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xuefeng Xia



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    FP10 - Small Cell Lung Cancer/NET (ID 231)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP10.03 - Multi-Region Exome Sequencing Reveals the Intratumoral Heterogeneity of Surgically Resected Small Cell Lung Cancer (ID 2079)

      00:00 - 00:00  |  Author(s): xuefeng Xia

      • Abstract
      • Slides

      Introduction

      Small cell lung cancer (SCLC) is a highly malignant tumor with extensive genomic alterations detected by single-region sequencing. But the intratumoral heterogeneity (ITH) of SCLC remains unknown. Elucidating the heterogeneity of SCLC by multi-region sequencing help the understanding of disease and the improvement of clinical outcomes.

      Methods

      Multi-region exome sequencing was performed on 120 FFPE samples from 40 staged I-III SCLC patients (three regions for each patient). All the tissue samples were collected by surgical resection from Sun Yat-sen University Cancer Center and confirmed as SCLC by immunohistochemistry. Intratumoral heterogeneity (ITH) was defined as percentage of branch/subclonal somatic non-silent mutations or copy number variations. We further analyzed the correlation of ITH and clinical phenotype to evaluate the impact of genomic alterations on outcome, including disease-free survival and overall survival.

      Results

      We subjected 120 FFPE SCLC samples to multi-regional whole-exome sequencing. In total, 48818 somatic mutations were identified with average 239x sequencing depth. The most significantly and frequently mutant genes were TP53 (88%) and RB1 (70%), which dominate truncal mutations (Fig.1A). In addition to a medium tumor mutation burden (TMB, 15/Mb range 2~66), SCLC exhibited somatic copy number variation (CNV) across all patients. Using CNV ITH, an average of 0.49 (range 0.22~1 per sector) was found in SCLC (Fig.1B). The age-associated, tobacco-associated, and aflatoxin-associated signatures were major mutational signatures in these patients (Fig.1C). We found a medium mutational heterogeneity (0.50, range 0.22~1) in our SCLC cohort, in contrast to low ITH in previous reported NSCLC and LUAD cohort (Fig.1C). Combined SCLC patients behaved in much the same way as pure SCLC patients, both in terms of mutation distribution, ITH, TMB, mclone (number of tumor molecular clones) and gene signatures (Fig. 1D). This condition is also present in smoker patients and those with EGFR mutations. A higher CNV ITH was observed in stage I-II of SCLC than stage III (p < 0.001) (Fig.1E). Less mClone were associated with better DFS of SCLC (Fig. 1E).

      wclc2020-2079-submit-image.jpg

      Conclusion

      Despite moderate mutation burden, SCLC showed a medium intratumoral heterogeneity with high genomic instability. CNV exhibited a high heterogeneity at early stage and mclone may serve as a prognostic biomarker for SCLC.

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    P07 - Early Stage/Localized Disease - Imaging and Biomarkers (ID 116)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P07.04 - Using ctDNA to Detect Minimal Residual Disease after Surgery in Resectable Lung Cancer (ID 1775)

      00:00 - 00:00  |  Author(s): xuefeng Xia

      • Abstract
      • Slides

      Introduction

      ctDNA is a blood-based biomarker with promising potential in lung cancer for minimal residual disease (MRD) assessment and early detection of recurrence. However, there are few studies about ctDNA in postoperative monitoring for resectable lung cancer.

      Methods

      We retrospectively analyzed paired surgical tissues and postoperative ctDNA next-generation sequencing (NGS) results from 49 lung cancers patients (pts) who underwent surgery. We used 1021-gene panel to assess the genetic variations. ctDNA positive defined as at least one mutation from tissue was detected in postoperative plasma. The cutoff value of TMB-H/L in tissue samples was 9.0 Muts/Mb.

