Aim A number of germline polymorphisms have shown promising predictive role for chemotherapy related toxicity in colorectal cancer patients. However, large-scale validation trials are necessary before pharmacogenetic findings are incorporated into clinical practice. We investigated 17 polymorphisms in 11 genes for their association with toxicity of fluoropyrimidines and oxaliplatin (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT, GSTP, GSTM, ABCC1, ABCC2) in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. Methods TOSCA is a non-profit, Italian, multicentre, randomized, non-inferiority phase III study conducted in high-risk stage II and stage III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemoterapy. A planned sample of patients was accrued in the ancillary pharmacogenetic study. The primary endpoint was the evaluation of the relationship of genetic polymorphisms with occurrence of grade 3-4 CTCAE toxicity event (grade 2-4 for neurotoxicity). Results From July 2007 to October 2011, 531 patients were enrolled from 26 experimental centres (194 patients in 6-month FOLFOX-4 arm, 194 patients in 3-month FOLFOX-4 arm, 74 patients in 6-month XELOX arm, 69 patients in 3-month XELOX arm). Grade ≥3 neutropenia and grade >2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade > 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Conclusions In the studied population, we ruled out a strong predictive role of known genetic variants for toxicity. Future investigations should address novel polymorphisms emerging from genome-wide association studies. Disclosure All authors have declared no conflicts of interest.

Pharmacogenetic profiling for toxicity of oxaliplatin and fluoropyrimidines. Final report from an ancillary protocol to the TOSCA (Three Or Six Colon Adjuvant) trial

RUZZO, ANNAMARIA;MAGNANI, MAURO
2014

Abstract

Aim A number of germline polymorphisms have shown promising predictive role for chemotherapy related toxicity in colorectal cancer patients. However, large-scale validation trials are necessary before pharmacogenetic findings are incorporated into clinical practice. We investigated 17 polymorphisms in 11 genes for their association with toxicity of fluoropyrimidines and oxaliplatin (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT, GSTP, GSTM, ABCC1, ABCC2) in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. Methods TOSCA is a non-profit, Italian, multicentre, randomized, non-inferiority phase III study conducted in high-risk stage II and stage III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemoterapy. A planned sample of patients was accrued in the ancillary pharmacogenetic study. The primary endpoint was the evaluation of the relationship of genetic polymorphisms with occurrence of grade 3-4 CTCAE toxicity event (grade 2-4 for neurotoxicity). Results From July 2007 to October 2011, 531 patients were enrolled from 26 experimental centres (194 patients in 6-month FOLFOX-4 arm, 194 patients in 3-month FOLFOX-4 arm, 74 patients in 6-month XELOX arm, 69 patients in 3-month XELOX arm). Grade ≥3 neutropenia and grade >2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade > 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Conclusions In the studied population, we ruled out a strong predictive role of known genetic variants for toxicity. Future investigations should address novel polymorphisms emerging from genome-wide association studies. Disclosure All authors have declared no conflicts of interest.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2602581
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