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Peng Wang



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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-06 - Loss of Heterozygosity of Oncogene ERBB2 with an Activating Mutation Was Identified as Driver Eventin Leptomeningeal Metastasis of NSCLC (ID 1184)

      08:00 - 18:00  |  Presenting Author(s): Peng Wang

      • Abstract

      Background

      Due to limited access to leptomeningeal lesions, cerebrospinal fluid (CSF) may be the most representative liquid biopsy to get genomic information from leptomeningeal metastases (LM) in non-small-cell lung cancer (NSCLC). Loss of heterozygosity (LOH) is a common genetic event during cancer tumorigenesis. LOH of tumor suppressor gene in which loss-of-function occurs on alternative allele serves as “second hit” and leads to loss of the remaining functional allele. LOH of tumor suppressor gene, such as TP53,in CSF had been reported for its associated with EGFR-TKI resistance in LM. Here, through CSF derived liquid biopsy, we report a LOH of oncogene ERBB2 in LM of NSCLC patient. To the best of our knowledge, this is the first report of LOH of oncogene, no matter in a primary or metastatic tumor.

      Method

      Three CSF biopsies and matched peripheral blood were collected within 6 months from one NSCLC patient with LM. Cell-free DNA (cfDNA) was extracted, and somatic mutations were examined using a designed lung cancer panel of 180 genes. SCNAs were further identified through 2x whole genome sequencing (WGS). Genomic alternations identified in all three matched biopsies were included in the subsequent analysis.

      Result

      A rare oncogene ERBB2 activating mutation (V659E) was identified in CSF but not in plasma. V659E lies within the transmembrane domain and results in constitutive activation of Src and Akt signaling. Extreme high variants allele fraction (96.8%) of ERBB2 V659E in CSF implied the LOH of ERBB2 in LM. SNPs heterozygosity analysis and low pass WGS were further carried out and confirmed the LOH of entire chromosome 17, but not limited to ERBB2 region. Furthermore, A consecutive an amplification was observed on the remaining copy of chromosome 17q, on which the activated oncogene ERBB2 located. The amplification, following ERBB2 LOH with a concomitant activating mutation, may enhance constitutively active ERBB2 expression and drive the evolution of LM. Besides, there were two more unique mutations in CSF, TP53 T256fs (45.31%) and JAK3 R582Q (32.85%). Relatively Low variants allele fraction indicated that they were subclonal mutation occurring after ERBB2 activating mutation and LOH of chromosome 17.

      Conclusion

      We first reported an oncogene ERBB2 LOH in CSF from one NSCLC patient with LM. Based on phylogeny inference, the ERBB2 activating mutation and LOH of chromosome 17 were likely to be the earliest driver event.

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      EP1.01-52 - Preferable Intracranial Chemotherapy for Lung Cancer Patients with Meningeal Metastasis Harboring CIN in CSF (ID 2262)

      08:00 - 18:00  |  Presenting Author(s): Peng Wang

      • Abstract

      Background

      Brain metastases occur in about half of the NSCLC patients throughout the course of disease, including brain parenchymal metastasis and meningeal metastasis. It has been reported that compared with plasma detection, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) is capable of more comprehensively characterizing the genomic alterations of brain tumor, so as to identify actionable variants.

      Method

      We conducted a small sample study consisting of 7 patients with brain metastasis, including 3 lung cancer patients with meningeal metastasis (P314, P316, P318), a lung cancer patient with brain parenchymal metastasis (P323), 2 breast cancer patients with meningeal metastasis (P324 and P328) as well as a gastric cancer patient with meningeal metastasis (P326). Profiling of the specimens from CSF, brain parenchyma and plasma of these 7 patients was performed using NGS along with bioinformatics analysis.

      Result

      Among the three patients P314, P316 and P318, high-frequency driver mutations including ERBB2 p.V659E, EGFR p.L858R & MET amplification, EGFR 19del were detected in the CSF respectively, but all of these variants were not observed in the plasma. Notably, these three patients’ brain lesions continued to progress after receiving corresponding targeted agents, while their conditions remained stable in the presence of switching to intracranial chemotherapy. Following bioinformatic analysis revealed the occurrence of chromosome instability (CIN). We wonder if it is a special case or a common phenomenon. To further explore whether there is similar phenomenon in brain parenchymal metastasis, we examined the patient P323. The detection results of his brain parenchyma, CSF and plasma showed that there was no variation of CIN in brain parenchyma and CSF. In view of this, we hypothesized that CIN variants might exist only in lung cancer patients with meningeal metastasis. In addition, our results displayed that no chromosome instability was identified in the CSF of patients P324, P328 and P326.

      Conclusion

      In summary, CIN is likely an important genomic feature of lung cancer with meningeal metastasis and is apt to be detected in the CSF. According to our observation, NGS of CSF specimen rather than plasma sample may be more favorable to the selection of appropriate treatment options for lung cancer patients with meningeal metastasis. For such patients with CIN variation, intracranial chemotherapy possibly offers more significant clinical benefit than other treatments such as targeted therapy. It still requires more investigations to verify above hypothesis.