Intensification thérapeutique dans les cancers colorectaux par des études pharmacogénétiques et pharmacogénomiques

Abstract : Colorectal cancer is one of the commonest tumours in France with 38,000 cases annually diagnosed. Treatment options for metastatic colorectal cancer (mCRC) patients have rapidly increased in the past years, but 50-70% of mCRC patients are still unlikely to undergo radical resection of metastases and are candidates for palliative chemotherapy only. Since 1996 the chemotherapeutic armamentarium has grown beyond 5-fluorouracil -corner stone of treatment-, to include irinotecan (CPT-11) and oxaliplatin (L-OHP) as well as three targeted monoclonal antibodies (Moabs): bevacizumab (an anti-vascular endothelial growth factor Moab) and cetuximab/panitumumab, both anti-epidermal growth factor receptor inhibitors. The purpose of our Thesis was to analyse the possible correlation between germinal polymorphism implicated in metabolisms of these drugs on efficacy and toxicity of 5-FU based chemotherapy regimens in mCRC patients. Our results confirm the interest in optimizing treatment for the pre-therapeutic detection of genetic factors such as DPYD following by 5-FU pharmacokinetic monitoring. We isolated a population (TYMS 3R/3R genotype associated with MTHFR C/C for 677 C>T or A/A for 1298 A>C) with a higher risk of response and survival failure under exclusive 5-FU treatment. This risk disappeared with added CPT-11. Tailored FOLFIRI regimen (5-FU plus irinotecan) with cetuximab and adapted doses according to pharmacokinetic monitoring for 5-FU and UGT 1A1 genotype status for irinotecan, showed excellent response and survival rates never previously observed in second line of treatment to our knowledge. For oxaliplatin, we identified a subgroup of patients with a higher risk of late neurotoxicity: T/T for 118 C>T ERCC1 or C/C for XPD 751 A>C. Finally regarding tumoral polymorphisms, in addition to Kras and Braf status, mutated PI3KCA appeared as a potential predictive biomarker of anti-EGFR resistance. In conclusion pharmacogenetic, pharmacokinetic and pharmacogenomic approaches should be considered in order to optimize chemotherapy treatments in mCRC.
Document type :
Theses
Medication. Université d'Angers, 2010. French


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Submitted on : Monday, November 15, 2010 - 12:20:00 PM
Last modification on : Monday, November 15, 2010 - 12:25:30 PM

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Olivier Capitain. Intensification thérapeutique dans les cancers colorectaux par des études pharmacogénétiques et pharmacogénomiques. Medication. Université d'Angers, 2010. French. <tel-00536079>

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