Biomarkers in metastatic colorectal cancer

Bevacizumab, a humanised monoclonal antibody against the Vascular Endothelial Growth Factor A (VEGF-A), is the first anti-angiogenic therapy proven to slow metastatic disease progression in metastatic colorectal cancer (mCRC) patients. In patients with liver-limited disease, neoadjuvant chemotherapy including Bevacizumab and subsequent liver resection are increasingly applied and the concept of neoadjuvant therapy followed by potential curative liver resection is the only treatment option associated with long-term survival. Yet, a substantial number of patients do not sufficiently respond or eventually become unresponsive to chemotherapy, resulting in rather modest gains in terms of overall survival. It is essential to understand why tumours from some patients respond to Bevacizumab, and based on these insights, to identify response markers that predict which patients are more likely to benefit from neoadjuvant chemotherapy including Bevacizumab and liver resection. The aim of this project is to investigate germline polymorphisms of the VEGF-dependent and VEGF-independent angiogenesis that are associated with response to therapy and long-term survival in resected colorectal cancer liver metastases (CLM) after neoadjuvant chemotherapy including Bevacizumab. Furthermore, comparative gene expression and genomic analyses in a subset of patients with matched pairs of primary tumours and metastases will be performed and related to response and clinical outcome. (Revision). The results of this project will contribute to the effort to develop a personalized treatment concept for future patients with metastatic colorectal cancer.

The liver is most common metastatic site in patients with metastatic colorectal cancer. Patients with colorectal liver metastases can be cured in a multidisciplinary treatment approach (approx. 25%) or long-term survival can be achieved. This approach comprises surgical resection of the liver metastases in combination with perioperative chemotherapy. The monoclonal antibody bevacizumab blocks the most important growth factor (vascular endothelial growth factor, VEGF) for blood vessel formation (angiogenesis) and blood supply of the tumor and is administered together with combination chemotherapy. Biomarkers can predict response to therapy or survival and can guide treatment decisions. Currently, no predictive and prognostic biomarkers are available for therapy with bevacizumab in patients with metastatic colorectal cancer and liver metastases that could help identifying patients who benefit from this potentially demanding and complication-associated treatment approach.The aim of this project was to identify predictive and/or prognostic biomarkers in patients who underwent liver resection and perioperative chemotherapy including bevacizumab for colorectal liver metastases. To identify these biomarkers, variations of genes, so-called single nucleotide polymorphisms (SNPs), involved in cell signaling pathways of the VEGF-dependent and independent angiogenesis and vessel maturation and their association with response and survival were investigated, as these pathways facilitate potential mechanisms of resistance to therapy with bevacizumab and/or could be novel treatment targets. On one hand, SNPs in genes involved in angiogenesis and vessel maturation were identified that were associated with response to chemotherapy including bevacizumab, recurrence-free survival, probability of cure, overall survival and patterns of disease recurrence. On the other hand, a hierarchical order of the investigated genes and SNPs was discovered that identified subgroups of patients, for which these biomarkers are relevant. The results of these investigations can contribute to the effort to identify novel predictive and/or prognostic biomarkers and novel treatment targets in patients with colorectal liver metastases who undergo perioperative chemotherapy including bevacizumab and liver resection.In additional investigations, SNPs in genes involved in key signaling pathways modulating response of the immune system and for cancer dormancy were identified that were associated with response and survival in these patients.