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Yayi He
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MA04 - Models and Biomarkers (ID 122)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Montse Sanchez-Cespedes, Kwok-kin Wong
- Coordinates: 9/08/2019, 13:30 - 15:00, Interlaken (1988)
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MA04.02 - Molecular Profiling of Adenocarcinoma and Squamous Cell Lung Cancer at Single Cell Resolution (Now Available) (ID 1358)
13:30 - 15:00 | Author(s): Yayi He
- Abstract
- Presentation
Background
Adenocarcinoma and squamous are two main subgroups of lung cancer: adenocarcinoma (ADC) accounts for 30-50% and squamous cell carcinoma (SCC) accounts for nearly 30% of all cases respectively. ADC and SCC have different pathological phenotypes and respond differently to various therapies, including immunotherapy. However, the underlying molecular mechanism of such differentiated drug responses still needs to be further characterized.
Method
To achieve high resolution of both tumor cells and their tumor microenvironment (TME), we used single cell RNA sequencing method to characterize ADC and SCC tumors from Stage IV NSCLC patients. Tissue biopsy samples from 21 patients (12 patients with ADC, 9 with SCC) were collected. For each sample, single cell RNA sequencing was performed on an average of 1930 cells. A graph-based clustering approach was used to classify cells into different cell types based on their gene expression patterns. The cellular subtypes of both cancer cells and TME in ADC and SCC samples were analyzed.
Result
ADC and SCC show distinct patterns at single cell resolution. Cancer cells from all ADC patients form two closely related clusters, while cancer cells from SCC patients show high intra-and inter-patient heterogeneity. Gene Ontology (GO) analysis demonstrated that ADC samples are enriched in genes of neutrophil degranulation and activation, while SCCs are enriched in genes related to epidermal cell differentiation and glutathione metabolic process. Genes related to cancer progression and metastasis, such as LSD1 and FASCIN, are normally expressed at higher level in SCC than in ADC. Furthermore, ADC samples contain higher percentage of a specific myeloid cell population, while SCC has higher percentage of fibroblasts, demonstrating the difference also in TMEs of ACD versus SCC.
Conclusion
The significantly higher level of heterogeneity for SCC can be a possible reason for poor responses to standard lung cancer therapies, including immunotherapy. Accurate characterization of SCC with single cell resolution could hold the key to more effective therapeutic strategies.
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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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P1.01-62 - Association of Baseline Pulmonary Fibrosis with the Outcome of PD-1 Inhibitor in Patients with Advanced Non-Small Cell Lung Cancer (ID 2942)
09:45 - 18:00 | Author(s): Yayi He
- Abstract
Background
PD-1/PD-L1 inhibitors have become standard care for previously treated advanced non-small cell lung cancer (NSCLC). However, not all patients are suitable for the immunotherapy. This study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitors in patients with advanced NSCLC and pre-existing pulmonary fibrosis (PF).
Method
Patients who had a NSCLC diagnosis, received anti-PD-1/PD-L1 monotherapy and had baseline chest HRCT screen at Shanghai Pulmonary Hospital, Tongji University were retrospectively collected from January 2016 to February 2019. The pre-existence of PF was identified by reviewing baseline chest imaging. Baseline clinicopathologic characteristics, treatment outcomes and immune-related pneumonitis were collected.
Result
116 patients were included with 61 age < 65. Among them, 97 (83.6%) were male, 76 (65.5%) were smoker, 51 (44%) were squamous, 61 (52.6%) received anti-PD-1 monotherapy (Pembolizumab n=62, Nivolumab n=28) as 2nd line setting, 28 (24.1%) had PF prior to PD-1 inhibitors. Baseline characteristics such as age, gender, ECOG PS, smoking history, pathology are similar between patients with or without PF. Patients with PF had a comparable response (ORR: 25% vs 15.9%, p=0.277, figure A), disease control (DCR: 60.7% vs 48.9%, p=0.274, figure B) and PFS (median 2.5 vs 2.8 months, p=0.950). The incidence of immune-related pneumonitis in the entire cohort was 9.2%, which was numerally higher in PF group (17.9% vs 6.8%, p=0.172, figure C). No death from immune-related pneumonitis occurred.
