DEBIRI TACE Patterns and Predictors of Response Robert Jones Declaration Robert Jones is a consultant to Biocompatibles UK LTD.

Pathological response to chemotherapy predicts survival 100 90 80 70 60 50 40 30 20 10 Major response Complete response Minor response % survival 1 2 3 4 5 6 7 8 9 10 Years Blazer, JCO 2008

Pathological Response Rates after Treatment 70 60 50 40 30 20 10 55% 55% FOLFOX/FOLFIRI DEBIRI-TACE 36% % patients 30% 15% 9% Minor Major Complete Pathological response

Metabolism of Irinotecan (CPT-11) APC SN-38 CYP3A4 Blood CPT-11 CES2 Topo-1

“…tumour CES2 expression may contribute to variable response to irinotecan containing chemotherapy” Clinical Cancer Research 2002; 8: 2605-11

“…23 fold variation in CES-2 expression in colon cancers, which directly correlated with conversion from irinotecan to SN-38” Clinical Cancer Research 2003; 9: 4983-91

“Absolute levels of CES-2 appear highest in hepatic parenchyma, with colorectal primary tumour having levels two to three fold lower ” British Journal of Cancer 1999; 80: 364-70

“Only 10% of cells need to express CES-2 for 48% growth suppression… “Only 10% of cells need to express CES-2 for 48% growth suppression…..bystander growth suppression may play a role in the effect of CPT-11 ” Journal of Clinical Investigation 1998; 101:1789-96

Hypothesis Variation in pathological response to DEBIRI-TACE is due to inter-patient variation in metabolism of Irinotecan Metabolism within tumour Metabolism in surrounding tissue

Identification of Biomarkers Prognostic Predictive

Fresh metastatic tumour Fresh hepatic tissue FFPE primary tumour

Metabolomic Analysis n=3

Immunohistochemistry Primary tumour Metastatic tumour Hepatic parenchyma CES-2 in primary colorectal cancer CYP3A4 in hepatic parenchyma

Proteomic Analysis

Summary Wide variation in response to DEBIRI-TACE Exploration of reasons behind variation in response will define approach to treatment Identification of potential biomarkers of response will help guide personalisation of therapy