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Han Han-Zhang
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 3
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-18 - Integrated Genomic and DNA Methylation Analyses of Non-Small Cell Lung Cancer Patients with Brain Metastases (ID 1570)
09:45 - 18:00 | Author(s): Han Han-Zhang
- Abstract
Background
Brain metastases (BM), with a dismal prognosis, are a common and lethal complication of non-small cell lung cancer. Approximately, 10% patients present with BM at their initial diagnosis. Although, surgery and/or radiation therapy remain to be the mainstay treatment, targeted therapies are finding increasing application in treating BM. However, due to the very limited accessibility of brain lesions, its genomic and epigenomic landscape remain elusive.
Method
Capture-based targeted sequencing for somatic mutation profiling was performed on 27 treatment-naïve advanced NSCLC patients with paired lung primary and BM lesions using a pane consisting of 520 cancer related genes. DNA methylation analyses was performed on same samples using a DNA methylation panel consisting of 100,000 CpG sites.
Result
Collectively, we identified 370 (291 SNVs+Indels, 78 CNVs and 1 rearrangement) and 574 (245 SNVs+Indels, 327 CNVs and 2 rearrangements) mutations from lung primary lesions and BM, respectively. Among them, 242 mutations were shared; 128 were lung primary-specific and 332 were BM-specific. Among the BM specific mutations, a majority of them (82%, 272/332) were copy number variations (CNVs). Only 16% of CNVs were shared by lung lesions and BM. The concordance for SNVs and indels were much higher-54% between the two sources of tissues. Furthermore, we observed a much higher concordance rate (79%) in TP53 and classic lung cancer driver genes than other genes (p<0.001), indicating that they might be stem mutations. Next, we performed pathway analysis of genes that were only mutated in BM and revealed an enrichment of genes participating in PI3K-AKT and focal adhesion pathways. We also compared tumor mutation burden (TMB) between them and revealed comparable TMB (p=0.1). Our DNA methylation analysis revealed distinct methylation patterns with 268 blocks that are significantly differentially methylated between primary lung lesions and BM. Among them, 211 blocks were hypermethylated in BM and the remaining 57 blocks were hypermethylated in lung lesions. These blocks were enrichment in genes participating in cell adhesion, Rap1 signaling and calcium signaling pathways.
Conclusion
We revealed diverse somatic mutation and DNA methylation profiles between lung primary lesions and BM. BM had significantly more unique CNVs. A great concordance was observed for classic lung cancer driver genes and TP53. Our study provided a comprehensive view of genomic and DNA methylation profiling for lung primary lesions and BM, paving the avenue for the development of targeted therapies for treating BM.
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P1.01-20 - The Association Between BRAF Mutation Class and Clinical Features in BRAF-Mutant Chinese Non-Small Cell Lung Cancer Patients (ID 1482)
09:45 - 18:00 | Author(s): Han Han-Zhang
- Abstract
Background
BRAF mutations, occurring in 2-4% NSCLC patients, can be classified into 3 classes based on signaling mechanism and kinase activity: V600-mutant RAS-independent kinase activating monomers (class I), RAS-independent kinase activating dimers (class II) and RAS-dependent kinase inactivating heterodimers (class III). The association between functional classes and clinical features of Chinese NSCLC patients remain elusive.
Method
Sequencing data of either plasma or tissue samples obtained from 8,405 Chinese (Stage I-IV NSCLC) patients were retrospectively analyzed to screen for BRAF mutations. Of the patients with BRAF mutations, 79% (188/238) were diagnosed with adenocarcinoma,7.6% with squamous cell carcinomas (SCC) and the remaining patients were either adenosquamous carcinoma or large cell carcinoma.
