Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 May 20;6(14):12783-95.
doi: 10.18632/oncotarget.3727.

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

Emilio Bria  1 , Sara Pilotto  1 , Eliana Amato  2 , Matteo Fassan  2 , Silvia Novello  3 , Umberto Peretti  1 , Tiziana Vavalà  3 , Stefania Kinspergher  1 , Luisella Righi  3 , Antonio Santo  1 , Matteo Brunelli  4 , Vincenzo Corbo  2 , Eliana Giglioli  4 , Isabella Sperduti  5 , Michele Milella  6 , Marco Chilosi  4 , Aldo Scarpa  2   4 , Giampaolo Tortora  1
Affiliations

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

Emilio Bria et al. Oncotarget. .

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.

Keywords: EGFR; gefitinib; lung cancer; next-generation sequencing.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST

E.Bria has a consultancy role for Celgene, boards' participation for Novartis, Astra-Zeneca, Pierre-Fabre, and speaker's fee from Pfizer; S.Novello declares boards' participation for Novartis, Astra-Zeneca, MSD, Boehringer Ingelheim, Eli Lilly, Roche and speaker's fee from Pfizer; M. Milella declares boards' participation for Celgene, Astra-Zeneca, Boehringer Ingelheim, and speaker's fee from Pfizer, Novartis, and Celgene; A. Scarpa declares consultancies for Amgen, and boards' participation for Novartis, Sanofi; G.Tortora has consultancy role for Novartis, Pfizer and GSK. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1
Figure 1. Distribution of TP53, KRAS and CTNNB1 gene mutation according to group (p-value: Fisher's exact test - panel A)
A representative case of intratumor histologic and molecular heterogeneity (panel B-C). The poor responder case presented well-differentiated coexisting with de-differentiated areas within the same specimen (panel B; original magnifications 4x and 20x). Of interest, an EGFR deletion in exon 19 was observed in the well-differentiated adenocarcinoma, that was associated with a concomitant TP53 mutation (R248W) in the more de-differentiated area. The representation of the reads obtained by Ion Torrent sequencing, aligned to the reference genome as provided by the Integrative Genomics Viewer (IGV v.2.1, Broad Institute) software for the mutations in EGFR and TP53 genes, and the corresponding Sanger sequencing are reported. (panel C).
Figure 2
Figure 2. Progression-Free Survival according to PMA (cut-off 0.36)
Solid line: patients with PMA ≥ 0.36; dashed line: patients with PMA < 0.36 (panel A). Overall Survival according to PMA (cut-off 0.36). Solid line: patients with PMA ≥ 0.36; dashed line: patients with PMA < 0.36 (panel B). Progression-Free Survival according to the presence of additional coexisting mutations (ACM). Solid line: patients with ACM = 0; dashed line: patients with ACM ≥ 1 (panel C). Overall Survival according to the presence of additional coexisting mutations (ACM). Solid line: patients with ACM = 0; dashed line: patients with ACM ≥ 1 (panel D).
Figure 3
Figure 3. Progression-Free Survival according to the TP53 Mutation
Solid line: patients with wild type TP53; dashed line: patients with mutant TP53 (panel A). Overall Survival according to the TP53 Mutation. Solid line: patients with wild type TP53; dashed line: patients with mutant TP53 (panel B). Progression-Free Survival according to the combination of PMA (cut-off 0.36) and the presence of additional coexisting mutations (ACM). Solid line: patients with PMA ≥ 0.36 and ACM = 0; dashed line: patients with PMA < 0.36 and ACM ≥ 1 (panel C). Overall Survival according to the combination of PMA (cut-off 0.36) and the presence of additional coexisting mutations (ACM). Solid line: patients with PMA ≥ 0.36 and ACM = 0; dashed line: patients with PMA < 0.36 and ACM ≥ 1 (panel D).
See this image and copyright information in PMC

References

    1. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–246. - PubMed
    1. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–128. - PubMed
    1. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. - PubMed
    1. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334. - PubMed
    1. Pilotto S, Di Maio M, Peretti U, Kinspergher S, Brunelli M, Massari F, Sperduti I, Giannarelli D, De Marinis F, Tortora G, Bria E. Predictors of outcome for patients with lung adenocarcinoma carrying the epidermal growth factor receptor mutation receiving 1st-line tyrosine kinase inhibitors: Sensitivity and meta-regression analysis of randomized trials. Crit Rev Oncol Hematol. 2014;90:135–145. - PubMed

Publication types

MeSH terms