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Haihua Yang



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    EP1.17 - Treatment of Early Stage/Localized Disease (ID 207)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.17-35 - CBCT Radiomics May Predict Short-Term SBRT Effect in Early Stage Lung Cancer Patients (Now Available) (ID 501)

      08:00 - 18:00  |  Author(s): Haihua Yang

      • Abstract
      • Slides

      Background

      This study aimed to determine whether radiomics features can be obtained from cone-beam CT (CBCT) through the linac based onboard-imaging systems.

      Method

      Thirty consecutive patients with early stage lung cancer treated with stereotactic body radiation therapy (SBRT) (Total dose:50-60Gy, Fraction:5-8) were included. CBCT scan were performed before delivery of each SBRT treatment. Diagnostic CT scan before Radiation Therapy (diagnostic CT) and follow-up CT at one month after radiotherapy (follow-up CT) were analyzed. Primary tumors were delineated manually and modified on diagnostic CT, CBCT and follow-up CT. Tumor size on diagnostic CT and follow-up CT were used to calculate the reduction rate. The primary endpoint was average daily tumor reduction rate. Radiomics features were extracted from first fraction CBCT (CBCT first), last fraction CBCT (CBCT last) and diagnostic CT by Imaging Biomarker Explorer (IBEX) software. Radiomic features were selected using correlation coefficient and LASSO dimensionality reduction based on R.

      Result

      A total of 222 radiomics features were obtained from CBCT first, CBCT last and diagnostic CT of each patient. Based on correlation coefficients>0.70 and with LASSO dimensionality reduction, 5, 4 and 5 features were selected in diagnostic CT, CBCT first and CBCT last, respectively. Comparing the features in three CT subsets, two features were same between diagnostic CT and CBCT first, three features were the same between diagnostic CT and CBCT last. Two features are common in all three CT imaging sets. (Table 1)

      Table 1 Different characteristic values of different CT radiomics be predicted SBRT reduction rate.

      Images

      diagnostic CT

      CBCT first

      CBCT last

      Feature

      Inverse Variance

      Inverse Variance

      Inverse Variance

      Percentile

      Percentile

      Percentile

      Complexity

      Cluster Shade

      Cluster Shade

      Correlation

      Max3D Diameter

      Correlation

      Inverse Diff Moment Norm

      Information MeasureCorr1

      Conclusion

      A few radiomics features may be robust to the noise in daily CBCT images which are often considered of poor quality. Study with larger sample size are needed to verify this interesting finding.

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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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      JCSE01.17 - Modelling the Immunosuppressive Difference of SBRT and CRT by Simulating the Dose to Circulating Lymphocytes in Non-Small Cell Lung Cancer (ID 3431)

      07:00 - 11:15  |  Presenting Author(s): Haihua Yang

      • Abstract
      • Slides

      Abstract
      Background
      Radiation-dose delivered to circulating lymphocyte (CL) has detrimental effect on immune system for cancer patients. Our study established a model to compare the cumulative dose on CL of patients with conventional fractionation radiotherapy (CRT) and stereotactic body radiation therapy (SBRT) in lung cancer with different target volume.

      Methods
      The improved model is based on convolution algorithm suggested by Yovino(Cancer Investigation, 2013). The current blood DVHs of each organ were multiplied with treatment field DVH to generate original DVHs. During one second, 0.6% of whole-body blood circulates through each organ and rest body according to blood circulating pattern and then new DVHs of organ were generated. The new DVHs would be used for next second’s calculation with treatment field DVH. Conventional fractionated non-small cell lung cancer plan 60Gy (30 fractions*2.0Gy) and SBRT plan 50Gy (5fractions*10Gy) are constructed for three patients with different target volumes. The primary endpoint is peak cumulative blood dose (PCBC).

      Results
      PCBC of three patients with CRT and SBRT were calculated as Figure 1. PCBC with CRT to circulating lymphocyte (CL) were 2.5Gy, 5.6Gy, 9.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. And PCBC with SBRT to circulating lymphocyte (CL) were 2.1Gy, 2.9Gy, 6.0Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. PCBC gap of SBRT to circulating lymphocyte (CL) was decreased 0.4Gy, 2.7Gy, 3.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively.



      Conclusion
      An improved simulation-model was established, SBRT, compared to CRT, will lead to decreased cumulative dose on CL, which may cause less impact on immune system with the enlargement of PTV-volume.

