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Lian-peng Chang



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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): Lian-peng Chang

      • 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): Lian-peng Chang

      • 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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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-126 - The Co-Occurring Genomic Landscape of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib (Now Available) (ID 1284)

      09:45 - 18:00  |  Author(s): Lian-peng Chang

      • Abstract
      • Slides

      Background

      Human epidermal growth factor receptor 2 (ERBB2, HER-2) 20 exon insertion (ERBB2ex20ins) has been identified as an oncogenic driver in lung cancer, for which no valid therapy is currently approved. Concurrent alterations may elucidate its refractory features. Previous studies on Afatinib, a pan-ERBB inhibitor, have revealed an inconsistent clinical activity of it for this group of patients.

      Method

      Plasma or tissue samples of 112 patients with ERBB2ex20ins were performed next generation sequencing (NGS) for 59 or 1021 cancer-related genes in a Clinical Laboratory Improvement Amendments-certified Laboratory from July 2016 to December 2018. The sequencing data of MSKCC Cohort was downloaded from the public Cancer Genome Atlas Database. The clinical outcomes of 18 patients receiving Afatinib treatment were collected by each contributing doctor in charge and pooled for analysis.

      Result

      Among the 112 patients, most of cases were female (54%, 60/112) and adenocarcinoma (68%, 76/112). Considering the insertions sites, three subtypes were A775ins (71%; 79/112), G776indel (17%; 19/112) and P780ins (12%; 14/112) in the order of frequency. 80.4% (90/112) of patients had at least one additional alteration. The most frequent co-occurring genes were TP53 (66.1%, 74/112), LRP1B (18.2%, 10/55), EPHA5 (9.1%, 5/55), MLL3 (9.1%, 5/55) and RB1 (8.0%; 9/112). Putative other driver aberrations were mutually exclusive from ERBB2ex20ins. Furthermore, cell cycle pathway was the most commonly involved pathway (84.0%; 94/112) of all the concurrent genes. No substantial differences of concurrence in genomic or pathway level were observed among the three ERBB2 insertion subtypes. The co-occurring genomic feature of ERBB2ex20ins in Our Cohort of Chinese people had an overall strong concordance with the MSKCC Cohort from the United States (R2=0.74, P<0.01). For the prognosis, patients had a worse OS when co-occurring mutation in TP53 [median OS:14.5m (95%CI: 12.7m-16.3m) vs 30.3m (95% CI: not reached)], while the OS was not significantly different among three subtypes. The median duration time for patients with disease control of Afatinib was 4.5 months (95%CI: 3.6m-5.4m; range: 2.5m-13.4m). Of note, ERBB2ex20ins in subclonal status was a significantly independent factor relating to shorter PFS of Afatinib [median PFS: 1.2m (95%CI: 0.8-1.6m) vs 4.3m (95%CI: 3.3m-5.3m), P<0.05]. Dynamic detection in two patients found ERBB2 amplification may be a resistance mechanism for Afatinib.

      Conclusion

      Concurrence of genetic alterations in NSCLC patients with ERBB2ex20ins was common. The complex genomic characteristic should be fully considered by stratifying patients according to potentially relevant co-mutations other than ERBB2 insertion sites in the designing regimens for them. In addition, the therapeutic effect of Afatinib on patient with ERBB2ex20ins is limited, the clonal status of ERBB2ex20ins may be an important factor with prognosis value.

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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): Lian-peng Chang

      • 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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    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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      P1.14-11 - A Prospective Multicenter Study of Target-Capture Deep Sequencing in Paired Tissue and ctDNA to Guide EGFR-Mutated Lung Cancer Treatment (Now Available) (ID 1542)

      09:45 - 18:00  |  Author(s): Lian-peng Chang

      • Abstract
      • Slides

      Background

      TKIs have significantly improved the survival of NSCLC pts carrying sensitive mutations. However, heterozygous responses were observed. We conducted a prospective multicenter clinical trial to explore factors associated with the efficacy of EGFR-TKI, and assess the mutation and TMB concordance between plasma and tissue NGS.

      Method

      Paired tumor and plasma samples were obtained from treatment naïve advanced NSCLC pts whenever applicable. DNA was sequenced by target-capture deep sequencing of 1021 tumor-related genes (pan-cancer panel). PFS was estimated using Kaplan-Meier method and compared using log-rank test. Tissue TMB (tTMB) and plasma TMB (bTMB) analysis interrogated SNVs/Indels with VAF ≥3 % and ≥0.5 %, respectively. TMB-H pts were identified with ≥9 muts/Mb.

      Result

      From Feb. 2017 to Jan. 2019, 262 advanced NSCLC pts were enrolled from 12 centers. In 224 pts with paired tumor and plasma samples, 144 had EGFR sensitive mutations in tumor samples (L858R, 46%; Ex19Indel, 42%), of whom, 106 (74%) had the identical mutations detected in plasma. The detection rate of tissue EGFR mutations in paired plasma was significantly higher in pts with extrathoracic metastasis (81% vs. 61%, p = 0.03). In 38 pts lacking paired samples, 20 pts had EGFR sensitive mutations detected. Thus, 164 pts were identified as EGFR positive by either plasma or tissue NGS. One hundred of them were treated EGFR TKIs (ORR: 70%, mPFS: 20 mo). The ORR was affected by EGFR subtypes (Ex19Indel vs. L858R: 72% vs. 45%, p = 0.02), concomitant CNV/fusion (with vs. without: 11% vs. 68%, p = 0.002) and CDKN2A mutations (with vs. without: 0% vs. 66%, p = 0.007). Mutations in p53 pathway (p = 0.02), CDK12/13 (p = 0.0002), concomitant CNV/fusion (p = 0.003), and high number of alterations (≥ 5) (p = 0.003) significantly shortened mPFS. tTMB was correlated with bTMB (rPearson = 0.9, p < 0.0001), with a concordance rate of 90% for TMB-H and TMB-L classification. Interestingly, 9.8% of the EGFR positive pts were bTMB-H, and mPFS was shorter in bTMB-H pts (6 mo, 95% CI: 5 - NR) than in bTMB-L pts (NR, 95%: 13 - NR) (p = 0.2).

      Conclusion

      Deep sequencing with the pan-cancer panel effectively detected mutations and evaluated TMB in both tissue and plasma with a high consistence. Moreover, the presence of structure variation, high tumor heterogeneity and concomitant mutations in genes such as CDKN2A were associated with worse prognosis. Further studies of predictive factors are ongoing (NCT03059641).

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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): Lian-peng Chang

      • 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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    P2.17 - 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): Lian-peng Chang

      • 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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