Resistances to EGFR tyrosine kinase inhibitors in lung cancer— how to routinely track them in a molecular pathology laboratory?

Patients with advanced or metastatic forms of lung cancer with an activating mutation in epidermal growth factor receptor (EGFR) are given tyrosine kinase inhibitors (TKIs) targeted therapies that are more efficient than chemotherapy. These patients are excluded from first-line immunotherapy. After a phase of regression these tumors develop systematically resistance requiring a rapid change in therapy. At present two strategies are being discussed. The first strategy, so called “historical’ sequential treatment strategy, is based on the administration of first- or second-generation TKIs until the emergence of therapeutic resistance and, in the case of a EGFR T790M mutation, on the administration of third-generation TKIs. The recently proposed second strategy, so called the “next-generation” TKIs strategy, concerns initial treatment with third-generation TKIs. This latter strategy appears to be promising but needs to be confirmed by data comparing survival curves of patients treated in a sequential manner. Several criteria influence the choice of these strategies, in particular the presence of brain metastases, the potential toxicity and the economic model. The selected therapeutic algorithm has certainly an impact on the activity of laboratories. The sequential approach requires investigation into EGFR T790M resistance mutations, using blood and then possibly a tissue biopsy, or into other mechanisms of resistance in the absence of this mutation. In the case of tumor progression under treatment with third-generation TKIs the EGFR C797S mutation in the cis or trans positions is looked for. In the absence of this latter mutation other mechanisms of resistance are then investigated. We describe here the different methodological approaches used to identify resistance mechanisms linked to treatment with TKIs targeting mutations in EGFR.