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Junyi Ye
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EP1.12 - Small Cell Lung Cancer/NET (ID 202)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.12-10 - Molecular Characterization of NSCLC-Like and SCLC-Like Subsets in Chinese Pulmonary Large-Cell Neuroendocrine Carcinoma (LCNEC) (Now Available) (ID 1341)
08:00 - 18:00 | Author(s): Junyi Ye
- Abstract
Background
LCNEC is an aggressive, biologically heterogenous carcinoma which can be molecularly characterized as SCLC-like and NSCLC-like. Accurate distinction of molecular subset is of major clinical relevance since it may guide treatment choices in LCNEC. Here we determined the genomic characteristics of the two LCNEC subsets in a Chinese cohort to clarify their correlations with traditional lung cancer histologies.
Method
FFPE samples from 31 LCNECs were sequenced using a 520-cancer-related gene panel, with an average sequencing depth of 1385X. Comparative mutational analysis was conducted between NSCLC-like LCNECs from our cohort and adenocarcinomas from TCGA dataset
Result
Despite similar clinical features in terms of stage and age at diagnosis, NSCLC-like (42%, 13/31) and SCLC-like (32%, 10/31) subsets from LCNEC displayed distinct molecular characteristics. NSCLC-like subset harbored significant higher mutation frequencies of STK11, KEAP1 and FAT3 (53.8%, 38.5% and 38.5%, p=.007, .046 and .046), while SCLC-like subset was characterized by highly mutated RB1 (100%, p<.001) and PTEN (50%, p=.007). Compared with TCGA adenocarcinomas, NSCLC-like LCNEC displayed more frequent mutations in TP53, STK11, APC, KMT2D and SMARCA4 (76.9%, 53.8%, 30.8%, 30.8% and 23.1%; p=.043, .004, .045, .005 and .049). In addition, potential targetable alterations were present in 46.2% (6/13) pts of NSCLC-like subset. For those advanced stage pts, 2/5 NSCLC-like and 5/5 SCLC-like pts received relevant chemotherapy according to their molecular characteristics. The clinical outcomes of these pts are still under follow-up.
Conclusion
This study demonstrates the distinct molecular features between NSCLC-like and SCLC-like subsets, and highlights the predominant genomic similarity and separate entities between NSCLC-like LCNEC with adenocarcinoma. Given the evidence that genomic profiling may aid in informing treatment decisions for pts with LCNEC, our study indicates that, based on accurate molecular typing, 46.2% NSCLC-like pts may benefit from potential targeted therapy and the rest of them may be more suitable to receive NSCLC-chemotherapy
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OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
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OA03.05 - Characterization of Genomic Alterations in Chinese LCNEC and SCLC via Comprehensive Genomic Profiling (Now Available) (ID 1486)
13:30 - 15:00 | Author(s): Junyi Ye
- Abstract
- Presentation
Background
LCNEC and SCLC are aggressive neuroendocrine carcinomas with overlap in clinical, histopathologic, morphologic and genomic features. Differential molecular features between the two subtypes have not been well elucidated, contributing the uncertainty for optimal clinical strategy for each subtype. Here we interrogated the genomic characteristics in LCNEC as compared to SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids via comprehensive genomic profiling.
Method
FFPE samples from 31 LCNECs, 35 SCLCs, 14 carcinoids and 22 atypical carcinoids were sequenced in a CLIA-certified sequencing laboratory using 520-cancer-related gene panel, with an average sequencing depth of 1385X.
