Background: Pharmacogenetic studies support the predictive impact of DPYD variants on fluorouracil-related adverse events. Further prospective validation in homogeneous patient populations uniformly treated with current standard combination therapies used in colon cancer is needed. An ancillary pharmacogenetic study, supported by the University of Urbino, addressed this need by association analysis of known genetic DPYD variants with samples from the TOSCA trial, supported by GISCAD (Italian Group For The Study Of Gastrointestinal Cancer) and Italian Medicines Agency (AIFA). Methods: TOSCA was an Italian, multicentre, randomized, phase III study in radically resected high risk stage II and III colon cancer patients treated with 3 or 6 months of either FOLFOX-4 or XELOX. All patients provided written informed consent for blood sampling. We analyzed 9 DPYD polymorphisms, rs1801159 A/G, rs1801265 T/C, rs1801158 G/A, rs55886062 T/G, rs3918290 +1G G/A, rs1801160 G/A, rs17376848 T/C, rs67376798 A/T, rs2297595 A/G, by the MassARRAY® System (Agena Bioscience) using the MYRIAPOD® ADMET kit (Diatech Pharmacogenetics). The impact of each polymorphism on time to toxicity (TTT), defined as the time from randomization to the date of first severe (grade= >3) toxicity (neutropenia, diarrhea and neurotoxicity), was analyzed using Cox proportional hazard models. For each polymorphism, the more frequent homozygous genotype served as the reference group. Results: 534 samples have been collected and 195 have been currently analzyed. Severe neutropenia, diarrhea and neurotoxicity occurred in 55 (28.2%), 15 (7.7%) and 54 (27.7%) patients, respectively. TTT for neutropenia was shorter with rs1801160 G/A [Hazard ratio, HR 1.93 (95%CI 1.01-3.67), p=0.046] compared to G/G genotype and rs3918290 G/A [HR 9.23 (95%CI 2.15-39.59), p=0.003] compared to G/G genotype. The rs1801265 C/T genotype conferred shorter TTT for diarrhea [HR 3.72 (95%CI 1.27 - 10.89), p=0.017] compared to T/T genotype and the presence of allele C (T/C+C/C) conferred a longer TTT for neurotoxicity [HR 0.55 (95%CI 0.30 - 0.99), p=0.047]. Complete data on all patients will be available October 2016. Conclusion: These encouraging preliminary data support the role of DPYD polymorphisms for predicting toxicity in the adjuvant

Dihydropyrimidine dehydrogenase (DPYD) gene polymorphisms profiling in colon cancer patients treated with adjuvant chemotherapy in the randomized phase III TOSCA trial

RUZZO, ANNAMARIA;MAGNANI, MAURO
2016-01-01

Abstract

Background: Pharmacogenetic studies support the predictive impact of DPYD variants on fluorouracil-related adverse events. Further prospective validation in homogeneous patient populations uniformly treated with current standard combination therapies used in colon cancer is needed. An ancillary pharmacogenetic study, supported by the University of Urbino, addressed this need by association analysis of known genetic DPYD variants with samples from the TOSCA trial, supported by GISCAD (Italian Group For The Study Of Gastrointestinal Cancer) and Italian Medicines Agency (AIFA). Methods: TOSCA was an Italian, multicentre, randomized, phase III study in radically resected high risk stage II and III colon cancer patients treated with 3 or 6 months of either FOLFOX-4 or XELOX. All patients provided written informed consent for blood sampling. We analyzed 9 DPYD polymorphisms, rs1801159 A/G, rs1801265 T/C, rs1801158 G/A, rs55886062 T/G, rs3918290 +1G G/A, rs1801160 G/A, rs17376848 T/C, rs67376798 A/T, rs2297595 A/G, by the MassARRAY® System (Agena Bioscience) using the MYRIAPOD® ADMET kit (Diatech Pharmacogenetics). The impact of each polymorphism on time to toxicity (TTT), defined as the time from randomization to the date of first severe (grade= >3) toxicity (neutropenia, diarrhea and neurotoxicity), was analyzed using Cox proportional hazard models. For each polymorphism, the more frequent homozygous genotype served as the reference group. Results: 534 samples have been collected and 195 have been currently analzyed. Severe neutropenia, diarrhea and neurotoxicity occurred in 55 (28.2%), 15 (7.7%) and 54 (27.7%) patients, respectively. TTT for neutropenia was shorter with rs1801160 G/A [Hazard ratio, HR 1.93 (95%CI 1.01-3.67), p=0.046] compared to G/G genotype and rs3918290 G/A [HR 9.23 (95%CI 2.15-39.59), p=0.003] compared to G/G genotype. The rs1801265 C/T genotype conferred shorter TTT for diarrhea [HR 3.72 (95%CI 1.27 - 10.89), p=0.017] compared to T/T genotype and the presence of allele C (T/C+C/C) conferred a longer TTT for neurotoxicity [HR 0.55 (95%CI 0.30 - 0.99), p=0.047]. Complete data on all patients will be available October 2016. Conclusion: These encouraging preliminary data support the role of DPYD polymorphisms for predicting toxicity in the adjuvant
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2639530
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