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Yun Fan



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    OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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      OA13.06 - Final Report of a Prospective Randomized Study on Thoracic Radiotherapy Target VolumesĀ in Limited-stage Small Cell Lung Cancer with Radiation Dosimetric and Pathologic Analyses (ID 11970)

      11:25 - 11:35  |  Author(s): Yun Fan

      • Abstract
      • Presentation
      • Slides

      Background

      The interim analysis of our prospective trial, which compared irradiation to pre-chemotherapy or post-chemotherapy tumour extent while application of involved field radiotherapy (IFRT) for limited-stage small cell lung cancer (SCLC), showed that reduced field did not result in increased local/regional out-field recurrence. This report presents the final results of the clinical study with radiation dosimetric and pathologic analysis as interpretations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Chemotherapy consisted of 4 to 6 cycles of etoposide and cisplatin (EP). After 2 cycles of EP, patients were randomly assigned to receive thoracic radiotherapy (TRT) to either the post- or pre-chemotherapy tumour extent as study arm or control. TRT was administered concurrently with cycle 3 chemotherapy. IFRT was applied for both arms. The lymph node regions (groups 1 to 10) were contoured in treatment planning system. The intentional or incidental radiation doses to each lymph node regions were recorded. Patients with stage T1-2N0-1M0 SCLC received radical lobectomy. The minimal distances between microscopic nidus and the edge of gross tumor were measured. The clinical target volume of the primary tumor (CTV-T) was defined as the margins covering 95% of microscopic disease extension.

      4c3880bb027f159e801041b1021e88e8 Result

      Between June, 2002 and January, 2017, 159 and 150 patients were randomly assigned to study arm or control. The 1-, 3-, and 5-year local/regional progression free probability were 79.4%, 60.1% and 60.1% respectively in the study arm versus 79.8%, 64.5%, and 57.3% in the control (p=0.73). The median overall survival (OS) time was 22.1 months in the study arm (95% CI, 18.2-26.0) and 26.9 months (95% CI, 23.5-30.3) in the control, the 1-, 3-, 5-, and 7-year OS rates were 81.1%, 31.6%, 23.9% and 22.2% respectively in the study arm versus 85.3%, 36.6%, 26.1% and 20.0% in the control arm (p=0.51). A total of 1680 lymph node regions in 105 patients were contoured. The lymph node regions that received incidental radiation doses over 30Gy were: 7, 3P, 4L, 6, 4R, 5 and 2L. Eight patients were enrolled in the pathologic evaluation of CTV-T. The median range of CTV-T in patients received or did not receive neoadjuvant chemotherapy were 0.4mm and 1.7mm respectively, a margin of 1.4mm and 10.2mm could cover 95% of microscopic nidus extension respectively (p=0.00).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Irradiating post-chemotherapy tumour extent and applicant of IFRT didn't increase local/regional failure, and the OS difference wasn't statistically significant between the two arms. TRT could be limited to post-chemotherapy tumour extent, while IFRT could be routinely applied for limited-stage SCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-43 - Next-Generation Sequencing in the Exploration of Genetic Heterogeneity for Lung Adenocarcinoma Patients with EGFR Activating Mutations (ID 11194)

      16:45 - 18:00  |  Author(s): Yun Fan

      • Abstract
      • Slides

      Background

      Increasing evidence leads to a ratiocination that genetic heterogeneity of the lung adenocarcinoma patients with sensitive EGFR mutations may impact clinical responses and outcomes to EGFR-TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed targeted NGS with a gene panel covering 416 cancer-related genes to profile genetic characteristics of 69 lung adenocarcinoma patients with activating EGFR mutations and assessed the contribution of targeted NGS to exploration of genetic heterogeneity of such cohort.

