KRAS mutation (exon 2) is an established predictive biomarker resistant to antipidermal growth factor receptor (EGFR) therapy in patients with metastaic colorectal cancer.
Activating mutation in RAS (KRAS or NRAS) in addiction to KRAS mutations in exon 2 have been suggested as negative predictive biomarkers for anti-EGFR therapy. As suggested in the Consortium data (Lancet august 2010) other downstream mutations (RAS, PIK3CA and BRAF) could affect the efficacy of the anti-EGFR therapy. If RAS seems to be mainly a predictive biomarkers, BRAF has certainly confirmed it to be a very powerful prognostic factor. Although the low prevalence of BRAF mutations makes it difficult to evaluate them as predictive biomarkers. Furthermore, previous studies of anti-EGFR therapies combined with oxaliplatin-cointaining regimes have shown negative outcomes in KRAS.
In the PRIME trial, the authors have presented the data of the prospective-retrospective biomarker analysis of the treatment effect of the full spectrum of currently characterized RAS (KRAS and NRAS) and BRAF mutation on progression free survival (PFS) and overall survival (OS) in a randomized phase 3 study of panitumumab plus oxaliplatin, fluoruracil and leucovorin (Folfox 4) as compared to Folfolx4 alone in metastatic colorectal cancer patients naive for treatment.
Mutation analysis were performed on KRAS exon 2, 3 and 4 as well as on NRAS exon 2,3,4, and on BRAF exon 15. The RAS status was ascertained in 1060 of the 1183 patients (90%) who underwent randomization. Of these 1060 patients, 512 (49%) were identified as having tumours with non-mutated RAS and 548 (52%) were identified as having tumours with mutated RAS (any KRAS or NRAS).
In the not RAS mutated group the PFS was 10.1 months vs 7.9 months and the OS was 26 months vs 20.1 months (p 0.04) in favor of the experimental arm (panitumumab-folfox4). On the other hand in the 108 patients with any RAS mutation (KRAS or NRAS) the the PFS and the OS were consistent with mutated KRAS (exon 2), and the panitumumab had a detrimental effect.
In the patients’subgroup without RAS and BRAF mutations, a 7.4 month increase in OS was observed in the panitumumab arm. As suggested previously, BRAF mutations appeared to conferm a poor prognosis, regardless the treatment group.
This analysis was retrospective end exploratory in nature and therefore subject to limitations.
The author's conclusions was that RAS mutations, in addiction to KRAS exon 2 mutation, predict a lack or response to anti-EGFR therapy in patients with metastatic colorectal cancer. Panitumumab plus oxaliplatin-cointaing regimens have no value in patients with metastatic colorectal cancer and mutated RAS. The risk-benefit profile of panitumumab-Folfox4 was improved by excluding patients with mutated RAS. Pooled analyses of anti-EGFR are needed to confirm these findings.
- Is it time to extend the RAS analysis?
- Would the anti-EGGFR be the first line for all the fit RAS wild type patients?
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.