      Results

      A total of 49 pts included in this analysis with median age 59 (range 37-76), 30 were males. Histologically contained 47 adenocarcinoma, 1 squamous cell carcinoma, 1 LCNEC, and 1 SCLC. One patient had simultaneous multiple primary lung adenocarcinoma and squamous cell carcinoma in different left lobes. Tumors were in different stages, 17 were stage I, 17 were stage II, 15 were stage III and 1 was unknown. Genetic variations were found in all tissue samples. TP53 (60%) was the most common gene, followed by EGFR (42%), LRP1B (16%), KRAS (16%), et. And a total of 63 actionable mutations were found in 84.0% (42/50) tissue samples, including EGFR, KRAS, PIK3CA, ALK, RET, ERBB2, et. Meanwhile, 11 (22.9%) were high tumor mutation burden (TMB) in 48 samples which met TMB assessment conditions. Plasma samples were collected within a few weeks after surgery. Postoperative ctDNA positive rate was 26.5% (13/49) in all patients, and 17.6% (3/17) in stage I, 29.4% (5/17) in stage Ⅱ and 33.3% (5/15) in stage Ⅲ. The ctDNA status had no relationship with collection time from surgery. The median mutation number in ctDNA was 2 (range 1-27). ctDNA positive rate was higher in TMB-H group 63.6% (7/11) than TMB-L 13.5% (5/37) (p=0.003). Considering the possible interference caused by the mutation number in tissue, we limited the top10 genes from tissues to analyze ctDNA again. And the result was the same as previous (p=0.027). Interestingly, in the patient with simultaneous adenocarcinoma and squamous cell carcinoma, we found that the six mutations in ctDNA were 100% matched to adenocarcinoma, and very different from squamous cell carcinoma.

      Conclusion

      CtDNA is a meaningful and feasible biomarker for postoperative monitoring in resectable lung cancer. Moreover, it can identify the source of MRD in multiple primary lung cancer.

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    P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P76.35 - Genomic Characristic and Prognosis of Concomitant with EGFR Copy Numbers Variations in EGFR Mutated Lung Cancer Patients (ID 1708)

      00:00 - 00:00  |  Author(s): xuefeng Xia

      • Abstract

      Introduction

      Concomitant Genetic Alterations with EGFR could affect the response to treatment of EGFR-TKI. EGFR copy numbers variations (CNV) as a common concomitant alteration with EGFR, has been reported in several studies. However, the effect of conconmitant EGFR CNV to treatment of EGFR-TKI remained controversial. This study aims to investigate whether EGFR CNV affecting the frequency of EGFR mutation affect the treatment outcomes of EGFR-TKI.

      Methods

      We screened 262 patients concomitant with EGFR CNV from 3449 newly diagnosed EGFR mutated lung cancer patients. All the patients were detected by hybridization capture-based NGS 1021-gene panel sequencing with tumor biopsy. We hypothesized that frequency of EGFR mutation is affected by EGFR CNV and divided 262 patients into three groups based on the frequency of EGFR mutations. The Group 1(n=69): The frequency of EGFR sensitive mutations was not the highest one in all detected mutations. Then, other patients were assigned to other two group based on the effect of EGFR CNV. And the effect was determinant by Nadeem Riaz et al reported mutation clonal classified methods (Ratio=frequency of highest non-EGFR mutations /frequency of EGFR mutation ≥ 0.5). Group 2: Ratio ≥0.5 means frequency of EGFR mutation was not significant affected by EGFR CNV (n=97); Others were assigned to Group 3(Ratio˂0.5,n=96).

      Results

      The mutational landscape of 262 patients was summarized. Except for EGFR, mutations in TP53 were the most prominent and significant variation (79%). Significantly more TP53 mutations, MYC CNV, and CCND1 CNV mutation were detected in group 1 than in group 2 and 3 (96% vs 81% vs 65%; 19% vs 5% vs 6%; 8% vs 1% vs 1%); And group 2 has more TP53 mutation and less MDM2 CNV mutation compared with group 3 (p=0.009,p=0.0006). The numbers of genetic characterization was also analyzed. Group 3 showed significantly higher EGFR copy numbers than group 1 (p˂0.0001) and 2 (p=0.0013; copy numbers:2.2 vs 2.3 vs 3.5). However, group 1 was detected significantly more numbers of gene of CNV mutation than group 2(p˂0.0001) and 3 (p˂0.0001; CNV numbers:2 vs 1 vs 1). Further, the survival of EGFR-TKI of three groups was compared. Group 1 showed a significantly shorter media PFS than group 2 and 3(mPFS=4.5 vs 9 vs 12; Figure 1).

