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Rui Lin



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    EP1.14 - Targeted Therapy (ID 204)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.14-26 - Uncommon EGFR Mutations Sensitive to First-Generation EGFR-TKI, Icotinib (Now Available) (ID 2091)

      08:00 - 18:00  |  Author(s): Rui Lin

      • Abstract
      • Slides

      Background

      The first-generation EGFR-TKIs are the standard of care for non-small cell lung cancer patients withEGFR activating mutations. Patients with EGFR L858R (p.L858R) or exon 19 deletions are the most prevalent subgroup sensitive to EGFR-TKIs. Previous reports showed that the minority of lung cancer patients with rare EGFR mutations still achieved clinical benefit with EGFR-TKIs. Here, we profiled the landscape of gene mutations in lung cancer patients who responded to Icotinib (a first- generation EGFR-TKI approved in China) treatment without classic EGFR activating mutations.

      Method

      We performed a comprehensive sequencing study by a NGS-based panel on a cohort of eleven lung adenocarcinoma patients without common EGFR sensitive mutations and receiving Icotinib treatment in a previous clinical trial (ICOGEN, NCT01040780). The pre-treatment FFPE tissues from all eleven patients were sequenced using a 500-gene panel.

      Result

      Six patients responded to Icotinib treatment including three patients with partial response (PR) and three patients with stable disease (SD). The other five patients showed immediate disease progression (PD) after the treatment of Icotinib. Rare EGFR mutations in the EGFR tyrosine kinase domain , including EGFR mutations W731C (exon 19), M793I (exon 20), and V845L (exon 21), were detected in the PR and SD groups but not in the PD group. EGFR somatic mutation M793I has been detected in the lung tissue of a patient according to the COSMIC record (COSM1716335). In the PR and SD groups, ERBB2 I655V and JAK2 R215Q were identified as potential mutations which could relate to Icotinib sensitivity.

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      Conclusion

      This study uncovered potential new biomarkers predicting the clinical benefit to Icotinib. With further validation and evidence, it may expand the current patient populations which benefits from the first-generation EGFR-TKIs.

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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-04 - Use Supernatant of Malignant Pleural Effusion to Identify Driver Mutants and Monitor Response to Targeted Therapy (ID 2036)

      09:45 - 18:00  |  Presenting Author(s): Rui Lin

      • Abstract
      • Slides

      Background

      Malignant pleural effusion (MPE) from patients with non-small cell lung cancer (NSCLC) is useful for genetic testing due to advantages including availability, less-invasiveness, and less-heterogeneity. Generally, cell pellets of MPE are used. This study is to further address whether supernatant of MPE is a suitable source to identify key oncogenic mutants in NSCLC patients and provide evidence for clinical molecular testing.

      Method

      MPE samples from 12 NSCLC patients were centrifuged to obtain supernatants and cell pellets, and DNA were extracted. The DNA samples were analyzed by next generation sequencing (NGS) panels using Illumina HiSeq platform.

      Result

      First, MPE samples with the corresponding cancer tissues were collected from 3 NSCLC patients and analyzed with a 500-gene comprehensive cancer panel. Nine mutants were identified in both the paired MPE and cancer tissue samples. We then analyzed nine more NSCLC patient samples using an 18-gene panel to detect key oncogenic mutants; in total, 8 mutants including EGFR L858R, 19DEL, or T790M were identified in the MPE samples. For all of the 17 mutants from the 12 MPE samples, 10 mutants were observed in both the supernatants and pellets of the matched sample sets, of which more pairs (6 out of 10) had supernatants with higher abundance of mutants than the corresponding cell pellets. Importantly, 7 of the 17 mutants were detected only in the supernatants but not the pellets of the paired MPE samples. These results suggest that supernatant of MPE is a better source to detect key oncogenic mutants of NSCLC. Interestingly, 2 patients had both sensitive and resistant mutants to EGFR tyrosine kinase inhibitor (TKI) detected in supernatants of MPE; both patients had treated with EGFR TKI previously, suggesting the development of TKI resistant mutant and supporting the usage of MPE supernatants in monitoring TKI resistance.