Result
Comparative mutational analysis revealed that both LCNEC and SCLC sub-cohorts displayed higher rate of TP53 alterations than that of carcinoid (p<0.001, p<0.001). SCLC patients harbored more RB1 and PIK3CA mutations than LCNECs (p<0.001, p=0.014) and carcinoids (p<0.001, p=0.018). In addition, mutation frequencies of LRP1B, FAT1, PRKDC, PIK3CA, NOTCH1, SPTA1 and EPHA3 in SCLC were significantly higher than that in carcinoid. Mutations in TP53 and RB1 occurred concurrently in 83% (29/35) SCLC patients, whereas in only 32.3% (10/31) LCNECs.（Fig.1） We further investigated the distribution of mutations across KEGG pathways and found that mutation frequencies in both HIF-1 and Notch signaling pathways were lower in LCNEC than SCLC (p=0.032, p=0.025). Copy number variation (CNV) analysis revealed that LCNEC and SCLC had comparable CNVs which were significantly higher than carcinoid (p<0.001, p<0.001) and atypical carcinoid (p=0.010, p=0.028). TMB analysis also revealed a comparable TMB status of LCNEC (12.7/Mb) and SCLC (11.9/Mb), and relatively lower TMB in both carcinoid (2.4/Mb, p<0.001, p<0.001) and atypical carcinoid (5.6/Mb, p=0.003, p=0.009) than LCNEC and SCLC.
Conclusion
We demonstrated the differential genomic characteristics in the four subtypes of neuroendocrine carcinomas. Compared with SCLC, LCNEC has lower mutation frequencies in RB1, PIK3CA, as well as HIF-1 and Notch signaling pathways. In addition, LCNEC and SCLC had comparable CNV and TMB status, which significantly higher than that of carcinoids and atypical carcinoid.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- 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): Junyi Ye
- 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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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-88 - Molecular Alterations in Cerebrospinal Fluid Predict Clinical Outcomes of Central Nervous System Metastases in Lung Cancer (ID 1511)
10:15 - 18:15 | Author(s): Junyi Ye
- Abstract
Background
Cerebrospinal fluid (CSF) has been proven as good media for genetic profiling of central nervous system (CNS) metastases. However, the association of genetic alterations in CSF and clinical outcomes remains elusive.
Method
A total of 94 lung cancer patients with CNS metastases underwent lumbar puncture. Circulating tumor DNA were extracted from CSF and profiled by next-generation sequencing. The effect of genetic alterations in CSF on survival and treatment outcomes were evaluated.
Result
The most common genes seen in CSF were EGFR, TP53, MET, CDKN2A, MYC, NTRK1 and CDK6. Kaplan-Meier survival analysis indicated that CDK4, CDK6, FGFR1, MET and MYC alterations, which were also characterized by more copy number changes, were associated with poor survival. Multivariate analysis found only MET (HR, 2.01; 95% CI, 1.15 to 3.52) and MYC alterations (HR, 2.31; 95% CI, 1.27 to 4.21) were correlated to poor OS. Forty-two patients harbored high n-CNVs (defined as the number of genes with copy number variations >2) while 50 patients carried low n-CNVs (defined as the number of genes with copy number variations <=2). Median overall survival (OS) of patients with high n-CNVs in CSF was 14.9 months (95% CI, 9.2 to 25.8 months), significantly shorter than those with low n-CNVs (21.6 months, 95% CI, 17.9 months to not reached (NR); HR, 1.9; 95% CI, 1.11 to 3.24; P=0.016). Patients with high n-CNVs and MET and MYC CNVs (copy number variations) were associated with the poorest OS. Osimertinib significantly prolonged OS only among patients with high n-CNVs (with vs. without osimertinib, 25.8 vs. 9.2 months; P=0.004). Among T790M negative patients, high n-CNVs seemed to positively associate with better response to osimertinib (OS with vs. without osimertinib, 23 vs. 7.8 months; P=0.058). Further analysis indicated that EGFR and FGFR1 CNV were the most significant factors associated with OS benefit from osimertinib among the high n-CNVs group (P=0.014; P=0.02). TP53_LOH and Wnt pathway alterations were significantly more prevalent in the high n-CNVs group than in the low n-CNVs group (P=0.016, P=0.006). With regard to clinical characteristics, higher performance status score (HR, 2.06; 95% CI, 1.38 to 3.07; P=0.0004) and occurrence of extracranial metastases (HR, 3.21; 95% CI, 1.25 to 8.24; P=0.015) suggested poor OS.
Conclusion
While genetic profiles in CSF, like high n-CNVs as well as MET and MYC CNV were related to poor prognosis, patients with high n-CNVs, especially those with EGFR or FGFR1 CNV might benefit more from osimertinib, further supporting CSF as liquid biopsy of CNS metastases in lung cancer.
