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Wen-Zhao Zhong



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    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 2
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      JCSE01.16 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 3430)

      07:00 - 11:15  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Abstract
      Background
      Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC).

      Methods
      We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs).

      Results
      290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs.



      Conclusion
      Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment.

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      JCSE01.22 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (ID 3436)

      07:00 - 11:15  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Abstract
      Background
      Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.

      Methods
      A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells.

      Results
      In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor.



      Conclusion
      PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.

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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.02 - Genomic Origin and EGFR-TKI Efficacy of Pulmonary Adenosquamous Carcinoma (Now Available) (ID 578)

      14:30 - 16:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Presentation
      • Slides

      Background

      Lung adenosquamous carcinoma (ASC) is a heterogeneous disease that comprises of both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components. Their genomic profile, evolutionary origin, and clinical management remain controversial. Objective of this study is to define the genomic origin of this heterogeneous tumor by independent genomic analyses of the AC and SCC components.

      Method

      Surgical ASCs were collected. AC component and SCC component were obtained separately by microdissection, and Lymph node (LN) metastases were gathered. Targeted sequence was performed for the two components using a 1021-gene panel, independently. Evolutionary relationship of the two components was analyzed. The independent cohorts of adenocarcinoma (n=170) and squamous cell carcinomas (n=62) were used for comparison. EGFR and concomitant mutations with response to EGFR-TKI were analyzed. Retrospective 517 ASCs underwent EGFR detections were collected from 11 centers. Objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) were analyzed in EGFR-positive patients received EGFR-TKIs.

      Result

      28 ASCs were collected. NGS was performed on AC component and SCC component samples, respectively. The most frequent alterations in 28 ASCs were EGFR mutation (79%), TP53 mutation (68%), MAP3K1 mutation (14%), EGFR amplification (32%), and MDM2 amplification (18%). 27 patients had trunk variations in the both components suggesting the monoclonal origin of ASCs. The prevalence of trunk mutations was correlated to those of AC, indicating that ASC might originate from AC. Only one patient did not carry any trunk variations between AC and SCC components, which were clearly and geographically distinguishable under the microscope. 22 had AC component or/and SCC component specific variations suggesting the common event of branch evolution. The 23 LNs of 13 patients mainly contained AC and ASC components (AC, SCC, and ASC: 11, 1, and 11, respectively), and each of the LNs carried the trunk mutations of the primary ASC. Like pure AC, the alterations of L858R and Exon 19 Dels of EGFR were common in the 28 ASCs. Unfortunately, these patients have not been treated with TKIs. Further, of 517 retrospective ASCs from 11 centers, 51.8% were EGFR-positive. For the 129 EGFR-positive ASCs who had received TKIs, the ORR and DCR were 56.6% and 89.1%, respectively. The median PFS was 10.1 months (95% CI: 9.0-11.2).

      figure-1-wclc.jpg

      Conclusion

      The AC and SCC components share a monoclonal origin, and a majority have branching evolution. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR-TKIs.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-81 - A New Prognostic Index Combines the Metabolic Response and RECIST 1.1 to Evaluate the Therapeutic Response in Patients with Lung Cancer (ID 752)

      09:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Response Evaluation Criteria in Solid Tumors (RECIST) is occasionally insufficient for evaluation. We propose a new prognostic index (NPI) that combines the standardized uptake value (SUV), metabolic tumor volume (MTV) and RECIST.

      Method

      In total, 163 patients with lung cancer who underwent positron emission tomography-computed tomography prior to and after treatment were included. We formulated the NPI by estimating the hazard ratios of overall survival for ∆MTV, ∆SUVmax and ∆D (tumor size based on RECIST). Then the regression coefficients were used, which gave rise to the HRs, as weights to formulate the new prognostic index (NPI). Progression-free survival (PFS) and overall survival (OS) were compared between RECIST and the NPI.

      Result

      ROC curve analysis identified two cutoff values based on the NPI (≤-44.0% and >40.4%) to discriminate partial remission (NPR), stable disease (NSD) and progressive disease (NPD). The concordance rate between RECIST and NPI was 74.2% (κ = 0.572, P<0.001). Based on RECIST, survival analysis did not discriminate significantly on either PFS or OS between the PR, SD and PD groups. However, according to the NPI, PFS and OS differed significantly between the NPR, NSD, and NPD groups (training set: PFS, P = 0.007; OS, P = 0.027; validation set: PFS, P = 0.003; OS, P = 0.044). In total, 83 patients with SD were reclassified based on the NPI (20 with NPR, 57 with NSD, 6 with NPD), and the patients reclassified as NPR showed prolonged PFS (P = 0.004) and OS (P = 0.026) compared with those in the NSD+NPD group.wclc图形.jpg

      Conclusion

      The NPI shows superiority for evaluation of the therapeutic response and survival for patients with lung cancer, especially in the assessment of SD patients based on RECIST.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-42 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (Now Available) (ID 651)

      09:45 - 18:00  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.

      Method

      A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells.