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      Conclusion

      In our study, frequency of EGFR mutation affected by copy numbers of EGFR CNV and related with treatment of EGFR-TKI, especially patients with a lower frequency of EGFR with an inferior treatment.

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    P85 - Targeted Therapy - Clinically Focused - MET (ID 262)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P85.06 - Clinical and Genomic Features of Middle Intensity cMET Stain of Chinese Lung Cancer Patients (ID 1661)

      00:00 - 00:00  |  Author(s): xuefeng Xia

      • Abstract
      • Slides

      Introduction

      Background:cMET overexpression has been identified as an oncogenic driver in Non-small cell lung cancer(NSCLC). About 25% NSCLC patients was detected cMET positive by immunohistochemistry(IHC) and has been studied for clinical and genomic features. Similarly, the clinical and genomic features of cMET negetive patients are need to be better understood.

      Methods

      Methods: Protein expression of cMET of 196 Chinese NSCLC patients by IHC was determined by measuring the intensity of the stain (0, 1+, 2+, 3+) and the percent staining (0-100%). We reviewed 132 of middle intensity cMET stain (cMET 1+/2+, negetive) with paired tumor-normal samples sequenced by 1021/59 gene panel.

      Results

      Results: In this study, 67.3% (132/196) were detected middle intensity cMET stain including 50.8% (67/132) cMET 2+. All of the patients were lung adenocarcinoma and the average age at diagnosis was 61.4 (range 33-80 years). 43.8% patients had a history of smoking. All of these characteristics were not significantly different between cMET 1+ and cMET 2+ groups. Differences was found in genomic. The common mutations were TP53(76/132), EGFR (74/132) and KRAS (23/132). 5 patients were found cMET activation mutations including 2 of cMET amplification and 3 of cMET mutation(Table 1). More non-synonymous mutation were found in cMET 2+ groups than cMET 1+ (media: 6 versus 5,p=0.02). Significantly higher number of copy numbers variations(CNV) was found in cMET 2+ groups (media: 2 versus 1, p=0.04,Fig 1). However, the gene mutations and actionable mutations were no differences in two groups except that MDM2 CNV mutation was higher in cMET 2+ groups(p=0.03).

      Table1. Genetic aberrations of MET.

      Patients Age Gender Smoking IHC of cMET NGS of cMET
      P1 61 Male NA cMET(2+) MET c.3028G>C
      P2 70 Femal NA cMET(1+) MET c.3028+3A>G
      P3 71 Male No cMET(2+) MET c.2888-19_2888-13delinsAAA
      P4 64 Male Yes cMET(1+) MET CNV
      P5 68 Femal No cMET(1+) MET CNV

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      Conclusion

      Conclusion: Our data suggest that 3.8% middle intensity cMET stain patients had cMET activation which is a clearly therapeutic target to cMET inhibitors. cMET 2+ patients had more non-synonymous mutation and CNV than cMET 1+ patients which may be related to treatment and prognosis.

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    P89 - Targeted Therapy - Clinically Focused - Translational (ID 266)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P89.01 - Clinical and Genomic Features of EGFR-KDD/EGFR Rearrangements of Chinese Lung Cancer Patients (ID 2854)

      00:00 - 00:00  |  Author(s): xuefeng Xia

      • Abstract
      • Slides

      Introduction

      Background:The most frequent epidermal growth factor receptor (EGFR) mutations of lung cancer include exon 19 in deletion and the exon 21 L858R mutation. And EGFR-tyrosine kinase inhibitor (TKI) as the standard first line treatment show good response to classical/sensitizing EGFR mutations. With the development of detection methods, some uncommon genomic mutation events such as exon 18-25 kinase domain duplications (KDD) and EGFR rearrangements are found. EGFR-KDD/EGFR rearrangements have been identified and implicated to be oncogenic in nonsmall cell lung cancers (NSCLCs). However, its prevalence and clinical contributions in lung cancer are largely unknown.

      Methods

      Methods: Here, we conducted our database record review of 10,560 lung cancer patients who underwent 1021-gene panel sequencing using next-generation sequencing (NGS). The panel contains EGFR exons and the introns involved in EGFR-KDD and EGFR rearrangements.