Result
BRAF mutations were detected in 238 patients, revealing a prevalence of 2.8%. Among them, 32% (75/238), 21% (51/238) and 13% (31/238) had class I, II and III mutations, respectively. The remaining 35% (81/238) had other BRAF mutations. V600 (32%, 75/238) and G469 (13%, 32/238) were the 2 most predominant mutations. BRAF mutations, when considered collectively, including non-class I-III mutations, were more likely to occur in males (p<0.01). However, class I mutations have a female predominance (p=0.003); whereas, class II mutations showed a trend of male predominance (p=0.09) and class III had no gender preference (p=0.22). We also revealed no association between histology types and the class of BRAF mutations. Next, we investigated co-occurring classic lung cancer driver mutations in this cohort and revealed that patients with class II and III mutations were more likely to have concurrent KRAS mutations (p=0.001). We also compared the overall survival (OS) of chemotherapy-treated patients and revealed comparable OS among the 3 groups.
Conclusion
Our study revealed a 2.8% BRAF mutation rate in Chinese NSCLC patients. Our data also showed a male predominance when all BRAF mutations were considered collectively, and a female predominance for class I mutations. Furthermore, patients with BRAF V600E is less likely to have concurrent KRAS mutations.
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P1.01-91 - Clinical Outcomes of Various Resistance Mechanisms of Osimertinib in Chinese Advanced Non-Small Cell Lung Cancer Patients (Now Available) (ID 1264)
09:45 - 18:00 | Author(s): Han Han-Zhang
- Abstract
Background
Increasing efforts have been invested in elucidating the resistance mechanisms to osimertinib. Major resistance mechanisms include but not limited to acquired EGFR mutations, predominantly C797, mutations in bypass pathways and small cell lung cancer (SCLC) transformation. However, no study has comprehensively investigated clinical outcomes of various mechanisms of resistance.
Method
103 T790M positive advanced Chinese non-small cell lung cancer (NSCLC) patients who progressed on 1st generation EGFR-TKI were enrolled. Targeted sequencing, using a panel consisting of 168 lung cancer related genes, was performed on paired plasma samples collected prior to osimertinib and after the development of disease progression (PD) to profile mutation spectrum. 7 patients with no mutation detected at PD were excluded from analyses.
Result
Major acquired mutations included 25% EGFR mutations, predominantly C797 and L792, 16% MET amplification, 8% TP53 mutations, 4% KRAS mutations, 4% RET fusions, 4% ERBB2 amplification and 6.25% RB1 mutations. Acquired RB1 mutation may indicate the possibility of SCLC transformation. Approximately, 30% of patients with no known resistance mechanisms at PD. In this cohort, we had 61 patients with 19 deletion and 35 patients with EGFR L858R prior to the initiation of osimertinib. We revealed patients with 19del acquired more mutations (p=0.014) and were more likely to acquire mutations in MAP/PI3Kpathway (p=0.04) and TP53 at PD (p=0.021). On the other hand, acquired ERBB2 amplifications were only detected in L858R-mutant patients (p=0.047). Furthermore, 36 patients preserved T790M and 60 patients lost T790M at PD. Our data revealed patients retaining T790M, often associated with activation of bypass signaling pathways or continued EGFR activation through tertiary mutations, had a longer progression-free survival (PFS) (p=0.047) and overall survival (OS) (p=0.04) comparing to patients with T790M loss, often with diverse and EGFR-independent mechanisms. We also show that patients with acquired C797S had significantly longer PFS (p=0.031), while patients with acquired MET amplifications had significantly shorter PFS (p=0.033).
Conclusion
Collectively, we revealed differential clinical outcomes associated with various resistance mechanisms, representing an important step in advancing the understanding of resistance mechanisms of osimertinib.
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-31 - Clinicopathological Features and Genomic Profiling of Pulmonary Blastoma with High-Grade Fetal Adenocarcinoma Component (ID 1615)
09:45 - 18:00 | Author(s): Han Han-Zhang
- Abstract
Background
Pulmonary blastoma (PB) is a very rare subtype of sarcomatoid carcinoma with typically low-grade fetal lung adenocarcinoma (L-FLAC) and primitive mesenchymal components. Very few cases of PB contain the high-grade fetal lung adenocarcinoma (H-FLAC) component. The present study was designed to investigate the clinicopathological characteristics and the genomic heterogeneity of epithelial and mesenchymal in PB with H-FLAC.