      Result

      In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor.

      ll.jpg

      Conclusion

      PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-88 - Molecular Alterations in Cerebrospinal Fluid Predict Clinical Outcomes of Central Nervous System Metastases in Lung Cancer (ID 1511)

      10:15 - 18:15  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Cerebrospinal fluid (CSF) has been proven as good media for genetic profiling of central nervous system (CNS) metastases. However, the association of genetic alterations in CSF and clinical outcomes remains elusive.

      Method

      A total of 94 lung cancer patients with CNS metastases underwent lumbar puncture. Circulating tumor DNA were extracted from CSF and profiled by next-generation sequencing. The effect of genetic alterations in CSF on survival and treatment outcomes were evaluated.

      Result

      The most common genes seen in CSF were EGFR, TP53, MET, CDKN2A, MYC, NTRK1 and CDK6. Kaplan-Meier survival analysis indicated that CDK4, CDK6, FGFR1, MET and MYC alterations, which were also characterized by more copy number changes, were associated with poor survival. Multivariate analysis found only MET (HR, 2.01; 95% CI, 1.15 to 3.52) and MYC alterations (HR, 2.31; 95% CI, 1.27 to 4.21) were correlated to poor OS. Forty-two patients harbored high n-CNVs (defined as the number of genes with copy number variations >2) while 50 patients carried low n-CNVs (defined as the number of genes with copy number variations <=2). Median overall survival (OS) of patients with high n-CNVs in CSF was 14.9 months (95% CI, 9.2 to 25.8 months), significantly shorter than those with low n-CNVs (21.6 months, 95% CI, 17.9 months to not reached (NR); HR, 1.9; 95% CI, 1.11 to 3.24; P=0.016). Patients with high n-CNVs and MET and MYC CNVs (copy number variations) were associated with the poorest OS. Osimertinib significantly prolonged OS only among patients with high n-CNVs (with vs. without osimertinib, 25.8 vs. 9.2 months; P=0.004). Among T790M negative patients, high n-CNVs seemed to positively associate with better response to osimertinib (OS with vs. without osimertinib, 23 vs. 7.8 months; P=0.058). Further analysis indicated that EGFR and FGFR1 CNV were the most significant factors associated with OS benefit from osimertinib among the high n-CNVs group (P=0.014; P=0.02). TP53_LOH and Wnt pathway alterations were significantly more prevalent in the high n-CNVs group than in the low n-CNVs group (P=0.016, P=0.006). With regard to clinical characteristics, higher performance status score (HR, 2.06; 95% CI, 1.38 to 3.07; P=0.0004) and occurrence of extracranial metastases (HR, 3.21; 95% CI, 1.25 to 8.24; P=0.015) suggested poor OS.

      figure 300dpi.jpg

      Conclusion

      While genetic profiles in CSF, like high n-CNVs as well as MET and MYC CNV were related to poor prognosis, patients with high n-CNVs, especially those with EGFR or FGFR1 CNV might benefit more from osimertinib, further supporting CSF as liquid biopsy of CNS metastases in lung cancer.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-32 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 289)

      10:15 - 18:15  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC).

      Method

      We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs).

      Result

      290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs.

      all.png

      Conclusion

      Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-36 - Identification of Genomic Features in Tumor-Derived Organoids from Resectable NSCLC (Now Available) (ID 1275)

      10:15 - 18:15  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Patient-derived tumor organoids (PDOs) have recently emerged as robust preclinical models. However, few studies were published on lung cancer organoid. This study aims to describe the genomic characteristics of PDOs as a disease model of NSCLC.

      Method

      Samples from resected tumors were collected for organoid culture. DNA was extracted from tumor, organoids and matched PBLs samples and sequenced with whole-exome sequencing.

      Result

      Seven pts were enrolled, including six LUAD (86 %) and one LUSC (14 %). A total of 1625 somatic mutations were detected in tumors. TP53 (71%), EGFR (43%), and KRAS (29%) mutated most frequently in this cohort, and occurred with frequencies of (57%), (43%) and (29%) in matched PDOs. Based on gene catalog related to lung cancer, the median consistency between tumor and organoid was 87 % (0% ~ 100%). Sample purity was significantly positively related to the variant allele frequency (r=0.82, P=0.0005), and may result in the inconsistence between paired samples. Besides, number of driver gene showed no difference between first- and second-generation organoids.


      table1.jpgfigure1.jpg

      Conclusion

      This study firstly revealed genomic landscape of NSCLC organoid. In spite of heterogeneity, driver mutations presented high consistency between PDOs and paired tumor. Further study is continuing to evaluate outcomes from patients enrolled.

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    P2.17 - Treatment of Early Stage/Localized Disease (ID 189)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.17-16 - Genomic Heterogeneity and Evolutionary Trajectory in Multifocal Synchronous Lung Cancer (ID 2082)

      10:15 - 18:15  |  Author(s): Wen-Zhao Zhong

      • Abstract
      • Slides

      Background

      Multifocal synchronous lung cancer (MSLC) presented as coexistence of multiple tumor lesions that share an identical germline genetic background and environmental exposure in individual patients. Along with the improved resolution of cross-sectional imaging, multiple types of ground glass opacities (GGOs) have been detected in increasing frequency as well as solid nodules even in an unique patient. However the molecular origins and relationships among the synchronous lesions remain unclear.

