DEBIRI TACE Patterns and Predictors of Response

Robert Jones

DeclarationRobert Jones is a consultant to Biocompatibles UK LTD.

Pathological response to chemotherapy predicts survival

Blazer, JCO 2008

0 1 2 3 4 5 6 7 8 9 10

100

90

80

70

60

50

40

30

20

10

0

Years

%

surv

ival

Complete response

Major response

Minor response

Pathological Response Rates after Treatment

70

60

50

40

30

20

10

0

%

pati

en

ts

Minor Major Complete

Pathological response

FOLFOX/FOLFIRI

DEBIRI-TACE

55%

36%

9%

30%

55%

15%

CPT-11CPT-11

APCAPC

SN-38SN-38

CYP3A4CYP3A4

Blood

CES2CES2 Topo-1Topo-1

CPT-11CPT-11

Metabolism of Irinotecan (CPT-11)

“…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

British Journal of Cancer 1999; 80: 364-70

“Absolute levels of CES-2 appear highest in hepatic parenchyma, with colorectal primary tumour having levels two to three fold lower ”

“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