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Li Liu



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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • 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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      P1.13-08 - Distribution, Differences in Clinical Characteristics and Resistance Mechanism of ALK Variants in Chinese Lung Cancer Patients. (ID 13678)

      16:45 - 18:00  |  Author(s): Li Liu

      • Abstract
      • Slides

      Background

      ALK rearrangements are established targetable drivers in NSCLC. Recent reports indicate differential progression-free survival to ALK inhibitors according to specific EML4-ALK variant.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 172 unique Chinese lung cancer patients with tumors harboring ALK rearrangements (ALK+) were enrolled in the study from 2016 to 2018. ALK+ were detected by Ventana, FISH, or next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across at least 59 genes (59-1021). Tissue biopsy was the first choice for NGS mutation profiling, and ctDNA or pleural effusion testing was used as an alternative.

      4c3880bb027f159e801041b1021e88e8 Result

      Of these 172 cases, the median diagnosis age was 50 (range 24-78), 58% were female, 90% was NSCLC. Of the 147 ALK+ cases detected by NGS, we identified 65 (44%) EML4-ALK v1 (E13; A20), 18 (12%) EML4-ALK v2 (E20; A20), 43 (29%) EML4-ALK v3 (E6; A20), 13 (9%) other EML4-ALK, and 8 (5%) non-EML4-ALK rearrangements. 2 new fusion genes were found in non EML4-ALK rearrangements (SRBD1-ALK (EX20; EX20) and CLIP4-ALK (EX9; EX20)), and the CLIP4-ALK patient’s tissue was also ALK positive by Ventana. V1 found a higher proportion of pleural effusion at baseline than non-v1 (12% v.s.5%). Mutation profiling by NGS were performed after disease progression in 55 patients treated with crizotinib. mPFS was 8.1 months, no significant difference existed between v1 and v3 (P=0.69). But the presence of known ALK resistance mechanisms was significantly higher in v3 as compared to non-v3 (67% v.s. 27%, P=0.038).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Next generation sequencing allows for detection of the specific ALK fusion partner and variants, increases the understanding of the biology of ALK+ NSCLC, and may have value to foretell potential mechanisms of resistance.

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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
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-107 - Analysis of Mutation Detection by ctDNA on the Basis of Metastatic Sites in Lung Adenocarcinoma Patients (ID 13635)

      16:45 - 18:00  |  Author(s): Li Liu

      • Abstract

      Background

      Circulating tumor DNA (ctDNA) testing represents a powerful tool to detect gene alterations in patients. However, differences in mutation detected by ctDNA related to metastatic sites in lung cancer have not been addressed before and remain to be explored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed 317 ctDNA samples from 310 lung adenocarcinoma patients with definite metastasis at our institute. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of 1021 genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients were divided into two groups according to metastatic sites. Any case with metastasis to the bone, liver or adrenal gland falls into the major organ metastasis group, while any case with metastasis to the lung, pleura or lymph node belongs to the local metastasis group. No genetic alteration was detected in 14 (11.5%) of 122 samples in the major organ group and 35 (17.9%) of 195 in the local group. And distant metastasis is associated with more mutations on average detected by ctDNA (5.26 for the major organ group vs 3.72 for the local group; p=0.0039). As for genes involved, the most common mutated ones are EGFR and TP53 for both groups, with an overall mutation rate being 40.6% and 33.2% respectively. And just as average gene alterations mentioned above, the mutation rates of EGFR and TP53 are much higher in the major organ group (49.6% vs 35.2% for EGFR; 43.6% vs 26.9% for TP53). Besides, mutations of NF1, MLL3, KRAS and KEAP1 are more frequent in the major organ group while mutation rate of PIK3CA is slightly higher in the local group (Table).

      Table. Some mutated genes detected by ctDNA

      major organ metastasis (117)

      local metastasis (193)

      EGFR

      58 (49.6%)

      68 (35.2%)

      TP53

      51 (43.6%)

      52 (26.9%)

      KRAS

      9 (7.7%)

      7 (3.6%)

      MLL3

      9 (7.7%)

      6 (3.1%)

      NF1

      9 (7.7%)

      3 (1.6%)

      ERBB2

      5 (4.3%)

      6 (3.1%)

      PIK3CA

      3 (2.6%)

      7 (3.6%)

      KEAP1

      7 (6.0%)

      3 (1.6%)

      8eea62084ca7e541d918e823422bd82e Conclusion

      More gene alterations were detected by sequencing of ctDNA in patients of lung adenocarcinoma with major organ metastasis compared to those with only local metastasis.