Conclusion
NSCLC patients with pre-existing PF showed comparable response to PD-1 inhibitors but a higher incidence to immune-related pneumonitis.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-50 - Type- and Stage-Specific Genomic Profiles in East Asian Lung Cancer Patients with No TKI-Related Driver Gene Mutations (ID 1196)
09:45 - 18:00 | Presenting Author(s): Yayi He
- Abstract
Background
It is widely accepted that the development of advanced lung cancer or distant metastases rely on driver gene mutations, but the carcinogenesis of lung cancers without key driver gene mutations has not been fully understood. The genomic landscape of lung adenocarcinoma (LADC), lung squamous cell carcinoma (LUSC) and small cell lung cancer (SCLC) without TKI-related driver gene mutations in East Asian has not been well investigated. Systematic study of these subtypes may identify biomarkers to distinguish different types and find novel tractable targets for therapy. We have therefore studied the genomic profiles of these types of lung cancers to identify type-specific and stage-specific gene mutations.
Method
32 LADC patients, 43 LUSC patients and 26 SCLC patients with no TKI-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET, HER2) mutations were included in this study. Genomic profiles were determined with lung cancer tissue by whole-exome sequencing (WES). Sequencing data were analyzed with R packages and statistics was performed with SPSS 20.
Result
In 101 patients enrolled, TP53, TTN, MUC4, ZFHX4 and CSMD3 mutations were commonly detected in all 3 types of lung cancer, and TP53 was the commonest mutated gene. Markedly, KRAS mutations were found only in LADC, and CSMD1 mutations were more frequent in LUSC, whereas RB1 mutations were observed exclusively in SCLC. LRP1B and RYR2 mutations were found more frequently at late stages. Copy number variations (CNV) in TERT, RICTOR and FGFR1 were seen in all 3 subtypes. The PIK3CA copy number gain was commonly seen in LUSC and SCLC other than that in LADC. In contrast, the CDKN2A copy-number loss was found in LADC and LUSC, but not in SCLC. The PTEN copy number loss was only identified in LUSC. No significant differences in TMB were observed among these 3 subtypes of lung cancer. However, statistical significance in TMB was attained between non-small cell lung cancer (NSCLC) and SCLC (P=0.022) in stage Ⅳ patients when the cut-off of TMB was set to 4.5 muts/MB.
Conclusion
Results from this genomic study confirmed the mutual and exclusive gene variations (including gene mutations and copy number variations) in 3 subtypes of lung cancer. It showed that gene variations were associated with lung cancer subtypes in patients with no TKI-related driver gene mutations. These findings might detecte subtype-specific biomarkers to assist histological-based diagnosis, and help to identify potential type-specific targets for lung cancer therapy.
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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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P2.01-30 - Hepatitis B Infection or Aminotransferase Increase Associate with Poor Outcome of Anti-PD-1 Monotherapy in Patients with Advanced NSCLC (ID 2508)
10:15 - 18:15 | Author(s): Yayi He
- Abstract
Background
Previous study demonstrated that the existence of liver metastases at the commencement of immunotherapy was associated with poor response. Since hepatitis B infection and liver dysfunction were higher prevalent in China, this study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitor in Chinese NSCLC patients with hepatitis B infection or liver dysfunction.
Method
We retrospectively collected the patients who were diagnosed with non-small cell lung cancer and received anti-PD-1 monotherapy at Shanghai Pulmonary Hospital, Tongji University School of Medicine, China, from January 2016 to February 2019. Detailed clinicopathologic characteristics, therapeutic outcomes, hepatitis biomarker test and liver function test were collected.
Result
135 patients were enrolled with 73(54.1%) aged <65 years old. Among them, 113(83.7%) were male, 84(62.2%) were smoker, 57(42.2%) were squamous, 69(44.4%) received anti-PD-1 monotherapy (Pembolizumab n=28, Nivolumab n=21) as 2nd line setting, 5(3.7%) patients had hepatitis B infection and 17(12.6%) had increased ALT or AST. The baseline characteristics such as age, gender, smoking status, histology, PD-1 mono-antibodies, line of therapy was similar between hepatitis infection or liver dysfunction group vs. normal group. Hepatitis infection or liver dysfunction group had a lower ORR (9.5% vs. 17.5%, p=0.553, Figure A), significantly shorter PFS (1.6 months vs. 3.0 months, p<0.050, Figure B) when compared with these patients without. Out of the 22 patients with hepatitis or increase transaminase, 35.7% deteriorated the grading of alanine or aspartate aminotransferase increased.
Conclusion
NSCLC patients with hepatitis B infection or increased transaminase showed a high incidence of hepatic disfunction and poor outcome to anti-PD-1 monotherapy.
