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Jian Su
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JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)
- Event: WCLC 2019
- Type: Joint IASLC-CSCO-CAALC Session
- Track:
- Presentations: 1
- Moderators:Chunxue Bai, Tony Mok, Yi-Long Wu, Qing Zhou, Nan Wu
- Coordinates: 9/07/2019, 07:00 - 11:15, Toronto (1985)
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JCSE01.16 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 3430)
07:00 - 11:15 | Author(s): Jian Su
- Abstract
Abstract
Background
Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC).
Methods
We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs).
Results
290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs.
Conclusion
Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment.
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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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P1.01-85 - Treatment for Advanced NSCLC with EGFR Mutations and De Novo MET Amplification/Overexpression (ID 2190)
09:45 - 18:00 | Author(s): Jian Su
- Abstract
Background
Combination of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitors (TKIs) are effective in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation and acquired MET-amplification. However, there are few reports about treatments of patients with EGFR mutation and de novo MET amplification/ overexpression.
Method
We retrospectively screened 88 consecutive advanced NSCLC patients harboring EGFR mutation and de novo MET amplification/overexpression at Guangdong Provincial People's Hospital of China from January, 2014 to December, 2018. Among them, a total of 41 patients receiving first-line targeted therapy were included and stratified into EGFR-driven, MET-driven and EGFR/MET co-driven groups illustrated respectively in Table 1.
Table 1. Classification of advanced NSCLC with EGFR mutation and MET overexpression/amplification. Group EGFR mutation MET overexpression/amplification Response to first-line TKI EGFR-driven Exon 19 deletion or exon 21 L858R mutation (tested by next generation sequencing (NGS) or amplification refractory mutation system (ARMS) or polymerase chain reaction (PCR)). Overexpression: strong intensity staining was in more than 50% of tumor cells (tested by immunohistochemistry (IHC)).
Amplification: CNG≥5, or MET/centromeric portion of chormosome 7 ratio≥2.2, with an additional criterion of focal amplification was in more than 10% of tumor cells (tested by fluorescence in situ hybridization (FISH)).
PFS＞3 months, best response is complete response (CR)/partial response (PR)/stable disease (SD); not receiving MET-TKIs in later-line treatment, or had MET-TKIs but PFS≤3 months. MET-driven PFS≤3 months, receive MET-TKIs monotherapy or MET-TKIs plus EGFR-TKIs in later-line treatment and PFS＞3months, or PFS≤3 months，but with acquired mechanism to MET. EGFR/MET co-driven Response to EGFR-TKIs at least one time, receiving EGFR-TKIs plus MET-TKIs in later-line treatment and PFS＞3 months, or PFS≤3 months, but with acquired mechanism to MET.
Result
Among enrolled patients, 40 of them received first-line first-generation EGFR-TKIs while 1 treated with MET-TKI. Twenty-eight received targeted therapy in the later-line treatments after resistance. Thirty-one (75.6%), 5 (12.2%) and 5 (12.2%) patients were classified into EGFR-driven, MET-driven and EGFR/MET co-driven groups. Median progression-free survival (PFS) was 12.1, 1.0 and 5.3 months respectively in the first-line setting. Objective response rates were 58.1%, 0.0% and 20.0% (P=0.028) respectively. Among 28 patients receiving subsequent targeted therapies, 58.1% (18/31), 100.0% (5/5) and 100.0% (5/5) were EGFR-driven, MET-driven and EGFR/MET co-driven respectively. Median PFS was 7.0, 6.5 and 10.3 months for the EGFR-driven group receiving subsequent EGFR-TKIs, the MET-driven group receiving MET-TKIs with or without EGFR-TKIs, and the EGFR/MET co-driven group treating with EGFR-TKIs plus MET-TKIs respectively (P=0.399). Also, no significant difference was observed in overall survival for these 28 patients (33.8 vs. 11.8 vs. 27.9 months, P=0.098).
Conclusion
Subsequent individualized targeted therapy or co-targeted therapies might favor clinical outcomes for both MET-driven and EGFR/MET co-driven patients with advanced NSCLC after resistance to first-line EGFR-TKIs.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-13 - EGFR Amplification Mediates Resistance to Third-Generation EGFR TKIs and in Vitro Validation of Combination Strategies to Overcome Resistance (Now Available) (ID 762)
09:45 - 18:00 | Author(s): Jian Su
- Abstract
Background
As a concurrent genomic alteration in EGFR-mutant NSCLC, whether all detected EGFR amplification serve as a driver of resistance to third-generation EGFR-TKIs remains controversial. Furthermore, which subtype of EGFR amplification-mediated resistance is actionable has been poorly elucidated. Our study aims to investigate the driver role of EGFR amplification in mediating resistance to third-generation EGFR TKIs and potential strategy to overcome resistance mediated by EGFR amplification.
Method
44 resistance samples from 32 patients who experienced disease progression from to a third-generation EGFR TKI abivertinib in Guangdong Lung Cancer Institute underwent NGS-based genomic profiling (data cutoff: october 30, 2018). FISH analysis of tissue samples from patients with EGFR amplification detected by NGS was performed. Different alleles of EGFR over-expressed PC9GR cell line models was established. Cell proliferation assay and western blot were performed to determine the sensitivity of these cell lines to third-generation EGFR TKI abivertinib and osimertinib, and to screen for potential strategies to overcome resistance mediated by EGFR amplification.
