Virtual Library
Start Your Search
Naixin Liang
Author of
-
+
MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 16:45 - 17:45, Scientific Program Auditorium
-
+
MA08.09 - Clinical Management of Lung Adenocarcinoma Patients With HER2 V659E Mutation (ID 962)
16:45 - 17:45 | Author(s): Naixin Liang
- Abstract
Introduction
ERBB2 mutations, mostly affecting the kinase domain (KD), were later found in the transmembrane domain (TMD), most frequently seen in residues V659, G660, but with a much lower prevalence. Comparing to other solid tumors, ERBB2-mutant NSCLC shows a lower response rate to HER2 inhibitors (HER2i). ERBB2 V659E has been reported to respond to lapatinib in combination with carpecitabine, afatinib, or ado-trastuzumab emtansine (TDM-1). However, since the prevalence of ERBB2 V659E is low, no study has reported the subsequent clinical management after developing resistance to HER2i.
Methods
We retrospectively screened genomic profiles of 7,812 lung adenocarcinoma (LADC) patients. Molecular docking of lapatinib, afatinib and pyrotinib with the HER2 KD was simulated with AutoDock 4.2 and the binding affinity was predicted by MMPBSA.py program in AmberTools18.
Results
We analyzed NGS data of 7812 LADC patients and identified 14 patients (0.18%) with HER2 TMD mutation, mostly V659E mutation (11/7812, 0.14%); other mutations included V664F, T652M, V664F; each occurred in 1 patient. In this cohort, all adenocarcinomas harbor a dinucleotide missense mutation, including 10 TT→AA and 6 TT→AG (c.1976_1977). TP53 was the most frequently co-mutated gene (n=4) followed by HER2 amplification (n=2), NSD1 (n=2) and RARA (n=2). Treatment history of 9 advanced LADC patients was collected and analyzed. 3 of them had chemotherapy as first-line therapy. 5 patients were treated with HERi as first-line therapy, achieving a median PFS of 192 days (ranged from 60-515days), comparing to patients treated with chemotherapy (71.7±53.3days). 1 patient who was treated with different HERi sequentially in the order of lapatinib, afatinib, TDM-1, achieving an overall PFS of 515 days. Subsequently, she was treated with pyrotinib and had a PFS of 92 days. Molecular docking simulation showed the covalent inhibitors Afatinib and Pyrotinib are more favorable for blocking HER2 KD than non-covalent inhibitor Lapatinib. Between the two covalent inhibitors, Pyrotinib (∆GPyrotinib = -65.92kcal/mol) shows stronger non-covalent binding ability than Afatinib (∆GAfatinib = -59.71 kcal/mol) (p<0.001).
Conclusion
To the best of our knowledge, this is the largest-reported HER2 V659E mutation cohort. We revealed the prevalence of ERBB2 V659E in Chinese LUAD patients and elucidated the genomic profile of ERBB2 V659E mutant. This study paves avenue for the utilization of the novel HER2 inhibitors pyrotinib in ERBB2 V659E mutant LUAD patients.
-
+
P43 - Screening and Early Detection - Biomarkers (ID 178)
- Event: WCLC 2020
- Type: Posters
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P43.04 - Efficient Isolation and Quantification of CTC in NSCLC Patients using Peptide-Functionalized Magnetic Nanoparticles (ID 2089)
00:00 - 00:00 | Presenting Author(s): Naixin Liang
- Abstract
Introduction
Circulating tumor cells (CTCs) carry a wealth of information on primary and metastatic tumors critical for enhancing the understanding of the occurrence, progression and metastasis of non-small cell lung cancer (NSCLC). However, the low sensitivity of traditional tumor detection methods limits the application of CTCs in the treatment and disease surveillance of NSCLC. Therefore, CTCs isolation and detection with high sensitivity is highly desired especially for NSCLC patients, which is significant because of high occurrence and mortality. While it is very challenging because of the lower expression of CTC positive biomarkers such as epithelial cell adhesion molecules and cytokeratins (EpCAM and CKs), herein we report a method based on peptide-functionalized magnetic nanoparticles with high CTC capture efficiency, which demonstrates superiority in NSCLC clinical applications.
Methods
For analysis and comparison of the peptide-functionalized magnetic nanoparticles (TumorFisher, Nanopep Corp.) and the antibody-modified magnetic beads (CellSearch, Janssen Diagnostics, LLC), two NSCLC cell lines, A549 and NCI-H1975 were choosed to measure the binding affinity and capture efficiency. In order to compare the effect of the clinical application of these two detection systems, 7 early stage patients with NSCLC were enrolled in this study. To further explore the clinical utility of CTC counting in different stages, 81 NSCLC patients in stage Ⅰ-Ⅳ were enrolled for CTC enumeration and statistical analysis.
Results
The binding affinities of the recognition peptide to A549 and NCI-H1975 are 76.7 ± 11.0 % and 70.1 ± 4.8 % respectively, which is similar with the positive control group (anti-EpCAM antibodies). CTCs were captured in 5/7 (71.4 %) of early stage NSCLC patients with NSCLC in TumorFisher system, which is higher than CellSearch, and the false negative of TumorFisher is much lower than CellSearch. In a larger clinical cohort, the CTC numbers of NSCLC patients varied in different stages and the overall detection rate of TumorFisher was 59/81 (72.8 %), with the similar proportion in stage Ⅰ (21/29, 72.4 %), Ⅱ (17/22, 77.3 %) and Ⅲ (16/21, 76.2 %).