      Results

      Results: EGFR-KDD/EGFR rearrangements were identified in a total of 24 patients, which is approximately 0.23% of the total population reviewed, and also consisted of 0.39% (24/6188) of EGFR mutation-positive patients. A total of 30% of patients (8/24) were identified with EGFR-KDD which were the canonical EGFR-KDD duplication of exons 18–25, and 7 patients were adenocarcinoma and 1 patients was adenosquamous carcinoma. Importantly, none of the 8 patients had other coexisting driver mutations, highlighting the potential oncogenic role of this type of alteration. The others 16 patients were identified EGFR rearrangements, in which 2 patients were identified with the previously described EGFR rearrangements (EGFR-RAD51, EGFR-SEPT14), while the remaining 14 patients harbored not reported rearrangements. Different to the EGFR-KDD, 68.75% of patients (11/16) harbored other EGFR driver mutations including 7 of L858R, 3 of 19 deletions, and 1 of 20 insertions. As reported, we also found 56.25% of patients (9/16) harbored EGFR copy numbers variations. Most of the patients (12/16) were adenocarcinoma, and 4 of patients were NSCLC. Some reports had shown that several types of EGFR rearrangements were sensitive to EGFR-TKI therapists, but EGFR rearrangements were also found in 4 EGFR-TKI resistance patients. One of the patients harbored EGFR 19deletion and had 16 months therapy of osimertinib. Then, a VOPP1-EGFR was detected in the patients’ tissue after EGFR-TKI therapy, highlighting the potential resistance role of this type of alteration.

      Conclusion

      Conclusion: Our findings provide valuable insight into the prevalence of EGFR-KDD/EGFR rearrangements in Chinese lung cancer, and suggested that such rearrangements are clinically important genomic alterations.

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    P92 - Mesothelioma, Thymoma and Other Thoracic Malignancies - Misc. Topics (ID 269)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P92.01 - Genetic Landscape and Potential Therapy Regimen of Thymic Tumor (ID 1685)

      00:00 - 00:00  |  Author(s): xuefeng Xia

      • Abstract
      • Slides

      Introduction

      Thymomas and thymic carcinomas, which are rare epithelial tumors arising from the thymus gland, are the most common tumors of the anterior mediastinum. The National Comprehensive Cancer Network guidelines recommend resection followed by adjuvant platinum-based chemotherapy for resectable tumors. However, the outcomes for thymic tumors are poor with no regimen showing a consistent benefit. To investigate the possibility of targeted therapy for thymic tumor patients, a deeper understanding of the genetic basis is required.

      Methods

      We retrospectively evaluated our database and identified 36 patients of thymic tumor in which 12 of patients were thymomas . All the patients were detected by hybridization capture-based NGS 1021-gene panel sequencing with tumor tissue, peripheral blood and hydrothorax.

      Results

      We analyzed the genetic profiling of the 36 Chinese patients. The most frequently mutated genes were TP53 (11/36), followed by CDKN2A (6/36), BAP1 (5/36), BRD4 (4/36), and KIT (4/36). The common mutation types of TP53 and CDKN2A were single nucleic acid variation (SNV) and copy numbers variation (CNV). 16 of patients were detected targeted gene mutation. The common targeted mutation were CDKN2A(6/16), EGFR (2/16), FBXW7(2/16), KIT(2/16), and PIK3CA (2/16) as shown in Figure 1. CDK4/6 inhibitor like palbociclib may be a consideration targeted therapy regimen. Then, the genetic profiling of thymomas and thymic carcinomas was compared. The proportion of TP53 in thymic carcinomas was higher than thymomas, and proportion of CDKN2A was similar in two groups. However, no significant difference was found in two groups. The media number of nonsynonymous mutation detected was 4 of all patients, and thymomas and thymic carcinomas were 2 and 5, respectively. This may be indicated a poor survival in immunotherapy.

      figure 1.png

      Conclusion

      In conclusion, we identified genetic mutations comprehensively and provide predictive implications for thymic tumor patients. 44.4% thymic tumor patients of chinese were detected targeted mutation and 37.5% of them was CDKN2A mutation, which suggested that CDK4/6 inhibitors will be a consideration treatment regimen for Chinese patients.

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