04/11/2022

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REVEAL- New Potential Target Structures in Metastasized Colorectal Cancer

The biomarker study REVEAL, funded by the German Cancer Consortium (DKTK), coordinated by PD Dr. Julian Holch, DKTK partner site Munich, and Prof. Dr. Reinhold Schäfer, DKTK partner site Berlin, demonstrated the serial analysis of mutation status as well as gene expression under standard therapy (first-line therapy) in patients with metastatic colorectal cancer. The study offers a promising approach to better understand secondary resistance mechanisms. Remarkably, changes in gene expression correlated with the development of resistance. In further studies, these findings will be further validated and their influence on the selection of other treatment methods (second-line therapy) will be evaluated.

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© J. Kumbrink / LMU, J. Holch / LMU Klinikum (Kumbrink J et al (2022), Figure 1)

For patients with metastatic colorectal cancer, the combination of chemotherapy with a monoclonal antibody directed against the target structures of the tumor represents an important treatment option. If the tumors cannot be completely removed surgically after the initiation of such a therapy, almost all patients develop a progressive disease with recurrence of the tumor caused by therapy-resistant cells (secondary resistance). Since these patients have a very poor prognosis, it is necessary to better understand secondary resistance mechanisms.

This was the starting point of the multi-center, prospective biomarker study REVEAL (ReEVAluation of Liver metastasis), coordinated at the two DKTK partner sites Munich and Berlin. The results were published in July. By analyzing the mutation status as well as gene expression, molecular changes were identified in order to better understand potential resistance mechanisms and to be able to respond to them in the future. For this purpose, the REVEAL study relied not only on the analysis of primary colorectal tumors but also on the analysis of liver metastases obtained under standard first-line therapy. This approach was complemented by the targeted search for molecular changes in patient blood samples – so-called liquid biopsies – which could be obtained during therapy without significant patient burden.

Between 2014 and 2018, a total of 64 patients, where an extended molecular diagnosis was possible during their treatment course, were recruited at six German cancer centers and medical practices. It was shown that changes in gene expression of the tumors contribute to secondary resistance rather than alterations in mutation status. A gene expression signature was identified that can precisely differentiate intestinal tumors from liver metastases. This signature was subsequently validated in two independent patient cohorts. Finally, two genes of this signature (SFRP2 and SPP1) were identified as prognostic biomarkers as well as potential therapeutic targets.

Here you can find the original publication Kumbrink J et al (2022).