KRAS, BRAF May Predict Metastatic CRC Survival

Tumour mutations may influence survival independently of treatment received for metastatic colorectal cancer

medwireNews: Pooled clinical trial results point to a possible prognostic role for KRAS and BRAF mutations in patients undergoing first-line therapy for metastatic colorectal cancer (mCRC).

Of 1239 mCRC participants of five AIO Colorectal Cancer Study Group trials, 462 had tumours positive for KRAS exon 2 and 3-4 mutations, 74 patients were positive for the BRAF V600E mutation and 39 for NRAS exon 2-4 mutations, say Dominik Modest, from University Hospital Grosshadern in Munich, Germany, and co-workers.

Patients with KRAS mutation-positive tumours had poorer progression-free survival (PFS) and overall survival (OS) than the 664 patients without a known mutation, giving significant multivariate hazard ratios (HRs) of 1.20 and 1.41, respectively.

Further analysis confirmed mutation status as a significant predictor of poorer OS for the 28 patients with the KRAS G12C mutation and the 71 patients with the KRAS G13D mutations, with HRs of 2.26 and 1.46, respectively.

However, the more common exon 2 KRAS variants, such as G12D detected in 152 patients and G12V in 92 patients, did not significantly influence OS, the team notes in the Annals of Oncology.

“This observation supports the hypothesis that KRAS exon 2 mutation variants are associated with a differing spectrum of clinical outcome”, the authors write.

Individuals whose tumours tested positive for a BRAF mutation had inferior PFS and OS than those without a mutation, with corresponding significant HRs of 2.19 and 2.99, whereas the NRAS mutation did not influence OS.

The researchers emphasize that the negative impact of KRAS and BRAF mutations was “consistently observed across different treatment regimens” of irinotecan , oxaliplatin and bevacizumab .

“Given that some biomarkers (i.e. KRAS mutation variants) were identified as potential prognostic markers, validation of our findings within alternative study-sets appears justified”, the team concludes.


Modest DP, Ricard I, Heinemann V, et al. 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. Ann Oncol 2016; Advance online publication 29 June. doi: 10.1093/annonc/mdw261

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