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

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Gewählte Publikation:

Suppan, C.
Applications of Liquid Biopsy in Breast Cancer
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medical University Graz; 2021. pp. 81 [OPEN ACCESS]


Autor*innen der Med Uni Graz:
Balic Marija
Dandachi Nadia
Heitzer Ellen

Background The analysis of tumor components in blood such as circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) represents an easy, fast, non-invasive and cost-effective tool for both the assessment of tumor dynamics during the treatment of metastatic breast cancer patients and the detection of targetable alterations. Methods In a first step, tumor fractions in plasma of metastatic breast cancer patients were assessed using the untargeted mFAST-SeqS method from 127 serial blood samples. Resulting z-scores for the ctDNA were compared to tumor fractions established with the ichorCNA algorithm and associated with the clinical outcome. Then, we compared the performance of ctDNA, CTCs detected by size-based CTC microfilter enrichment, and blood-based parameters CEA and CA15-3. In a second step, plasma samples and tumor tissue from 69 patients with metastatic hormone-receptor positive breast cancer were analyzed for PIK3CA hotspot mutations. A high-resolution SiMSen-Seq method was used for plasma samples covering 11 PIK3CA mutations. Again, mFAST-SeqS was used to estimate the tumor fractions in the plasma samples. Results We observed a close correlation between mFAST-SeqS z-scores and ichorCNA ctDNA quantifications. Patients with mFAST-SeqS z-scores above three (34.5%) showed significantly worse overall (p=0.014) and progression-free survival (p=0.018) compared to patients with lower values. The baseline CTC count, CEA, and CA15-3 had no prognostic impact on the outcome of patients in the analyzed cohort. PIK3CA mutations were detected in 46.1% of the tissue samples and in 50.7% of the plasma samples. In 7 patients, PIK3CA mutations were found only in plasma. In 5 patients, such mutations found in tissue were not detectable in ctDNA, 2 of which had a low tumor fraction. Together, in 33/67 plasma samples without detectable PIK3CA mutations, 18 samples had elevated tumor fraction, implicating true negative results. In the remaining 15 patients with low tumor fraction, additional tissue analysis was needed. Conclusion Here, the prognostic impact of ctDNA levels detected with mFAST-SeqS demonstrates a tool to assess the ctDNA fraction without prior knowledge of the genetic landscape of the tumor. In addition, SiMSen-Seq-based detection of PIK3CA mutations in plasma shows advantageous concordance with the tissue analyses. A combination with an untargeted, mutation-independent approach for detecting ctDNA fractions may confirm a negative PIK3CA result and thereby enhance the performance of the SiMSen-Seq test.

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