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Yi-Long Wu
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FP01 - Early Stage/Localized Disease (ID 111)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP01.03 - Genetic Predisposition for Pre-Invasive Lung Adenocarcinoma Manifesting as Ground-Glass Nodules with Family History of Lung Cancer (ID 1512)
00:00 - 00:00 | Author(s): Yi-Long Wu
- Abstract
Introduction
Lung cancer with family history have been increasing gradually of late years in East Asian, especially those presenting as pulmonary ground-glass nodules (GGNs). The predisposition of GGN with lung cancer family history remains baffling.
Methods
This prospective study (NCT04220268) enrolled patients with pulmonary pre-invasive or invasive adenocarcinoma, which presenting as GGN in computer tomography (CT) scans. We used extreme phenotype approach to select 50 GGN patients with a family history of lung cancer (FHLC) in one or more first-degree relatives. Blood samples were collected and sequenced by whole exome sequencing (WES) to investigate rare but potential pathogenic germline mutations with a stepwise filtering strategy including: variant quality and classification, minor allele frequency (MAF) < 0.01 in public and local database, functional prediction and family segregation.
Results
In total, 2325 single nucleotide variants (SNVs) and 238 frameshift mutations with MAF <0.01 were finally identified through the filter. The number of these rare, damaging germline mutations in non-smoking patients were significantly higher than those in smoking patients (Spearman’s ρ= -0.33, p=0.02). Fifty-nine SNVs and 10 frameshifts were not only rare and deleterious but also presented in more than two families. Importantly, twenty of them had been reported to be associated with higher risk or carcinogenesis of lung cancer. Two of them were validated in 126 nonoverlapping susceptibility loci for lung carcinogenesis identified by genome-wide association studies (GWAS).
Conclusion
Patients with GGNs and FHLC may have inheritable carcinogenesis mutations. These variants may potentially contribute to the risk of pulmonary pre-invasive adenocarcinoma susceptibility in Chinese population. Non-smoking patients with GGN probably had higher genetic predisposition than the smoking patients.
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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.16 - Tamoxifen Might Enhance the Effect of EGFR-TKIs on EGFR-Mutant NSCLC Cells (ID 1004)
00:00 - 00:00 | Author(s): Yi-Long Wu
- Abstract
Introduction
Postmenopausal females with epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC) have longer progression free survival than premenopausal females when they receive EGFR tyrosine kinase inhibitors (TKIs) treatment. The level of estrogen and estrogen receptors (ERs) in lung cancer tissue might affect the response of EGFR-TKIs. This experiment aims to study the expression of ERs in EGFR-mutant NSCLC cell lines and explore the method to improve the efficacy of EGFR-TKIs from the perspective of estrogen.
Methods
The level of ERs protein in the nucleus, cytoplasm and membrane of EGFR-mutant NSCLC cell lines was evaluated by western blot. The EGFR-mutant NSCLC cell lines were treated with anti-estrogen, EGFR-TKIs, or the combination; the effect of treatment on cells viability was determined by CCK8 arrays.
Results
Both ERα and ERβ expressed in multiple NSCLC cell lines. The ERα protein in MCF7 cell line was as much as the ERβ protein, but the ERα protein in EGFR-mutant NSCLC cell lines was much less than the ERβ protein. ERβ was detected in nucleus, cytoplasm and membrane of EGFR-mutant NSCLC cell lines. Compared with Tamoxifen or Erlotinib alone, the combination of the two drugs significantly inhibited the viability of PC9 cell line; compared with Tamoxifen or Osimertinib alone, the combination significantly inhibited the viability of H1975 cell line. But Fulvestrant showed little effect on the prohibition of both PC9 cell line and H1975 cell line.
Conclusion
Tamoxifen might improve the efficacy of EGFR-TKIs on EGFR-mutant NSCLC cell lines. Estrogen might interact with EGFR pathway through the ERβ in the cytoplasm and membrane to promote the proliferations of EGFR-mutant NSCLC cells. More information will be shown in the conference.
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P59 - Tumor Biology and Systems Biology - Basic and Translational Science - Genomics (ID 197)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P59.04 - Sex-Related Differences in Genomic and Immune Profiling of Lung Adenocarcinoma (ID 1404)
00:00 - 00:00 | Author(s): Yi-Long Wu
- Abstract
Introduction
The responses to therapeutic treatment can be finely tuned by sex-related cellular and/or molecular biology. Such sex determination for the disease onset and progression has been recognized in many tumor types. However, the sex disparities in genomic and immune profiles of lung adenocarcinoma (LUAD) remain poorly understood. The aim of this study is to explore the sex-associated biases in mutation and immune portrait across Asian and non-Asian LUADs.
