Author of

• 28971

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  Lunch & Poster Display session (ID 58)

  • Event: ELCC 2019
  • Type: Poster Display session
  • Track:
  • Presentations: 2
  • Moderators:
  • Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1

  • 29066

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    132P - New insights into acquired resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor therapy in lung cancer (ID 307)

    12:30 - 13:00  |  Author(s): Carina Heydt
    • Abstract

    Background
    

    The emergence of acquired resistance (AR) against third-generation epidermal growth factor receptor tyrosine kinase inhibitors (TKI) remain a major clinical challenge in lung adenocarcinoma patients. Here we characterized the role of acquired resistance mechanism with a focus on inter-individual heterogeneity and co-occurring genetic aberrations. We could analyze pre- and post-treatment samples of patients treated with third-generation EGFR TKIs.

    a9ded1e5ce5d75814730bb4caaf49419 Methods
    

    We characterized 128 patients, which are EGFR p.T790M positive to early generation EGFR TKIs within thedatabases of the Network Genomic Medicine (NGM), the NOWEL network, the Department of Thoracic Oncology of the Netherlands Cancer Institute and the Vall d’Hebron University Hospital. In 60 patients, corresponding analyses of third generation EGFR TKI treatment outcomes and molecular analyses were practicable.

    20c51b5f4e9aeb5334c90ff072e6f928 Results
    

    Co-occurring aberrations were found in 75% of the samples with acquired resistance to early-generation TKI. TP53mutations were the most frequent aberrations detected. In MET, copy number variants were found (n = 6). In a subgroup, we identified 4 patients with the new EGFRresistance mutation p.G724S after third-generation TKI treatment. Still, loss of the EGFRp.T790M mutation and METamplification are the most common aberrations after third-generation TKI treatment.

    fd69c5cf902969e6fb71d043085ddee6 Conclusions
    

    EGFR inhibitors represent a powerful tool for precision cancer medicine in genetically selected patients. We could show in this study that additional genetic aberrations are frequent in the setting of AR to EGFR TKIs and may mediate innate and acquired resistance to third-generation EGFR TKIs. Amplification of METwas strongly associated with primary treatment failure and thus the strongest factor in innate resistance. AR to third-generation EGFR TKI (p.G724S) can possibly be overcome with second-generation EGFR TKI.

    b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
    

    The authors.

    213f68309caaa4ccc14d5f99789640ad Funding
    

    Deutsche Forschungsgemeinschaft, Cluster of Excellence RESOLV, the Bundesministerium für Bildung und Forschung, Else Kröner-Fresenius Stiftung, Deutsche Krebshilfe, European Union, (NRW) as part of the EFRE initiative (EMODI, grant no. EFRE-0800397 to R.B. and M.L.S.) and by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303A to R.B. and J.W). E.F. received funding by the Instituto de Salud Carlos III (PI17/00938), NEGECA, ITMC of TU Dortmund.

    682889d0a1d3b50267a69346a750433d Disclosure
    

    J. Fassunke: Honoraria: AstraZeneca. C. Heydt, S. Merkelbach-Bruse: Speaking honoraria: AstraZeneca. J. Wolf: Consulting, lecture fees: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly, MSD, Novartis, Pfizer, Roche; Funding for scientific research: BMS, Johnson&Johnson, MSD, Novartis, Pfizer. R. Buettner: Employee: Targos Molecular Pathology. M.L. Sos: Commercial research grant: Novartis. D. Rauh: Consultant, lecture fees: AstraZeneca, Merck-Serono, Takeda, Pfizer, Novartis, Boehringer Ingelheim, Sanofi-Aventis. All other authors have declared no conflicts of interest.

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    27P - Comparison of three different gene panels for determination of tumor mutational burden by next generation sequencing (ID 371)

    12:30 - 13:00  |  Author(s): Carina Heydt
    • Abstract

    Background
    

    The introduction of cancer immunotherapies has improved survival rates of certain groups of patients. According to first studies, that used whole exome sequencing, the accumulation of tumor neoantigens and therefore tumor mutational burden (TMB) could be used as molecular marker for prediction. In this study, large gene panel assays of different suppliers were tested on 28 DNA samples derived from formalin fixed, paraffin-embedded (FFPE) tumor tissue with regard to implementation in routine diagnostics.

    a9ded1e5ce5d75814730bb4caaf49419 Methods
    

    After DNA isolation the following kits of three different suppliers have been used for library preparation: A custom SureSelect^XTHS Target Assay (Agilent Technologies, Santa Clara, CA, USA), the NEOplus v2 RUO assay (New Oncology, Cologne, Germany) and the TruSight Oncology 500 kit (Ilumina, San Diego, CA, USA, TSO500) following manufacturers’ protocol. All assays were sequenced on the NextSeq 500 system (Illumina). For quality control the TapeStation 4200 System (Agilent Technologies) was used.

    20c51b5f4e9aeb5334c90ff072e6f928 Results
    

    All kits tested showed different final concentration after library preparation. Fragment sizes were as expected and libraries were suitable for sequencing. In terms of time needed for library preparation the NEOplus v2 RUO assay was the most laborious kit. The resulting TMB-scores showed similar picture for all kits and samples tested. For all panels access to the results of the sequenced genes and detected variants is possible. Data access differs between the developers in terms of availability and manageability. Since not all kits use unique molecular identifiers (UMI) the filtering capabilities are different.

    fd69c5cf902969e6fb71d043085ddee6 Conclusions
    

    In this study, three different gene panel assays for TMB-determination were tested. All panels provided a similar TMB-score for the analysed samples. In terms of usage and in respect of implementation in routine diagnostics, time and efficiency are the most important parameters. Here, the TSO500 kit and the SureSelect^XTHS Target Assay showed the best potential for the use in routine diagnostics.

    b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
    

    The authors.

    213f68309caaa4ccc14d5f99789640ad Funding
    

    Has not received any funding.

    682889d0a1d3b50267a69346a750433d Disclosure
    

    C. Heydt: Honoraria: AstraZeneca, BMS, Illumina. S. Merkelbach-Bruse: Honoraria: AstraZeneca; Advisory role: AstraZeneca, Roche. All other authors have declared no conflicts of interest.

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