      Method

      10 treatment-naive MSLC patients were retrospectively collected while 25 tissue samples were performed whole exosome sequencing. In addition, we constructed phylogenetic trees to estimate the ancestral relationships of individual foci.

      Result

      79 somatic mutations in average were identified in MSLC tissues. The most significant mutated gene EGFR has been detected in 10 samples from 7 patients in our cohort. Tumor mutation burden as was significantly higher in IAC lesions than AIS/MIA ones. The mutation spectra of single-nucleotide variations (SNVs) were fairly consistent across the same histologic type even from different patients. Compared to AIS/MIA, IAC samples displayed a preponderance of A>T/T>A transition (Ti) while less frequency of A>C/T>G transversion (Tv). However few share mutations were located by pair of lesions in individual patients. Distinct genomic profiles suggested all were primary tumours. WNT pathway was enriched in AIS/MIA lesions exclusively while IAC appeared TGFβ/TP53 pathway mutation associated with cell proliferation and apoptosis.

      图1.jpg

      组图2.jpg

      Conclusion

      Even in the same individual patient different lung cancer lesions may be driven by distinct genomic profiles so that each presented its own evolutionary trajectory. A deeper understanding of tumorigenesis is still in need to improve the diagnosis and treatment of MSLC.

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    PC03 - Adjuvant Therapy for Resected NSCLC Harboring EGFR Mutation, Chemotherapy or Targeted Therapy (ID 85)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      PC03.01 - PROs (Now Available) (ID 3567)

      15:45 - 17:15  |  Presenting Author(s): Wen-Zhao Zhong

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is so far the leading cause of cancer death worldwide. Complete surgical resection remains the most effective approach for patients with early-stage non-small cell lung cancer (NSCLC). Patients with completely resected stage I NSCLC could have a 5-year survival of ~80%, whereas it fails to ~30%. Since 2003, adjuvant chemotherapy became the standard of care showing 4% absolute 5-year survival benefit compared to surgery alone [1]. Following randomized control trials revealed similar results [2-4], yet limited survival benefit, low therapeutic completed rate plus high toxicities rate may somehow hinder its clinical applicability. In the past decade, targeted therapies had achieved tremendous success in oncogene-driven advanced NSCLC showing both high efficacy and low toxicities [5]. As a matter of course, targeted therapy had its baby steps in early-stage NSCLC. However, no positive results were found in these trials which should probably be blame for large proportion of stage IB patients and incorrect detection methods for EGFRmutation. Besides, conservative trial design without head to head comparison could not fully address toxicities issues caused by chemotherapy. Precise target population seemed to be an essential key point to adjuvant targeted therapies and ADJUVANT as well as EVAN trial came into being [6, 7]. Although overall survival (OS) was not mature enough to measure, significantly prolonged disease-free survival (DFS) was observed in both trials along with better tolerability. Indeed, questioning around adjuvant targeted therapy has never been adjourned such as the optimal duration of targeted therapies, study design and lack of OS data. Ross et al brought up with an informative comment for ADJUVANT trial bringing the concept of MRD (molecular residual disease) into adjuvant treatment [8]. Based on the ctDNA testing after standard of care adjuvant chemotherapy, patients of high risk of recurrence will be given further treatments while observation for the others. It highlighted the significant role of discriminating beneficiaries from adjuvant targeted therapies instead of simply providing more efficient treatment modalities. Previous biomarker-based studies regarding adjuvant treatment among different tumor types [9, 10]had provided inspirational examples, and as well shown clinical feasibility and urgent need for personalized adjuvant treatment after complete surgical resection. For ADJUVANT trial, we established a comprehensive signature of genetic-features (MEDUSA) to guide personalized adjuvant treatment in EGFR-mutant stage II-III NSCLC. Results would be unleashed in upcoming ESMO meeting. Through utilizing multi-omics data, we could predict whether additional treatments, adjuvant chemotherapy only or observation would be adequate for each individual and provide optimal sequential treatments. Further translational researches and corresponding trials regarding resectable NSCLC should decipher the issues. Fortunately, several trials regarding dynamic monitoring postoperative ctDNA or genomic profile of primary cancer to guide sequential treatments are ongoing and the results should be expected.

      figure 1.png

      Reference:

      1. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350: 351-360.

      2. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597.

      3. Strauss GM, Herndon JE, 2nd, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26: 5043-5051.

      4. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7: 719-727.

      5. Hirsch FR, Scagliotti GV, Mulshine JL et al. Lung cancer: current therapies and new targeted treatments. Lancet 2017; 389: 299-311.

      6. Zhong WZ, Wang Q, Mao WM et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018; 19: 139-148.

      7. Yue D, Xu S, Wang Q et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018; 6: 863-873.

      8. Ng TL, Camidge DR. Lung cancer's real adjuvant EGFR targeted therapy questions. Lancet Oncol 2018; 19: 15-17.

      9. Sparano JA, Gray RJ, Makower DF et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373: 2005-2014.

      10. Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol 2015; 33: 1787-1796.

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