Methods
DNA sequencing (n=305) and mRNA expression profiles (n=172) of Asian LUADs are downloaded from OncoSG together with related clinical records. To assess possible interaction between sex and genetic background, the somatic mutational profiles (n=614) and mRNA expression profiles (n=425) of Non-Asian LUADs were also downloaded from The Cancer Genome Atlas. The relative abundance of different immune cells in tumor was determined using a method for deconvolving the cell composition of complex tissues from gene expression data. We then compared somatic mutation profiles and the abundance of tumor-infiltrating immune cells between male and female LUADs. Additionally, mRNA expression data from a Chinese CHOICE cohort (n=128 LUADs) were used to validate the sex-specific immune infiltrates deconvolved from OncoSG cohort.
Results
The major clinicopathological features of two cohorts are summarized in Figure 1. EGFR mutation was more frequent in smoker females than males across the two cohorts. While in non-smokers, EGFR mutation showed not significant gender disparities. A higher EGFR mutation frequency was observed in male non-smokers than smokers (P=0.004), regardless of ethnic origin. Interestingly, in the non-Asian cohort, EGFR mutation presented a significantly higher frequency in female non-smokers than female smokers (P<0.0001), but this divergence was not observed between Asian female smokers and non-smokers. Among smokers, EGFR mutation type in females can be described by the substitutions pointing out unique oncogenic etiologies including "UV light" (COSMIC Signature 7), “APOBEC”(Signature 2) and“Defective DNA MMR”(Signature 15), but not in males. While among non-smokers, “Smoking” signature (Signature 4) was preeminent in Asian males, but no in other subpopulations. Moreover, in silico analysis of cellular composition disclosed an increase of resting CD4 memory T cells and dendritic cells in Asian females compared to males. Additionally, Macrophages M2 were more abundant in Asian males compared to females.
Conclusion
Our findings provided evidence that sex-related molecular and cellular components are involved in shaping tumor distinct genomic and immune features, which might have important impact on personalized targeted and immune therapy. Further research is warranted to identify the molecular mechanisms underlying sex-related differences.
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P72 - Tumor Biology and Systems Biology - Basic and Translational Science - Tumor Microenvironment (ID 211)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P72.02 - Cellular Landscape of Tumor Immune Microenvironment and Genetic Signatures Identify Prognostic of LUAD (ID 736)
00:00 - 00:00 | Author(s): Yi-Long Wu
- Abstract
Introduction
Tumour microenvironment (TME) has been recognized to support the initiation and progression of lung adenocarcinoma (LUAD). The innate and adaptive immune cells in the lung TME harbour both tumour-promoting and tumour-suppressing activities, which may also predict clinical outcome. Therefore we carried out a systematic analysis of cellular interactions in tumor immune microenvironment. And identify cell-intrinsic and cell-extrinsic pathways cell types and activation states that may serve as biomarkers of overall survival (OS).
Methods
Public gene-expression data and relevant clinical annotation were obtained from Gene-Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) database. Three TME infiltration patterns were comprehensively analyzed in 442 LUAD patients using CIBERSORT algorithm and the LM22 gene signature. Based on the TME patterns, we build a model to calculate TMEscore based on gene set variation analysis via ssGSEA algorithm. Functional enrichment analysis were performed by GO and KEGG.
Results
Four datasets with available outcome data and clinical information in GEO and TCGA-LUAD were enrolled in our study. GSE72094 was used as the training cohort, while GSE11969, GSE26939, GSE31210 and TCGA-LUAD was used as validation cohorts. TME cell network established based on GSE72094 depicted a comprehensive landscape of tumor-immune cell interactions, cell lineages, and their correlation with OS (Fig. 1A, 1B). Three subgroups with distinct TME signature gene sets were obtained/identified based on unsupervised hierarchical clustering in 442 LUAD cases. OS in TME gene subgroup B was significantly longer than which in TME gene subgroup A and subgroup C. TME gene group B was associated immune activation (Fig. 1C). TMEscore was further constructed using principal component analysis algorithms. Lower TMEscore is significantly associated with better prognosis. Functional annotation analysis showed TMEscore had a positive correlation with cell cycle, DNA replication, homologous recombination, mismatch repair, nucleotide excision repair and DNA damage repair (Fig. 1D). The enriched pathways in subtype with lowest/low TMEscore involved bile_acid_metabolism, fatty_acid_metabolism and myogenesis. While high TMEscore subtype was characterized by significant enrichment of interferon_alpha_response, myc_targets and unfolded_protein_response pathway (Fig. 1E). TMEscore model was then validated on 525 patients from GEO datasets and 585 patients from TCGA-LUAD project and proved to be a valuable method for prognostic stratification of LUAD except for TNM stage(Fig. 1F).
Conclusion
Variability in the composition of the tumor immune microenvironment contributes to heterogeneity in OS. Deeper validation is in need to define the positive association between lower TMEscore and longer OS.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.19 - Clinical Outcomes of Lung Cancer Patients Who Acquired EGFR T790M/in trans-C797S Mutations After Resistance to Osimertinib (ID 1260)
00:00 - 00:00 | Author(s): Yi-Long Wu
- Abstract
Introduction
EGFR C797S is a well-established mechanism of resistance to osimertinib. Previous studies have documented whether C797S occurred in cis (on the same allele) or trans (on a different allele) with T790M affects the efficacy of subsequent therapies, and in trans C797S/T790M remain sensitive to a combination of first- and third-generation EGFR TKIs. To date, no standard treatment is available for patients with lung cancers harboring EGFRT790M/in trans-C797S mutations. We set out to characterize the clinical outcomes in this subset of patients.
