Personalisation of therapy in advanced colorectal cancer

Personalisation of therapy is an important goal in modern oncology, however routes for biomarker discovery and validation are challenging with a high level of evidence required prior to application into routine care. Whilst cancer care is stratified by biomarker status in some tumour sites, less progress is evident in advanced colorectal cancer (aCRC). In this thesis candidate clinical and molecular biomarkers have been tested within the datasets and biobanks of randomised controlled trials in aCRC (FOCUS, PICCOLO and COIN). Specifically, the utility of routine clinical information as biomarkers, the mechanisms of the poor prognosis of BRAF-mutant aCRC, predictive markers of efficacy for anti-EGFR agents in RAS-wt patients, and testing of pharmacogenomic markers of toxicity and efficacy for irinotecan have been tested. Routinely measured markers of the systemic inflammatory response, the derived neutrophil-lymphocyte ratio and platelet count, were validated as independent adverse prognostic markers in aCRC and may help identify patients who are not disadvantaged more conservative upfront treatment approach. It has been demonstrated that the poor prognosis conferred by BRAF-mutation is mainly driven by rapid progression following first-line therapy, rather than chemo-resistance. Knowledge of BRAF-mutation status therefore provides useful clinical information beyond the context of prognostication and selection for anti-EGFR therapy, with particular implications for treatment sequencing. mRNA overexpression of EGFR ligands and HER3 were both shown to be promising positive predictive markers for anti-EGFR therapy in aCRC in RAS-wt patients. In both studies a population of RAS-wt patients who fail to benefit from anti-EGFR agents were clearly identified. Both markers warrant urgent further validation and clinical development. Therefore further clinical and molecular biomarkers have shown potential clinical utility in aCRC, which all hold promise for routine application and to further personalise treatment in aCRC.