In 2005, the importance of KRAS mutations in the development of resistance to treatment with gefitinib (Iressa) and erlotinib (Tarceva) in non-small cell lung cancer (NSCLC) were first reported by Pao and colleagues.

The same year, another study (Moroni et al., ) assessed the relationship between epidermal growth factor receptor (EGFR) gene copy number, and KRAS and BRAF mutations as biomarkers of response to EGFR-targeted monoclonal antibodies for metastatic colorectal cancer.

The study found that in patients treated with cetuximab (Erbitux) or panitumumab (Vectibix), a correlation existed between clinical response and tumour EGFR copy number, and that KRAS or BRAF mutations occur mainly in patients with metastatic colorectal cancer resistant to treatment with these drugs.

Subsequent studies confirmed the association of KRAS mutations and resistance with such compelling evidence that led to the approval of panitumumab in Europe for the treatment of KRAS wild-type only metastatic colorectal cancer. As for EGFR copy number, later studies also confirmed an association with clinical outcome.

In a recent article, Moroni et al., conceded that the new challenge in metastatic colorectal cancer is that EGFR FISH pattern is often not homogeneous and has variable ratios, which makes the scoring of EGFR signals and defining the EGFR pattern by FISH difficult. Standardisation of methods is, therefore, needed to reach better reproducibility and optimum sensitivity.

As the authors explained, "From a clinical point of view, we can risk treating a non-responsive patient, but we cannot risk not treating a potentially responsive one."