Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Gewählte Publikation:

Riedl, J.
Molecular profiling of tumor DNA for treatment selection in patients with advanced cancer
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2021. pp. 92 [OPEN ACCESS]


Autor*innen der Med Uni Graz:
Gerger Armin
Höfler Gerald
Speicher Michael

Introduction Precision oncology incorporates the concept of molecular profiling-based treatment allocation. To date precision oncology trials have focused on molecular profiling of tissue biopsy-derived DNA. In the Individualized Cancer Treatment (ICT) trial we aimed to evaluate the feasibility and efficacy of targeted cancer therapy selected by molecular profiling of circulating tumor DNA (ctDNA) and/or tumor tissue in patients with advanced and refractory carcinoma in a prospective setting. Methods A mandatory blood draw as well as an optional tissue biopsy were obtained for molecular profiling. Shallow whole-genome sequencing and a cancer hotspot panel were performed on plasma and tissue DNA. Publicly available databases were used to match the molecular profile to targeted treatments based on the annotated results, which were discussed at a molecular tumor board. The primary endpoint was the progression-free survival (PFS) ratio (PFS on molecular profiling guided therapy / PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ≥ 1.2. Secondary endpoints were the number of patients for whom an anti-tumor drug could be defined based on the molecular profiling results, the overall survival (OS) and the overall radiographic response rate (ORR). Results Due to slow patient accrual and lack of clinical benefit an interim analysis was performed after inclusion of 24 patients and the study was terminated prematurely. Molecular profiling yielded informative results from 20 patients (83%), meaning that tumor-specific DNA content in plasma was above 5% and that either a somatic mutation or copy number alteration could be detected from plasma or tissue. A potential tumor-specific drug could be matched in 11 out of 24 patients (46%). Eight patients (33%) received a matched treatment of which two experienced a numerically longer PFS compared to the PFS under last evidence-based therapy line. None of the 8 treated patients met the primary endpoint of a PFS ratio ≥ 1.2. Conclusion This study is the first to report prospective outcome results on the efficacy of ctDNA profiling-based treatment. Despite the premature study termination and the small samples size, this study provides important insights that are critical to further advancing the implementation of precision medicine. Among other the ICT trial indicates that molecular profiling of ctDNA harbours great potential for the concept of personalized cancer treatment. Still, at present its use should be primarily limited to clinical trials evaluating new concepts of ctDNA based treatment allocation.  

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