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

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

doi:10.18632/oncotarget.3727

Emilio Bria, Stefania Kinspergher + Show 16 more

Open Access

https://doi.org/10.18632/oncotarget.3727

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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.

Highlights

Randomized clinical trials conducted in non-smallcell lung cancer (NSCLC) carrying activating mutations of the epidermal growth factor receptor (EGFR) have clearly shown that tyrosine kinase inhibitors (TKIs) dramatically contribute to improve prognosis, disease control, symptoms and quality of life when compared to traditional platinum-based chemotherapy [1,2,3,4,5]
A recent meta-analysis confirmed that EGFR mutant NSCLC patients derived a significant progression-free-survival (PFS) advantage from TKIs over platinum-doublet chemotherapy as first-line treatment, a significant differential benefit may be observed according to smoking status (HR for never-smokers 0.29 versus 0.54 for eversmokers; p < 0.007) and to the type of EGFR mutation www.impactjournals.com/oncotarget (HR for exon 19 deletion 0.25 versus 0.44 for exon 21 substitution; p < 0.001) [6]
Despite exploratory and unpowered for conclusive interpretations, the results reported indicate that the application of next-generation sequencing (NGS) technology may furnish a baseline genetic portrait of advanced NSCLC that gives information on the presence of actionable and additional mutations that may impair the efficacy of targeted therapies

Summary

Introduction

Randomized clinical trials conducted in non-smallcell lung cancer (NSCLC) carrying activating mutations of the epidermal growth factor receptor (EGFR) have clearly shown that tyrosine kinase inhibitors (TKIs) dramatically contribute to improve prognosis, disease control, symptoms and quality of life when compared to traditional platinum-based chemotherapy [1,2,3,4,5]. The resistance develops after an initial response to therapy (acquired resistance) and may be pharmacological (failure of delivery of the drug to its target) or biological, primarily deriving from the activation of coexisting pathways, bypassing the oncogenic dependency of a given driven alteration [7]

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