Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Hammer, S.
ctDNA as a predictor of treatment response in NSCLC patients treated with immune modulating therapy
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2025. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Dandachi Nadia
- Geigl Jochen Bernd
- Heitzer Ellen
- Altmetrics:
- Abstract:
- Non-small cell lung cancer (NSCLC) remains one of the most lethal malignancies worldwide, and while immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advances stages, reliable biomarkers to predict treatment response and guide clinical decision-making are still lacking. This study investigated the potential of circulating tumor DNA (ctDNA) dynamics as a minimally invasive biomarker to predict and monitor treatment outcomes in NSCLC patients undergoing ICI therapy. The study evaluated both the technical feasibility and clinical relevance of ctDNA profiling, leveraging high- sensitivity next-generation sequencing (NGS) approaches. To identify the most suitable ctDNA detection method, multiple commercial assays were rigorously validated using standardized reference materials with known variant allele frequencies (VAF). The AVENIO ctDNA Expanded Kit demonstrated the highest sensitivity and specificity, detecting 65% of expected variant even at a 0.1% VAF. Based on this performance, the assay was applied to a cohort of 167 patients with IIIB-IV NSCLC treated with ICIs. ctDNA was extracted from plasma samples at two time points: before treatment start (t0) and after two cycles (t1). ctDNA levels were quantified using multiple proxies, including average mutant molecules per milliliter (aMM) and VAF metrics. Dynamic changes in ctDNA levels, particularly a ≥50% reduction in aMM were strongly correlated with improved progression-free survival (median 10.0 vs. 2.0 months) and overall survival median (18.4 vs. 5.9 months). Furthermore, a landmark analysis at two months confirmed the early predictive value of molecular response, supporting its utility for real-time clinical decision-making. To ensure specificity of tumor-derived variants, paired sequencing of peripheral blood mononuclear cells (PBMCs) was performed to exclude clonal hematopoiesis (CH)-related mutations, which were found in about 45% of patients. This correction substantially improved response classification and reduced false-positive ctDNA signals. Additionally, patients with STK11 or KEAP1 mutations exhibited significantly poorer outcomes. These findings demonstrate that ctDNA dynamics, when corrected for CH interference and measured using a validated assay, serve as a robust early biomarker of treatment response and survival in advanced NSCLC, offering valuable guidance for personalized treatment strategies.