Introduction: NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking. Methods: This study enrolled p.T790M-positive patients (n=49) affected by EGFRmutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib. Cell-free circulating tumor DNA (cftDNA) was extracted from plasma and the quantitative analysis of EGFR ex19del, p.L858R and p.T790M was performed by digital droplet PCR. Results: The mean amount of mutated alleles at progression to first-line EGFRTKIs was 108,492 copies/ml for ex19del, 97,336 copies/ml for p.L858R, but only 8,754 copies/ml for p.T790M. There was no significant correlation between progressionfree survival and the ratio of p.T790M over EGFR activating mutations. The analysis of cftDNA in 5 patients treated with osimertinib revealed a marked decrease of all EGFR mutant alleles.

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Keywords Circulating tumor DNA, EGFR, Personalized medicine, Predictive biomarkers
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Journal Oncotarget
Del Re, M, Bordi, P. (Paola), Petrini, I. (Iacopo), Rofi, E, Mazzoni, F. (Francesca), Belluomini, L. (Lorenzo), … Danesi, R. (2017). Patients with NSCLC may display a low ratio of p.T790M vs. activating EGFR mutations in plasma at disease progression: Implications for personalised treatment. Oncotarget, 8(49), 86056–86065. doi:10.18632/oncotarget.20947