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.03 - The Third Generation EGFR Inhibitor (EGFR-TKI) HS-10296 in Advanced NSCLC Patients with Resistance to First Generation EGFR-TKI (Now Available) (ID 766)

      10:30 - 12:00  |  Author(s): Haihua Yang

      • Abstract
      • Presentation
      • Slides

      Background

      HS-10296 is an oral, potent, high selective third generation EGFR tyrosine-kinase inhibitor (EGFR-TKI) for sensitizing mutations, and the EGFR Thr790Met (T790M) resistance mutation which has been demonstrated by phase I study. This phase II, open-label, multicenter single-arm study was designed to confirm the efficacy and safety of HS-10296 in a large population of non-small-cell lung cancer (NSCLC) patients with EGFR T790M mutation, who had progressed after first generation EGFR-TKI treatment.

      Method

      Patients aged at least 18 years with centrally confirmed EGFR T790M-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC after first generation EGFR-TKI treatment received HS-10296 110 mg orally once daily until disease progression, or intolerable toxicity, or patient withdrawal. Patients with asymptomatic, stable brain metastases not requiring steroids were allowed to enroll. The primary endpoint was the objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1 every 6 weeks. Response endpoints (ORR and disease control rate [DCR]) were assessed in response analysis set. Secondary end points including progression-free survival (PFS), duration of response (DoR), depth of response (DepOR), overall survival (OS) and safety were evaluated in full analysis set. The final data cutoff was on Jan 5, 2019. The study is still ongoing.

      Result

      Totally, 244 patients (median age 60.8) entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients) between May 16, 2018 to Oct 23, 2018. 2 patients were excluded from the evaluable for response analysis set (n=242) due to absence of measurable disease at baseline by independent central review. At data cutoff, 182 (74.6%) patients remained on treatment. The median duration of follow-up was 4.7 months. 160 of 242 patients achieved confirmed partial responses by independent central review. The ORR was 66.1% (95% CI: 59.8-72.1). The DCR was 93.4% (95% CI: 89.5-96.2). The most common adverse reactions (≥ 10%) were blood creatine phosphokinase increased (43 [17.6%]), aspartate aminotransferase increased (29 [11.9%]), pruritus (28 [11.5%]), rash (28 [11.5%]) and alanine aminotransferase increased (26 [10.7%]). The most common all-causality grade 3 and 4 adverse events were blood creatine phosphokinase increased (14 [5.7%]) and hyponatraemia (4 [1.6%]). Serious adverse events were reported in 30 (12.3%) patients, of which 19 (7.8%) were investigator assessed as possibly treatment-related to HS-10296. Three deaths were due to adverse events; one was related to cardiopulmonary failure, other two events occurred after disease progression. There was no interstitial lung disease during study treatment.

      Conclusion

      HS-10296 has demonstrated good clinical benefit with minimal toxicity in patients with EGFR T790M-positive NSCLC patients who have progressed after first generation EGFR-TKI treatment. The Phase III study has already launched comparing HS-10296 with gefinitib in advanced NSCLC patients with EGFR sensitizing mutations. (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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    OA06 - Refining Lung Cancer Screening (ID 131)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Screening and Early Detection
    • Presentations: 1
    • Now Available
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      OA06.07 - Discrimination of Lung Invasive Adenocarcinoma with Micropapillary Pattern Based on CT Radiomics (Now Available) (ID 399)

      11:00 - 12:30  |  Presenting Author(s): Haihua Yang

      • Abstract
      • Presentation
      • Slides

      Background

      To develop and validate the radiomics nomogram on the discrimination of lung invasive adenocarcinoma (IAC) with micropapillary pattern from non-micropapillary pattern lesion and improve the diagnostic accuracy rate of lung invasive adenocarcinoma with micropapillary pattern before operations and provide guidance for follow-up treatments.

      Method

      Forty-one pathologically confirmed lung invasive adenocarcinomas with micropapillary pattern from January 2014 to December 2018 were included. Eighty-two pathologically confirmed lung invasive adenocarcinomas without micropapillary pattern from January 2018 to December 2018 were collected. Select 86 patients (70%) randomly from the 123 patients as the primary cohort, and the other 37 patients (30%) were set as an independent validation cohort. Least absolute shrinkage and selection operator (Lasso) was used for feature selection based on contrast enhancement CT images and then radiomics signature building. ROC analysis and AUC were used to value the ability to identify the lung invasive adenocarcinomas with micropapillary pattern.

      Result

      According to GrayLevelCooccurenceMatrix3, Intensity Histogram and Shape, nine hundred and eighty-five radiomics features were extracted by IBEX. And after data pre-processing such as eliminating missing items, strong correlation variables and multicollinear variables, the features were reduced to 40 features. Based on Mann-Whitney U Test, 28 features were figured out from the 40 features. Then Lasso was used to reduce the features to 3 features (10-1clusterprominenc, -333-4clusterprominence, 8-1contrast) as the most meaningful discriminators to build the radiomics signatures (Table 1). According to SPSS21.0 binary logistic regression analysis, ROC analysis and AUC show that the radiomics signature have effective discrimination performance of lung invasive adenocarcinoma with micropapillary pattern from non- micropapillary pattern lesion (AUC=0.766) and it reflects better in the independent validation cohort (AUC=0.807) (Figure 1).

