Virtual Library
Start Your Search
Si-yang Liu
Author of
-
+
JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)
- Event: WCLC 2019
- Type: Joint IASLC-CSCO-CAALC Session
- Track:
- Presentations: 2
- Moderators:Chunxue Bai, Tony Mok, Yi-Long Wu, Qing Zhou, Nan Wu
- Coordinates: 9/07/2019, 07:00 - 11:15, Toronto (1985)
-
+
JCSE01.16 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 3430)
07:00 - 11:15 | Author(s): Si-yang Liu
- 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. -
+
JCSE01.23 - Specific TP53 Mutation Subtypes as Biomarker for Response to PD-1/L1 Blockade Immunotherapy in NSCLC (ID 3437)
07:00 - 11:15 | Author(s): Si-yang Liu
- Abstract
Abstract
Background
Although TP53 co-mutation with KRAS have been proved to have predictive value for response to PD-1/L1 blockades, not all TP53 mutations are equal in this context. TP53 subtypes as independent factors to predict the response to PD-1/L1 blockade have not yet reported.
Methods
We performed an integrated analysis on the multiple-dimensional data types including genomic and clinical data from cohorts of NSCLC public (240 from MSK database) and local databases (224 patient with PD-L1 IHC score, 1986 NSCLC with TMB data). Durable clinical benefit (DCB) was defined as partial response/stable disease that lasted more than 6 months.
Results
The presence of mutant TP53 was associated with longer median progression free survival (mPFS) in NSCLC taking PD-1/L1 blockade therapy compared with TP53 wild-type group in the MSK-cohort (4.3 vs2.6 months, P=0.0027, HR=0.6409, 95%CI, 0.49 to 0.88). TP53 frameshift seemed to predict longer mPFS (6.6 months, P=0.0159, HR= 0.41, 95%CI, 0.26 to 0.65) than TP53 wild-type, TP53 missense (mPFS=4.27 months, P=0.17) and TP53 nonsense status (mPFS=2.7 months, P=0.002).NSCLC with TP53 frameshift mutation had a 52.9% rate of DCB, which was higher than TP53 missense (34.4%) and nonsense (21.1%) group. Besides, in the MSK cohort, five of six patients with TP53 truncated mutation in proline-rich (PR) domain (residues 58--101) achieved DCB, and one patient achieved 5.5 months of PFS and did not progress. Fractions of PD-L1 low-positive (1% - 49%) and PD-L1 high-positive (≥50%) tumors between each TP53 mutation subtype and wild-type groups are analyzed based on local data. The TP53 mutation rate was significantly higher in NSCLC with PD-L1 score >50% (P=0.004). But NSCLC with TP53 frameshift showed lower fractions of PD-L1 high-positive (12.5%, 2/16) compared with TP53 missense group (27.5%, 33/120) and TP53 nonsense group (25.8%, 8/31). PD-L1 low-positive rate is also lower in TP53 frameshift group (25.0%, 4/16) than TP53 missense (30.8%, 37/120) and nonsense group (29.0%, 9/31). Among 1986 NSCLC patients with TMB data, each TP53 mutation subtype is associated with significantly higher TMB than TP53 wildtype, especially among NSCLC with TP53 truncated mutation in PR domain (median TMB= 9 mut/Mbs). But no significant difference was found between TP53 mutation subtypes in TMB.
Conclusion
Our study demonstrated heterogeneity among TP53 mutations in predicting the response to PD-1/L1 blockade therapy. TP53 frameshift mutation may contribute to better PD-1/L1 blockade therapy response beyond PD-1/L1 IHC status. And the truncated TP53 mutation in PR domain may contribute to DCB.
-
+
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
-
+
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): Si-yang Liu
- 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.
-
+
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
-
+
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): Si-yang Liu
- 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.
