Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma

Emilio Bria, Giampaolo Tortora, Sara Pilotto, Eliana Amato, Matteo Fassan, Silvia Novello, Umberto Peretti, Tiziana Vavalà, Stefania Kinspergher, Luisella Righi, Antonio Santo, Matteo Brunelli, Vincenzo Corbo, Eliana Giglioli, Isabella Sperduti, Michele Milella, Marco Chilosi, Aldo Scarpa

Risultato della ricerca: Contributo in rivistaArticolo in rivista

42 Citazioni (Scopus)

Abstract

Cancer molecular heterogeneity might explain the variable response of EGFR mutant lung adenocarcinomas to tyrosine kinase inhibitors (TKIs). We assessed the mutational status of 22 cancer genes by next-generation sequencing (NGS) in poor, intermediate or good responders to first-line gefitinib. Clinical outcome was correlated with Additional Coexisting Mutations (ACMs) and the EGFR Proportion of Mutated Alleles (PMA). Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each). TP53 mutations were exclusive of poor/intermediate responders (66.7% versus 0, p=0.009). Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03). TP53 mutation was the strongest negative modifier (median PFS 4.0 versus 14.0 months). Higher EGFR PMA was present in good versus poor/intermediate responders. Median PFS and survival were longer in patients with EGFR PMA ≥0.36 (12.0 versus 4.0 months, p=0.31; not reached versus 18.0 months, p=0.59). Patients with an EGFR PMA ≥0.36 and no ACMs fared significantly better (p=0.03), with a trend towards increased survival (p=0.06). Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.
Lingua originaleEnglish
pagine (da-a)12783-12795
Numero di pagine13
RivistaOncotarget
Volume6
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • Adenocarcinoma
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • DNA Mutational Analysis
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • EGFR
  • Female
  • Gefitinib
  • Genes, erbB-1
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms
  • Lung cancer
  • Male
  • Middle Aged
  • Multiplex Polymerase Chain Reaction
  • Mutation
  • Next-generation sequencing
  • Oncology
  • Proportional Hazards Models
  • Quinazolines
  • Sequence Analysis, DNA

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