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Tao Jiang
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.11 - Distinct Mutational Landscape and Evolutionary Trajectories of Brain Metastasis and Liver Metastasis in Lung Adenocarcinoma (ID 9282)
16:55 - 17:00 | Presenting Author(s): Tao Jiang
- Abstract
- Presentation
Background:
Distant metastases confer mainly resistance to improving the long-term survival of patients with lung cancer. The major reason was that the genetic heterogeneity and evolutionary patterns between primary tumor and their distant metastases or among distinct metastatic sites remains poorly understood. The current study aimed to depict the distinct mutational landscape of primary lung adenocarcinoma and their distant metastases (brain or liver) and reconstruct the evolutionary history of metastases.
Method:
Seventeen patients with primary lung adenocarcinoma and distant metastases [5 with primary lesion and matched brain metastases (BM), 6 with primary lesion and matched liver metastases (LM), 6 with sole BM] were included. All tissues (by either biopsy or surgical resection) and matched peripheral blood samples were collected before systemic treatment. We performed whole-exome (150×) and targeted 416-gene panel sequencing for these samples.
Result:
In the matched cases, the mutational landscape of primary lesions for BM was distinctly different from those for LM. Compared to the primary lesions, BM had the significantly different patterns of somatic genome alterations while LM had the similar ones. In six cases with sole BM, both intratumoral and intertumoral genetic homogeneity of BM were observed. By using a set of genes which were frequently found in the primary lesions, we can clearly segregate the copy number variations (CNV) pattern of patients with BM from those with LM. Moreover, when we performed the hierarchical clustering based on these genes, we saw clear segregation between BM and LM. Patients with BM had dramatically higher tumor mutational burden (TMB) than those with LM in both primary (P < 0.01) and metastatic lesions (P < 0.001). Significant differences in TMB were also observed between primary and metastatic lesions in patients with BM (P < 0.001) instead of LM (P > 0.05). Phylogenetic analysis showed that LM followed the liner progression whereas BM followed the parallel progression. In patients with sole BM, both intratumoral and intertumoral lesions have a monoclonal origin and descend from a common ‘metastatic precursor’.
Conclusion:
The current evidence suggested that BM had distinctly different mutational landscape from LM in lung adenocarcinoma. Patients with BM had higher TMB than those with LM. BM followed the parallel progression whereas LM followed the liner progression. Intratumoral and intertumoral lesions of BM had genetic homogeneity and originated from the same precursor. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung adenocarcinoma and distant metastases.
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MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M.I. Abdul Wahid, Martin Reck
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 313 + 314
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MA 11.07 - Exosomes-Transmitted MicroRNAs Promote EGFR-TKIs Resistance in NSCLC by Activating PI3K/AKT Signaling Pathway (ID 9446)
11:40 - 11:45 | Author(s): Tao Jiang
- Abstract
- Presentation
Background:
Acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) resistance is a major factor contributing to targeted therapy failure in EGFR mutant non-small cell lung cancer (NSCLC), among which T790M mutation accounts for 50-60%. Emerging evidence has shown that as mediators between cells, exosomes shed by drug resistant cancer cells have the ability to horizontally transfer drug resistant phenotype to drug sensitive cells, which has been described as an important mechanism of dissemination of drug resistance. However, whether exosomes derived from EGFR-TKIs resistant NSCLC cells harboring T790M mutation could transfer resistance to sensitive cells has not been understood and the potential mechanism also remains unknown.
Method:
Exosomes were isolated from supernatants of T790M mutant NSCLC cell line (H1975) and characterized by transmission electron microscopy, nanosight and western blot. Their potential roles in mediating gefitinib resistance in sensitive cell line (PC9) were investigated in vitro and in vivo. Cell viability and the effects of exosomes on downstream signaling pathways were analyzed by CCK-8 assays and western blot. The roles of exosomes in regulating gefitinib resistance in vivo were assessed by subcutaneous transplantation tumor model in athymic nude mice. Exosomes miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were used for exploring the underlying mechanism.
