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Clinical Trial
. 2014 Dec;25(12):2378-2385.
doi: 10.1093/annonc/mdu464. Epub 2014 Oct 6.

Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset

H Blons  1 , J F Emile  2 , K Le Malicot  3 , C Julié  4 , A Zaanan  5 , J Tabernero  6 , E Mini  7 , G Folprecht  8 , J L Van Laethem  9 , J Thaler  10 , J Bridgewater  11 , L Nørgård-Petersen  12 , E Van Cutsem  13 , C Lepage  14 , M A Zawadi  15 , R Salazar  16 , P Laurent-Puig  1 , J Taieb  17
Affiliations
Free article
Clinical Trial

Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset

H Blons et al. Ann Oncol. 2014 Dec.
Free article

Erratum in

  • Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset.
    PETACC-8 study investigators; Thaler J, Greil R, Gaenzer J, Eisterer W, Tschmelitsch J, Samonigg H, Zabernigg A, Schmid F, Steger G, Steinacher R, Andel J, Lang A, Függer R, Hofbauer F, Woell E, Geissler D, Lenauer A, Prager M, Van Laethem JL, Van Cutsem E, D'Haens G, Demolin G, Kerger J, Deboever G, Ghillebert G, Polus M, Van Cutsem E, RezaieKalantari H, Delaunoit T, Goeminne JC, Peeters M, Vergauwe P, Houbiers G, Humblet Y, Janssens J, Schrijvers D, Vanderstraeten E, Van Laethem JL, Vermorken J, Van Daele D, Ferrante M, Forget F, Hendlisz A, Yilmaz M, Nielsen SE, Vestermark L, Larsen J, Ychou M, Zawadi A, Zawadi MA, Bouche O, Mineur L, Bennouna-Louridi J, Dourthe LM, Ychou M, Boucher E, Taieb J, Pezet D, Desseigne F, Ducreux M, Texereau P, Miglianico L, Rougier P, Fratte S, Levache CB, Merrouche Y, Ellis S, Locher C, Ramee JF, Garnier C, Viret F, Chauffert B, Cojean-Zelek I, Michel P, Lecaille C, Borel C, Seitz JF, Smith D, Lombard-Bohas C, Andre T, Gornet JM, Fein F, Coulon-Sfairi MA, Kaminsky MC, Lagasse JP, Luet D, Etienne PL, Gasmi M, Vanoli A, Nguyen S, Aparicio T, Perrier H, Stremsdoerfer N, Laplaige P, Arsene D, Auby D, Bedenne L, Coriat R, Denis B, Geoffroy P, Piot G, Be… See abstract for full author list ➔ PETACC-8 study investigators, et al. Ann Oncol. 2015 Apr;26(4):822-825. doi: 10.1093/annonc/mdv070. Ann Oncol. 2015. PMID: 25814651 No abstract available.

Abstract

Background: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial.

Patients and methods: We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model.

Results: KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051).

Conclusion: KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors.

Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

Keywords: KRAS mutation; cetuximab; colorectal cancer; distal colon; prognosis; proximal colon.

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