Background: In the TOSCA trial, an ancillary pharmacogenetic study was conducted for a prospective association analysis of known genetic variants with toxicity, useful for optimizing the management of patients during adjuvant chemotherapy. Current evidence is often limited to retrospective and not powered studies. Methods: TOSCA is a multicentre, randomized, phase III study conducted in radically resected high risk stage II and III colon cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX. We analyzed 17 polymorphisms in 11 genes related to 5-fluorouracil/oxaliplatin pathways, detoxification, transport and DNA repair (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) and investigated their association with the maximum grade of toxicity (MGT) and the time to toxicity (TTT) as recorded for its maximum grade. Sample size calculation was based on an expected prevalence of an unfavourable genotype profiling of at least 30%. 105 grade 3-4 (also 2 for neurotoxicity) selected toxicity events (approximately 440 patients) allowed to detect an odds ratio (OR) of at least 2.0 associated to the group with unfavourable genotypes with a power of 90% and a I -type error of 5%, for a bilateral test. Results: 534 patients were enrolled (195 in the 6-month FOLFOX-4 arm, 194 in the 3-month FOLFOX-4 arm, 69 in the 6-month XELOX arm, 76 in the 3-month XELOX arm). Regarding the proportion of stage II-III patients, the study sample is representative of main study sample, according to the two options of adjuvant chemotherapy and treatment duration (3 versus 6 months). 517 patients were analyzed. For neurotoxicity and neutropenia we have observed the required events. The XRCC3 TT (rs# 861539) genotype was protective for neurotoxicity (TTT) with a 0.58 HR (95%CI=0.35-0.96; p=.03), the GST-T1/M1 null/+ genotype was associated with risk of neurotoxicity (TTT) with a 2.46 HR (95%CI=1.07-5.65; p=.03). The GST-T1/M1 +/+ genotype was associated with protection risk of netropenia (MGT) with a 0.51 HR (95%CI=0.27-0.95; p=.03). Conclusions: The results of this study are useful for improving the monitoring of potentially cured colon cancer patients undergoing adjuvant chemotherapy. It will be evaluated whether the genetic profiles, for which a statistically significant association in terms of MGT/TTT was observed, will determine different dose intensity and then possible different clinical outcomes.
PHARMACOGENETIC PROFILING FOR TOXICITY OF OXALIPLATIN AND FLUOROPYRIMIDINES. FINAL REPORT FROM AN ANCILLARY PROTOCOL TO THE TOSCA TRIAL
RUZZO, ANNAMARIA;MAGNANI, MAURO;
2013
Abstract
Background: In the TOSCA trial, an ancillary pharmacogenetic study was conducted for a prospective association analysis of known genetic variants with toxicity, useful for optimizing the management of patients during adjuvant chemotherapy. Current evidence is often limited to retrospective and not powered studies. Methods: TOSCA is a multicentre, randomized, phase III study conducted in radically resected high risk stage II and III colon cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX. We analyzed 17 polymorphisms in 11 genes related to 5-fluorouracil/oxaliplatin pathways, detoxification, transport and DNA repair (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) and investigated their association with the maximum grade of toxicity (MGT) and the time to toxicity (TTT) as recorded for its maximum grade. Sample size calculation was based on an expected prevalence of an unfavourable genotype profiling of at least 30%. 105 grade 3-4 (also 2 for neurotoxicity) selected toxicity events (approximately 440 patients) allowed to detect an odds ratio (OR) of at least 2.0 associated to the group with unfavourable genotypes with a power of 90% and a I -type error of 5%, for a bilateral test. Results: 534 patients were enrolled (195 in the 6-month FOLFOX-4 arm, 194 in the 3-month FOLFOX-4 arm, 69 in the 6-month XELOX arm, 76 in the 3-month XELOX arm). Regarding the proportion of stage II-III patients, the study sample is representative of main study sample, according to the two options of adjuvant chemotherapy and treatment duration (3 versus 6 months). 517 patients were analyzed. For neurotoxicity and neutropenia we have observed the required events. The XRCC3 TT (rs# 861539) genotype was protective for neurotoxicity (TTT) with a 0.58 HR (95%CI=0.35-0.96; p=.03), the GST-T1/M1 null/+ genotype was associated with risk of neurotoxicity (TTT) with a 2.46 HR (95%CI=1.07-5.65; p=.03). The GST-T1/M1 +/+ genotype was associated with protection risk of netropenia (MGT) with a 0.51 HR (95%CI=0.27-0.95; p=.03). Conclusions: The results of this study are useful for improving the monitoring of potentially cured colon cancer patients undergoing adjuvant chemotherapy. It will be evaluated whether the genetic profiles, for which a statistically significant association in terms of MGT/TTT was observed, will determine different dose intensity and then possible different clinical outcomes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
