title: 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.
abstract: BACKGROUND
  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).
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Del Re
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bordi
authors.affiliation: Medical Oncology Unit, AUSL6, Istituto Toscano Tumori, Livorno, Italy.
authors.forename: Armida
authors.initials: A
authors.lastname: D'Incecco
authors.affiliation: Medical Oncology Unit, AUSL12, Istituto Toscano Tumori, Lido di Camaiore, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Camerini
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Petrini
authors.affiliation: Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria, Pisa, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Lucchesi
authors.affiliation: Medical Oncology Unit, Ospedale Sacro Cuore, Negrar, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Inno
authors.affiliation: Medical Oncolgy Unit, Ospedale Santa Maria della Misericordia, Urbino, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Spada
authors.affiliation: Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria, Pisa, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Vasile
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Citi
authors.affiliation: ARC-NET Research Centre and Department of Pathology and Diagnostics, Azienda Ospedaliero-Universitaria, Verona, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Malpeli
authors.affiliation: Medical Oncolgy Unit, Ospedale Santa Maria della Misericordia, Urbino, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Testa
authors.affiliation: Medical Oncology Unit, Ospedale Sacro Cuore, Negrar, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gori
authors.affiliation: Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria, Pisa, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Medical Oncology Unit, AUSL12, Istituto Toscano Tumori, Lido di Camaiore, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Amoroso
authors.affiliation: Lung Diseases Unit, Azienda Ospedaliero-Universitaria, Pisa, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Chella
authors.affiliation: Medical Oncology Unit, AUSL6, Istituto Toscano Tumori, Livorno, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
authors.affiliation: ARC-NET Research Centre and Department of Pathology and Diagnostics, Azienda Ospedaliero-Universitaria, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; KRAS; activating mutation; cell-free circulating tumor DNA; tyrosine kinase inhibitors