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. 2016 Sep;27(9):1746-53.
doi: 10.1093/annonc/mdw261. Epub 2016 Jun 29.

Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group

D P Modest  1 , I Ricard  2 , V Heinemann  3 , S Hegewisch-Becker  4 , W Schmiegel  5 , R Porschen  6 , S Stintzing  3 , U Graeven  7 , D Arnold  8 , L F von Weikersthal  9 , C Giessen-Jung  10 , A Stahler  11 , H J Schmoll  12 , A Jung  13 , T Kirchner  13 , A Tannapfel  14 , A Reinacher-Schick  15
Affiliations

Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group

D P Modest et al. Ann Oncol. 2016 Sep.

Abstract

Background: To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy.

Patients and methods: A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan-Meier method, log-rank tests and Cox models.

Results: In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) [multivariate hazard ratio (HR) for PFS: 1.20 (1.02-1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17-1.70), P < 0.001]. BRAF mutation was also associated with inferior PFS [multivariate HR: 2.19 (1.59-3.02), P < 0.001] and OS [multivariate HR: 2.99 (2.10-4.25), P < 0.001]. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors [multivariate HR 2.26 (1.25-4.1), P = 0.001]. A similar trend for OS was seen in the KRAS G13D-variant [n = 71, multivariate HR 1.46 (0.96-2.22), P = 0.10]. More frequent KRAS exon 2 variants like G12D [n = 152, multivariate HR 1.17 (0.86-1.6), P = 0.81] and G12V [n = 92, multivariate HR 1.27 (0.87-1.86), P = 0.57] did not have significant impact on OS.

Conclusion: Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.

Keywords: BRAF; RAS; colorectal cancer; mutation; prognostic factor.

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Figures

Figure 1.
Figure 1.
Prognostic role of alterations in KRAS-, NRAS- and BRAF-genes. (A) Progression-free survival (PFS) according to molecular subgroups. (B) Overall survival (OS) according to molecular subgroups. (C) PFS in KRAS exon 2 variants. (D) OS in KRAS exon 2 variants, P values below 0.05 by log-rank test indicate at least one significant difference between two groups.
Figure 2.
Figure 2.
Forest plots of metastatic colorectal cancer (mCRC) molecular subgroups as well as mutation variants compared with KRAS/NRAS/BRAF wild-type mCRC. (A) Progression-free survival (PFS) according to molecular subgroups. (B) Overall survival (OS) according to molecular subgroups. (C) PFS according to mutation variants. (D) OS according to mutation variants; hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for multiplicity indicate results drawn from the multivariate model. An HR >1 indicates a higher hazard rate for death or progression in patients with mutated tumors compared with patients with unmutated tumors. Only mutation variants with >10 patients were included into the analysis in C and D. All variants in C and D represent respective KRAS mutations except NG12D, NRAS G12D; V600E, BRAF V600E; bev., bevacizumab; WT, unmutated tumors.
Figure 2.
Figure 2.
Forest plots of metastatic colorectal cancer (mCRC) molecular subgroups as well as mutation variants compared with KRAS/NRAS/BRAF wild-type mCRC. (A) Progression-free survival (PFS) according to molecular subgroups. (B) Overall survival (OS) according to molecular subgroups. (C) PFS according to mutation variants. (D) OS according to mutation variants; hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for multiplicity indicate results drawn from the multivariate model. An HR >1 indicates a higher hazard rate for death or progression in patients with mutated tumors compared with patients with unmutated tumors. Only mutation variants with >10 patients were included into the analysis in C and D. All variants in C and D represent respective KRAS mutations except NG12D, NRAS G12D; V600E, BRAF V600E; bev., bevacizumab; WT, unmutated tumors.
Figure 2.
Figure 2.
Forest plots of metastatic colorectal cancer (mCRC) molecular subgroups as well as mutation variants compared with KRAS/NRAS/BRAF wild-type mCRC. (A) Progression-free survival (PFS) according to molecular subgroups. (B) Overall survival (OS) according to molecular subgroups. (C) PFS according to mutation variants. (D) OS according to mutation variants; hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for multiplicity indicate results drawn from the multivariate model. An HR >1 indicates a higher hazard rate for death or progression in patients with mutated tumors compared with patients with unmutated tumors. Only mutation variants with >10 patients were included into the analysis in C and D. All variants in C and D represent respective KRAS mutations except NG12D, NRAS G12D; V600E, BRAF V600E; bev., bevacizumab; WT, unmutated tumors.
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