Mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) are associated with resistance to the tyrosine kinase inhibitors (TKI) Tarceva (erlotinib) and Iressa (gefitinib) (Pao et al., 2005, Eberhard et al., 2005). Approximately 15 to 30% of tumours from NSCLC patients have mutations in the KRAS gene and clinical studies have shown that this information plays an important role in making treatment decisions.
Image of the Epidermal Growth Factor Receptor (EGFR) via Wikipedia
Recent clinical studies have shown that mutations in the KRAS gene are found more frequently in patients who show limited clinical response or who have a shorter time to disease progression with TKI treatment. The Eberhard study was a retrospective analysis that demonstrated a decrease in time to disease progression and overall survival in patients with mutant KRAS mutation status when treated with Tarceva plus chemotherapy, versus chemotherapy treatment alone. Conversely, with TKI treatment, NSCLC patients with mutations in the epidermal growth factor receptor (EGFR) gene have shown improved response rates, and longer time to disease progression.
Since then, a number of other trials have matured and the data reported at the ASCO meeting. Overall, at ASCO 2008, there were 15 abstracts that mentioned KRAS in the title and another 20 that mentioned the mutation in the abstract; many of these were posters and therefore very little information is available beyond the abstract. While discussing the FLEX trial in the plenary session, the discussant, Thomas Lynch suggested that:
“Biomarker analysis, particularly KRAS and FISH mutations, may allow us to enrich the population of patients likely to benefit and may improve the cost effectiveness of th(ese) agents.”
More recently, the predictive value of KRAS mutation in metastatic colorectal cancer (mCRC)
patients treated with monoclonal antibodies in combination with chemotherapy has been suggested. A total of 1200 patients with mCRC have now enrolled in randomized studies of either cetuximab or panitumumab, demonstrating inferior progression free survival (PFS) in the KRAS mutant type, as opposed to wild type, subset.
The significance of this finding is that in the clinic and in future trials, patients will need to be tested for their KRAS status prior to receiving therapy with a monoclonal antibody for treatment of mCRC. Conversely, those who test positively for mutant KRAS will not be eligible for monoclonal therapy, although chemotherapy alone is still very active in the disease. In the plenary session, the discussant, Gail Eckhardt was moved to note that:
“Academic groups, industry, NCI and the FDA will need to move quickly to develop valid assays for KRAS testing that are sensitive, reproducible and feasible.”
In the academic setting, it is relatively easy to perform Q-PCR analyses, however, in the community setting common in the United States, these tests are not yet mainstream because they require DNA extraction.
Ideally, it should be possible to order them either through central labs such as LabCorp and Quest or via the surgeon-pathologist in a multi-factorial treatment team. As with many of these type of analyses, the onus is on the medical oncologist to participate in an engaged way and ensure the testing is done early at the time of surgical intervention. A number of commercial companies such as DxS and Invitek are providing these tests in Europe to enable genotyping to be performed and hence appropriate therapy considered. These tests are not yet approved for commercial use by the FDA in the US, although Q-PCR and ELISA for KRAS and EGFR mutations are now widely used in academic centres and are beginning to be used to subset patients in clinical trials.
Eventually, as more information becomes available about the specific mutations associated with each cancer type, a new era of truly personalised medicine will be ushered in and patients will be more effectively treated dependent upon the genetic makeup of their tumours.