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FE Liquid Biopsies and Precision Medicine

General overview

Precision medicine helps get the right treatment for the right patient at the right time.

In the context of cancer, this means that treatments will be tailored to the genetic changes in each person’s cancer. Therefore, a precision oncology approach to cancer treatment would require the identification and establishment of predictive biomarkers based on the individual tumor of a patient.

Recent technological advancements revealed an increasing number of molecular aberrations that have now been rendered actionable targets and although many targeted therapies resulted in dramatic improvements in patient outcomes, comprehensive genomic profiling of tumors has also demonstrated the incredible complexity of molecular alterations.

With tissue biopsies, there are inherent limitations of a single biopsy reflecting the genetic complexity of an advanced tumor and heterogeneity of the tumor microenvironment. A simple and minimal-invasive alternative to surgical biopsies is the so call liquid biopsy (LB), which refers to the sampling and analysis of non-solid biological tissue.

Tumors release components such as of cell-free DNA fragments (ctDNA, circulating tumor DNA) or viable cells (CTC, circulating tumor cells) into the circulation, which reflect their genetic or epigenetic landscape. Therefore, CTC and ctDNA can be used for molecular profiling and prognostication purposes for malignant diseases from blood and other body fluids. The LB holds great promise for precision and personalized medicine and in particular, ctDNA has been demonstrated to be a valuable tool to detect cancer recurrence, to predict tumor burden and treatment response, as well as to identify resistance mechanisms and the emergence of novel actionable targets has been proven in numerous studies summarized monitor recurrence, resistance, metastasis and minimal residual disease.

Moreover, it has been shown that patients having higher ctDNA levels at certain time points, i.e. prior to therapy initiation, prior or after tumor resection had significantly shorter PFS (progression-free survival) and/or overall survival (OS).

Furthermore, ctDNA levels can indicate recurrence of a tumor long before progression is clinically obvious and it was shown that the analysis of ctDNA is a better marker for the detection of recurrence of breast and colorectal cancer than conventional protein tumor markers.

A continuous monitoring of changing levels of ctDNA during initiation and maintenance of cancer therapy can be used to assess the patient´s response without burdening the patient, and more importantly, progression can be detected before it is clinically obvious. Another attractive aspect of using ctDNA is the potential to infer the mechanism resistance that inevitably arise for almost all targeted therapies across all tumor entities.

The potential of ctDNA is not limited to patients already suffering from cancer but it may also play a crucial role in the detection of pre-clinical cancer. However, very few studies have focused on the evaluation of ctDNA detection in early-stage cancers (i.e. stage I-II tumors) with even less data available on the detection of ctDNA in blood samples from pre-symptomatic cancer patients.

Background

Tumors release components such as of cell-free DNA fragments (ctDNA, circulating tumor DNA) or viable cells (CTC, circulating tumor cells) into the circulation, which reflect their genetic or epigenetic landscape. Therefore, CTC and ctDNA can be used for molecular profiling and prognostication purposes for malignant diseases from blood and other body fluids. A liquid biopsy (LB) refers to the sampling and analysis of non-solid biological tissue, and therefore is a simple and minimal-invasive alternative to surgical biopsies.

The LB holds great promise for precision and personalized medicine and in particular, ctDNA has been demonstrated to be a valuable tool to detect cancer recurrence, to predict tumor burden and treatment response, as well as to identify resistance mechanisms and the emergence of novel actionable targets has been proven in numerous studies summarized monitor recurrence, resistance, metastasis and minimal residual disease (1-4).

Moreover, it has been shown that patients having higher ctDNA levels at certain time points, i.e. prior to therapy initiation, prior or after tumor resection had significantly shorter PFS (progression-free survival) and/or overall survival (OS).

Furthermore, ctDNA levels can indicate recurrence of a tumor long before progression is clinically obvious and it was shown that the analysis of ctDNA is a better marker for the detection of recurrence of breast and colorectal cancer than conventional protein tumor markers (5, 6).

A continuous monitoring of changing levels of ctDNA during initiation and maintenance of cancer therapy can be used to assess the patient´s response without burdening the patient, and more importantly progression can be detected before it is clinically obvious (7-9). Another attractive aspect of using ctDNA is the potential to infer the mechanism resistance that inevitably arise for almost all targeted therapies across all tumor entities (10-15).

The potential of ctDNA is not limited to patients already suffering from cancer but it may also play a crucial role in the detection of pre-clinical cancer. However, very few studies have focused on the evaluation of ctDNA detection in early-stage cancers (i.e. stage I-II tumors) with even less data available on the detection of ctDNA in blood samples from pre-symptomatic cancer patients. 

Objectives

Despite promising data, the analytical validity and clinical utility of ctDNA have not yet been shown for the vast majority of available ctDNA assays. To this end, a core understanding of the mechanisms and dynamics underlying ctDNA and the resolution of important technical issues is indispensable. At the D&R Institute of Human Genetics at the D&R Centre of Molecular Biomedicine we aim to elucidate the biology and dynamics of ctDNA to eventually bring a a broad spectrum ctDNA approaches to the clinic.

The main objectives of our ongoing projects are: 

  • Development, validation, and standardization of ctDNA analysis approaches
  • ctDNA analysis to monitor treatment response of metastatic cancer patients 
  • ctDNA analysis to identify novel driver genes and alterations in genes related to drug resistance 
  • ctDNA as a predictive marker for response to immune checkpoint inhibitors or neo-adjuvant treatment 
  • Elucidation of the release and biology of ctDNA
  • Analysis of nucleosome occupancy patterns in plasma DNA in healthy and diseased individuals
  • Application of multi-parameter approached aided by artificial intelligence

Strengths

Our LB group at the D&F Institute of Human Genetics has extensive experience in the analysis of plasma DNA, which is reflected in numerous publications in high-ranking journals. We have established a plethora of plasma DNA based approaches to study genome-wide SCNAs and high-sensitivity approaches to detect specific mutations occurring at low allele frequencies. In this highly competitive field, our group is one of the most renowned in the field.

Our expertise has been recognized internationally by invitations to international congresses, reviews and book chapters in international journals. Moreover, in the last years our group leaders (Jochen Geigl, Ellen Heitzer, and Michael Speicher) have been exceptionally successful in the acquisition of research grants, such as FWF, OeNB, or EU-funded IMI grants. Recently, we were granted a Christian Doppler (CD) laboratory with a seven-year budget of 2.08 mio. EUR and two industry partner, i.e. Freenome and PreAnalytix.

The CD lab enables scientific collaboration between globally leading biotech companies in the fields of pre-analytics and molecular diagnostics, and scientists at the MUG.

 

 

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