      Table 1 Three characteristic prediction parameters in radiomics label

      prediction parameter P value U value W value AUC
      10-1clusterprominence <0.005 765.000 4168.000 0.772
      -333-4clusterpromise <0.005 790.000 4193.000 0.765
      8-1contrast <0.005 919.000 4322.000 0.727

      figure 1.jpg

      Conclusion

      The radiomics signature established in this study have effective prediction of lung invasive adenocarcinoma with micropapillary pattern and non- micropapillary pattern lesion.

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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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      P1.01-90 - Update Phase II Results of Early Primary Tumor Stereotactic Body Radiotherapy Combined with First-Line EGFR-TKI in Advanced EGFR Mutated NSCLC (Now Available) (ID 903)

      09:45 - 18:00  |  Author(s): Haihua Yang

      • Abstract
      • Slides

      Background

      Our previous work (ChiCTR-OIN-17013920) has reported the efficacy and safety of early primary tumor stereotactic body radiotherapy (SBRT) combined with Icotinb in advanced EGFR mutated (EGFRm) NSCLC patients (2018 IASLC WCLC Abstract #11985). Hani Ai-halabi et al. reported that about 80% of EGFR TKI drug resistance was at the primary site. Here we report the updated results.

      Method

      Patients with pathologically confirmed advanced NSCLC with 19/21 EGFRm were enrolled between September 2016 and March 2019. SBRT was performed during the first month of oral first-line EGFR-TKI (Icotinib 125mg three times daily or Gefitinib 250mg once daily) in patients who were assessed as partial response or stable disease according to RECISE v1.1 assessment. The primary tumor was given SBRT at dose of 50Gy/5F or 60Gy/8F for peripheral and central primary, respectively. The primary endpoints were progression free survival ] (PFS) and pattern of failure, while the second endpoints were overall survival time (OS) and adverse events (AEs).

      Result

      36 patients were recruited in this study. The follow-up time was 14.5 months (range 3.4-30.4). Median age was 66 years (range 49-83). There were 20 males and 16 females. Eighteen patients with 19-del mutation and 18 had L858R mutation. Overall, median PFS and median OS was 14.1 months and 26.3 months (Figure 1), respectively. Three patients had progression at the primary site, 5 patients had mixed progression and 19 patients with distant progression only. In subgroup analysis, the median PFS was 14.1 months vs. 12.8 months in 19-del vs. L858R mutation patients. The median OS was 19.4 months in L858R mutation group while that in 19-del mutation was immature. Additionally, there was no ≥grade 3 AEs in patients treated with this regimen.

      figure 1.jpg

      Conclusion

      This study suggested that early primary tumor SBRT may play a role to delay resistance of first-line EGFR-TKI in advanced EGFRm NSCLC patients. Patients with 19-del mutation may gain a better survival time compared with L858R mutation. The promising results are to be validated in a multi-center, comparable randomized phase III clinical trial (Target-SBRT, NCT03727867).

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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-17 - Function of Antisense LncRNA RP11-539E17.5 and FAM83A-AS1 Up-Regulating FAM83A in Lung Adenocarcinoma Tumorigenesis and Development (Now Available) (ID 502)

      09:45 - 18:00  |  Author(s): Haihua Yang

      • Abstract
      • Slides

      Background

      Chromosome 8q24 lies in a gene desert with only a few predicted coding genes, but its variation is associated with multiple tumors. FAM83A in this region activates both PI3K/AKT/TOR and RAS/MAPK signaling cascades downstream of EGFR. The contribution of long noncoding gene in the antisense chain of FAM83A (RP11-539E17.5 and FAM83A-AS1) to the risk of lung adenocarcinoma (LUAD) need to be studied.

      Method

      We use systematic informatics method to identify the differential expression genes of the Cancer Genome Atlas (TCGA) LUAD transcriptome sequencing data. Then use data mining method to analysis the lncATLAS, USCS, Cistrome, and ENCODE database to infer the biological role of these two lncRNAs. Significant analysis of gene ontology (GO) terms enrichment analyzed the co-expression genes of RP11-539E17.5 in the LUAD and adjacent tissues. At last we use cell experiment to verify the lncRNA function.

