Patients with NSCLC may display a low ratio of p.T790M vs. activating EGFR mutations in plasma at disease progression: implications for personalised treatment

• Published in: Oncotarget 2017-10, Vol.8 (49), p.86056-86065
• Main Authors: Del Re, Marzia, Bordi, Paola, Petrini, Iacopo, Rofi, Eleonora, Mazzoni, Francesca, Belluomini, Lorenzo, Vasile, Enrico, Restante, Giuliana, Di Costanzo, Francesco, Falcone, Alfredo, Frassoldati, Antonio, van Schaik, Ron H N, Steendam, Christi M J, Chella, Antonio, Tiseo, Marcello, Morganti, Riccardo, Danesi, Romano
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.20947

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. This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated 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. The mean amount of mutated alleles at progression to first-line EGFR-TKIs 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 progression-free 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. The amount of p.T790M in plasma can be much lower than activating EGFR mutations. Despite this finding, osimertinib is effective in p.T790M-positive patients. These results indicate that clones driving resistance to EGFR-TKIs represent a minority among cells bearing activating EGFR-mutations. In addition, the identification of a threshold level of p.T790M is not a strict requirement for the selection of patients to be treated with osimertinib, since treatment showed a decrease in all EGFR mutated cells.