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Xu-Chao Zhang
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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)
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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): Xu-Chao Zhang
- 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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JCSE01.22 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (ID 3436)
07:00 - 11:15 | Presenting Author(s): Xu-Chao Zhang
- Abstract
Abstract
Background
Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.
Methods
A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells.
Results
In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor.
Conclusion
PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.
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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
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-104 - Survivals in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer Treated with First-Line Crizotinib (ID 1735)
09:45 - 18:00 | Author(s): Xu-Chao Zhang
- Abstract
Background
The c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) can be treated effectively with crizotinib, a tyrosine kinase inhibitor (TKI) of anaplastic lymphoma kinase (ALK), ROS1, and mesenchymal-epithelial transition (MET). However, few studies have investigated on survivals in ROS1-rearranged advanced NSCLC patients treated with first-line crizotinib.
Method
We retrospectively analyzed clinicopathological and survival data of ROS1-rearranged patients with advanced NSCLC treated with crizotinib between August 2013 and January 2019 at the Guangdong Provincial People's Hospital. ROS1 rearrangements were detected by Reverse Transcription-Ploymerase Chain Reaction(RT/PCR),Fluorescence in situhybridization (FISH), or Next-generation Sequencing (NGS) . Overall survival (OS) and progression-free survival (PFS) were compared between first-line crizotinib, chemotherapy followed by crizotinib and first-line chemotherapy without any subsequent targeted therapy.
Result
Among totally 40 patients with ROS1-rearranged advanced NSCLC, 29 were treated with crizotinib (16 with first-line; 13 with second- or further-line), and 11 were not treated with crizotinib at data cutoff (April 4, 2019). Median OS was significantly prolonged in patients with first-line crizotinib (N=16) than those with first-line chemotherapy followed by subsequent crizotinib (N=9), not reached vs. 27.1 months, P=0.042. However, there was no significant difference in median PFS between the two groups, 16.3 vs. 5.7 months, P=0.054. Meanwhile, first-line crizotinib (N=16) was significantly superior to first-line chemotherapy without any subsequent targeted therapy (N=8) in both median OS (not reached vs. 9.1 months, P=0.024) and PFS (16.3 vs. 4.8 months, P=0.017).
Conclusion
First-line crizotinib prolongs survivals than chemotherapy for patients with ROS1-rearranged advanced NSCLC.
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P1.01-82 - The Different Frequencies and Genetic Profiles of Histologic Transformation After Different EGFR-TKIs in EGFR-Mutant Adenocarcinomas (ID 418)
09:45 - 18:00 | Author(s): Xu-Chao Zhang
- Abstract
Background
Histologic transformation is a mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor(TKIs) in EGFR-mutant non-small cell lung cancers（NSCLCs）. Those adenocarcinomas with histologic transformation usually underwent poor prognosis. However, few studies have focused on the different occurrence rates and genetic profiles between EGFR-mutant adenocarcinomas treated with different generations of EGFR-TKIs.
Method
Pathology was confirmed in 345 EGFR-mutant patients at baseline and recurrence. Among these patients，235 patients were treated with gefitinib or erlotinib，54 with afatinib and 56 with osimertinib. But only 11 patients with sufficient tumor specimens could be evaluated for the genetic profiles by next-generation sequencing (NGS). Demographics, disease features, and outcomes of these patients were analyzed.