      Result

      FAM83A-AS1 and RP11-539E17.5 located in Chromosome 8q24 were significantly different expressed between cancer and adjacent tissues (log2foldchange>5, p<0.05). The two lncRNA expression levels had notable correlation with FAM83A expression (coR> 0.8, P<0.005) and were significantly associated with patient overall survival and clinical stage (p<0.05). RP11-539E17.5, located in the enhancer element GH08J123181,belong to the enhancer lncRNA group. lncRNA subcellular localization data (lncATLAS) results showed that RP11-539E17.5 transcripts in K562 cells is mainly distributed in the nucleus, and most around the nucleolus and chromosomes. USCS, Cistrome, and ENCODE data mining identified four transcription factors (FOSL2, CTBP2, CEBPB, and MAFK) have significant correlation with the expression of FAM83A-AS1 and RP11-539E17.5. In K562 cell line with high expression of FAM83A-AS1, RP11-539E17.5 and FAM83A showed that expanded regions of RP11-539E17.5 gene sequence were marked by enhancer-specific modifications (H3K27ac domains and H3K4me3 domains). This region also showed an excellent source of DNase sensitive site, and with several binding sites for CTCF, FOSL2, CTBP2, CEBPB and MAFK. In addition, RP11-539E17.5 gene also with enriched DNA methylation feature. RP11-539E17.5 and FAM83A-AS1 knocked down both inhibited the expression of FAM83A the proliferation of PC9, and RP11-539E17.5 gene owning a more significant effect. GO terms enrichment analysis of the co-expressed genes with RP11-539E17.5 showed that the most significantly activated biological pathways is involved with Cell cycle,and cell mitotic signaling pathway, while the molecular function involved with transcription factor binding, DNA binding, ATP binding, endonuclease activity, DNA topoisomerase activity.

      figure 1.jpg

      Conclusion

      We found a LncRNA RP11-539E17.5 with enhancer character up regulate FAM83A expression in LUAD. These results can lay a theoretical foundation for LUAD corresponding countermeasures.

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      P1.03-34 - The lncRNA NEAT1 Promotes Radioresistance via the MiR-491-5p/CAPG Axis in NSCLC (Now Available) (ID 89)

      09:45 - 18:00  |  Author(s): Haihua Yang

      • Abstract
      • Slides

      Background

      Long noncoding RNAs (lncRNAs) have been implicated in various biological processes and pathological conditions in cancer. However, the exact roles of LncRNA NEAT1 and its underlying mechanisms in radioresistance of non-small cell lung cancer (NSCLC) remain largely unclear.

      Method

      The expression of LncRNA NEAT1 was measured in NSCLC tissues and cell lines by reverse transcription‑quantitative polymerase chain reaction (RT-qPCR). The radiosensitivity of NSCLC cells including H358, H226, HCC827, H1975, H1395 and H23 were detected by colony formation. Lentivirus-mediated short hairpin RNAs were used to knock down NEAT1 expression in H358 cells. Furthermore, the role of NEAT1 on tumor cell biological behavior and radioresistance were explored through MTT, colony formation, transwell migration, and invasion assays in vitro. Luciferase reporter assay was used to verify interaction between miR-491-5p and NEAT1, CAPG. The potential mechanism of LncRNA NEAT1 was identified by Western blot. Additionally, the association between the survival time and miR-491-5p expression in lung adenocarcinoma patients were evaluated based on the TCGA data.

      Result

      NEAT1 was highly expressed in NSCLC tissues and cell lines. NEAT1 was up-expressed in radiosensitive NSCLC cells and low-expressed in radioresistant NSCLC cells. Conversely, miR-491-5P was low-expressed in radiosensitive NSCLC cells and up-expressed in radioresistant NSCLC cells. In addition, we revealed a reciprocal repression between NEAT1 and miR-491-5P. CAPG was identified as a down-stream target of miR-491-5P. Further experiments revealed that lncRNA NEAT1 silencing inhibited cell proliferation, invasion and radioresistance in vitro. Overexpression of CAPG rescued the effects of NEAT1 downregulation on proliferation, invasion and radioresistance. In addition, mechanistic analysis showed that lncRNA NEAT1 upregulated the miR-491-5p-targeted gene CAPG through acting as a competitive “sponge” of miR-491-5p. By cox regression analysis, a tendency towards a survival benefit in patients with high miR-491 expression was observed in 430 lung adenocarcinoma patients of the TCGA database.

