EGFR mutation heterogeneity and mixed response to EGFR tyrosine kinase inhibitors of non small cell lung cancer: a clue to overcoming resistance

The presence of an EGFR activating mutation is predictive of benefit from reversible and irreversible EGFR tyrosine kinase inhibitor (EGFR-TKI) allowing personalized medicine in lung cancer. However, intratumoral heterogeneity in EGFR mutation status has recently been described and ranged from 13.9% to 27% in some studies. Intratumor heterogeneity may have important consequences for personalized-medicine approaches that commonly rely on a single tumor-biopsy to portray tumor mutational landscape. EGFR mutation heterogeneity could also explain the mixed responses phenomenon and act as a mechanism of acquired resistance to EGFR-TKI. In order to a better tailored treatment in advanced NSCLC, it is extremely important to elucidate the relevance and degree of heterogeneous distribution of the targeted biomarker regarding the metastasis localisation, previous systemic treatments and interval between primary tumor and metastasis. Additionally, these findings would also help us to design new strategies for patients with lung cancer harboring heterogeneous EGFR mutations.