Answer: When we talk about biomarkers in treatment options for colorectal cancer, one thing that really stands out are KRAS mutations as a negative predictive marker for epidermal growth factor (EGFR) antibodies, cetuximab and panitumumab. This is probably the highlight of a predictive biomarker: if the patient has the KRAS mutation, no treatment; if they have a wild type EGFR mutation, the antibodies have a chance to work.
This assumption was recently challenged with data presented at ASCO 2011, and again counterpointed at the European Society for Medical Oncology (ESMO) 2011 European Multidisciplinary Cancer Congress (EMCC) in Stockholm. KRAS mutations can occur at various codons. About 80% of all mutations are in codon 12. About 10%-12% of mutations are in codon 13, and there are some other mutations in codon 61 and other areas. What we saw in the presentation at ASCO this year confirmed the findings of an earlier paper, indicating that patients with a so-called G13D mutation, meaning codon 13 mutation, might actually still benefit from cetuximab. (Table 1) These were pooled retrospective analyses of cetuximab trials CRYSTAL and OPUS.1,2 The findings implied that not all KRAS mutations are the same, and that cetuximab plus chemotherapy might benefit patients with this particular KRAS mutation.
Data presented at the EMCC looked at pooled analyses of trials with panitumumab.3 In data from more than 1,400 patients, the G13D mutation was absolutely not associated with improved outcome with panitumumab. There was no consistent difference in benefit across trials in terms of progression-free survival (PFS) and overall survival (OS) for patients having the most common codon 12 and 13 KRAS mutant alleles.
How are we to interpret these data? Either the G13D mutation matters for cetuximab but not for panitumumab, which I don't think is true, or we can just say that cetuximab analysis is just a fluke. I think right now we are still back to the point that KRAS mutations are clearly negative predictive markers for panitumumab and I would also say for cetuximab. So I would not use EGFR antibodies in any KRAS-mutated tumors.
Now the other biomarker that I think is interesting in this context is BRAF. BRAF is in the signal transduction pathway just one step below KRAS. It might seem that BRAF mutations would also result in resistance to cetuximab and panitumumab, but what's really pronounced in BRAF-mutated tumors is the very poor prognosis. So BRAF could very well be a negative predictive marker but it's definitely a very strong poor prognostic marker – patients with BRAF mutated tumors live half as long as patients with non-BRAF mutated tumor, so this is a very strong biologic effect. It is very interesting to see that these molecules are only one step apart in our diagrams, but have very different biologic consequences when they are activated.
Beyond KRAS and BRAF, there are other interesting markers, particularly in terms of treatment with EGFR antibodies such as cetuximab and panitumumab. NRAS for instance is a parallel protein for KRAS and we know that the NRAS mutation, although found in just 1%-2% of patients, also serves as a negative predictive marker for cetuximab and panitumumab. This was highlighted in some of the analysis from PICCOLO trial, which used panitumumab in the second-line setting in combination with irinotecan.4 Patients who had any mutations in the KRAS, NRAS, or BRAF did not benefit from these antibodies.
I think in the future we won’t just focus on KRAS, we’ll integrate BRAF and NRAS, and probably PI3 kinase and Akt mutations, as well as PTEN and ligand expression levels to really crystallize the optimal patient that can benefit from EGFR antibody therapy. These are studies that are ongoing right now, and I think in the future will go beyond just using KRAS as a predictive marker for EGF receptor antibodies.
We're already using gene profiles at key cancer treatment centers, such as MD Anderson in Houston, Dana Farber in Boston, Memorial Sloan Kettering in New York, Vanderbilt in Nashville, and very soon at the Mayo Clinic. When patients with metastatic colon cancer come to these centers, they will have a profile of different mutations tested. PCR methodology is a cost-effective, robust, and reliable way to test for various mutations in one sample, and then hopefully be able to identify those patients who are most likely to benefit from EGFR antibodies.
For now, guidelines strongly recommend KRAS testing at the time of diagnosis in all patients with metastatic colorectal cancer.[5,6] Under both sets of guidelines, anti-EGFR antibody therapy with cetuximab or panitumumab is recommended in the setting of wild-type KRAS disease.