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      P2.01-116 - The Potential of Assessing Blood Tumor Mutation Burden (bTMB) Using a Large Panel  (ID 13224)

      16:45 - 18:00  |  Author(s): Li Liu

      • Abstract
      • Slides

      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-naïve advanced NSCLC patients by performing WES on tissue samples as well as targeted sequencing on matched tissue and plasma samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      WES was performed on tissue samples with an average sequencing depth of 300x. Targeted sequencing was performed on matched tissue and plasma using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. An average sequencing depth of 1,000X and 10,000x were achieved for tissue and plasma samples, respectively. TMB was calculated as the ratio of mutation count to the size of coding region of the panel (1.26Mb), excluding copy number variations, fusions, large genomic rearrangements and mutations occurring on the kinase domain of EGFR and ALK.

      4c3880bb027f159e801041b1021e88e8 Result

      In tissue samples, TMB derived from WES and our panel is comparable with a R2 value of 0.87, and a correlation value of 0.86. cfDNA from 8 patients had no mutation detected using the 520 panel potentially due to low fraction of ctDNA present in the circulation. TMB derived from cfDNA of the remaining 22 patients showed a good correlation with TMB derived from tissue using either our panel (R2=0.94, correlation =0.93) or WES (R2= 0.85, correlation=0.87), demonstrating the feasibility of assessing TMB from cfDNA using a large panel. Next, using TMB calculated from WES as gold standard, we attempted to derive a cutoff to stratify TMB high patients from TMB low patients. Our data revealed 15 mutations per mb as an optimal cutoff using the 520 panel, achieving an AUC of 97.6% for tissue samples and 97.2% for plasma samples.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study demonstrated the feasibility of evaluating TMB from cfDNA using a large panel, opening the avenue of TMB estimation using liquid biopsy. Further validations in prospective clinical trials are needed to solidify its predictive value in response to immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)

    • 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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      P3.04-09 - Analysis of Repertoire Features of T Cell Receptor in Treat-Naïve EGFR Wild-Type Lung Cancer Patients by High-Throughput Sequencing (ID 13898)

      12:00 - 13:30  |  Author(s): Li Liu

      • Abstract

      Background

      T cells can recognize peptides encoded by mutated genes. Assessment of the repertoire features of TCR is vital for us to deeper understand of immune behavior and immune response. However, detailed characterization of the peripheral blood T cell receptor (TCR) repertoire and its interaction with treat-naïve EGFR wild-type lung cancer patients have not been systemically studied.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We used ultra-deep sequencing of rearranged genes in TCR β-chain (TCRβ) to profile the basic characteristics of T cells in peripheral blood samples of 27 treat-naïve EGFR wild-type lung cancer patients received chemotherapy as well as age- and gender-matched healthy donors without any history of cancer.

      4c3880bb027f159e801041b1021e88e8 Result

      Data showed that healthy donors had more TCR clonotypes and higher diversity while patients represented with restricted TCR repertoire. Interestingly, TCR repertoire was associated with TP53 mutation status, tumor volume, rapid progression and squamous cell carcinoma antigen (SCC) level in patients, but not with metastasis. Patients with TP53 mutation had fewer clonotypes (p=0.011), lower diversity (p=0.006) and higher clonality (p=0.054), while those with larger tumor volume and rapid progression following chemotherapy had fewer clonotypes (p=0.046 and p=0.011, respectively) in peripheral blood. peripheral blood TCR repertoire was not significant correlated with brain metastasis or bone metastasis. In addition, clonality was positive correlation with SCC Concentration (p=0.024,R=0.48,n=22).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study promote a better knowledge about the T cells among treat-naïve EGFR wild-type lung cancer patients and provides new insight into the TCR repertoire associated with clinical presentation in lung cancer patients. And the TCR repertoire in peripheral blood samples before treatment may be used as a predictor of rapid progression in lung cancer patients treated with chemotherapy.

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