Method
Three surgically resected PB cases with H-FLAC component were enrolled in the study. The epithelial of the first case consisted of mostly H-FLAC mixed with limited amount of L-FLAC. The other two PB tumors contained pure H-FLAC and mesenchymal components. Clinic-pathologic information and prognostic data were retrospectively reviewed. Diagnostic immunohistochemistry was performed. The epithelial and mesenchymal components were macroscopically dissected to profile the genetic alterations separately using capture-based targted sequencing. A commercialized panel, consisting of 520 cancer-related genes, was used.
Result
The cells of H-FLAC components in PB showed obvious atypia with more necrosis and enteric adenocarcinoma-like morphology. The squamoid morules were absent in H-FLAC. Proliferation index of the H-FLAC components (30%-80%) was higher than that of the mesenchymal (15%-20%). No aberrant nuclear expression of β-catenin protein and missense mutation in exon 3 of CTNNB1 gene were observed in H-FLAC and all mesenchymal cells. Within a tumor, epithelial and mesenchymal components exhibited relatively comparable molecular profile. In patient 1, 4 mutations: PB1, FAT3, PTCH1 and LRP1B were shared by both epithelial and mesenchymal components. Epithelial component had additional mutations in BCOR, CTNNB1, CTCF, FAT1 and DICER1. In patient 2, 12 mutations were shared. The epithelial component had BRCA2 mutations and the mesenchymal component had mutations in CREBBP, ALK, DNMT3A, ASXL2, MYCN and RICTOR. Patient 3 had 6 shared mutations. The epithelial component had an additional mutation in KAT6A and the mesenchymal had an additional mutation in APC. Furthermore, both epithelial and mesenchymal components showed significant interpersonal heterogeneity. In other words, the mutation spectrum of the same component (epithelial or mesenchymal )varies significantly among patients. Surprisingly, not a single common mutation was found in the same component among the 3 patients.
Conclusion
Collectively, we observed heterogeneity between epithelial and mesenchymal components of the same tumor. In addition, we also observed significant inter-personal heterogeneity of the same component among different patients. Parallel detection of genetic abnormalities in epithelial and mesenchymal could provide further evidence to clarify the histopathological difference and molecular heterogeneity in pulmonary blastoma.
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-11 - Genomic Profiling of Pulmonary Lymphoepithelioma-Like Carcinoma (PLELC) (ID 1520)
10:15 - 18:15 | Author(s): Han Han-Zhang
- Abstract
Background
PLELC, a rare and distinct type of primary lung cancer, is characterized by Epstein-Barr virus (EBV) infection. Histologically, it resembles undifferentiated nasopharyngeal carcinomas (NPC). Only a few hundred cases have been reported since its discovery. Due to the extreme rareness, its genomic landscape remains elusive.
Method
Tissue samples of 27 PLELC patients (13 males and 14 females) with various stages (Ib to IV) were subjected to targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome.
Result
Collectively, we identified 184 somatic mutations spanning 109 genes, including 107 SNVs, 12 insertions or deletions (INDELs) and 65 copy-number amplifications (CNAs). Approximately, 50% of patients had CNAs. One patient had no mutation detected from this panel. Except for 2 patients, 1 with HER2 amplification and another with KRAS mutation, no other classic NSCLC driver genes were detected. The most frequently mutated genes were CCND1, TP53, DAXX and NFkBIA, occurring in 30%, 26%, 22% and 22% of patients, respectively. Interestingly, 78% (21/27) patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in epigenetics-related genes. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of PLELC with lung adenocarcinoma and EBV positive NPC. The frequency of TP53 mutations was significantly higher in lung adenocarcinoma (68% vs 26%, p=0.021). Comparing to NPC, PLELC had significantly more mutations in epigenetic regulators. TMB analysis revealed a median TMB of 1.6/Mb, significantly lowered than lung adenocarcinomas (p<0.01). We also assessed PD-L1expression and revealed that 67% had an overexpression of PD-L1. Interestingly,TP53-mutant patients were more likely to associated low PD-L1 expression (p<0.01).
Conclusion
In this study, we elucidated a distinct genomic landscape associated with PLELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for PLELC.
