Liquid biopsy in the clinic – highlights from the European Congress of Pathology

The Swiss Cancer Institute’s (SCI) Young Oncology Academy (YOA) is a support and mentorship program for young oncologists. Academy participants are supervised by a renowned faculty member for almost a year and are required to write a review paper on a topic of interest. Today we present Dr. med. Albert Baschong’s review paper about the European Congress of Pathology 2025. Dr. med. Baschong was a YOA participant in 2025 with the specialty pathology and was mentored by Prof. Dr. med. Matthias Matter.

In recent years, it has been evident that pathology is in a state of profound change. The advent of novel molecular and digital methods has influenced pathology substantially. This was also demonstrated at this year’s European Congress of Pathology in Vienna, which took place under the motto «Tradition meets Future».

I would therefore like to give a brief insight into the session «Liquid biopsy in solid tumors» and introduce an exciting analysis method and its potential applications in Ewing sarcoma. This review has been adapted from a presentation given to the SCI Sarcoma Interest Group.

Liquid biopsy is a procedure that extracts molecular information from bodily fluids. Tumor cells release their molecular signature in various forms, whether as circulating tumor cells (CTCs), in exosomes or as free DNA (circulating tumor DNA [ctDNA]) after apoptosis. CtDNA is a part of cell-free DNA (cfDNA). The majority of cfDNA consists of leukocyte residues. Blood is typically used as the fluid for liquid biopsy, but other body fluids can also be employed (e.g. pleural effusion, ascites, cerebrospinal fluid).

This «liquid» molecular tumor analysis has a wide range of applications but includes mainly the analysis of mutational signatures, methylation, and changes in fragmentation. The ease with which samples can be obtained also highlights their greatest advantage over traditional tissue biopsies: low invasiveness. In addition, multiple metastatic sites can be detected in their entirety as can the reflection of a tumor’s heterogeneity. On the other hand, ctDNA may be completely absent or only present at low concentration in liquid samples. This makes the samples very sensitive and requires highly sensitive detection methods (e.g. Droplet Digital PCR, NGS). In addition, some analyses, such as fusion analyses, CNV and TMB, are more challenging. CtDNA levels can also vary greatly within and between tumor types. Consequently, the use of liquid biopsy is not yet widely adopted. However, there are various established applications of liquid biopsies. Examples include ESR1 testing in breast cancer and resistance mutation testing in lung cancer.

Liquid biopsy is not yet widely used in soft tissue tumors. Ewing sarcoma is a tumor that develops in bones and soft tissues. It has a low mutational rate and highly fragmented DNA. Its detection in liquid biopsies proves difficult.

Peneder et al. developed a bioinformatic tool, called LIQUORICE, to detect ctDNA by using fragmentation patterns. Interestingly, DNA methylation influences fragmentation patterns by affecting chromatin structure. The developed algorithm uses epigenetic signals and fragmentation patterns for determining the tumor of origin. With this, Peneder et al. were able to distinguish liquid biopsies from Ewing sarcoma patients from other sarcomas, quantify tumor burden and track treatment response.

In summary, liquid biopsy is an exciting analytic method. Combining it with digital solutions opens up new possibilities for its broader application.