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Shannon Chuai



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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
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
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      JCSE01.11 - Dynamic ctDNA Monitoring Revealed Novel Resistance Mechanisms and Response Predictors of Osimertinib Treatment in East Asian NSCLC Patients (Now Available) (ID 14716)

      10:35 - 10:45  |  Author(s): Shannon Chuai

      • Abstract
      • Presentation
      • Slides

      Background

      Advanced NSCLC patients, harboring EGFR T790M, exhibit marked diversity in tumor behavior and response to AZD9291, yet a discriminable molecular profile remains elusive. In addition, although EGFRC797S was involved in 30% of AZD9291 resistance cases in Western patients, mechanisms for the rest patients remain unclear, especially for the East Asian population. We utilized circulating tumor DNA (ctDNA) profiling to conduct dynamic monitoring in patients undergoing AZD9291, thus characterizing mutational heterogeneity and genomic evolution.

      Longitudinal plasma samples were collected before, during and post of the AZD9291 treatment in Chinese NSCLC patients with acquired T790M mutation. A ctDNA panel, spanning 160KB of human genome, was used to perform capture-based targeted sequencing that comprises critical exons and introns of 168 genes. The EGFR mutation abundance and dynamic changes of allele fraction (AF) were analyzed with progression-free survival (PFS) after AZD9291 treatment.

      A total of 61 samples were collected longitudinally from 14 patients, of which 9 have experienced progressive disease (PD). Six patients exhibited a rebound of ctDNA prior to radiographic PD, suggesting the potential of ctDNA in early detection of PD. Several acquired mutations were detected with the AZD9291 resistance, including newly identified EGFR G796S, L792H/F/R/V, V802F, V843I mutations, expect for the previously reported RB1 and EGFR C797S, L718Q mutations. Patients with a higher ratio of T790M and EGFRactivating mutation at baseline had a significantly longer PFS (9.6m vs 4.5m, p=0.008). A lower ratio of EGFRactivating mutation AF compared to baseline at first follow-up was significantly correlated with a longer PFS (8.5m vs 5.0m, p=0.027). Furthermore, patients harboring other known driver mutations in addition to T790M at baseline had an inferior PFS (4.9m vs 7.8m, P=0.039).

      Several novel resistance mechanisms were identified by ctDNA monitoring in the East Asian patients treated with AZD9291. Relative AF of T790M, changes of AF after treatment and the presence of concurrent driver mutations at baseline could predict clinical benefit of AZD9291 treatment.

      a9ded1e5ce5d75814730bb4caaf49419

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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.10 - Clinical Utility of Cerebrospinal Fluid Cell-Free DNA for Clarifying Genetic Features of Leptomeningeal Metastases in ALK Rearrangement NSCLC (Now Available) (ID 12142)

      14:35 - 14:40  |  Author(s): Shannon Chuai

      • Abstract
      • Presentation
      • Slides

      Background

      Leptomeningeal metastases (LM) were associated with a poor prognosis in non small cell lung cancer (NSCLC). LM were much more frequent in EGFR mutant patients, and cerebrospinal fluid (CSF) cell-free DNA (cfDNA) has shown unique genetic profiles of LM in patients harboring EGFR mutations in our previous studies. However, studies in ALK positive NSCLC patients with LM are scarce.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Lung cancer patients with ALK rearrangement were screened from Sept 2011 to Feb 2018 at our institute. Leptomeningeal metastases were diagnosed by MRI or CSF cytology or next-generation sequencing (NGS) of CSF cfDNAs. Paired plasma were also tested by NGS.

