Research Papers:

Early prediction of resistance to tyrosine kinase inhibitors by plasma monitoring of EGFR mutations in NSCLC: a new algorithm for patient selection and personalized treatment

Fiamma Buttitta, Lara Felicioni, Alessia Di Lorito, Alessio Cortellini, Luciana Irtelli, Davide Brocco, Pietro Di Marino, Donatella Traisci, Nicola D’Ostilio, Alessandra Di Paolo, Francesco Malorgio, Pasquale Assalone, Sonia Di Felice, Francesca Fabbri, Giovanni Cianci, Michele De Tursi and Antonio Marchetti _

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Oncotarget. 2020; 11:982-991. https://doi.org/10.18632/oncotarget.27517

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Fiamma Buttitta1,2,3, Lara Felicioni3, Alessia Di Lorito2, Alessio Cortellini4, Luciana Irtelli5, Davide Brocco5, Pietro Di Marino5, Donatella Traisci6, Nicola D’Ostilio6, Alessandra Di Paolo7, Francesco Malorgio7, Pasquale Assalone8, Sonia Di Felice9, Francesca Fabbri9, Giovanni Cianci9, Michele De Tursi2,5 and Antonio Marchetti1,2,3

1 Laboratory of Diagnostic Molecular Oncology, Center for Advanced Studies and Technology (CAST), University of Chieti, Chieti, Italy

2 Department of Medical and Oral Sciences and Biotechnologies, University of Chieti, Chieti, Italy

3 Department of Pathology, SS Annunziata Clinical Hospital, Chieti, Italy

4 Department of Oncology, San Salvatore Hospital, L’Aquila, Italy

5 Department of Oncology, SS Annunziata Clinical Hospital, Chieti, Italy

6 Department of Oncology, Floraspe Renzetti Hospital, Lanciano, Italy

7 Department of Oncology, Spirito Santo Hospital, Pescara, Italy

8 Department of Oncology, “S.S. Giovanni Paolo II” Veneziale Hospital, Isernia, Italy

9 Department of Oncology, Giuseppe Mazzini Hospital, Teramo, Italy

Correspondence to:

Antonio Marchetti,email: [email protected]

Keywords: epidermal growth factor receptor (EGFR); tyrosine-kinase Inhibitors; circulating tumor-DNA (ct-DNA); massive parallel sequencing (MPS); resistance-inducing mutation

Received: January 08, 2020     Accepted: February 17, 2020     Published: March 17, 2020


In Non-Small-Cell Lung Cancer (NSCLC) patients treated with Tyrosine Kinase-Inhibitors (TKIs) therapy, the emergence of acquired resistance can be investigated by plasma monitoring of circulating tumor DNA (ctDNA). A series of 116 patients with EGFR-positive lung adenocarcinomas were treated with first/second generation EGFR TKIs. At clinical progression, 64 (55%) EGFR T790M plasma positive patients were subjected to second line-treatment with osimertinib and strictly monitored during the first month of therapy. Plasma analysis by the EGFR Cobas test showed in 57 (89%) cases a substantial decrease in the levels of the sensitizing EGFR mutant allele (sEGFRma), down to a not detectable value. These patients were defined as plasmatic good responders (PGR). In 7 (11%) patients, the sEGFRma did not drop to zero (plasmatic poor responders, PPR). In these latter cases, Massive Parallel Sequencing (MPS) analysis at the end of the first month and at clinical progression showed the presence of resistant-inducing mutations, including MET and HER2 gene amplification, KRAS and PIK3CA gene mutations. PPR showed disease progression in 5 (71%) cases, stable disease in 2 (29%) cases, and a shorter median Progression-free survival (PFS) (4.3 ± 1.1 months) than that observed in PGR (13.3 ± 1.2 months) (P < 0.0001). Our data indicate that plasma monitoring by a simple RT-PCR-based EGFR mutation test in the first month of treatment may be useful for a rapid identification of patients to be subjected to further characterization by MPS. A diagnostic algorithm for an early detection of resistance-inducing mutations and patient management is reported.

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