Result:
Exosomes isolated from conditioned medium of NSCLC cell lines were cup-shaped membranous vesicles with a diameter of 30-100 nm and expressed the exosomal marker CD63. Exosomes derived from H1975 could transmit gefitinib resistance to PC9 (P＜0.01) in vitro while exosomes released from PC9 cell don’t have this effect. Treatment of PC9 with H1975-derived exosomes and the inhibitor of exosomes production (GW4869) could restore gefitinib response. In vivo, the tumor volume of xenograft model of PC9 cells treated with gefitinib plus H1975-derived exosomes was significantly larger than those mice treated with gefitinib alone (P＜0.05). Furthermore, H1975 xenografts could disseminate gefitinib resistance to PC9 xenografts in the same mice. This difference disappeared by the addition of GW4869. Mechanistically, intercellular transfer of microRNAs (miR-522-3p and miR-454-3p) by exosomes disseminated gefitinib resistance through activating PI3K/AKT and MEK/ERK signaling pathways
Conclusion:
Our findings demonstrate that EGFR-TKIs resistant cells could disseminate drug resistance to sensitive cells by intercellular transfer of exosome-transmitted microRNAs and then activating PI3K/AKT and MEK/ERK signaling pathways, which reveals a novel mechanism of acquired resistance to EGFR-TKIs in NSCLC.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-045 - HER-2 Mutation Is Not a Prognostic Factor Treated with First-Line Chemotherapy in NSCLC Patients (ID 10386)
09:30 - 09:30 | Presenting Author(s): Tao Jiang
- Abstract
Background:
Human epidermal growth fator2 (HER-2) is a driver gene in non-small cell lung cancer (NSCLC), however, the effect of chemotherapy in patients with HER-2 mutation has not been studied.
Method:
HER-2 mutation was detected in 1041 EGFR/ALK/ROS1/KRAS/BRAF wild type NSCLC patient samples in Shanghai Pulmonary Hospital using ARMS method, and the mutation positive samples were confirmed by DNA sequencing. The clinicopathologic features and prognosis of the HER-2 mutation patients were analyzed.
Result:
63 samples (6.1%) were HER-2 mutation positive, and 53 samples (84.1%) were confirmed by DNA sequencing. 5(7.9%) were point mutation and 58(92.1%) were insertion mutations with 33 (52.4%) A775_G776insYVMA. Patients with A775_G776insYVMA mutation had no association with other mutations in sex, age, smoking status, and pathological types, as well as in objective response rate (ORR, 40.0% vs 28.6%, p=1.000) and progression-free survival (PFS, p=0.069). Patients with six gene wild type were matched with the 63 HER-2 mutation patients in clinicopathologic features. We found that there was no significant difference between HER-2 mutation and wild type patients in ORR (30.4% vs 29.3%, p=0.157) and PFS (7.0month vs 4.5month, p=0.086), although the PFS was longer in HER-2 mutation patients.
Conclusion:
HER-2 mutation was 6.1% in EGFR/ALK/ROS1/KRAS/BRAF wild type NSCLC patients. There was no significant difference between HER-2 mutation and wild type patients in ORR and PFS treated with first-line chemotherapy. Target therapy maybe needed to treat these patients.
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P1.03-052 - Comparing EGFR-TKI with EGFR-TKI plus Chemotherapy as 1st Line Treatment in Advanced NSCLC Patients with Both Mutated EGFR and Bim Polymorphism (ID 10516)
09:30 - 09:30 | Author(s): Tao Jiang
- Abstract
Background:
Not all advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations could get benefit from 1[st] line treatment of EGFR tyrosine kinase inhibitors (TKIs). Our previous study indicated that B-cell chronic lymphocytic leukemia/lymphoma-like 11 (Bim) deletion polymorphism was about 10% and was significantly associated with a poor clinical response to EGFR-TKIs in EGFR mutation-positive NSCLC. This retrospective study compared efficacy and tolerability of the EGFR-TKI alone versus EGFR-TKI plus chemotherapy as the 1[st] line treatment in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism.