      4c3880bb027f159e801041b1021e88e8 Result

      LM were diagnosed in 22 (7.6%) of 288 ALK rearrangement patients with lung cancer. A total of 11 ALK positive patients with LM were enrolled with CSF cfDNA tested by NGS (one case used CSF precipitates instead of CSF cfDNA). Paired plasma were available in 11 patients. Driver genes were detected in 75.0% CSF samples and 45.5% plasma respectively (P=0.214). Max allele fractions were higher in CSF cfDNA than in plasma (40.8% versus 0%, P=0.021). ALK variant 1 (E13:A20) was detected in 3 cases of CSF and paired plasma, respectively. ALK variant 2 (E20:A20) was identified in 5 cases of CSF and 1 paired plasma. Multiple copy number variants (CNV) were mainly found in CSF cfDNA, including EGFR copy number gains. Resistance mutations including gatekeeper gene ALK G1202R was identified in CSF cfDNA with ALK variant 1 and ALK G1269A was detected in plasma. The detection rate of TP53 was 45.4% versus 27.3% in CSF cfDNA and plasma.

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      8eea62084ca7e541d918e823422bd82e Conclusion

      CSF cfDNA was more sensitive than plasma to reveal genetic features of ALK-fusion LM, confirming its role as a liquid biopsy medium for LM in driver gene positive NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.05 - Comprehensive Genomic Characterization and Prognostic Nomogram Developed by 295-Gene Panel Targeted Sequencing (Now Available) (ID 13664)

      15:45 - 15:50  |  Author(s): Shannon Chuai

      • Abstract
      • Presentation
      • Slides

      Background

      The genomic landscape of lung cancer has been thoroughly studied in the western population. But comprehensive genetic profiling reports have been limited for the Chinese patients. Here we conducted deep targeted sequencing on a large cohort of Chinese treatment-naïve lung cancer patients and identified novel molecular patterns. We developed nomogram models for prognosis prediction by integrating genetic and clinical characteristics and aim to explore more precise models for risk stratification beyond TNM staging.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was a retrospective study, enrolling diagnosed lung cancer patients at Tianjin Medical University Cancer Institute & Hospital from 2009 to 2012. We developed genomic landscape by targeted sequencing using a panel consisting of exons and critical introns of 295 cancer-related genes. Nomogram models were established to provide risk stratification in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients

      4c3880bb027f159e801041b1021e88e8 Result

      513 tumor tissue samples were collected at very beginning of treatment (stage I, n=193; stage II, n=140; stage IIIA, n=140; stage IIIB, n=5; stage IV, n=28; unknown, n=7). The most frequently mutated oncogenic genes in LUAD were EGFR (55%) and KRAS (11%), compared to 14% and 33% in TCGA. Heterogeneity existed in terms of mutual exclusive and co-occurrent mutated gene pairs between LUAD and LUSC. In LUAD, pairs with most significant exclusivity was EGFR/KRAS and co-occurrent was NOTCH3/GRIN2A, whereas the most significant concurrent gene pair in LUSC was ZNF703/FGFR1. To predict survival, our nomograms identified that, in stage I-IIIA LUAD and LUSC, mutated TET2 contributed to more favorable DFS while mutations in EPHA3 and ETV5 indicated better OS. Stage and mutated KRAS were associated with inferior DFS and OS (DFS, n=222, c-index=0.714; OS, n=308, c-index=0.706). In the T1+2&N0&M0 subgroup, which is considered clinically low risk for relapse, older patients who carry BRCA2 mutations were found to strongly correlate with poor DFS (n=121, c-index=0.709), while age and mutated KRAS were distinct indicators of inferior OS (n=163, c-index=0.725). The calibration for survival probability displayed well agreement between nomogram prediction and actual outcomes. Stratification of different risk groups based on nomogram prediction displayed significant differences among Kaplan-Meier curves for survival outcomes (p<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the so far largest cohort of Chinese lung cancer patients with comprehensive genomic profiling reported. We revealed unique molecular profiles than TCGA and distinct mutual exclusivity and co-occurrence patterns between LUAD and LUSC. In addition, the nomogram models show promise of more precise prognostic prediction of NSCLC patients when integrating genetic information with clinical characteristics.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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): Shannon Chuai

      • 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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

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      8eea62084ca7e541d918e823422bd82e 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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