Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA
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Marzia Del Re1, Marcello Tiseo2, Paola Bordi2, Armida D’Incecco3, Andrea Camerini4, Iacopo Petrini5, Maurizio Lucchesi6, Alessandro Inno7, Daniele Spada8, Enrico Vasile6, Valentina Citi1, Giorgio Malpeli9, Enrica Testa8, Stefania Gori7, Alfredo Falcone6, Domenico Amoroso4, Antonio Chella10, Federico Cappuzzo3, Andrea Ardizzoni2, Aldo Scarpa9, Romano Danesi1
1Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
2Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy
3Medical Oncology Unit, AUSL6, Istituto Toscano Tumori, Livorno, Italy
4Medical Oncology Unit, AUSL12, Istituto Toscano Tumori, Lido di Camaiore, Italy
5Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
6Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria, Pisa, Italy
7Medical Oncology Unit, Ospedale Sacro Cuore, Negrar, Italy
8Medical Oncolgy Unit, Ospedale Santa Maria della Misericordia, Urbino, Italy
9ARC-NET Research Centre and Department of Pathology and Diagnostics, Azienda Ospedaliero-Universitaria, Verona, Italy
10Lung Diseases Unit, Azienda Ospedaliero-Universitaria, Pisa, Italy
Romano Danesi, email: firstname.lastname@example.org
Keywords: cell-free circulating tumor DNA, KRAS, EGFR, activating mutation, tyrosine kinase inhibitors
Received: June 24, 2015 Accepted: December 29, 2015 Published: January 20, 2016
Introduction: KRAS oncogene mutations (MUTKRAS) drive resistance to EGFR inhibition by providing alternative signaling as demonstrated in colo-rectal cancer. In non-small cell lung cancer (NSCLC), the efficacy of treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) depends on activating EGFR mutations (MUTEGFR). However, inhibition of EGFR may select resistant cells displaying alternative signaling, i.e., KRAS, or restoration of EGFR activity due to additional MUTEGFR, i.e., the c.2369C > T (p.T790MEGFR).
Aim: The aim of this study was to investigate the appearance of MUTKRAS during EGFR-TKI treatment and their contribution to drug resistance.
Methods: This study used cell-free circulating tumor DNA (cftDNA) to evaluate the appearance of codon 12 MUTKRAS and p.T790MEGFR mutations in 33 advanced NSCLC patients progressing after an EGFR-TKI.
Results: p.T790MEGFR was detected in 11 (33.3%) patients, MUTKRAS at codon 12 in 3 (9.1%) while both p.T790MEGFR and MUTKRAS codon 12 were found in 13 (39.4%) patients. Six patients (18.2%) were KRAS wild-type (WTKRAS) and negative for p.T790MEGFR. In 8 subjects paired tumor re-biopsy/plasma samples were available; the percent concordance of tissue/plasma was 62.5% for p.T790MEGFR and 37.5% for MUTKRAS. The analysis of time to progression (TTP) and overall survival (OS) in WTKRAS vs. MUTKRAS were not statistically different, even if there was a better survival with WTKRAS vs. MUTKRAS, i.e., TTP 14.4 vs. 11.4 months (p = 0.97) and OS 40.2 vs. 35.0 months (p = 0.56), respectively.
Conclusions: MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance.
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