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Yan-Fang Guan



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    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 1
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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): Yan-Fang Guan

      • Abstract
      • Slides

      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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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.01 - Clinical and Genomic Features of Chinese Lung Cancer Patients with Germline Mutations (Now Available) (ID 682)

      15:45 - 17:15  |  Author(s): Yan-Fang Guan

      • Abstract
      • Presentation
      • Slides

      Background

      Recent studies on next generation sequencing (NGS) data from cancer patients have demonstrated that germline mutations in genetic predisposition genes were more common than previous known in many cancer types including lung cancer. However, most previous studies have focused on western patient population and the germline mutation landscape in Asian lung cancer patients and the clinical and genomic features in these patients are largely unknown.

      Method

      NGS data from a targeted panel of 1,021 known cancer genes from paired cancer and germline DNA of 1,797 Chinese lung cancer patients was analyzed to identify pathogenic or likely pathogenic (P/LP) germline variants in predisposition genes based on American College of Medical Genetics and Genomics (ACMG) 2015 guideline.

      Result

      Totally, 5.95% of lung patients were found to harbor germline variants in 35 cancer predisposition genes. The prevalence of germline mutations was higher in patients under 40 compared to older counterparts (10.1% vs 5.74%, p=0.103, Chi-Square test ) although it did not reach statistical significance. However, germline BRCA1/2 mutations were associated with earlier age of onset (median 52.5 vs 60 years-old, p=0.0080 by Mann-Whitney test). Furthermore, patients with P/LP germline mutations had significantly more somatic mutations in KRAS (p=0.012, fisher’s exact test) and c-MET (p=0.018, fisher’s exact test) oncogenes, but less in tumor suppressor gene TP53 (p=0.019, fisher’s exact test). Compared to western lung cancer patients enrolled in TCGA, P/LP germline mutations in BRCA2, FANCA, ATM, MUTYH, BLM, TP53, BRCA1, CHEK2, PMS2, NBN and FANCC were identified in both current Chinese cohort and TCGA cohort with BRCA2 germline mutations significantly more common in Chinese cohort than TCGA cohort (p=0.015, Fisher’s exact test). In addition, RAD51D, FANCD2, BRIP1, MSH6, PMS1, PALB2, RAD51C, SDHA, TSC2, BAP1, CDH1, FLCN, NF1 and RUNX1) were exclusively identified in Chinese patients, while RET, ERCC3, FANCG and VHL were only detected in TCGA cohort.

      Conclusion

      These results implied that there might be both common and unique cancer predisposition germline mutations for lung cancer between Asian and Western patient populations.

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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.02 - Genomic Origin and EGFR-TKI Efficacy of Pulmonary Adenosquamous Carcinoma (Now Available) (ID 578)

      14:30 - 16:00  |  Author(s): Yan-Fang Guan

      • Abstract
      • Presentation
      • Slides

      Background

      Lung adenosquamous carcinoma (ASC) is a heterogeneous disease that comprises of both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components. Their genomic profile, evolutionary origin, and clinical management remain controversial. Objective of this study is to define the genomic origin of this heterogeneous tumor by independent genomic analyses of the AC and SCC components.

      Method

      Surgical ASCs were collected. AC component and SCC component were obtained separately by microdissection, and Lymph node (LN) metastases were gathered. Targeted sequence was performed for the two components using a 1021-gene panel, independently. Evolutionary relationship of the two components was analyzed. The independent cohorts of adenocarcinoma (n=170) and squamous cell carcinomas (n=62) were used for comparison. EGFR and concomitant mutations with response to EGFR-TKI were analyzed. Retrospective 517 ASCs underwent EGFR detections were collected from 11 centers. Objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) were analyzed in EGFR-positive patients received EGFR-TKIs.

      Result

      28 ASCs were collected. NGS was performed on AC component and SCC component samples, respectively. The most frequent alterations in 28 ASCs were EGFR mutation (79%), TP53 mutation (68%), MAP3K1 mutation (14%), EGFR amplification (32%), and MDM2 amplification (18%). 27 patients had trunk variations in the both components suggesting the monoclonal origin of ASCs. The prevalence of trunk mutations was correlated to those of AC, indicating that ASC might originate from AC. Only one patient did not carry any trunk variations between AC and SCC components, which were clearly and geographically distinguishable under the microscope. 22 had AC component or/and SCC component specific variations suggesting the common event of branch evolution. The 23 LNs of 13 patients mainly contained AC and ASC components (AC, SCC, and ASC: 11, 1, and 11, respectively), and each of the LNs carried the trunk mutations of the primary ASC. Like pure AC, the alterations of L858R and Exon 19 Dels of EGFR were common in the 28 ASCs. Unfortunately, these patients have not been treated with TKIs. Further, of 517 retrospective ASCs from 11 centers, 51.8% were EGFR-positive. For the 129 EGFR-positive ASCs who had received TKIs, the ORR and DCR were 56.6% and 89.1%, respectively. The median PFS was 10.1 months (95% CI: 9.0-11.2).

      figure-1-wclc.jpg

      Conclusion

      The AC and SCC components share a monoclonal origin, and a majority have branching evolution. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR-TKIs.

