Epidermal growth factor receptor (EGFR) inhibitor agents have an important role in the treatment of patients with metastatic CRC (mCRC). Although the clinical trials for the two agents approved in the treatment of this disease required testing for EGFR, it is now known that positive EGFR expression by immunostaining does not predict the outcome of therapy with EGFR inhibitor agents.1
Additional markers have been under study for this common cancer. Signaling pathways downstream of the EGFR have been identified and mutations in these markers such as KRAS, BRAF, PIK3CA or PTEN may affect the progression of CRC.1 Tumor KRAS mutations may occur in 35%-45% of patients with CRC.1 Recent data on the importance of KRAS has allowed clinicians to accurately determine appropriate patients for treatment with cetuximab and panitumumab. This has led to a recent label change for both products clearly stating that the two monoclonal antibody agents should only be administered to patients with wild-type(WT) KRAS versus those with mutated KRAS, since patients with the mutation will derive virtually no benefit from therapy with cetuximab and panitumumab. Mutations in KRAS codons 12, 13 or 61 are commonly seen in patients with CRC, producing an active ras protein which then creates an EGFR-independent activation of the signaling pathway, producing tumor growth and proliferation.2
BRAF is an additional biomarker which has generated interest for those treating patients with CRC and is also vulnerable to a common activating mutation, V600E, which can be associated with sporadic microsatellite instability (MSI) following somatic hypermethylation of the MLH1 promoter.2 A recently reported trial examined the effect of KRAS and BRAF mutations in patients with advanced colorectal cancer (aCRC) to determine if the mutations would affect therapy with oxaliplatin or irinotecan, two important agents in the treatment of mCRC. The Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in patients with aCRC.
Study facts include:
- Of the 1,425 patients in FOCUS, tumor blocks were obtained from 711 consenting patients
- DNA was obtained and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing
- Mutation status was initially assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU
- The association of BRAF-mutation with loss of MLH1 was assessed by immunohistochemistry
- Baseline characteristics were well balanced and similar to the full trial population as were the survival outcomes; performance status and overall survival (OS) status was available on 97.5% (n=693) of the patients. 97.3% developed progression of disease during the follow-up period and 87.7% of those patients died. Over 90% of the patients died from CRC.
Results of the study showed:
- Mutations were found in KRAS codons 12 or 13 in 288 (40.5%) of the patients; 422 (59.4%) were WT; mutations in KRAS for codon 61 were found in 23 (3.2%) of the patients (two had double mutations) and 684 (96.2%) were WT
- Overall, 308 (43.3%) patient samples were mutated KRAS and 399 (55.1%) were KRAS WT.
- 56 samples were BRAF mutation and 654 were BRAF WT; the rate of BRAF mutation was 7.9% (95% CI, 6.0% to 10.1%)
- Only four tumors had mutations for both BRAF and KRAS (0.6%)
- When combining the results for KRAS and BRAF, 360 (50.6%) of the samples had at least one mutation
Patients with a mutation showed an effect on progression free survival (PFS) (HR, 1.16; 95% CI, 1.00 to 1.36 to 2.43; P <.0001) and there was clear evidence that patients with a mutation have a worse OS compared to patients without mutation (HR, 1.40; 1.20 to 1.65; P< .0001)
The results showed that activating mutations in the KRAS and BRAF oncogenes are associated with shorter survival even in patients treated without targeted therapies but interestingly, patients with the activation of KRAS/BRAF may still derive benefit from other chemotherapy agents. irinotecan and oxaliplatin is still of clinical benefit for both mutated or WT KRAS/BRAF and despite the fact that mutations are linked to reduced OS, PFS on first-line cytotoxic therapy was not reduced significantly. Patients with mutated BRAF tumors had greater treatment effects with oxaliplatin therapy but it was not statistically significant.
Personalized medicine has made significant strides in the care of the patients with cancer, and patients with aCRC have been able to take advantage of new information to tailor their therapy appropriately, thus avoiding costly therapy with significant side effects when diagnosed with mutated KRAS. This trial adds to the body of information currently available on specific oncogenes and biomarkers in CRC and helps clinicians determine the role of other chemotherapy agents in the treatment of this common disease. Future research should continue the search for additional biomarkers and gene signatures for other therapies in the treatment of CRC.
References
- Siena, S, Sartore-Bianchi, A, Di Nicolantonio et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009;101:1308-1324. Free full text may be viewed at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758310/pdf/djp280.pdf.
- Richman, SD, Seymour, MT, Chambers, P et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: Results from the MRC FOCUS trial. J Clin Oncol. 2009 Nov 2 [epub ahead of print]. Abstract may be viewed at: http://www.ncbi.nlm.nih.gov/pubmed/19884549?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2