with a combination of first- and third-generation EGFR TKIs (gefitinib or erlotinib+ osimertinib); the median PFS was 3.7 months (95%CI 3.3-4.1 months). The median PFS of patients who underwent other therapies (platinum-based chemotherapy, osimertinib+cabozantinib, osimertinib+brigatinib, or osimertinib+cetuximab) was 3.2 months (95%CI 1.7-4.7 months). At the time of reporting, overall survival data were not mature.

      Conclusion

      The clinical outcomes of patients who acquired EGFR T790M/in trans-C797S mutations after resistance to osimertinib were relatively poor. Further researches are required to investigate the biology of these compond mutations and to establish the optimal therapeutic option.

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