Background: Prognostic value of KRAS mutations in resected colon adenocarcinoma remains debated. We examined the prognostic impact of KRAS exon 2mutations in stage III patients receiving adjuvant FOLFOX + /- cetuximab patients from the PETACC8 Phase III trial. Methods: KRAS exon 2 mutations in codon 12 (p.G12V, p.G12R, p.G12S, p.G12A, p.G12C, p.G12D) and codon 13 (p.G13D) were examined in all patients with available material and signed translational research informed consent enrolled in the PETACC8 trial. Analyses were restricted to BRAF wild type tumors, since the prognostic impact of BRAFV600E in this population has already been described. Because no benefit or deleterious effect from adjuvant cetuximab was reported in this trial, tumors from both study arms were pooled for analysis. Association between time to recurrence (TTR) and disease-free survival (DFS) and type of KRAS mutation was evaluated using Cox proportional hazard model. Results: KRAS mutations were found in 638/1657 tumors, including 502 codon 12 and 136 codon 13 alterations. KRAS mutations in codon 12 (HR: 1.67; 95% confidence interval [CI] [1.35-2.04]; P<0.001) but not in codon 13 (HR: 1.23; 95% confidence interval [CI] [0.85-1.79]; P=0.26) were significantly associated with shorter TTR as compared to patients with KRAS/BRAF wild-type tumors, independently of other covariates. Similar results were found for DFS. When anatomic sites were taken into account, the impact of KRAS mutations on TTR was only found for distal tumors (n=1043) with an increased risk of relapse (HR: 1.96; 95% confidence interval [CI] [1.51-2.56]; P<0.0001) for KRAScodon 12 mutated tumors and a trend for codon 13 (HR: 1.59; 95% confidence interval [CI] [1.00-2.56]; P=0.051), as compared to KRAS/BRAFwild type patients. Similar results were found for DFS. Conclusions: KRAS exon 2 mutations are independent predictors of TTR or DFS for patients with stage III distal colon cancer receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider tumor location and type of KRAS mutation as important stratification factors.
Prognostic value of KRAS exon 2 gene mutations in stage III colon cancer: Post hoc analyses of the PETACC8 trial / Taïeb, Julien; Emile, Jean-François; Le Malicot, Karine; Zaanan, Aziz; Tabernero, Josep; Mini, Enrico; Rougier, Philippe; VAN Laethem, Jean Luc; Bridgewater, John A.; Folprecht, Gunnar; Salazar, Ramon; Zawadi, Ayman; Van Cutsem, Eric; Lepage, Come; Laurent-Puig, Pierre; Blons, Helene. - In: JOURNAL OF CLINICAL ONCOLOGY. - ISSN 0732-183X. - ELETTRONICO. - 32:(2014), pp. 3549-3549. [10.1200/jco.2014.32.15_suppl.3549]
Prognostic value of KRAS exon 2 gene mutations in stage III colon cancer: Post hoc analyses of the PETACC8 trial
Mini, Enrico;
2014
Abstract
Background: Prognostic value of KRAS mutations in resected colon adenocarcinoma remains debated. We examined the prognostic impact of KRAS exon 2mutations in stage III patients receiving adjuvant FOLFOX + /- cetuximab patients from the PETACC8 Phase III trial. Methods: KRAS exon 2 mutations in codon 12 (p.G12V, p.G12R, p.G12S, p.G12A, p.G12C, p.G12D) and codon 13 (p.G13D) were examined in all patients with available material and signed translational research informed consent enrolled in the PETACC8 trial. Analyses were restricted to BRAF wild type tumors, since the prognostic impact of BRAFV600E in this population has already been described. Because no benefit or deleterious effect from adjuvant cetuximab was reported in this trial, tumors from both study arms were pooled for analysis. Association between time to recurrence (TTR) and disease-free survival (DFS) and type of KRAS mutation was evaluated using Cox proportional hazard model. Results: KRAS mutations were found in 638/1657 tumors, including 502 codon 12 and 136 codon 13 alterations. KRAS mutations in codon 12 (HR: 1.67; 95% confidence interval [CI] [1.35-2.04]; P<0.001) but not in codon 13 (HR: 1.23; 95% confidence interval [CI] [0.85-1.79]; P=0.26) were significantly associated with shorter TTR as compared to patients with KRAS/BRAF wild-type tumors, independently of other covariates. Similar results were found for DFS. When anatomic sites were taken into account, the impact of KRAS mutations on TTR was only found for distal tumors (n=1043) with an increased risk of relapse (HR: 1.96; 95% confidence interval [CI] [1.51-2.56]; P<0.0001) for KRAScodon 12 mutated tumors and a trend for codon 13 (HR: 1.59; 95% confidence interval [CI] [1.00-2.56]; P=0.051), as compared to KRAS/BRAFwild type patients. Similar results were found for DFS. Conclusions: KRAS exon 2 mutations are independent predictors of TTR or DFS for patients with stage III distal colon cancer receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider tumor location and type of KRAS mutation as important stratification factors.
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