Oncogenic variants guiding treatment in thoracic malignancies

Pei Meng

    Research output: ThesisThesis fully internal (DIV)

    810 Downloads (Pure)

    Abstract

    The aim of this research project was to improve diagnostic methods, explore resistance mechanisms to targeted therapy and establish prognostic value of molecular biomarkers in non-small cell lung cancer (NSCLC) and esophageal squamous cell carcinoma (ESCC). We set up and validated the performance of an RNA-based assay allowing simultaneous testing of multiple therapeutic targets. This effort was successful and can be applied on biopsies in clinical practice. However, tumor-educated platelets of patients with known driver variants and NSCLC showed no tumor-derived mRNA molecules, so this cannot be implemented in clinical practice. Circulating tumor DNA levels in low disease-stage ESCC patients were associated with tumor load in real-time and may be used to monitor disease load.
    Personalized medicine facilitated by routine molecular diagnostics has markedly improved clinical management of cancer patients. We showed that high EGFR copy numbers as determined by amplicon-based NGS data predicts a worse overall survival in EGFR mutated patients treated with first-line EGFR-TKI, especially in those who developed a T790M mutation. To explore resistance mechanisms in BRAF p.(V600E) mutated patients treated with BRAF/MEK inhibitors we analyzed the presence of concurrent mutations of genes in the PI3K or MAPK pathways. This study revealed a comparable survival of patients with or without concurrent mutations. Finally, we described treatment response of two EGFR mutant patients who developed a BRAF V600E resistance mutation. Combined treatment with BRAF/MEK inhibitors and the EGFR-TKI osimertinib showed promising results, also in additional cases reported in the literature.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • van den Berg, Anke, Supervisor
    • Groen, Harry, Supervisor
    • Kok, Klaas, Co-supervisor
    • van der Wekken, Anthonie, Co-supervisor
    Award date15-Mar-2021
    Place of Publication[Groningen]
    Publisher
    DOIs
    Publication statusPublished - 2021

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