      Conclusion

      This study demonstrates that supernatant of MPE is a suitable source for identifying key oncogenic driver mutants for NSCLC and can also be used to monitor response to targeted therapy. The study provides evidence of using supernatant of MPE as an alternative for molecular testing and thus direct precise targeted therapy and surveillance of the therapy effect.

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      P1.03-22 - A Novel Method for Detecting Low Abundant Mutants in Three Types of Liquid Biopsies by Capturing Mutant-Alleles (ID 1332)

      09:45 - 18:00  |  Presenting Author(s): Rui Lin

      • Abstract
      • Slides

      Background

      Liquid biopsy can facilitate early detection of cancers, treatment selection, and disease monitoring. Improved methods to detect low abundant circulating tumor DNA (ctDNA) are needed for clinical samples including plasma, pleural effusion, and cerebrospinal fluid that carry a large amount of wild-type DNA.

      Method

      We have developed a novel method, namely PEAC, with an ultra-high sensitivity to detect low abundant mutants from ctDNA through mutant capturing followed by Sanger sequencing or next-generation sequencing (NGS). This novel approach combines the high discrimination power of locked–nucleic acid (LNA) modified nucleotide sequence and short probes as bait to capture mutant fragment under an optimized temperature. Mutant fragments bound by biotin-labelled, LNA-modified probes are enriched by streptavidin beads and amplified by PCR, and then sequenced for detection.

      Result

      Using circulating cell-free DNA (cfDNA) reference standards, we demonstrated that PEAC technology can enrich mutants up to 5000-fold (panel B of the figure below) and empower to detect clinically relevant EGFR mutants such as L858R, 19Del, and T790M mutant at the abundance as low as 0.01-0.1% by Sanger sequencing or NGS analysis. The clinical implications of PEAC technology were further validated using ctDNA from liquid biopsy specimens of non-small cell lung cancer (NSCLC) patients. EGFR L858R, 19DEL or T790M mutants were detected at the abundance >50% after PEAC enrichment from plasma samples of NSCLC patients, whereas the corresponding ctDNA samples without PEAC enrichment were undetectable by Sanger sequencing and hardly detected by NGS analysis. One cerebrospinal fluid and two pleural effusion samples had dominated 19DEL, L858R and T790M peaks after PEAC enrichment, respectively, but exhibited almost the background signal levels prior to PEAC.

      peac fig.png

      Conclusion

      PEAC technology can enrich ctDNA from body fluids of cancer patients to detect ultra-low abundant clinically relevant mutants. Combined with other methods including NGS, the technology may serve as an attractive detection method in clinical practice.

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    P1.15 - Thymoma/Other Thoracic Malignancies (ID 184)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.15-05 - Genomic Variation Landscape of Thymoma and Thymic Carcinoma in Chinese Patients (Now Available) (ID 2147)

      09:45 - 18:00  |  Author(s): Rui Lin

      • Abstract
      • Slides

      Background

      Background: Thymoma and thymic carcinoma (TC) are rare diseases of thymus with relatively good prognosis. Though pathological sub-types of thymoma and TC show clear differences on clinical characteristics, morphology, molecular markers, and prognosis, little is known on either the etiology or the molecular mechanism of the two tumor types.

      Method

      Method: In this study, 27 thymoma and thymic carcinoma patients with most common thymic epithelial tumor subtypes were enrolled, including 2 type A, 6 type AB, 3 type B1, 1 type B1/B2, 5 type B2, 2 type B2/B3, 5 type B3, and 3 type TC patients in total. The Masaoka stage status of the cohort was 15 stage I, 5 stage II, 3 stage III, and 4 stage IV patients. DNA samples extracted from the frozen tissues were sequenced using a 500-gene NGS panel.