Methods
Patients with a pathologically confirmed diagnosis of stage IV lung cancer harboring EGFR T790M/in trans-C797S mutations were analyzed. EGFR mutation was identified by DNA-based next-generation sequencing. A retrospective review of clinicopathologic and treatment information was performed. Response to subsequent therapy was determined (RECIST v1.1). Progression-free survival (PFS) in patients were determined using Kaplan-Meier estimates. Survival was measured from the date of the first subsequent treatment start.
Results
29 patients with EGFR T790M/in trans C797S-mutant lung cancers were identified. The median age was 55 (range 31-71 years), 69% were women. All had adenocarcinoma. Accurate information of previous and subsequent treatment were available for 16 patients. All patients had previous osimertinib administration, mostly at the 2nd line (n = 7) or 3rd line (n = 5). The majority (88%, 14/16) received subsequent therapy, of whom under half (n = 6) were treated with a combination of first- and third-generation EGFR TKIs (gefitinib or erlotinib+ osimertinib); the median PFS was 3.7 months (95%CI 3.3-4.1 months). The median PFS of patients who underwent other therapies (platinum-based chemotherapy, osimertinib+cabozantinib, osimertinib+brigatinib, or osimertinib+cetuximab) was 3.2 months (95%CI 1.7-4.7 months). At the time of reporting, overall survival data were not mature.
Conclusion
The clinical outcomes of patients who acquired EGFR T790M/in trans-C797S mutations after resistance to osimertinib were relatively poor. Further researches are required to investigate the biology of these compond mutations and to establish the optimal therapeutic option.
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P76.96 - START: Real-world Prospective Study on Sequential Therapy with First-Line Afatinib in Chinese Patients with EGFRm+ Advanced NSCLC (ID 625)
00:00 - 00:00 | Author(s): Yi-Long Wu
- Abstract
Introduction
Afatinib is an orally administered irreversible ErbB family blocker that was approved as a first-line therapy in patients with EGFR mutation-positive (EGFRm+) NSCLC in China in 2017. There is currently a lack of large-scale real-world clinical evidence for afatinib as first-line treatment in Chinese patients. The development of acquired resistance to EGFR-targeted TKIs, mediated by the emergence of the T790M mutation, occurs in many patients. It is therefore important to determine the optimal treatment sequence for patients with EGFRm+ NSCLC, to maximise the duration of chemotherapy-free treatment regimens following first-line afatinib therapy. Whilst the GioTag study demonstrated that Asian patients with EGFRm+ NSCLC who received first-line afatinib followed by osimertinib had prolonged time to treatment failure,1 the time on treatment for Chinese patients who receive afatinib followed by a third-generation EGFR TKI has yet to be determined. Therefore, the aim of this study is to observe the effect of afatinib as a first-line treatment and determine the optimal chemotherapy-free sequential treatment strategy in Chinese patients with EGFRm+ advanced NSCLC.
Methods
NCT04206787 is a non-interventional, prospective, multicentre study of afatinib sequential therapy, conducted in a real-world setting. Approximately 750 Chinese patients, aged ≥18 years, with newly diagnosed locally advanced or metastatic NSCLC with EGFR-sensitive mutations will be enrolled at ~20 sites in China. Exclusion criteria include prior exposure to systemic therapy, symptomatic brain metastases, and concurrent participation in an interventional oncology clinical trial. The primary objective is to determine the time on treatment for patients who receive first-line afatinib followed by a third-generation EGFR TKI following development of the T790M resistance mutation. Secondary objectives include the assessment of the effectiveness and safety of afatinib, and time on treatment with first-line afatinib followed by second-line treatment in event of T790M-negative status.
Patients will receive afatinib as first-line treatment. The best subsequent treatment options will be determined by physicians based on genetic analysis and administered as indicated.
The primary outcome will be evaluated by time on treatment with afatinib as a first-line treatment followed by a third-generation EGFR TKI (e.g. osimertinib) in the event of the emergence of the T790M resistance mutation. Patients who receive afatinib (30 or 40 mg orally, QD) will be followed up on Day 28 (-7/+2) and thereafter at regular visits, until receiving their last dose of second-line treatment, loss to follow-up, or death. Following discontinuation of second-line treatment, patients will be followed until loss to follow-up or death. Secondary outcome measures include time on treatment in patients with T790M-negative status, progression-free survival, overall response rate (complete response + partial response) and disease control rate (complete response, partial response, + stable disease) according to RECIST Version 1.1, and resistance mechanisms after first-line afatinib treatment. Other secondary outcome measures include overall survival plus rates of adverse events (AEs), serious AEs, and afatinib-related AEs graded according to CTCAE Version 5.0.
1. Hochmair MJ, et al. Future Oncology. 2018; 14(27):2861–2874. doi:10.2217/fon-2018-0711.