Result
The frequency of these EGFR-mutant adenocarcinomas with histologic transformation after the treatment of different generation TKIs were quite different. The frequency of gefitinib/erlotinib group was 7.2% (17/235)，while the others were 5.6%（3/54, afatinib group）and 17.9%（10/56, osimertinib group）. The median progression free survival （PFS）to EGFR-TKIs of those patients were 12.2 months（gefitinib/erlotinib group）, 5.3 months （afatinib group）and 7.7 months（osimertinib group） respectively. Four adenocarcinomas treated with gefitinib/erlotinib all harbored TP53 mutations at baseline. One adenocarcinoma treated with afatinib was founded to have acquired MET amplification and transformed to small-cell lung cancer meanwhile. Moreover, the PFS of one patient to afatinib was just 3 months and her genetic profile at baseline was characterized by Rb1, TP53, and PIK3CA mutations. There were 3 patients treated with osimertinib underwent histologic transformation from adenocarcinomas to squamous carcinoma. One patient after progressive disease of osimertinib did not have enough tissue to detect NGS，and her blood NGS result just showed EGFR L858R and T790M mutation. The tissue NGS result of the second patient showed EGFR p.Glu746-Ala750 deletion, EGFR T790M and C797S mutations, CDK4/ CCND1/ EGFR/ KRAS amplifications. The second patient received the chemotherapy of pemetrexed+ carboplatin + bevacizumab and the best response was partial response. The third patient take palbociclib and osimertinib meanwhile and his symptoms improved with the tissue NGS of EGFR T790M mutation and CDK4/ MDM2/ EGFR amplifications. They were characterized by EGFR amplification and CDK4 amplification. The others transform from adenocarcinomas to small cell cancers or neuroendocrine tumors were seem to harbor with TP53, Rb1 and PIK3CA mutations.
Conclusion
It seems more common in some subtypes that the EGFR-mutant adenocarcinomas treated with osimertinib undergo histologic transformation. The genetic profiles vary greatly between transformation to squamous carcinomas and transformation to small-cell cancers/neuroendocrine tumors in EGFR-mutant adenocarcinomas treated with osimertinib. Further verification is needed.
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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): Xu-Chao Zhang
- 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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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-42 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (Now Available) (ID 651)
09:45 - 18:00 | Presenting Author(s): Xu-Chao Zhang
- Abstract
Background
Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.
Method
A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells.
Result
In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor.
Conclusion
PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.
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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): Xu-Chao Zhang
- 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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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-80 - Clinical Outcomes in Advanced EGFR-Mutant NSCLC Patients Treated with First-Generation EGFR TKIs Followed by Subsequent Osimertinib (ID 1732)
10:15 - 18:15 | Author(s): Xu-Chao Zhang
- Abstract
Background
Treatment with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) plus subsequent osimertinib is standard of care for advanced (EGFR)-mutant non-small cell lung cancer (NSCLC) harboring T790M mutation. However, few data are available that have assessed the cumulative survival benefit of sequential EGFR TKIs in patients with EGFR-mutant NSCLC with T790M mutations in ‘real-world’ clinical practice.
Method
We retrospectively identified advanced EGFR-mutant NSCLC patients treated with first-line EGFR TKIs plus subsequent osimertinib between January 27th, 2015 and December 1st, 2018 at our institute. Clinical outcomes were analyzed. Subsequent genetic profiling was performed at the time of progression by next-generation sequencing (NGS). The primary endpoint was overall survival (OS) calculated from first-line treatment start to death or the last follow-up, and the secondary endpoint was progression-free survival (PFS) with osimertinib defined as the time from the first dose of osimertinib to disease progression or death. Primary resistance to osimertinib was defined as PFS≤4 months for T790M-mutant patients treated with osimertinib. The last follow-up time was January 27th, 2019. Median follow-up time was 52.0 months (range, 9.0~108.0 months).
Result
Among 117 eligible patients treated with first-line EGFR TKIs plus subsequent osimertinib, 96 had T790M mutation and 21 showed negative T790M mutation or unknown status at the baseline of osimertinib treatment,. Median OS was significantly prolonged in T790M-mutant patients than those with negative/unknown T790M mutation (58.0 vs. 28.3 months, p＜0.001). However, there was no significant difference in median PFS with osimertinib between the two groups. Furthermore, there was no significant difference in both median OS and PFS with osimertinib between the non-brain metastatic and brain metastatic groups (median OS, 58.0 vs. 54.8 months, p=0.840; median PFS, 11.8 vs. 9.1 months, p=0.145). Median OS was significantly shortened in patients (N=20) with primary resistance to osimertinib than those (N=72) with PFS＞4 months (38.2 vs 54.8 months, p=0.027).
