PM.20.056 – Optimal survival and quality of life in metastatic colorectal cancer with irinotecan dosing based on UGT1A1 genotype and gut microbiome enzyme activity including a dietary intervention

Route: Personalised medicine: the individual at the centre

Cluster question: 095 How can we personalise health care, for example by using biomarkers?

Problem description: Irinotecan-based systemic therapy is one of the main chemotherapeutic agents used for metastatic colorectal cancer (mCRC). It can significantly improve overall survival (OS). Its downside is the late-onset gastrointestinal toxicity in 40% (> 24hrs after administration), particularly severe diarrhea, which cripples quality of life (Qol) and often results in dose reduction and even prevents treatment continuation in 12- 22%, thus threatening OS.
SN-38, irinotecan’s active metabolite is deactivated in the liver by UGT1A1 to SN-38-glucuronide (SN-38G) and via the gallbladder excreted into the bowel. Here the gut microbiota derived enzyme beta-glucuronidase (β-GUS) can reactivate SN-38G which, as proven in vitro, causes mucosal damage and so diarrhea, the late-onset gastrointestinal toxicity.
Therefore β-GUS is suggested as predictor for irinotecan-induced late-onset gastrointestinal toxicity, though human proof and tests lack. The diarrhea often instigates use of antibiotics, thereby further decreasing OS as shown in recent literature.

Further, SN-38 exposure also depends on UGT1A1 enzyme activity. Genetic polymorphism within UGT1A1 may result in decreased UGT1A1 enzyme activity and thereby increase SN-38 exposure.
Current clinical practice does not consider gut microbial β-GUS nor UGT1A1 activity. Consequently, irinotecan-based systemic therapy is employed in “trial and error” stance with no knowledge of which patients will fare poorly with respect to development of late-onset diarrhea, systemic toxicity, antibiotics need, decrease of OS and Qol.

Objectives:
1) Development of human β-GUS activity test
In mCRC patients treated with irinotecan-based systemic therapy
2) Examine whether high β-GUS activity in stool predicts late-onset gastrointestinal toxicity and assess impact on Qol/OS
3) Determine relationship between UGT1A1 genetic polymorphism and β-GUS on gastrointestinal and systemic exposure to SN-38(G)
4) Examine relationship between microbiome composition and abundance and β-GUS activity.
5) Start dietary intervention study aiming to decrease β-GUS activity producing microbiome.

This research is of importance for 6750 new mCRC patients yearly.

Keywords

beta-glucuronidase, dietary intervention, genetic polymorphism, gut microbiome, irinotecan, metastatic colorectal cancer, UGT1A1

Other organisations

CAPHRI, Catharina Ziekenhuis (Eindhoven), Danone Nutricia Research (Utrecht), DCCG, FHML GROW School for Oncology, M4I (Maastricht), PLCRC, School for Public Health and Primary Care, University of North Carolina (Chapel Hill, USA), Werkgroep Darmkanker (Utrecht)

Submitter

Organisation MUMC+/FHML GROW School for Oncology
Name Prof. dr. M.L. (Marjolein) Smidt
E-mail m.smidt@mumc.nl
Website https://www.linkedin.com/in/marjolein-smidt-2a9581103/