Medical Oncology Department, INSERM U776, Paul Brousse Hospital, Villejuif, France
Francis Levi , Abdoulaye Karaboué , Raphaël Saffroy , Elodie Peyric , Michel Ducreux , Denis Michel Smith , Mohamed Hebbar , Pasquale F. Innominato , Simon Pernot , Carlos Carvalho , Rosine Guimbaud , C. N. J. Focan , Mohamed Bouchahda , Rene Adam , Marie-Christine Etienne-Grimaldi , Gerard A. Milano , Antoinette Lemoine
Background: The combination of IV-CET and HAI of irinotecan , oxaliplatin and 5-fluorouracil displayed high activity as 2-4thchemotherapy line for initially unresectable wt KRAS LM-CRC, yielding a macroscopic complete resection rate (R0+R1) of 29.7% and an overall survival of 25.7 months (Ducreux, ASCO 2013). The purpose is to identify the pts whose constitutive SNPs predict for best outcomes on this neoadjuvant protocol. Methods: 192 constitutive SNPs from 36 pharmacogenetically-relevant genes were analysed in pt blood cells using the ADME PGx panel with the MassArray platform (Sequenom, USA). Relations between polymorphic genes with minor SNPs and grade distribution for main toxicities per pt over 6 courses, best tumor response, and R0+R1, were explored using Mann Whitney or Fisher Exact test. Results: Gene polymorphisms were assessed in 52/64 registered pts with unresectable LM-CRC (16F; 36M), aged 33-76 years with good PS (0-1: 98%) receiving IV-CET + IFO-HAI as 2nd line for 21 pts (40%) and 3rd-4thline for 31 pts (60%). Main grade 3-4 toxicities were neutropenia (40%), abdominal pain (29%), fatigue (21%), and diarrhea (17%). Objective response was achieved in 20 pts (39%). Secondary R0-R1 LM resection was performed in 14/52 pts (27%). None of the minor SNPs in the 36 genes studied was a potential predictor of LM resection, nor displayed any significant relation with pt characteristics except for Cyp2C19 and sex (p<0.05). Best objective response was associated with minor SNPs in SLC22A2 (p=0.049) and UGT2B15 (p=0.011). Neutropenia, fatigue and diarrhea were associated with minor SNPs in Cyp2C19 (p<0.05). Neutropenia was further related to minor SNPs in Cyp1A2 (p = 0.017) and SLC22A1 (p=0.027), while diarrhea was predicted by minor SNPs in Cyp2D6A (p<0.05). Conclusions: This selected pharmacogenetics analysis revealed six genes involved in drug metabolism and transport whose minor SNPs predicted safety and efficacy outcomes and could warrant treatment adjustment for pts on neoadjuvant triplet HAI and IV-CET for LM-CRC. Clinical trial information: NCT00852228.
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Abstract Disclosures
First Author: Abdoulaye Karaboué
2017 ASCO Annual Meeting
First Author: Francis Levi
2024 ASCO Gastrointestinal Cancers Symposium
First Author: Antoine Hollebecque
2017 ASCO Annual Meeting
First Author: Abdoulaye Karaboue