Conclusion
In real-world clinical practice, treatment with first-generation EGFR TKIs plus subsequent osimertinib for T790M-mutant patients can significantly prolong OS than those with negative/unknown T790M mutation. However, survivals are similar between the patients with and without brain metastases at the baseline of osimertinib. OS is significantly shorter in those with primary resistance to osimertinib.
Non-brain metastasis at the baseline
(n=55)
Brain metastasis at the baseline
(n=41)
P-value
Osimertinib PFS≤4m
(n=20)
Osimertinib PFS＞4m
(n=72)
P-value
Sex
Male
21 (38.2%)
20 (48.8%)
0.299
7 (35.0%)
32 (44.4%)
0.450
Femal
Age,years
≤55
＞55
34 (61.8%)
19(34.5%)
36(65.5%)
21 (51.2%)
18(43.9%)
23(56.1%)
0.357
13 (65.0%)
9 (45.0%)
11(55.0%)
40 (55.6%)
27(37.5%)
45(62.5%)
0.543
ECOG PS
0-1
54(98,2%)
38(92.7%)
0.000
20(100%)
68(94.4%)
0.281
2-4
1(1.8%)
3(7.3%)
0(0%)
4(5.6%)
Histology
adenocarcinoma
53 (96.4%)
41 (100%)
0.217
18 (90.0%)
72 (100%)
0.007
non-adenocarcinoma
2 (3.6%)
0 (0%)
2 (10.0%)
0 (0%)
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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): Xu-Chao Zhang
- 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.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-38 - Tumor-Associated Neutrophils as a Potential Predictor for Early Recurrence in Resectable I-IIIA Lung Adenocarcinoma (Now Available) (ID 1509)
10:15 - 18:15 | Author(s): Xu-Chao Zhang
- Abstract
Background
A recurrence of the early-stage non-small cell lung cancer (NSCLC) is usually unpredictable by clinical features alone. It has been appreciated that the high degree of infiltrated neutrophils is significantly associated with poor patient outcome in NSCLC.
Method
Transcriptional profiles and clinical information of 484 primary lung adenocarcinoma (ADC) subjects were retrieved from Gene Expression Omnibus (GEO). An additional cohort of mRNA expression, somatic mutations, and clinical data of 398 ADC were obtained from The Cancer Genome Atlas (TCGA). CIBERSORT algorithm was employed to infer the relative proportions of 22 sorts of leukocytes in each tumor using gene-expression profiles. Patients were stratified into two groups by the fraction of neutrophils using an optimal cutoff value (0.01) obtained with the "survminer" algorithm in R. We further investigated comprehensively the molecular differences between the high- and low-neutrophils patients.
Result
A significantly higher rate of 1-year recurrence was found in the high-neutrophils compared with the low-neutrophils group in both training (GEO,19.5% vs 6.1%) and validation (TCGA, 27.3% vs 19.0%) cohorts. However only in training cohort the patients with high neutrophils experienced a poorer recurrence-free survival (HR 1.95, 95% CI 1.47-2.51, P< 0.0001). The two groups were not only distinguished by clinical behaviors, but presented characteristic mutation genes and mutation patterns. EGFR and BRAF were more frequently mutated in low-neutrophils patients, whereas in high-neutrophils patients the most common mutation was found in STK11. Yet such molecular distinction was more pronounced in ADC with high tumor mutation load (TMB >=10). Gene Set Enrichment Analysis (GSEA) suggested that the common mutant genes in high-neutrophils patients were involved in the TP53 signaling, cell cycle pathways or associated with molecular functions including chemokine production and CD4 activation, while the common mutant genes in low-neutrophils patients were linked to RAS signaling pathway. Interestingly, we observed immune scene accompanied with good prognosis of ADC and concordant with limited infiltration of neutrophils, for instance high infiltration of B memory cells, resting memory CD4+T cells, resting mast cells and CD8+T cells.
Conclusion
Our findings suggested that local neutrophils are one of important components which are determinant for early recurrence of ADC, and it might serve as a simple predictor. Further research is warranted to identify the molecular mechanisms that neutrophils employed to exert, directly or indirectly, the regulatory effect on ADC progression.
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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): Xu-Chao Zhang
- 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.