Method:
Main included criterias were patients older than 18 years, histologically confirmed stage IIIB or IV NSCLC, EGFR mutation-positive (exon 19 deletion or 21 L858R mutation) and Bim polymorphism. Patients received gefitinib 250mg orally a day or gefitinib together with up to 4 cycles of pemetrexed/gemcitabine and platinum until disease progression or unacceptable toxic effects. The primary endpoint was progression-free survival (PFS); the second endpoint included objective response rate (ORR), overall survival (OS) and toxicity.
Result:
From June 2014 to September 2016, 65 patients were enrolled into this trial. 36 of them received gefitinib, and 29 received gefitinib plus pemetrexed/gemcitabine and platinum. Median PFS was significantly longer in EGFR-TKI plus chemotherapy-treated patients than in EGFR-TKI (7.2 [95% CI 5.35-9.05] vs 4.6 [4.01-5.19] months; p=0.008). The ORR was significantly lower in EGFR-TKI than in EGFR-TKI plus chemotherapy-treated patients (38.9% vs. 65.5% p=0.046). EGFR-TKI plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKI (8 neutropenia, 4 thrombocytopenia vs. no any event). Figure 1
Conclusion:
Compared with EGFR-TKI, EGFR-TKI plus chemotherapy conferred a significant higher ORR and longer PFS in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism. An open-label, multicenter, randomized, phase 2 study is ongoing to validate these results in our institute ( NCT03002844).
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-010 - Impact of Clinicopathological Features on the Efficacy of PD-1/PD-L1 Inhibitors in Patients with Previously Treated Non-Small Cell Lung Cancer (ID 8099)
09:30 - 09:30 | Presenting Author(s): Tao Jiang
- Abstract
Background:
The current study aimed to comprehensively investigate the impact of various clinicopathological features on the efficacy of programmed cell death 1 (PD-1) and ligand (PD-L1) inhibitors in patients with previously treated non-small cell lung cancer (NSCLC).
Method:
Randomized controlled trials that compared PD-1/PD-L1 inhibitors monotherapy with chemotherapy or placebo in patients with previously treated NSCLC were included.
Result:
Five trials were included (n = 3025). For all studies, PD-1/PD-L1 inhibitors significantly prolonged overall survival (OS) [hazard ratio (HR) = 0.70; P < 0.001] and progression-free survival (PFS) than chemotherapy (HR = 0.86; P = 0.020). Subgroup analysis showed that anti-PD-1/PD-L1 monotherapy could markedly improve OS in elderly (HR = 0.69; P < 0.001), female (HR = 0.70; P < 0.001), never-smoking (HR = 0.73; P = 0.001) and histology of squamous cell carcinoma (HR = 0.67; P < 0.001) patients but not PFS. Notably, PD-1/PD-L1 inhibitors can not prolong both the OS (HR = 0.76; P = 0.390) and PFS (HR = 0.74; P = 0.210) of patients with central nervous system (CNS) metastasis whereas patients without CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy on OS (HR = 0.71; P < 0.001).
Conclusion:
PD-1/PD-L1 inhibitors monotherapy could significantly prolong both OS and PFS in patients with previously treated NSCLC. Elderly, female, never-smoking and histology of squamous cell carcinoma patients could also benefit from PD-1/PD-L1 inhibitors monotherapy on OS. However, whether patients with CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy remains further validation.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-024 - Characterization of PD-L1 Expression and Its Predictive and Prognostic Significance in EGFR-Mutant NSCLC Patients Treated with EGFR-TKIs (ID 9002)
09:30 - 09:30 | Presenting Author(s): Tao Jiang
- Abstract
Background:
Not all the patients with EGFR-mutant non-small cell lung cancer (NSCLC) could benefit from EGFR-TKIs and both the predictive and prognostic markers remain undetermined. Previous study demonstrated that EGFR activation could up-regulate the PD-L1 expression and then contribute to immune escape, indicating the critical role of PD-L1 in EGFR-driven lung tumors. Therefore, we aimed to investigate the predictive and prognostic significance of PD-L1 expression in EGFR-mutant NSCLC treated with EGFR-TKIs. Characterization of PD-L1 expression in this populations were also explored.
