@phdthesis{01JBBX8KZZ2ESPZH8CR2H4EDZF,
  abstract     = {{Prostate cancer is the most commonly diagnosed cancer in males in Europe, with the number of cases projected to double by 2040. Although most men with localised prostate cancer are cured, a significant proportion presents with metastases at diagnosis or evolves into a metastatic state. Despite the enormous increase in therapy options over the last twenty years, the 5-year survival is only 32%. To better understand therapy resistance and to provide patient-specific treatment plans, the development of prognostic and predictive biomarkers is highly necessary.
Earlier studies gained knowledge on the molecular alterations via rapid autopsy cohort studies or metastatic tissue biopsies. A patient needs to be sedated for the latter because it is highly invasive and uncomfortable. Tissue biopsies also capture a very small proportion of the tumour and don’t account for spatial heterogeneity within the primary tumour and between the different metastases. Sampling over time to investigate temporal heterogeneity and the tumours response to treatment is next to impossible. Liquid biopsies and circulating biomarkers have emerged as an interesting option to circumvent these limitations. Most of the focus in this field has been on cell-free DNA and circulating tumour cells.
The objective of this thesis was to identify prognostic and predictive biomarkers in metastatic prostate cancer. This was tried to be achieved in both mHSPC and mCRPC. Firstly, I gathered all literature on genomic alterations detected in tissue- and plasma samples in mHSPC and provided a systematic overview. As a comprehensive review was lacking in this space, I felt it could be an asset to the community. Secondly, plasma samples of 46 mCPRC patients treated with lutetium-177-PSMA were subjected to targeted sequencing to associate genomic alterations with survival. This was the first, peer-reviewed study investigating cfDNA samples in the context of lutetium-177-PSMA therapy. Finally, I created an in-solution hybridization capture assay and a complementary computational pipeline to detect both AR splice variants and prostate cancer related genes in cfRNA samples from 1st line mCRPC patients treated with either an ARPi- or taxane chemotherapy regimen. Circulating AR-Vs have prognostic but not predictive value in mCPRC and previous studies have mostly focused on the presence of the AR-V7 transcript in either circulating tumour cells or whole blood samples.
The findings in this thesis add to the broader understanding of liquid biopsies and how it could be of additional value in the clinical management of metastatic prostate cancer patients. New prognostic biomarkers have been identified that will need prospective validation for their implementation in patient selection. A cfRNA capture assay with the ability to detect splice variants and potentially perform transcriptional subtyping was developed which could have major implications in the molecular characterization of tumours via liquid biopsies.}},
  author       = {{Vanwelkenhuyzen, Jan}},
  language     = {{eng}},
  pages        = {{XX, 151}},
  publisher    = {{Ghent University. Faculty of Medicine and Health Sciences}},
  school       = {{Ghent University}},
  title        = {{From mutations to splice variants : identifying liquid biopsy derived biomarkers in metastatic prostate cancer}},
  year         = {{2024}},
}