      Conclusion

      Our findings suggest that NEAT1 regulated proliferation, invasion and radioresistance by modulating the miR-491-5p/CAPG axis in NSCLC.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-69 - Modelling the Immunosuppressive Difference of SBRT and CRT by Simulating the Dose to Circulating Lymphocytes in Non-Small Cell Lung Cancer (Now Available) (ID 295)

      09:45 - 18:00  |  Presenting Author(s): Haihua Yang

      • Abstract
      • Slides

      Background

      Radiation-dose delivered to circulating lymphocyte (CL) has detrimental effect on immune system for cancer patients. Our study established a model to compare the cumulative dose on CL of patients with conventional fractionation radiotherapy (CRT) and stereotactic body radiation therapy (SBRT) in lung cancer with different target volume.

      Method

      The improved model is based on convolution algorithm suggested by Yovino(Cancer Investigation, 2013). The current blood DVHs of each organ were multiplied with treatment field DVH to generate original DVHs. During one second, 0.6% of whole-body blood circulates through each organ and rest body according to blood circulating pattern and then new DVHs of organ were generated. The new DVHs would be used for next second’s calculation with treatment field DVH. Conventional fractionated non-small cell lung cancer plan 60Gy (30 fractions*2.0Gy) and SBRT plan 50Gy (5fractions*10Gy) are constructed for three patients with different target volumes. The primary endpoint is peak cumulative blood dose (PCBC).

      Result

      PCBC of three patients with CRT and SBRT were calculated as Figure 1. PCBC with CRT to circulating lymphocyte (CL) were 2.5Gy, 5.6Gy, 9.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. And PCBC with SBRT to circulating lymphocyte (CL) were 2.1Gy, 2.9Gy, 6.0Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. PCBC gap of SBRT to circulating lymphocyte (CL) was decreased 0.4Gy, 2.7Gy, 3.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively.

      figure 1.jpg

      Conclusion

      An improved simulation-model was established, SBRT, compared to CRT, will lead to decreased cumulative dose on CL, which may cause less impact on immune system with the enlargement of PTV-volume.

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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-40 - EGFR-TKIs May Sensitize Radiation Lung Damage in Stereotactic Body Radiotherapy Based on Intensity Analyzing (ID 297)

      09:45 - 18:00  |  Author(s): Haihua Yang

      • Abstract

      Background

      To measure early radiographic changes of acute radiation pneumonitis after stereotactic body radiotherapy (SBRT) and compare the differences between patients treated with and without the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).

      Method

      Patients with SBRT with 3-month follow-up CT scans were eligible. 20 patients treated with EGFR-TKIs a month before stereotactic body radiotherapy (Target-SBRT group) were formed the primary study population. Another 20 patients received SBRT alone were selected from our SBRT data bank to serve as control, by matching dose prescription, tumor size and location. Pre- and post-SBRT CT scans from these 40 patients were registered to each other and the mean value of CT intensity (Hounsfield unit, HU) were extracted for regions of the lungs receiving the same dose at 10 Gy intervals to generate dose-response curves (DRC). The frequency of density changes>200 HU was modeled depending on the fractionation using a Probit model for different treatments.

      Result

      There were significant differences in the DRC of pre-SBRT, post-SBRT and the differences of HU value (△HU) in lung between the SBRT alone and Target SBRT groups (all P<0.050)(Figure 1). The respective dose for a 50% complication risk (TD50) for changes>200HU was 72Gy (95% confidence interval (CI 58-107) in SBRT alone group versus 52Gy (CI 46-59) in targeted SBRT group (Figure 2).

      figure 1.jpg

      figure 2.jpg

      Conclusion

      Compared to SBRT alone, targeted SBRT group has a lower TD50 and m value, both suggesting an increased complication probability of normal lung tissue.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-24 - Detection of Plasma T790M Mutation After the First Generation EGFR-TKI Resistance of Non-Small Cell Lung Cancer in the Real World (Now Available) (ID 304)

      09:45 - 18:00  |  Author(s): Haihua Yang

      • Abstract
      • Slides

      Background

      The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has shown efficacy in mutation non-small cell lung cancer(NSCLC), but acquired resistance is inevitable. It has been confirmed that the secondary EGFR Thr790Met (T790M) mutation accounted for about 50% at acquired resistance in tumor tissue. The third generation EGFR-TKI had significantly efficacy in T790M positive NSCLC . The purpose of this study was to investigate the positive rate of plasma T790M mutation and its relationship among the clinical characteristics and the frequency of T790M mutation in acquired resistance after first line EGFR‒ TKI treatment in the real world.

      Method

      Patients were recruited prospective from September 2017 to June 2018.The eligibility criteria of the trial included:1. Older than 18 years, histologically confirmed NSCLC stageⅢB/Ⅳ, EGFR mutation positive; 2.Had progressive disease (PD) after first generation EGFR-TKI by RECIST, PFS>3months; 3.excluded patients who had recevied the third generation TKI treatment. All patients take 10 ml of blood, and detected the T790M gene by amplification refractory mutation system(ARMS). The study was approved by the Ethics Committee of Taizhou Hospital, ethical batch number: 201637.