Method:
We analyzed a cohort of 73 NSCLC patients with EGFR mutations. PD-L1 expression were assessed by immunohistochemistry and staining > 5% of tumor cells were considered as positive. Published studies that assessed the predictive or prognostic value of PD-L1 expression in EGFR-mutant NSCLC patients treated with EGFR-TKIs were included.
Result:
19 (26.0%) patients had positive PD-L1 expression. Positive PD-L1 expression was significantly associated with non-adenocarcinoma histology in this population (P = 0.028). Two cases with positive PD-L1 expression had KRAS mutation while none of those with negative PD-L1 expression harbored KRAS mutation (11.8% vs. 0%, P = 0.109). Five publications had reported both the predictive and prognostic value of PD-L1 expression in EGFR-mutant NSCLC patients treated with EGFR-TKIs. The pooled analysis including the current study showed that overall survival (OS) was significantly shorter in PD-L1 positive group than in PD-L1 negative group (HR, 1.92; 95% CI, 1.15-3.22; P = 0.01). However, positive PD-L1 expression was not correlated with progression-free survival (PFS: HR, 0.82; 95% CI, 0.51-1.30; P = 0.39).
Conclusion:
Positive PD-L1 expression tends to correlate with non-adenocarcinoma histology and KRAS mutation in EGFR-mutant NSCLC. Positive PD-L1 expression was significantly associated with better OS instead of PFS in EGFR-mutant NSCLC patients treated with EGFR-TKIs.
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P3.01-067 - TP53 Mutations Could Involved in EGFR-TKI Primary Resistance in Advanced Non-Small Cell Lung Cancer (ID 10437)
09:30 - 09:30 | Presenting Author(s): Tao Jiang
- Abstract
Background:
Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations, acquired resistance is inevitable. The aim of study is to discover unknown resistant mechanisms and contribute to more precisely administrate advanced and metastatic NSCLC with EGFR mutations.
Method:
60 NSCLC patients with EGFR sensitive mutation were enrolled this study. All of patients received EGFR-TKI treatment. 21 of patients were primary resistance and 39 acquired resistance according to Jackman standard. Tumor tissues of all of patients were collected before EGFR-TKIs treatment, and rebiopsy tissues were gained after acquired resistance in 39 NSCLC patients. Whole exome sequencing were performed in Illumina HiSeq2000 platform. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNVs), short insertions/deletions (indels) and copy number variations (CNVs).
Result:
In primary resistance patients, 13 patients occurred rapid progress (PFS ≤60 days) were put into group 1, and other 8 patients with PFS within 90-180 days were into group 2; in acquired resistance patients, 9 patients were observed long-term clinical benefit (PFS≥540 days) were into group 3; remaining 30 patients with PFS between 180 to 540 days were into group 4. Median PFS were 29, 95, 761 and 311 days from group 1 to 4, respectively. More signaling pathways were activated in group 1, relative to other groups, including bypass activation, downstream signal activation, apoptotic pathways disturbance and EMT activation. Meanwhile, the activation of more signaling pathways were found in samples after acquired resistance compared with paired baseline samples. In all of baseline samples, 60.0% patients harbored TP53 mutations, and these mutations distributed in exon 2,4,5,6,7,8 and 11, respectively. Interestingly, TP53 mutations of 23% patients were in exon 6 in group 1, mutations in exon 5 occurred in 33.3% patients with long-term clinical benefit (group 3). Patients with exon 6 mutation had more shorter PFS than those with exon 5 mutation (105 days vs 284 days).
Conclusion:
For patients resistant to EGFR-TKI, more signal pathways were activation, and the heterogeneity of tumor cloning were complicated. TP53 mutations in different exons may have distinct effect on response to EGFR-TKI of patients with EGFR sensitive mutation.
