Oncotarget

Clinical Research Papers:

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 _ and Giampaolo Tortora

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Oncotarget. 2015; 6:12783-12795. https://doi.org/10.18632/oncotarget.3727

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Abstract

Emilio Bria1,*, Sara Pilotto1,*, Eliana Amato2, Matteo Fassan2, Silvia Novello3, Umberto Peretti1, Tiziana Vavalà3, Stefania Kinspergher1, Luisella Righi3, Antonio Santo1, Matteo Brunelli4, Vincenzo Corbo2, Eliana Giglioli4, Isabella Sperduti5, Michele Milella6, Marco Chilosi4, Aldo Scarpa2,4 and Giampaolo Tortora1

1 Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy

2 ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy

3 Department of Oncology, University of Torino, A.O.U. San Luigi, Orbassano, Torino, Italy

4 Department of Pathology and Diagnostics, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy

5 Biostatistics, Regina Elena National Cancer Institute, Rome, Italy

6 Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy

* These authors have contributed equally to this work

Correspondence to:

Aldo Scarpa, email:

Keywords: lung cancer, EGFR, next-generation sequencing, gefitinib

Received: February 05, 2015 Accepted: March 01, 2015 Published: March 30, 2015

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.


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