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Cited by 42Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Concomitant driver mutations in advanced EGFR -mutated non-small-cell lung cancer and their impact on erlotinib treatment

Open access
Jakobsen, Jan Nyrop, Santoni-Rugiu, Eric, Grauslund, Morten, Melchior, Linea, Sørensen, Jens Benn·2018·Oncotarget
DOI 10.18632/oncotarget.25490PMC PMC5995236
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Abstract

// Jan Nyrop Jakobsen 1, * , Eric Santoni-Rugiu 2, * , Morten Grauslund 2 , Linea Melchior 2 and Jens Benn Sørensen 1 1 Department of Oncology, Copenhagen University Hospital/Rigshospitalet, Copenhagen, Denmark 2 Department of Pathology, Copenhagen University Hospital/Rigshospitalet, Copenhagen, Denmark * Equal first authors Correspondence to: Jan Nyrop Jakobsen, email: jan.nyrop.jakobsen@regionh.dk Eric Santoni-Rugiu, email: eric.santoni-rugiu.02@regionh.dk Keywords: NSCLC; EGFR; erlotinib; tarceva; mutation Received: February 19, 2018 Accepted: May 05, 2018 Published: May 25, 2018 ABSTRACT Background: Patients with EGFR -mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes. Methods: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR -mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET -amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR -mutated tumor samples from erlotinib-treated patients. Results: Thirty-six patients (7%) had EGFR -mutations, including 2 with intrinsic resistance mutation p.T790M together with the p.L858R sensitizing mutation and 1 harboring the p.G719C/S768I double-mutation. Twenty-three patients had either locally advanced or advanced disease and received first-line erlotinib-treatment. Concomitant driver mutations were found in 15/21 (71%) of NGS-analyzed TKI-treated NSCLCs, involving in 67% of cases TP53 , in 13% CTNNB1 , and in 7% KRAS , MET , SMAD4 , PIK3CA , FGFR1 , FGFR3 , NRAS, DDR2 , and ERBB4 . No ALK-expression was found, whereas MET-overexpression and MET -amplification were observed in 5 and 4 patients, respectively. Objective responses occurred in 17/23 patients (74%), 4 did not respond (17%), and 2 harboring a SMAD4 -mutation (p.R135 * (stop)) and a FGFR3 -mutation (p.D785fs * 31), respectively, displayed mixed response with simultaneously progressing and responding tumors (8.7%). Thus, EGFR -mutated tumors harboring co-mutations were not less likely to respond. Conclusion: Co-mutations in other cancer-driver genes (oncogenes or tumor suppressor genes) were frequent in EGFR -mutated NSCLCs and few cases harbored concomitant activating and resistance EGFR -mutations before TKI-treatment. Most co-mutations did not impact the response to first-line erlotinib-treatment, but may represent potential additional therapeutic targets.

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  • Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%-12.5% of EGFR-mutant LUAD.

    “Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%−12.5% of EGFR-mutant LUAD72, 73, 103, 117.”

    From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [117]

  • TP53 and RB1 co-mutations mark the earliest ancestors of EGFR-mutant LUAD that transform to small cell carcinoma following exposure to EGFR TKIs and dramatically increase the risk of small cell transformation, although loss of RB1 is insufficient to directly induce neuroendocrine trans-differentiation.

    “TP53 and RB1 co-mutations mark the earliest ancestors of EGFR-mutant LUAD that transform to small cell carcinoma following exposure to EGFR TKIs and dramatically increase the risk of small cell transformation, although loss of RB1 is insufficient to directly induce neuroendocrine trans-differentiation.117–119.”

    From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [117]

  • Co-occurring alterations may influence how likely and how long a targeted therapy works, and also shape how resistance arises.

    “therefore co-occurring alterations can affect not only the likelihood and duration of response to targeted therapy but also impact mechanisms of acquired resistance117.”

    From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [117]

  • Baseline clonal TP53 and RB1 co-alterations, found in roughly 9% of EGFR-mutant LUAD, markedly raise the chance of small cell carcinoma transformation after EGFR TKI therapy.

    “co-occurring clonal alterations in both TP53 and RB1, present in ~9 % of EGFR-mutant LUAD at baseline, substantially increase the risk of transformation to small cell carcinoma upon treatment with EGFR TKI”

    From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [117]

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  1. [14]Travis WD Brambilla E Nicholson AG Yatabe Y Austin JH Beasley MB Chirieac LR Dacic S Duhig E Flieder DB Geisinger K Hirsch FR Ishikawa Y WHO Panel The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification J Thorac Oncol 2015 10 1243 60 https://doi.org/10.1097/JTO.0000000000000630 26291008 · DOI
  2. [50]Kim TM Song A Kim DW Kim S Ahn YO Keam B Jeon YK Lee SH Chung DH Heo DS Mechanisms of Acquired Resistance to AZD9291: A Mutation-Selective, Irreversible EGFR Inhibitor J Thorac Oncol 2015 10 1736 44 https://doi.org/10.1097/JTO.0000000000000688 26473643 · DOI

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Authors
Jakobsen, J. N., Santoni-Rugiu, E., Grauslund, M., Melchior, L., & Sørensen, J. B.
Affiliations
  • Copenhagen University Hospital (DK)
  • Department of Pathology, Copenhagen University Hospital/Rigshospitalet, Copenhagen, Denmark
Corresponding author
Jakobsen, Jan Nyrop
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2018-05-25
Volume
9
Issue
40
Pages
26195-26208
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.25490
PMC
PMC5995236
OpenAlex
W2804482009
Cited by
42
References
60
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 7 · 2020: 8 · 2019: 8 · 2018: 4
FWCI
5.09
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
EGFR-mutant non-small cell lung cancer, erlotinib, EGFR tyrosine kinase inhibitors, MET amplification, MET overexpression, ALK expression, TP53, CTNNB1, KRAS, PIK3CA, fibroblast growth factor receptor, NRAS, DDR2, ErbB4, first-line therapy, treatment resistance

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