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, I Ricard, V Heinemann, S Hegewisch-Becker, W Schmiegel, R Porschen, S Stintzing, U Graeven, D Arnold, L F von Weikersthal, C Giessen-Jung, A Stahler, H J Schmoll, A Jung, T Kirchner, A Tannapfel, A Reinacher-Schick, D P Modest, I Ricard, V Heinemann, S Hegewisch-Becker, W Schmiegel, R Porschen, S Stintzing, U Graeven, D Arnold, L F von Weikersthal, C Giessen-Jung, A Stahler, H J Schmoll, A Jung, T Kirchner, A Tannapfel, A Reinacher-Schick

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.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

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.

References

    1. Douillard JY, Oliner KS, Siena S et al. . Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369: 1023–1034.
    1. Heinemann V, von Weikersthal LF, Decker T et al. . FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15: 1065–1075.
    1. Van Cutsem E, Lenz HJ, Kohne CH et al. . Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015; 33: 692–700.
    1. Bazan V, Migliavacca M, Zanna I et al. . Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. Ann Oncol 2002; 13: 1438–1446.
    1. Cremolini C, Loupakis F, Antoniotti C et al. . FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol 2015; 16: 1306–1315.
    1. De Roock W, Claes B, Bernasconi D et al. . Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010; 11: 753–762.
    1. Bokemeyer C, Bondarenko I, Hartmann JT et al. . Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011; 22: 1535–1546.
    1. Modest DP, Brodowicz T, Stintzing S et al. . Impact of the specific mutation in KRAS codon 12 mutated tumors on treatment efficacy in patients with metastatic colorectal cancer receiving cetuximab-based first-line therapy: a pooled analysis of three trials. Oncology 2012; 83: 241–247.
    1. Peeters M, Douillard JY, Van Cutsem E et al. . Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol 2013; 31: 759–765.
    1. Tejpar S, Celik I, Schlichting M et al. . Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol 2012; 30: 3570–3577.
    1. Van Cutsem E, Kohne CH, Lang I et al. . Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29: 2011–2019.
    1. Seligmann J. Exploring the poor outcomes of BRAF mutant (BRAF mut) advanced colorectal cancer (aCRC): analysis from 2,530 patients (pts) in randomized clinical trials (RCTs). J Clin Oncol 2015; 33 (Suppl): abstr 3509.
    1. Corcoran RB, Atreya CE, Falchook GS et al. . Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol 2015; 33: 4023–4031.
    1. Fischer von Weikersthal L, Schalhorn A, Stauch M et al. . Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer 2011; 47: 206–214.
    1. Stahler A, Heinemann V, Giessen-Jung C et al. . Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial). Int J Cancer 2016; 138: 739–746.
    1. Stintzing S, Fischer von Weikersthal L, Decker T et al. . FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. Ann Oncol 2012; 23: 1693–1699.
    1. Stintzing S, Jung A, Rossius L, Modest DP et al. . Analysis of KRAS/NRAS and BRAF mutations in FIRE-3 A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type KRAS (exon 2) metastatic colorectal cancer patients. In ESMO/ECCO, 2013; Abstract E17-7073.
    1. Schmiegel W, Reinacher-Schick A, Arnold D et al. . Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group. Ann Oncol 2013; 24: 1580–1587.
    1. Hegewisch-Becker S, Graeven U, Lerchenmuller CA et al. . Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2015; 16: 1355–1369.
    1. Porschen R, Arkenau HT, Kubicka S et al. . Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol 2007; 25: 4217–4223.
    1. Reinacher-Schick A, Schulmann K, Modest DP et al. . Effect of KRAS codon13 mutations in patients with advanced colorectal cancer (advanced CRC) under oxaliplatin containing chemotherapy. Results from a translational study of the AIO colorectal study group. BMC Cancer 2012; 12: 349.
    1. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract 2009; 205: 858–862.
    1. Yokota T, Ura T, Shibata N et al. . BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer 2011; 104: 856–862.
    1. Simkens LH, van Tinteren H, May A et al. . Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015; 385: 1843–1852.
    1. Taieb J, Zaanan A, Le Malicot K et al. . Prognostic effect of BRAF and KRAS mutations in patients with stage iii colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: a post hoc analysis of the PETACC-8 trial. JAMA Oncol 2016; 1–11.
    1. Missiaglia E, Jacobs B, D'Ario G et al. . Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol 2014; 25: 1995–2001.
    1. De Roock W, Jonker DJ, Di Nicolantonio F et al. . Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 2010; 304: 1812–1820.
    1. Camaj P, Primo S, Wang Y et al. . KRAS exon 2 mutations influence activity of regorafenib in an SW48-based disease model of colorectal cancer. Future Oncol 2015; 11: 1919–1929.
    1. Lito P, Solomon M, Li LS et al. . Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 2016; 351: 604–608.
    1. Ostrem JM, Peters U, Sos ML et al. . K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013; 503: 548–551.
    1. Vincenzi B, Cremolini C, Sartore-Bianchi A et al. . Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients. Oncotarget 2015; 6: 31604–31612.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever