Author of

• 25950

  +

  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

  • 27192

    +

    P2.13-18 - A Multicenter Prospective Biomarker Study to Explore Mechanisms of Afatinib Resistance Based on Digita PCR and Next-Generation Sequencing (ID 12187)

    16:45 - 18:00  |  Presenting Author(s): Eiji Iwama
    • Abstract

    Background
    

    Afatinib is an oral irreversible blocker of ErbB-family kinases and shows a pronounced anti-tumor efficacy for advanced non–small cell lung cancer (NSCLC) positive for activating mutations of EGFR. We applied digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) to explore mechanisms of afatinib resistance.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations. Tumor and plasma samples were collected before afatinib treatment and after treatment failure with disease progression (systemic progressive disease, SPD). DNA from the samples was analyzed by dPCR and NGS.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Thirty-five patients were enrolled, with a median follow-up time of 15.8 months. Among 25 patients with SPD, tumor, plasma, or both samples were available for 18, 23, and 16 individuals, respectively. dPCR and NGS detected EGFR T790M mutation in 13 (56.5%) and 11 (47.8%) of 23 plasma samples at SPD, with sensitivity and specificity compared with tumor samples being 83.3% and 70.0% (dPCR) and 50.0% and 70.0% (NGS), respectively. Applying the ratio of the number of T790M alleles to that of activating mutations (T/A) for determination of the T790M positivity improved the sensitivity and specificity of plasma analysis compared with tumor analysis to 83.3% and 100% (dPCR) and 57.1% and 100% (NGS), respectively. Among 25 patients with SPD, the T790M mutation of EGFR alone (n = 11), copy number gain (CNG) of NRAS (n = 1), CNG of MET (n = 1), CNG of EGFR plus T790M (n = 1), and CNG and E545K of PIK3CA plus T790M of EGFR (n = 1) were identified by NGS as putative resistance mechanisms against afatinib. No tumor showed transformation to small cell carcinoma. Median progression-free survival was longer in patients with than in those without T790M at SPD (15.1 versus 10.9 months, P =0.25). Median time to SPD was much longer in patients with than in those without T790M at SPD (17.9 versus 10.9 months, P =0.18).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Assessment of T/A ratio with dPCR or NGS improved specificity of plasma analysis for determination of T790M positivity compared with tumor analysis. dPCR and NGS analysis in tumor and plasma samples shed light on exploring mechanisms of afatinib resistance.

    6f8b794f3246b0c1e1780bb4d4d5dc53

• 25963

  +

  P3.09 - Pathology (Not CME Accredited Session) (ID 975)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27592

    +

    P3.09-15 - Genetic Profiling of Idiopathic Pulmonary Fibrosis Associated Non-Small Cell Lung Cancer by Targeted Next-Generation Sequencing (ID 13842)

    12:00 - 13:30  |  Author(s): Eiji Iwama
    • Abstract

    Background
    

    Little is known about the pathogenesis or genetic profiles of idiopathic pulmonary fibrosis (IPF) associated non-small cell lung cancer (NSCLC). This study was performed to investigate the genetic profiles of IPF associated NSCLC and to explore the possibility of defining potential therapeutic targets by using next-generation sequencing (NGS).

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    The Oncomine Comprehensive Assay v3 (OCAv3) from Thermo Fisher was used to detect clinically relevant single nucleotide variants (SNVs), insertions/deletions (INDELs), copy number variations (CNVs), and gene fusions from 161 unique cancer-related genes.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Surgically resected tumor specimens from 18 patients with IPF associated NSCLC (adenocarcinoma, n=9; squamous cell carcinoma, n=9) were collected. A total of 61 gene mutations was identified by targeted NGS and a median number of mutated genes per patient was 5 (range, 2–26). No sensitizing EGFR mutation (exon 19 del, L858R, G719X, L861Q) and fusions genes (ALK, ROS1, RET) were identified. Fourteen samples had one or more mutations in oncogenes including PIK3CA (n=7, 39%), BRAF (n=5, 28%), PTEN (n=4, 22%), EGFR (n=4, 22%), MET (n=3, 17%), KRAS (n=2, 11%), HRAS (n=2, 11%), NRAS (n=1, 6%), ERBB2 (n=1, 6%) and DDR2 (n=1, 6%). In addition to these potentially druggable oncogenes, loss-of-function mutations in ARID1A (n=10, 56%) and TP53 (n=7, 39%), tumor suppressor genes regulating DNA damage checkpoint were frequently identified. Furthermore, loss-of-function deletions (P2415del) in NOTCH1 which plays a role in cell fate determination, growth, and survival was observed in six (33%) patients.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    This study demonstrated novel genetic profiles of IPF associated NSCLC using NGS.

    6f8b794f3246b0c1e1780bb4d4d5dc53