Stratifiers for oxaliplatin outcome in colorectal cancer

Thesis

Colorectal cancer (CRC) is the second most common cancer in terms of mortality in the world. Oxaliplatin is the one of the most common approved adjuvant chemotherapeutic drugs for advanced stage II and stage III. Despite the improvement in outcome, a high percentage of cases show lack of response and resistance. Thus, my aim for this thesis is to discover or validate a biomarker of oxaliplatin response with potential use in the clinic to guide therapy decisions. Response has been chosen as the primary end point because it presents a more direct measure of the drug effect. To this aim, I have used multiomic data from two clinical trials of the S:CORT consortium (Focus and Foxtrot) and generated transcriptome from another clinical trial (Coin) for deep bioinformatic interrogation of the clinical question. I first investigated 13 candidate biomarkers known for their prominent role in CRC biology. I have found that KRAS mutation is associated with poor response and survival to 5FUFA, but predicts benefit from the addition of oxaliplatin. Furthermore, DDRD signature positivity is predictive of no benefit of oxaliplatin compared to 5FUFA alone. Secondly, I have investigated 32 candidate biomarkers identified from a systematic literature review that I conducted for oxaliplatin resistance. High CDC6 expression and DNA repair score favours no oxaliplatin and predicts lack of response, while high NFE2L2 expression favours oxaliplatin response. Finally, I generated two signatures from RNA expression data of progressive versus non-progressors patients. From this study, I present predictive biomarkers of response for oxaliplatin, important in neoadjuvant clinical settings.

Authors: Hassanieh, S

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: colorectal cancer; genomics; cancer; oncology; transcriptomics; clinical research
• Subjects: Oncology