Purpose: UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent.Patients and Methods: In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy.Results: UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA₇/TA₇compared with wild-type TA₆/TA₆. The response rate was also higher in TA₇/TA₇patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA₆/TA₆. A nonsignificant survival advantage was observed for TA₇/TA₇when compared with TA₆/TA₆patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)×(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA₇/TA₇genotype and a higher response rate, indicating that the polymorphism is functionally relevant.Conclusion: The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.

Purpose: UGT1A1^★28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI). Patients and Methods: In addition to UGT1A1^★28, UGT1A1^★60, UGT1A1^★93, UGT1A7^★3, and UGT1A9^★22 were genotyped in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated. In a subset of 71 patients, pharmacokinetic data were also available. Results: UGT1A7^★3 was the only marker of severe hematologic toxicity after the first cycle (odds ratio [OR], 3.94; 95% CI, 1.05 to 14.82; P = .04) in a multivariate analysis. It was also associated with glucuronidation ratio (SN-38G area under the curve [AUC]/SN-38 AUC) and biliary index (irinotecan AUC) × (SN-38 AUC/SN-38G AUC). Haplotype I (all the reference sequence alleles but UGT1A9^★22) was a predictor of severe hematologic toxicity during the entire course of therapy (OR, 0.39; 95% CI, 0.19 to 0.82; P = .01), together with sex (OR, 2.08; 95% CI, 1.01 to 4.28; P = .05). In addition to UGT1A1^★28, haplotype II (all the variant alleles but UGT1A9^★22) was associated with a response rate (OR, 8.61; 95% CI, 1.75 to 42.38; P = .01). UGT1A1^★28 was the only marker associated with TTP. Conclusion: We propose that UGT1A variants additional to UGT1A1^★28 might improve the prediction of the outcome of colorectal cancer patients treated with FOLFIRI. A UGT1A haplotype-based approach might be an efficacious strategy to achieve treatment individualization of FOLFIRI.

Purpose: BRAF mutations are grouped in activating RAS-independent signaling as monomers (class 1–V600E) or as dimers (class 2–codons 597/601), and RAS-dependent with impaired kinase activity (class 3–codons 594/596). Although clinical, pathologic, and molecular features of V600EBRAF-mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes.Experimental Design: Data from 117 patients with BRAF (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 BRAF wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan–Meier and log-rank test.Results: Class 3 BRAF-mutated mCRC was more frequently left sided (P = 0.0028), pN0 (P = 0.0159), and without peritoneal metastases (P = 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with BRAF wt, was 2.38 [95% confidence interval (CI), 1.61–3.54] for class 1, 1.90 (95% CI, 0.85–4.26) for class 2, and 0.93 (95% CI, 0.51–1.69) for class 3 (P < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in BRAF-mutated class 2 (P = 0.033) compared with class 3 cases.Conclusions: For the first time, different clinical and pathologic features and outcome data were reported according to the three BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.

The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic polymorphisms in 16 genes relevant for treatment-associated pathways. Two polymorphisms were associated with TRG in a multivariate analysis: hOGG1-1245C>G, which can affect radiosensitivity and MTHFR-677C>T, which is involved in fluoropyrimidines action. Patients bearing at least one variant allele had a lower chance to get TRG2 (OR=0.46 95% CI 0.23–0.90, P=0.024; and OR=0.48 95% CI 0.24–0.96, P=0.034; respectively). An association trend was observed for ABCB1-3435C>T, which is responsible for the multi-drug resistance (odds ratio (OR)=1.96, 95% confidence interval (CI) 0.98–3.95, P=0.057). Exploratory classification and regression tree (CART) analysis highlighted high-order gene–gene and gene–environment interactions and a genetic signature associated with differential response, with hOGG1-1245C>G as the most predictive factor. Other significant variables were: ABCB1-3435C>T, MTHFR-677C>T, ERCC1-8092C>A, ABCC2-1249G>A, XRCC1-28152G>A, XRCC3-4541A>G and patients gender. On the basis of CART results, patients were categorized into three groups according to tumor response probability: intermediate and high profiles had a higher probability to get TRG2 as compared with low profiles (OR=4.12 95% CI 1.46–11.65, P<0.001 and OR=12.44, 95% CI 5.52–28.04, PG and MTHFR-677C>T polymorphisms in the tumor response of rectal cancer patients treated with chemo-RT in neo-adjuvant setting, and shows the relevance of gene–gene and gene–environment interactions for complex phenotypes as tumor response.