      4c3880bb027f159e801041b1021e88e8 Result

      We detected total 200 actionable genetic alterations (mean 2.9 variations per patient, range: 1-7 variations) in tumor DNA and 140 actionable genetic alterations (mean 2.0 variations per patient, range: 0-5 variations) in matched plasma ctDNA, respectively. The concurrent genes with the highest mutation rate were TP53 (observed in 72.5% patients), other uncommon EGFR mutations (observed in 21.7% patients), EGFR amplification (observed in 20.3% patients), RB1 (observed in 10.1% patients), PIK3CA (observed in 7.2% patients), and MYC (observed in 5.8% patients). NGS provides EGFR mutation detection in plasma with a test sensitivity of 88.2% and specificity of 100.0%. Novel mutations potentially related to primary drug resistance were identified including: CDC73, SMAD4, and CTNNB1 missense mutations; RB1, ARID1A, ARID2, DNMT3A, STK11, and ATR frameshift indel; CDKN2B-PATA31D1, NFKBIA-OR11H12 fusion gene; PRKCI, CCNE1, MCL1, ARAF copy number gain; RB1 loss. The pathways analysis showed that unique pathways in the primary resistant cohort included: 1) immune related pathways: Toll-like receptor signaling pathway, T cell receptor signaling pathway; 2) epithelial-mesenchymal transition (EMT) related pathways: TGF-beta signaling pathway; 3) downstream pathway of EGFR: PIK3CA/AKT/mTOR signaling pathway; 4) cell function related pathways: Mismatch repair pathway, AMPK signaling pathway, TNF signaling pathway, Notch signaling pathway, and Transcriptional misregulation in cancer.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, we note the complexity and heterogeneity of activating EGFR-mutant lung adenocarcinoma that may confer primary resistance to EGFR TKI using NGS platform. This study highlights the advantage of the NGS than traditional methods on testing EGFR mutations, enabling further refinement in sub-classification for the improved personalization of lung cancer treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.09 - Pathology (Not CME Accredited Session) (ID 958)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.09-31 - Cisplatinum Suppressed Metastasis of NSCLC by Inhibiting Macrophage M2-Like Polarization (ID 12542)

      16:45 - 18:00  |  Author(s): Yun Fan

      • Abstract
      • Slides

      Background

      Although M2-like tumor-associated macrophages (TAMs) have been considered as a vital therapeutic target in cancer therapy due to their role in promoting tumor progression and metastasis by inducing expression of CCR2 and CX3CR1 through IL-10 secretion, few compounds have been identified to inhibit M2-like polarization of TAMs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In vitro analysis of cisplatinum in preventing macrophage M2-like polarization was conducted. Expression of cell surface marker CD206 and CDH1, CCR2, CCL2 and CX3CR1 genes were detected.The migration of non-small lung cancer cells promoted by the conditioned medium from M2-like macrophages was conducted by Transwell migration assay. The percentage of M2-like macrophages in tumor and normal lung tissues were analysised after the administration of cisplatinum for one week.

      4c3880bb027f159e801041b1021e88e8 Result

      Here, we showed that cisplatinum significantly prevented macrophage M2-like polarization induced by IL-10 in vitro, as illustrated by reduced expression of cell surface marker CD206 and CDH1, CCR2, CCL2 and CX3CR1 genes. Furthermore, the migration of non-small lung cancer cells promoted by the conditioned medium from M2-like macrophages could be restrained by cisplatinum. Furthermore, cisplatinum reduced the number of metastasis of lung cancer without affecting tumor growth. Both in tumor and normal lung tissues, the percentage of M2-like macrophages decreased after the administration of cisplatinum for one week.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Taken together, these data suggest that cisplatinum is able to inhibit macrophage M2-like polarization, which plays a vital role in cisplatinum suppressed metastasis of NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-15 - Short-Term Responders of NSCLC to EGFR-TKIs Display High Prevalence of TP53 Mutations and Primary Resistance Mechanisms (ID 12540)

      16:45 - 18:00  |  Presenting Author(s): Yun Fan

      • Abstract

      Background

      Non-small cell lung cancer (NSCLC) with activating EGFR mutations in exon 19 and 21 usually responds to EGFR tyrosine kinase inhibitors (TKI), but sometimes the responses can only be maintained for a few months. The underlying mechanisms of such short responses have not been fully elucidated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The genomic profiles of sixteen short-term responders (SR) that had progression free survival (PFS) of less than 6 months on the first-generation EGFR TKI were interrogated, in comparison to twelve long-term responders (LR) that had more than 24 months of PFS. All patients were diagnosed with advanced lung adenocarcinoma and harbored EGFR 19del or L855R mutation before treatment. Paired tumor samples collected before treatment and after relapse (or at the last follow-up) were subjected to next-generation sequencing of 416 cancer-relevant genes.

      4c3880bb027f159e801041b1021e88e8 Result

      SR patients were significantly younger than LR patients (p<0.001). 88% of SR patients have TP53 variations compared to 13% in LR patients (p<0.001), and 37.5% SR patients carry EGFR amplification, which is much higher than LR patients (8%). In addition, 12 SR patients (75%) were identified with other potential primary resistance mechanisms in pre-treatment samples, including PTEN loss, BIM deletion polymorphism, amplifications of EGFR, ERBB2, MET, HRAS and AKT2. Comparatively, only 3 LR patients (25%) were detected with EGFR or AKT1 amplification that could possibly exert resistance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The diversified pre-existing resistance mechanisms in SR patients revealed the complexity of defining treatment strategies even for EGFR sensitive mutations.

      6f8b794f3246b0c1e1780bb4d4d5dc53