      Result

      Result: Forty-seven non-synonymous somatic variants in 38 genes were identified from the sequencing data. The average tumor mutation burden was low (0.83 mut/MB), which was consistent with the previous findings in the TCGA thymic epithelial tumor cohort study (0.48 mut/MB). The KEGG pathway enrichment analysis showed that the function of the mutated genes was closely related to cancer signaling pathways: 15 genes in “pathway in cancer”, 9 in “Ras signaling pathway”, and 10 in “PI3K-Akt signaling pathway”. GTF2I L424H mutation was observed in one type A (50% of type A), six type AB (100% of type AB), and four type B (25% of type B) samples. We observed the significantly higher GTF2I mutant prevalence on type B samples in our cohort than that in the TCGA cohort (p=0.024). NF1 and ATM were highly mutated genes in our cohort. Three type B samples had NF1 mutations (D1067V, P1087L, and G1090*). Two type B and one type A samples had ATM mutations (S169F, P424H, and R493G). Neither NF1 nor ATM was identified as frequently mutated genes in the TCGA cohort. One KRAS (A59del) and one NRAS (Q61K) mutations were detected in two type AB samples respectively. No KIT or EGFR mutation was found.

      Conclusion

      Conclusion: This study provided a comprehensive somatic mutation landscape of thymic epithelia tumor in a Chinese cohort. We compared our data to the TCGA cohort, most of which were Caucasian people. We identified higher mutation prevalence of GTF2I on type B samples in the Chinese cohort. Moreover, NF1 and ATM mutations were found to be highly mutated in our cohort but not in the TCGA cohort.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-21 - MUC16 Germline Mutations May Associate with Inherited Lung Cancer (ID 2150)

      10:15 - 18:15  |  Author(s): Rui Lin

      • Abstract
      • Slides

      Background

      Study of inherited cancer may facilitate the understanding of the molecular mechanism of tumorigenesis. Though sporadic reports have shown that mutations in EGFR or ERBB2 may associate with familial lung cancer, the knowledge of the genetic causes for inherited lung cancer is still limited.

      Method

      Genomic DNA (gDNA) from cancer patients or healthy people were extracted from whole blood samples and analyzed using a 500-gene next generation sequencing (NGS) panel. Variants identified by NGS panel were confirmed by Sanger sequencing.

      Result

      In November 2017, four siblings in a Chinese family were diagnosed with lung adenocarcinomas. Additionally, the 5th sibling in the family had prostate cancer. A questionnaire for the family did not reveal significant environmental or habitual reasons leading to cancer in the family, suggestive of possible genetic causes. NGS analysis for gDNA samples indicated all 4 siblings with lung cancer had 3 heterozygous alleles of SNPs in MUC16, namely rs754254000, rs754856910, and rs746152510. In contrast, the sibling with prostate cancer was wild-type for all of the three alleles (Figure below). The NGS results were then confirmed by Sanger sequencing. The three germline mutations in MUC16 all had very low population minor allele frequency (below 0.1%). We further analyzed the gDNA of the children in the family, and detected the 3 heterozygous SNPs in a child whose parent had lung cancer, whereas both children of the prostate cancer patient were wild-type for the 3 MUC16 alleles. Taken together, these results are consistent with a hypothesis that germline mutation of rs754254000, rs754856910, and rs746152510 may predispose the family members to lung cancer. MUC16, also known as CA125, is a biomarker for ovarian cancer, and also shown to be involved in tumorigenesis and metastasis of lung cancer cells. The child with heterozygous SNPs of MUC16 need be cautious in the future routine check-ups.

      muc16 3 snp.png

      Conclusion

      In this study, we have demonstrated that germline mutations of MUC16 may associate with inherited lung adenocarcinomas, which warrants further mechanistic study of MUC16 gene in lung cancer.

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      P2.03-27 - Discovery of WNK1-ROS1 Fusion in a Lung Adenocarcinoma Patient and the Precise Guidance for Targeted Therapies (ID 2122)

      10:15 - 18:15  |  Presenting Author(s): Rui Lin

      • Abstract
      • Slides

      Background

      Lung cancer can be driven by activation of tyrosine kinases including EGFR mutations, ALK, ROS1, RET, or NTRK fusions. New partners of gene fusions remain to be identified and their response to targeted therapy need be carefully evaluated in the clinical practice.

      Method

      A targeted next-generation sequencing (NGS) panel was used to analyze DNA extracted from tumor tissue and plasma samples from a lung adenocarcinoma patient. The fusion detected by NGS panel was confirmed by Sanger sequencing.