Conclusion
Highly efficient CTC isolation technique based on peptide-magnetic nanoparticles was firstly applied in NSCLC patients. Compared with the antibody-based the technique, the higher CTC detection rates (71.4 %) in NSCLC patient blood samples were demonstrated for the patients in different stages, I-IV, especially in early stages. This indicates the feasibility of the clinical utility of this new technique in early stage screening, prognosis and therapy evaluation of NSCLC.
-
+
P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P84.13 - Organoid Used as Preclinical Modal in ALK Inhibitor Selection: Report of a Case Harbouring LRRTM4–ALK Fusion (ID 1005)
00:00 - 00:00 | Author(s): Naixin Liang
- Abstract
Introduction
Increasing less common ALK gene fusion that results in overexpression of the kinase domain of the anaplastic lymphoma tyrosine kinase receptor (ALK) protein is reported recently due to the development of next-generation sequencing (NGS). Individual responses to therapeutic ALK inhibitors became topical issues. Patient-derived organoids (PDOs) created from lung adenocarcinomas (LADCs) can be used for the establishment of preclinical models that can recapitulate multiple features of the original tumors and enable the determination of drug sensitivity.
Methods
Targeted sequencing was performed with hybrid-capture-based targeted NGS. PDOs were established using previously described culture methods. PDO drug-sensitive tests were performed 48 h after plating with a dilution series of drugs. Cell viability was assayed 4 days after drug incubation. Normalized results were used to calculate IC50 values in GraphPad Prism 7.0 software.
Results
We report the case of a 76-year-old man with a resectable stage IIIA LADC involving a novel LRRTM4–ALK fusion, which was predicted by the results of PDO drug tests to be sensitive to crizotinib and ceritinib.
CT showed a right lower-lobe mass (abutting the pleura, spiculated margins, largest dimension 3.2 cm). 18FDG-PET/CT scanning showed the same mass with a SUVmax of 4.2. No enlarged lymph nodes or distant metastatic lesions were observed. Pathological diagnosis was LADC with metastasis at lymph-node stations 7 and 11. The tumor was staged as pT2aN2M0 (stage IIIA). NGS reported a novel fusion gene, LRRTM4–ALK. Immunohistochemistry with the Ventana anti-ALK D5F3 antibody showed strong, diffuse expression of ALK in the cytoplasm of tumor cells. The results of the drug-sensitive test performed on successfully-cultured PDO that is confirmed by histology and genetic recapitulation were: IC50 for ceritinib was 0.87 μM, and the values for crizotinib (0.71 μM) and for brigatinib (0.96 μM) did not differ significantly from those of the positive controls (EML4–ALK-fusion-positive organoids), but they did differ from those of negative controls (ALK-fusion-negative organoids).
After the stage ⅢA patient underwent R0 resection and experienced pleural effusion (with tumor cells that had the LRRTM4–ALK mutation), we chose adjuvant therapy as oral crizotinib (250 mg, twice daily). Pleural effusion did not recur, and no further notable events occurred during the remaining 6 months of this study.
Conclusion
Although IHC is a standard and accessible approach for the identification of ALK-positive disease in the clinical setting, it is also advisable to identify fusion partners prior to the selection of target therapy. No other oncogenic mutation was detected in this patient, and we speculated that this novel LRRTM4–ALK fusion served as the driver mutation for the patient’s cancer. Our results suggest that ALK tyrosine-kinase inhibitors might be effective for the treatment of tumors with this novel fusion gene.
-
+
P92 - Mesothelioma, Thymoma and Other Thoracic Malignancies - Misc. Topics (ID 269)
- Event: WCLC 2020
- Type: Posters
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P92.01 - Genetic Landscape and Potential Therapy Regimen of Thymic Tumor (ID 1685)
00:00 - 00:00 | Presenting Author(s): Naixin Liang
- Abstract
Introduction
Thymomas and thymic carcinomas, which are rare epithelial tumors arising from the thymus gland, are the most common tumors of the anterior mediastinum. The National Comprehensive Cancer Network guidelines recommend resection followed by adjuvant platinum-based chemotherapy for resectable tumors. However, the outcomes for thymic tumors are poor with no regimen showing a consistent benefit. To investigate the possibility of targeted therapy for thymic tumor patients, a deeper understanding of the genetic basis is required.
Methods
We retrospectively evaluated our database and identified 36 patients of thymic tumor in which 12 of patients were thymomas . All the patients were detected by hybridization capture-based NGS 1021-gene panel sequencing with tumor tissue, peripheral blood and hydrothorax.
Results
We analyzed the genetic profiling of the 36 Chinese patients. The most frequently mutated genes were TP53 (11/36), followed by CDKN2A (6/36), BAP1 (5/36), BRD4 (4/36), and KIT (4/36). The common mutation types of TP53 and CDKN2A were single nucleic acid variation (SNV) and copy numbers variation (CNV). 16 of patients were detected targeted gene mutation. The common targeted mutation were CDKN2A(6/16), EGFR (2/16), FBXW7(2/16), KIT(2/16), and PIK3CA (2/16) as shown in Figure 1. CDK4/6 inhibitor like palbociclib may be a consideration targeted therapy regimen. Then, the genetic profiling of thymomas and thymic carcinomas was compared. The proportion of TP53 in thymic carcinomas was higher than thymomas, and proportion of CDKN2A was similar in two groups. However, no significant difference was found in two groups. The media number of nonsynonymous mutation detected was 4 of all patients, and thymomas and thymic carcinomas were 2 and 5, respectively. This may be indicated a poor survival in immunotherapy.
Conclusion
In conclusion, we identified genetic mutations comprehensively and provide predictive implications for thymic tumor patients. 44.4% thymic tumor patients of chinese were detected targeted mutation and 37.5% of them was CDKN2A mutation, which suggested that CDK4/6 inhibitors will be a consideration treatment regimen for Chinese patients.
