title: Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma.
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.
authors.affiliation: Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.affiliation: Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pilotto
authors.affiliation: ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Amato
authors.affiliation: ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Oncology, University of Torino, A.O.U. San Luigi, Orbassano, Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.affiliation: Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Peretti
authors.affiliation: Department of Oncology, University of Torino, A.O.U. San Luigi, Orbassano, Torino, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Vavalà
authors.affiliation: Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Kinspergher
authors.affiliation: Department of Oncology, University of Torino, A.O.U. San Luigi, Orbassano, Torino, Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Righi
authors.affiliation: Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Santo
authors.affiliation: Department of Pathology and Diagnostics, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Corbo
authors.affiliation: Department of Pathology and Diagnostics, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Giglioli
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.affiliation: Department of Pathology and Diagnostics, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chilosi
authors.affiliation: ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|Department of Pathology and Diagnostics, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D018773:Genes, erbB-1 / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib
keywords: EGFR; gefitinib; lung cancer; next-generation sequencing