      Result

      Using a targeted NGS lung cancer panel, we identified a novel ROS1 fusion from a 39-year old Chinese female with lung adenocarcinoma. No EGFR, MET, KRAS, ALK, ROS1 or other driver mutations of lung cancer were detected in the patient. Intron 25 of WNK1 was translocated to intron 33 of ROS1 (Figure blow), which resulted in an in-frame fusion transcript of WNK1-ROS1 at the breakpoints of exon 25 and exon 34, respectively. Sanger sequencing confirmed the fusion and the breakpoints. This novel WNK1-ROS1 fusion encoded a chimera protein of which the transmembrane and kinase domains of ROS1 remained intact. The patient received treatment with crizotinib targeting to ROS1, and partial response was achieved 3 months later. Resistance to crizotinib occurred at 5 months after the treatment. Analysis of the ctDNA from the patient’s plasma sample identified ROS1 G2032R mutation, a well-known mechanism of ROS1 resistance to crizotinib. The patient was subsequently treated with TPX-0005, which is effective to ROS1 G2032R mutant. Decreased CEA level was observed 2 months after TPX-0005 treatment, suggesting the patient was responsive to the targeted therapy.

      wnk1-ros1 fusion.png

      Conclusion

      We identified a lung adenocarcinoma patient with a novel WNK1-ROS1 fusion who was sensitive to crizotinib and developed crizotinib resistant ROS1 G2032R mutation at progression but appeared to be responsive to the new generation of TPX-0005 therapy. These results suggest that WNK1-ROS1 fusion is a new molecular mechanism leading to lung adenocarcinoma and targetable to ROS1 tyrosine kinase inhibitors.

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      P2.03-28 - A 500-Gene Panel to Detect Tumor Mutation Burden of Tissue and Plasma Samples from Lung Cancer Patients (ID 2157)

      10:15 - 18:15  |  Author(s): Rui Lin

      • Abstract
      • Slides

      Background

      Tumor mutation burden (TMB) from cancer tissue is an FDA approved biomarker for selecting appropriate patients for immunotherapy. However, tissue samples are not readily accessible. Though reports have shown correlation between tissue TMB and plasma based TMB (bTMB), no FDA approved bTMB product is available yet. More assay needs to be evaluated for correlation analysis of TMB and bTMB.

      Method

      Matched gDNA, ctDNA, and tumor tissue DNA samples from the same patient with non-small-cell lung cancer (NSCLC) were extracted from blood, plasma, and formalin-fixed paraffin-embedded (FFPE) tissue using Qiagen DNA extraction kits. DNA libraries were prepared using Agilent SureSelectXT HS Reagent Ki and were sequenced by a comprehensive 500-gene NGS cancer panel. After variant calling, non-synonymous variants were included to calculate TMB and bTMB using allele frequency cutoffs at 5% and 0.8%, respectively. An in-house bioinformatics method to get rid of germline mutations were also validated in our dataset.

      Result

      To validate the 500-gene panel for TMB and bTMB analysis, we first retrieved TCGA whole exome sequencing (WES) data including 1144 lung cancer patients and about 15500 pan-cancer patients. We then calculated the correlations between the 500-gene panel and WES data on the two datasets and acquired R-square values of 0.93 and 0.94, respectively. Such data demonstrated that our 500-gene is a suitable panel to substitute WES for TMB analysis. We then used the 500-gene panel to analyze 17 NSCLC patients with matched FFPE, ctDNA, and gDNA samples. Using 5% and 0.8% as the allele frequency cutoffs for the variants called from the tissue DNA and ctDNA samples, we found a 0.84 R-square correlation between TMB and bTMB analysis. These results suggest that the bTMB from plasma samples of cancer patients highly correlates to the TMB of the paired tissues using our 500-gene panel.

      Conclusion

      We have demonstrated in this study that a 500-gene panel is suitable for TMB analysis of cancer tissues. We further show that bTMB analysis using the 500-gene panel is close and highly correlate to the TMB from paired cancer tissues. Upon further clinical studies, the TMB and bTMB analysis using the 500-gene panel may represent a good biomarker for patient selection using either cancer tissue or plasma samples.

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