      Result

      189 patients are in the analysis (Table 1). The overall plasma T790M mutation rate was 36.51 % (69/189). The positive rate of T790M mutation after the failure of first generation EGFR-TKI treatment was not correlated with the patient's age, sex and the type of first generation TKI drugs. However, it is related to the mutation type of EGFR in baseline and the mode of progression according to Wu YL et al. reports. The frequency of T790M mutation among patients with initial exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 45.44%, 26.19% and 33.33%. The mutation rate of T790M in 19del mutant patients was higher than that of L858R mutation and other mutations (p=0.026). The frequency of T790M mutation in local progression patients was 50% after the first generation EGFR TKI was resistant to drug, when in gradual progression was 26.92%, and in dramatic progression was 38.10%. The frequency of T790M mutation of patients with local progression was significantly higher (p=0.031).

      Table 1 Univariate analysis of the association between patients' characteristics and plasma T790M status.

      Characteristics

      NO.

      Plasma T790M mutation states

      P value

      Positive (+)

      Negative(-)

      Age(yr)

      ≤60

      64

      25(39.1%)

      39(60.9%)

      P=0.438

      >60

      125

      44(35.2%)

      81(64.8%)

      Sex

      Male

      64

      27(42.19%)

      37(57.81%)

      P=0.246

      Female

      125

      42(33.6%)

      83(66.4%)

      Baseline EGFR mutation status

      19-del

      99

      45(45.45%)

      54(54.55%)

      P=0.026

      21-L858R

      84

      22(26.19%)

      62(73.91%)

      others

      6

      2(33.33%)

      4(66.67%)

      First generation TKI

      Lcotinib

      96

      28(29.17%)

      68(70.83%)

      P=0.074

      Gefitinib

      90

      39(43.33%)

      51(56.67%)

      Erlotinib

      3

      2(66.67%)

      1(33.33%)

      Disease progression modes

      Gradual progression

      78

      21(26.92%)

      57(73.08%)

      P=0.031

      Local progression

      48

      24(50%)

      24(50%)

      Dramatic progression

      63

      24(38.10%)

      39(61.90%)

      Conclusion

      The overall plasma T790M mutation rate was 36.51% after first generation of EGFR-TKI acquired resistance of NSCLC in the real world. The frequency of T790M mutation with initial mutation of 19 Del was higher than that of L858R mutation, and local progression was higher than gradual progression and dramatic progression.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-15 - Dosimetric and Toxicity Benefits of Adaptive IMRT in Patients with Stage III Non-Small Cell Lung Cancer (ID 396)

      09:45 - 18:00  |  Author(s): Haihua Yang

      • Abstract
      • Slides

      Background

      Multiple studies observed anatomical changes or tumor shrinkage during concurrent chemoradiotherapy in patients with non-small cell lung cancer (NSCLC). Mid-treatment CT based adaptive radiotherapy targeting to the shrunken tumor can reduce the dose to adjacent normal tissue or potentially deliver a higher dose to the tumor. We aimed to quantitatively analyze the benefit of intensity-modulated radiotherapy (IMRT) adapting to CT changes at the 20th fraction in stage III NSCLC patients.

      Method

      We retrospectively evaluated consecutive patients with unresectable stage III NSCLC treated with adaptive IMRT from November 2017 to August 2018. The eligibility criteria included a mid-treatment CT simulation for replanning at the 20th fraction and a follow-up of at least 6 months. The prescribed dose was 64-66 Gy in 30 fractions unless exceeding the dose limit. Normal tissues were delineated according to RTOG1106 atlas on organs at risk under the supervision of a senior physician. Dose-volume histograms were calculated for the initial plans, composite adaptive plans, and lung isotoxic boost plans. Radiation pneumonitis (RP) and esophagitis (RE) were graded per CTCAE v4.03. Univariate logistic regression was applied to analyze the correlation between dosimetric factors and adverse events.

