Correspondence

Lack of Mutations in EGFR in Gastroenteropancreatic Neuroendocrine Tumors

N Engl J Med 2005; 353:209-210July 14, 2005

Article

To the Editor:

Lynch et al.1 and Paez et al.2 correlated the presence of somatic mutations in the tyrosine kinase domain of the gene that encodes the epidermal growth factor receptor (EGFR) with responsiveness to gefitinib in non–small-cell lung carcinoma. Neuroendocrine differentiation is present in a substantial number of gastroenteropancreatic neuroendocrine tumors,3 and EGFR expression occurs in such tumors.4

We sought EGFR-activating mutations in a series of rare gastroenteropancreatic neuroendocrine cancers. DNA was isolated from flash-frozen specimens of carcinoid and pancreatic endocrine tumors; EGFR exons 18, 19, and 21 were amplified by the polymerase chain reaction with primers described by Lynch et al.1; and amplicons were sequenced and assessed for predictive EGFR mutations (single-nucleotide substitutions in exons 18 and 21 and in-frame deletions in exon 19). Research authorization was obtained from all the patients, and the study was approved by the institutional review board.

No mutations in the EGFR kinase domain that were predictive of a response to gefitinib were detected in DNA from 62 human carcinoid tumors from a variety of sites, including both primary lesions (22 from the lung, 28 from the ileum, and 1 from the colon) and metastatic lesions (30 from the liver and 1 from the ovary). Most carcinoid tumors in this study were indolent; 20 matched sets, which included an ileal primary lesion and a hepatic metastatic lesion from the same patient, were examined.

As a verification of our detection procedure, DNA controls encoding EGFR mutations L858R within exon 21, delE746-A750 within exon 19, and delL747-P753insS within exon 19 (gifts from Drs. Daphne Bell and Daniel Haber, Massachusetts General Hospital, Charlestown, Mass.) were correctly identified. We noted in one ileal carcinoid the reported germ-line synonymous coding-region single-nucleotide polymorphism C/T in EGFR exon 21 (dbSNP:2229066; nucleotide position 2694 in GenBank accession number X00588); it was also detected in normal surrounding tissue. Similarly, no mutations in EGFR exons 18, 19, and 21 were found in DNA from 18 primary pancreatic endocrine carcinomas. In contrast to our results, Lynch et al.1 found no mutations in EGFR exons 19 and 21 in 40 primary pancreatic tumors (we do not know whether this group included rare pancreatic endocrine tumors) and one bronchial-carcinoid tumor-cell line.

Our results indicate that somatic activating mutations of the EGFR kinase domain that are predictive of responsiveness to gefitinib are uncommon in gastroenteropancreatic neuroendocrine cancers, pancreatic endocrine carcinomas, and carcinoid tumors (primary as well as metastatic lesions).

Judith A. Gilbert, M.S.
Ricardo V. Lloyd, M.D., Ph.D.
Matthew M. Ames, Ph.D.
Mayo Clinic College of Medicine, Rochester, MN 55905
ames.matthew@mayo.edu

4 References

1. 1

   Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139
   Full Text | Web of Science | Medline

2. 2

   Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500
   CrossRef | Web of Science | Medline

3. 3

   Howe MC, Chapman A, Kerr K, Dougal M, Anderson H, Hasleton PS. Neuroendocrine differentiation in non-small cell lung cancer and its relation to prognosis and therapy. Histopathology 2005;46:195-201
   CrossRef | Web of Science | Medline

4. 4

   Hopfner M, Sutter AP, Gerst B, Zeitz M, Scherubl H. A novel approach in the treatment of neuroendocrine gastrointestinal tumours: targeting the epidermal growth factor receptor by gefitinib (ZD1839). Br J Cancer 2003;89:1766-1775
   CrossRef | Web of Science | Medline

Citing Articles (12)

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   Mark Kidd, Irvin M Modlin. (2011) Small intestinal neuroendocrine cell pathobiology: ‘carcinoid’ tumors. Current Opinion in Oncology 23:1, 45-52
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   Ben Lawrence, Bjorn I. Gustafsson, Mark Kidd, Irvin Modlin. (2010) New Pharmacologic Therapies for Gastroenteropancreatic Neuroendocrine Tumors. Gastroenterology Clinics of North America 39:3, 615-628
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   Enrique Grande, Juan José Díez, Vanessa Pachón, Alfredo Carrato. (2010) Advances in the therapy of gastroenteropancreatic-neuroendocrine tumours (GEP-NETs). Clinical and Translational Oncology 12:7, 481-492
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   S. Gentile. (2010) Antipsychotic Therapy During Early and Late Pregnancy. A Systematic Review. Schizophrenia Bulletin 36:3, 518-544
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   Rabih Said, Eileen M. OʼReilly, Leslie Blumgart, Jinru Shia, Ghassan K. Abou-Alfa. (2010) Pancreatic islet cell carcinoma presenting with concurrent Cushingʼs and Zollinger–Ellison syndromes: case series and literature review. European Journal of Gastroenterology & Hepatology 22:2, 246-252
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   Gabriele Capurso, Nicola Fazio, Stefano Festa, Francesco Panzuto, Filippo De Braud, Gianfranco Delle Fave. (2009) Molecular target therapy for gastroenteropancreatic endocrine tumours: Biological rationale and clinical perspectives. Critical Reviews in Oncology/Hematology 72:2, 110-124
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   Nabahet Ameur, Ludovic Lacroix, Nelly Motte, Eric Baudin, Bernard Caillou, Michel Ducreux, Dominique Elias, Philippe Chanson, Martin Schlumberger, Jean Michel Bidart. (2009) Mutational status of EGFR , BRAF , PI3KCA and JAK2 genes in endocrine tumors. International Journal of Cancer 124:3, 751-753
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   Philipp C. Manegold, Georg Lurje, Alexandra Pohl, Yan Ning, Wu Zhang, Heinz-Josef Lenz. (2008) Can we predict the response to epidermal growth factor receptor targeted therapy?. Targeted Oncology 3:2, 87-99
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   Christoph J. Auernhammer, Burkhard Göke. (2007) Medical treatment of gastrinomas. Wiener klinische Wochenschrift 119:19-20, 609-615
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    Dorothee Karhoff, Susanne Sauer, Jörg Schrader, Rudolf Arnold, Volker Fendrich, Detlef K. Bartsch, Dieter Hörsch. (2007) Rap1/B-Raf Signaling Is Activated in Neuroendocrine Tumors of the Digestive Tract and Raf Kinase Inhibition Constitutes a Putative Therapeutic Target. Neuroendocrinology 85:1, 45-53
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    Guo, Mingzhou, , Liu, Shuang, , Lu, Fengmin, . (2006) Gefitinib-Sensitizing Mutations in Esophageal Carcinoma. New England Journal of Medicine 354:20, 2193-2194
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    T. Shah, D. Hochhauser, R. Frow, A. Quaglia, A. P. Dhillon, M. E. Caplin. (2006) Epidermal Growth Factor Receptor Expression and Activation in Neuroendocrine Tumours. Journal of Neuroendocrinology 18:5, 355-360
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