Result
Upon abivertinib progression, 27 patients provided plasma samples (six patients also provided paired samples from the progression sites) and five patients only provided samples from the progression sites for NGS. A heterogeneous landscape of resistance to abivertinib was observed with EGFR amplification being the most frequent, observed in 11 (34%) patients (Figure 1) , and considered a putative resistance mechanism in seven (22%) patients. FISH analysis of 3 patients who had available tissue samples further confirmed the presence of EGFR amplification detected by NGS. We established 3 different EGFR-overexpressed PC9GR cell lines by lentivirus transfection of Del 19 EGFR, Del19/T790M EGFR and wild-type EGFR. Among them, introduction of wild-type EGFR resulted in significantly loss of cellular sensitivity to abivertinib and osimertinib under EGF stimulation, but retains sensitivity to combination treatment of abivertinib and afatinib. In addition, abivertinib plus nimotuzumab also demonstrated preliminary inhibitory effect on phosphorylation of EGFR downstream pathway in wild-type EGFR overexpressed PC9GR. Finally, abivertinib plus nimotuzumab or afatinib in is effective and tolerable in treating 2 patients who developed EGFR amplification-mediated resistance to abivertinib. One of them experienced a long-term benefit from the combination treatments with an overall progression-free survival of 23 months.
Conclusion
Wild-type EGFR amplification mediates resistance to third-generation EGFR TKIs and could be overcome by combination treatments. Future studies need to more precisely determine the presence of wild-type EGFR amplification in third-generation EGFR TKIs resistant setting.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-32 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 289)
10:15 - 18:15 | Author(s): Jian Su
- Abstract
Background
Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC).
Method
We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs).
Result
290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs.
Conclusion
Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-36 - Identification of Genomic Features in Tumor-Derived Organoids from Resectable NSCLC (Now Available) (ID 1275)
10:15 - 18:15 | Author(s): Jian Su
- Abstract
Background
Patient-derived tumor organoids (PDOs) have recently emerged as robust preclinical models. However, few studies were published on lung cancer organoid. This study aims to describe the genomic characteristics of PDOs as a disease model of NSCLC.
Method
Samples from resected tumors were collected for organoid culture. DNA was extracted from tumor, organoids and matched PBLs samples and sequenced with whole-exome sequencing.
Result
Seven pts were enrolled, including six LUAD (86 %) and one LUSC (14 %). A total of 1625 somatic mutations were detected in tumors. TP53 (71%), EGFR (43%), and KRAS (29%) mutated most frequently in this cohort, and occurred with frequencies of (57%), (43%) and (29%) in matched PDOs. Based on gene catalog related to lung cancer, the median consistency between tumor and organoid was 87 % (0% ~ 100%). Sample purity was significantly positively related to the variant allele frequency (r=0.82, P=0.0005), and may result in the inconsistence between paired samples. Besides, number of driver gene showed no difference between first- and second-generation organoids.
Conclusion
This study firstly revealed genomic landscape of NSCLC organoid. In spite of heterogeneity, driver mutations presented high consistency between PDOs and paired tumor. Further study is continuing to evaluate outcomes from patients enrolled.
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P2.17 - Treatment of Early Stage/Localized Disease (ID 189)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.17-16 - Genomic Heterogeneity and Evolutionary Trajectory in Multifocal Synchronous Lung Cancer (ID 2082)
10:15 - 18:15 | Author(s): Jian Su
- Abstract
Background
Multifocal synchronous lung cancer (MSLC) presented as coexistence of multiple tumor lesions that share an identical germline genetic background and environmental exposure in individual patients. Along with the improved resolution of cross-sectional imaging, multiple types of ground glass opacities (GGOs) have been detected in increasing frequency as well as solid nodules even in an unique patient. However the molecular origins and relationships among the synchronous lesions remain unclear.
Method
10 treatment-naive MSLC patients were retrospectively collected while 25 tissue samples were performed whole exosome sequencing. In addition, we constructed phylogenetic trees to estimate the ancestral relationships of individual foci.
Result
79 somatic mutations in average were identified in MSLC tissues. The most significant mutated gene EGFR has been detected in 10 samples from 7 patients in our cohort. Tumor mutation burden as was significantly higher in IAC lesions than AIS/MIA ones. The mutation spectra of single-nucleotide variations (SNVs) were fairly consistent across the same histologic type even from different patients. Compared to AIS/MIA, IAC samples displayed a preponderance of A>T/T>A transition (Ti) while less frequency of A>C/T>G transversion (Tv). However few share mutations were located by pair of lesions in individual patients. Distinct genomic profiles suggested all were primary tumours. WNT pathway was enriched in AIS/MIA lesions exclusively while IAC appeared TGFβ/TP53 pathway mutation associated with cell proliferation and apoptosis.
Conclusion
Even in the same individual patient different lung cancer lesions may be driven by distinct genomic profiles so that each presented its own evolutionary trajectory. A deeper understanding of tumorigenesis is still in need to improve the diagnosis and treatment of MSLC.