      Result

      53 patients were eligible in this study. The average GTV shrinkage was -40.9% at the 20th fraction. Comparing the dosimetric factors of the composite adaptive plans to the initial ones, the GTV coverage was found marginally higher (P=0.002). The doses to normal tissues were significantly lower (all Ps<0.001) in heart mean dose by 109.5 cGy, esophagus V60 by 1.53%, cord maximum dose by -272.7 cGy, lung V20 and mean lung dose (MLD) by 1.11% and 79.2 cGy, respectively. The tumor targets could potentially get an average lung isotoxic boost of 481 cGy. Eight patients (15.1%) had grade 2 RP while no grade 3 or higher RP occurred. Twenty-three patients (43.4%) developed grade ≥ 2 RE. MLD was significantly associated with grade 2 RP with an odds ratio of 1.39 per 100 cGy increase (95% CI, 1.01 to 1.91; P=0.042). Esophagus V60 was significantly associated with grade ≥ 2 RE with an odds ratio of 1.15 per 1% increase (95% CI, 1.04 to 1.28; P=0.009). (Table 1)

      Factors

      Initial Plans

      Adaptive Plans

      Mean difference

      95%CI

      P Value

      Targets

      PGTV (%)

      92.96

      93.81

      0.85

      0.33

      1.37

      0.002

      PTV(%)

      94.13

      94.54

      0.41

      0.35

      0.80

      0.033

      Lung

      V5(%)

      46.77

      45.72

      -1.05

      -0.70

      -1.41

      <0.001

      V20(%)

      25.15

      24.04

      -1.11

      -0.80

      -1.42

      <0.001

      V30(%)

      18.62

      17.60

      -1.02

      -0.77

      -1.27

      <0.001

      MLD (cGy)

      1411.4

      1332.2

      -79.2

      -60.1

      -98.4

      <0.001

      Heart

      V30(%)

      17.40

      15.11

      -2.29

      -0.94

      -3.62

      0.001

      V40(%)

      10.87

      9.06

      -1.81

      -0.98

      -2.64

      <0.001

      V55(%)

      4.06

      2.79

      -1.27

      -0.76

      -1.77

      <0.001

      Mean Dose(cGy)

      1504.5

      1395.0

      -109.5

      -67.88

      -151.22

      <0.001

      Pericardium

      V30(%)

      32.17

      30.43

      -1.74

      -0.77

      -2.70

      0.001

      V40(%)

      25.70

      24.00

      -1.7

      -0.76

      -2.64

      0.001

      V55(%)

      13.87

      11.87

      -2

      -1.34

      -2.66

      <0.001

      Mean Dose(cGy)

      2192.9

      2091.2

      -101.7

      -60.00

      -143.3

      <0.001

      Esophagus

      V40(%)

      39.43

      36.49

      -2.94

      -1.62

      -4.27

      <0.001

      V50(%)

      27.89

      24.08

      -3.81

      -2.36

      -5.27

      <0.001

      V60(%)

      7.57

      6.04

      -1.53

      -0.96

      -2.09

      <0.001

      Max Dose(cGy)

      6498.3

      6336.7

      -161.6

      -101.99

      -221.3

      <0.001

      Cord

      Max Dose(cGy)

      4113.0

      3840.3

      -272.7

      -209.51

      -335.93

      <0.001

      Conclusion

      By adapting to the changes on CT scans at the 20th fraction, the adaptive IMRT approach provides significant dosimetric benefits and has the potential to lower the risk of symptomatic pneumonitis and esophagitis in stage III NSCLC.

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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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      P2.03-05 - PHLPP1 Expression Through AKT and ERK Dual Signaling Pathways May Slow Down the Resistance to TKI in EGFR-Mutated Lung Adenocarcinoma (ID 298)

      10:15 - 18:15  |  Author(s): Haihua Yang

      • Abstract

      Background

      The epidermal growth factor receptor (EGFR) kinase inhibitors are effective treatments for lung cancers with EGFR activating mutations, but the magnitude of tumor regression varies and drug resistance is unavoidable. Multiple mechanisms of resistance to EGFR-TKIs have been identified, including the occurrence of secondary mutations in the EGFR gene, MET amplification, acquired BRAF rearrangements and activation of bypass pathways. Central to these mechanisms of resistance is the re-activation of AKT and ERK signaling, which enables escape of tumor cells from EGFR inhibitor treatment. However, the mechanisms of reactivation of PI3K-AKT and ERK/MAPK pathway are unclear.

      Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase (PHLPP) acts as tumor suppressors in various types of human cancer by suppressing cell survival pathways and promoting apoptosis through inhibiting AKT and ERK pathway activation. Here, we hypothesize that PHLPP is a key regulator of EGFR-TKI resistance in lung cancer and a potential treatment target for overcoming resistance to EGFR-TKI treatment.

      Method

      A transcriptomic of PHLPP1 in non-small lung cancer cell according to gefitinib sensitivity obtained from Gene Expression Omnibus (GEO) database under accession number GSE4342 were analysis. The lentivirus-mediated delivery of shRNA was used to generated stable knockdown of PHLPP1 expression lung cancer cells, and retrovirus-mediated delivery was used to generated stable overexpression of PHLPP1 lung cancer cells. Western blotting, real-time PCR (RT-PCR) and immunofluorescence were used to determined PHLPP expression in vitro. PHLPP1 expression in clinical sample was determined by Immunohistochemical (IHC) staining. MTT assay was conducted to determine the cell proliferation. Xenografts bearing PHLPP overexpression and control were evaluated EGFR-TKI induced tumor regression.

