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

Emilio Bria, 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, Giampaolo Tortora

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)12783-12795
Number of pages13
JournalOncotarget
Volume6
Issue number14
Publication statusPublished - 2015

Keywords

  • EGFR
  • Gefitinib
  • Lung cancer
  • Next-generation sequencing

ASJC Scopus subject areas

  • Oncology

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