Current treatment for RAS mutant (mt) metastatic (m) CRC is based on 5-fluoruracil (5-FU) combinations +/- the anti-angiogenesis agent bevacizumab (BVZ). We have described a new classification system (based on copy number alterations (CNA) patterns) to predict metastatic mCRC patient response to SOC chemotherapy + BVZ and have recently published our findings (Smeets et al Nat Comms 2018). Specifically, tumours belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumours, which amongst others consist of POLE-mutated and microsatellite instable tumors, derive no further benefit from BVZ. Overall, we have identified copy number load as a novel potential predictive biomarker of BVZ combination therapy. We now wish to develop a non-invasive plasma-derived cell-free DNA (cfDNA) diagnostic assay to support the clinical translation of our newly discovered classifiers to predict BVZ response in mCRC. Such a blood-based test is important, as most mCRC patients do not undergo a second biopsy. Instead, only the initial diagnostic biopsy of an earlier CRC (often taken several years prior) is available, and the tumour molecular phenotype may have changed over time. Leveraging prospectively collected plasma and mCRC tumour tissue from two translational clinical trials (AC-ANGIORPEDICT NCT01822444 and COLOSSUS NCT03699111), we will develop and validate a non-invasive plasma-derived cfDNA diagnostic assay utilizing low coverage whole genome sequencing. We will confirm CNA profiles found in plasma are concordant with CNA profiles found in the matched patient tumour. The liquid biopsy assay will be used to stratify and predict which patients will gain benefit from BVZ + SOC chemotherapy. Finally, we will implement a multiplex immunohistochemical approach to functionally interrogate the underlying biology that underpins response to BVZ across copy number load subtypes predictive for BVZ outcome.
