Author of

• 18975

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  P3.01 - Advanced NSCLC (ID 621)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 23866

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    P3.01-007 - Heterogeneous Resistance Mechanisms in Rebiopsies from EGFR-Mutated NSCLC: Transformation to SCLC; FGFR3 and T790M Mutations (ID 8250)

    09:30 - 09:30  |  Author(s): E. Santoni-Rugiu
    • Abstract
    • Slides

    Background:
    Patients with epidermal growth factor receptor (EGFR) gene-mutated NSCLC initially show substantial clinical benefit from EGFR Tyrosine-Kinase Inhibitors (TKIs), but will ultimately develop resistance with a median progression-free survival of 9-15 months. However, the type and timing of TKI-resistance cannot be predicted and several mechanisms may occur simultaneously/subsequently during TKI-treatment. We present a patient case with advanced non-small cell lung cancer (NSCLC) of adenocarcinoma subtype (ADC) with EGFR-mutation and Erlotinib-treated Different mechanisms of TKI-resistance were detected in tumor biopsies during treatment time.
    
    Method:
    The patient was a 49 year-old, previously healthy, Caucasian male with metastatic ADC. A diagnostic biopsy from hepatic metastasis, cytology from metastatic pleural effusion at first progression during TKI-therapy and a biopsy from new liver metastasis at second progression were analyzed by histology, immunohistochemistry and targeted next-generation sequencing (NGS) of hot-spot mutations in 50 cancer-related genes (Ion AmpliSeq Cancer Hotspot Panel v.2, Ion Torrent, Thermo Fisher Scientific).
    
    Result:
    CT-scans revealed tumor in the right upper lobe with mediastinal infiltration and multiple pulmonary and hepatic metastases, stage T4N2M1b. Diagnostic liver biopsy revealed ADC (mucin-producing, CK7- and TTF1-positive epithelial acinar structures), which concomitantly harbored an EGFR exon 19-mutation (p.E746_A750delELREA) and a previously unreported 2 bp microdeletion in the fibroblast growth factor receptor 3 (FGFR3; p.D785fs*31) gene. The patient received first-line Erlotinib but progressed after 7 weeks with metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) and maintenance of EGFR-mutation and FGFR3-mutation was identified. The progression was treated with standard Carboplatin-Etoposide regimen for SCLC together with Erlotinib continuation. The second progression 7 months later was a new liver-metastasis with persistence of the original EGFR- and FGFR3-mutated ADC-phenotype and additional emergence of the Erlotinib-resistant T790M EGFR-mutation. The patient rapidly deteriorated and deceased.
    
    Conclusion:
    Thus, in this advanced EGFR-mutated NSCLC rapid onset and heterogeneous mechanisms of TKI-resistance occurred at different times of metastatic disease: 1. Concomitant FGFR3-mutation prior to and during TKI-treatment as potential intrinsic resistance-mechanism; 2. Transformation to SCLC at 1st progression during TKI-therapy; 3. Acquisition of T790M EGFR-mutation at 2nd progression. This suggests a continuous variation of TKI-resistant cells’ genetic and phenotypic behavior. Therefore, re-biopsies are important to provide the current status of the disease and better define subsequent treatment options. “Liquid biopsies” may potentially help identify heterogeneous genetic resistance-mechanisms; however assessment of mechanisms such as SCLC-transformation needs tissue biopsies
    
    

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