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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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P2.03-36 - tTMB and bTMB in East Asian Lung Cancer Patients with No TKI-Related Driver Gene Mutations (ID 1183)
10:15 - 18:15 | Presenting Author(s): Yayi He
- Abstract
Background
High-level TMB was shown to be correlated with the better response of immunotherapy in lung cancer patients. However, the correlation between tissue tumor mutational burden (tTMB) with the blood tumor mutational burden (bTMB) in lung cancer patients has not been fully defined, and the tTMB and bTMB of East Asian lung cancer patient harboring no TKI-related driver gene mutations remains unexplored. This study aimed to define the tTMB and bTMB in East Asian by whole-exome sequencing (WES) and panel-based sequencing, and interrogate the correlation between gene mutations and TMB in lung cancer patients with no TKI -related driver gene mutations.
Method
In this cohort study, 122 primary lung cancer patients without TKI-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET, HER2) mutations were included. tTMB and bTMB were determined by whole-exome sequencing (WES) and a targeted 451-gene panel sequencing. The correlation between any two among the WES-tTMB, the panel-tTMB and the panel-bTMB were determined, and the relationship between gene mutations and tTMB were analyzed. Statistics was performed with the SPSS 20 software.
Result
The mean tTMB measured by WES (WES-tTMB), the 451-gene panel (panel-tTMB) and bTMB measured by the 451-gene panel (panel-bTMB) was 4.5, 7.2 and 6.1 mutations/Mb, respectively. Significant correlation was found between panel-tTMB and WES-tTMB (Pearson r=0.76, P<0.001) or panel-bTMB (Pearson r=0.52, P<0.001), but WES-tTMB showed no correlation with panel-bTMB (Pearson r=0.189, P=0.75). The relationship between gene mutations and WES-tTMB was further explored. Patients with p53, TTN, CSMD3, ZFHX4, RYR2 , MUC16, MUC12 and USH2A gene mutations had dramatically higher tTMB (P<0.001), while no significant relationship between CDKN2A or KRAS gene mutations and TMB was identified (p>0.05). In contrast, patients harboring both KRAS and P53 mutations showed significantly higher TMB than those with either gene mutations or no mutations in both genes (P<0.001).
Conclusion
Our study suggested that discrepancies exist in TMB measurement using different NGS-based detecting methods with tissue or blood sample types. The cut-off values should be determined based on detecting methods and samples types. Panel-tTMB was stronger correlation with WES-tTMB and panel-bTMB. Gene mutations were correlated with high TMB might be stronger predictors for TMB status in lung cancer patients without TKI-related driver gene mutations. Our observations provided new insights in TMB determination in East Asian lung cancer patients with NGS-based methods in various samples types and might improve the prediction of therapeutic effect and prognosis in future immunotherapy.
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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
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-58 - The Correlation Between TMB and Clinical Factors in East Asian Lung Cancer Patients with No TKI-Related Driver Gene-Mutations (ID 1253)
10:15 - 18:15 | Presenting Author(s): Yayi He
- Abstract
Background
Clinical factors, such as stage, metastasis, pathological type, age, smoking, gender and tumor mutational burden (TMB), have been reported to correlate with the prognosis of lung cancer (LC). However, it is still unclear how these factors influence the outcomes of patients with no TKI-related driver gene-mutations, and how these factors inter-correlate with each other. The aim of this study was to investigate the inter-correlation of these clinical variables in East Asian LC patients with no TKI-related driver gene-mutations to provide suggestions for patient selection and prognosis prediction.
Method
122 primary lung cancer patients without TKI-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET, HER2) mutations were recruited, in which 67 patients were confirmed with stage IV LC. Gene variations were determined in tumor tissue by whole-exome sequencing (WES). SPSS 20 software were used for statistics analysis, and P-values < 0.05 were considered significant.
Result
In 122 enrolled patients, 110 (90.2%) were male, 87 (71.3%) had smoking history and 95 (77.9%) were older than 60 years old. Significant differences in TMB were observed between male and female (P <0.05), but not between patients with or without smoking history (P >0.05). Patients older than 60 years old had dramatically higher TMB than those younger than 60 (P <0.05). Gender, smoking history, age, lung cancer subtype were not associated with the occurrence of brain or bone metastases (P >0.05). The mean TMB measured by WES was 4.5 mutations/Mb for all lung cancer patients. It was notable that the ratio of patients with TMB ≤4.5 was 68.2% (15/22) and 41.7% (5/12) for bone and brain metastatic patients, respectively. .Although the difference was not significant (P=0.163), the trend suggests that there may be a metastasis-specific difference in TMB.
Conclusion
Result from this exploratory study confirmed the gender preference in patients without TKI-related driver gene mutations. Male and elder patients with higher TMB may be the population that benefits more in immunotherapy. Although clinical the factors were not found to correlate with metastatic sites in this study, larger cohorts may find significant correlation, which could lead to the identification of novel biomarker for patient stratification or selection in therapies.