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    P1.12 - Small Cell Lung Cancer/NET (ID 179)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.12-10 - The Genomic Profiles of Small Cell Lung Cancer in East Asian (Now Available) (ID 1608)

      09:45 - 18:00  |  Author(s): Yan-Fang Guan

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with poor survival, which is initially effective treated by chemotherapy and relapses rapidly. Comprehensive genomic analysis of SCLC contribute to the understanding of drug resistance mechanisms and discerning patients who respond to treatments, especially immunotherapy that has been proved to be efficient in SCLCs harboring high tumor mutational burden (TMB). This study was initiated to investigate the genomic profiles of SCLC in Chinese.

      Method

      SCLC specimens were obtained by surgery or biopsy from 64 patients. Whole-exome sequencing (WES) was performed on tumor samples without paired PBMCs. Alterations were confirmed with VAF between 5% and 90%, subsequently filtered by mutated genes above 5% in J.Geroge’s and LY. Jiang’s researches. Tumor mutational burden was calculated by the number of non-synonymous mutations. The mutations of highly mutated driver genes in SCLC was also determined based on MH. Bailey’s study.

      Result

      TP53 and RB1 were the most frequently mutated genes in SCLCs, occurred in 87.5% (56/64) tumors, and furthermore related to a higher mutational burden (P = 0.0008 and 0.0274, respectively). Tumor mutational burden after filtered by highly mutated genes in SCLC was 333 non-synonymous mutations per tumor, with high mutation rates exhibited in advanced stage of SCLCs, while the smoking history did not correlate with the number of mutations. Driver genes mutation in high frequency was detected almost in all tumors (63/64), with 17.4 mutations on average (0-144). Tumors with POLE mutation tended to harbor a higher driver genes mutation rates, as well as a higher TMB. Pathway analysis using altered driver genes showed enrichment of PI3K-Akt (adj. P = 8.38e-07), MAPK (adj. P = 1.63e-05), mismatch repair (adj. P = 4.55e-05), cell cycle (adj. P= 0.0016), and Wnt (adj. P= 0.0047) signaling pathways. We did not observe significant correlation of mutations in Wnt signaling pathway with survival, though it has proved to be a mechanism of chemoresistance in SCLCs.

      fig.1.jpg

      Conclusion

      SCLCs exhibited complex genomic features with extensive mutational burden and high numbers of altered driver genes. Various sorts of cancer-related pathways were enriched, highlighted the complicacy of SCLCs.

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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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      P2.03-32 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 289)

      10:15 - 18:15  |  Author(s): Yan-Fang Guan

      • Abstract
      • Slides

      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.

      all.png

      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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    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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      P2.04-54 - Characteristic of MSI-H Lung Cancer Patients Identified with Targeted Next-Generation Sequencing (Now Available) (ID 2435)

      10:15 - 18:15  |  Author(s): Yan-Fang Guan

      • Abstract
      • Slides

      Background

      MSI-H/dMMR predicts response to immune oncology (IO) agents and is an approved biomarker for pembrolizumab therapy irrespective of histologic diagnosis. In this study, we retrospectively analyzed a large cohort of lung cancer patients using targeted next generation sequencing to examine the prevalence and clinicopathologic associations of MSI-H in lung cancers.

      Method

      MSI and TMB status was derived from a 1021 gene targeted next generation sequencing panel. MSI was analyzed using MSIsensor 0.5, that relies on an empirically defined cutoff of MSI score>10%, as MSI-H. TMB analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3 %. TMB-H pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).

      Result

      5592 lung cancer patients were interrogated in the study, with 4753 lung adenocarcinoma, 559 lung squamous cell carcinoma, 112 small cell lung carcinomas (SCLC), and 168 rare lung cancer types including pulmonary sarcomatoid carcinoma, carcinoid and so on. A total of 12 lung tumors were identified as MSI-H (0.21%), and 5 were lung adenocarcinoma (0.1%), 3 were small cell lung cancer (2.7%), 1 was lung squamous cell carcinoma (0.18%), 2 were pulmonary sarcomatoid carcinomas, and 1 was pulmonary carcinoid (1.8%). The incidence was higher in small cell lung cancer and rare lung cancer subtypes. The average diagnosis age of the 12 patients were 53 years (range: 16-74). All the patients were TMB-H, with the TMB averaged 51.23 mut/Mb (range: 10-70 mut/Mb). Two of the 5 lung adenocarcinoma patients carried EGFR L858R or 19del mutation. One patient who had both NRAS G12V and EGFR Ex20 mutation had tried nivolumab (120mg) for one cycle with deteriorating of cough and progression of disease.

      Conclusion

      MSI-H is very rare in lung tumors, where it appears to enrich in small cell lung cancer and rare lung cancer subtypes. MSI-H lung cancer patients tend to have a younger diagnosis age. MSI-H may coexist with other driver alterations, including those negatively associated with IO response. Additional investigation is needed to determine efficacy of IO in these patients.

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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): Yan-Fang Guan

      • Abstract
      • Slides

      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.

      图1.jpg

      组图2.jpg

      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.

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