      Result

      PHLPP1 gene expression was higher in gefitinib-sensitive NSCLC cell lines than gefitinib-resistant NSCLC cell lines from a GEO public database. In vitro, EGFR mutated NSCLC cell line HCC827 continuously exposing to gefitinib exhibited dramatically reduced expression of PHLPP1 and increased phosphorylation AKT and ERK. Knockdown of PHLPP1 decreased cell death induced by the EGFR-TKI in EGFR-mutant lung cancer cells, overexpression of PHLPP1 enhanced gefitinib-induced apoptosis in gefitinib-resistance EGFR-mutant lung cancer cells. In xenograft model, overexpression of PHLPP showed significantly more tumor regression after gefitinib treatment at 1-week time point compared to control group. In patients, PHLPP1 were highly expressed in tumors with EGFR common mutations pre- and post-development of resistance to EGFR TKIs. PHLPP1 expression were down regulated in the post-relapse tumor samples compared to that of pre-treatment, and patients with higher PHLPP1 expression in pre-treatment had significantly longer progression-free survival (PFS).

      Conclusion

      PHLPP loss may be a key molecule contributing to the resistance of EGFR-TKI by activating PI3K-AKT and ERK/MAPK signaling pathway. PHLPP may serve as a potential predictor of EGFR-TKI treatment response in these patients. Up-regulating PHLPP expression may prevent or /and delay the emergence of EGFR-TKI resistance. Further study is warranted to prove PHLPP as an effective strategy.

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    P2.12 - Small Cell Lung Cancer/NET (ID 180)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.12-08 - Surprisingly Promising Tumor Control Rate of S1 Combination with Anlotinib with Refractory Relapsed SCLC Who Failed ≥ 2 Lines Chemotherapy (Now Available) (ID 885)

      10:15 - 18:15  |  Presenting Author(s): Haihua Yang

      • Abstract
      • Slides

      Background

      Patients with refractory relapsed small cell lung cancer (SCLC) who failed more than 2 lines chemotherapy have limited options. Objective Response Rate (ORR) of Immunotherapy (CheckMate-032 and Keynote-158) was only 20%. Anlotinib is a novel TKI on multi-kinase (VEGFR, c-Kit, PDGFR, FGFR) angionesis inhibitor, had ORR of only 4.9% in ALTER1202 for the third-line and further-line treatment of SCLC. S-1, a combination of three pharmacological compounds, namely tegafur (prodrug of 5-fluorouracil), gimeracil, and oteracil potassium, is a new oral fluoropyrimidine derivative designed to enhance anticancer activity and reduce gastrointestinal toxicity, has been used for treatment of SCLC with ORR of 4% (MOLECULAR AND CLINICAL ONCOLOGY 1: 263-266, 2013). In patients without any option of systemic therapy, our clinic started combined use of these drugs. This study aimed to report the preliminary results of combined S1 and anlotinib therapy in these refractory released SCLC.

      Method

      This study retrospectively analyzed refractory relapsed in SCLC who failed to more than 2 lines’ chemotherapy. Eligible patient must have received Anlotinib (12 mg PO QD from day 1 to 14, every 3 weeks) and S1(60mg PO Bid from day 1 to 14, every 3 weeks) combined therapy. The primary endpoints were ORR and disease control rate (DCR). The secondary endpoints were PFS, OS, and safety and tolerability.

      Result

      A total of 12 patients were recruited from Nov 2018 in this study. There were 2 females and 10 males. The median age was 64 years (37-75 years). 6 patients had failed 2 lines of refractory diseases and 6 cases failed 3 lines’s chemotherapy. Until 31 March 31, 2019, 2, 3, 3, 2, and 2 cases had accomplished 6, 5, 4, 3, and 2 cycles, respectively. The ORR and DCR were 50% and 100%, respectively (Figure 1). The median PFS and OS were not reached at the time of data analysis. The most common Treatment-related adverse events (TRAEs) were hypertension, anorexia, fatigue, blurred vision, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 5 (41.7%) of patients. Anlotinib was reduced to 8mg in 2 patients and 10mg in 3 patients due to grade 3 TRAEs.

      figure 1.jpg

      Conclusion

      The study demonstrates that S1 combination with anlotinib seemed to be an effective treatment option for patients with surprisingly promising response rate in refractory relapsed SCLC. Prospective clinical trial (SALTER Trial, ClinicalTrials.gov ID: NCT03823118) is ongoing to confirm the promising results.

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