Patients with NSCLC may display a low ratio of p.T790M vs. activating EGFR mutations in plasma at disease progression: implications for personalised treatment
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Marzia Del Re1,*, Paola Bordi2,*, Iacopo Petrini3,*, Eleonora Rofi1, Francesca Mazzoni4, Lorenzo Belluomini5, Enrico Vasile3, Giuliana Restante1, Francesco Di Costanzo4, Alfredo Falcone3, Antonio Frassoldati5, Ron H.N. van Schaik6, Christi M.J. Steendam7, Antonio Chella8, Marcello Tiseo2, Riccardo Morganti9 and Romano Danesi1
1Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
2Medical Oncology Unit, University Hospital of Parma, Parma, Italy
3Medical Oncology Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University Hospital of Pisa, Pisa, Italy
4Medical Oncology Unit, University Hospital Careggi, Firenze, Italy
5Medical Oncology Unit, Civil Hospital Arcispedale S. Anna, Ferrara, Italy
6Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
7Department of Pulmonology, Erasmus University Medical Center, Rotterdam, and Amphia Hospital, Breda, The Netherlands
8Lung Diseases Unit, Azienda Ospedaliero-Universitaria, Pisa, Italy
9Section of Statistics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
*These authors have contributed equally to this work
Iacopo Petrini, email: [email protected]
Keywords: circulating tumor DNA, EGFR, personalized medicine, predictive biomarkers
Received: July 12, 2017 Accepted: July 26, 2017 Published: September 15, 2017
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 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.
Results: 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.
Conclusions: 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.
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