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      Case report: small cell transformation and metastasis to the breast in a patient with lung adenocarcinoma following maintenance treatment with epidermal growth factor receptor tyrosine kinase inhibitors


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          Breast metastasis from lung cancer has been reported, but not from SCLC that is transformed from lung adenocarcinoma during maintenance treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Transformation to small cell lung cancer(SCLC), although uncommonly seen, has been associated with resistance to EGFR-TKI therapy in lung adenocarcinomas.

          Case presentation

          We describe a case of a 49-year-old man with lung adenocarcinoma harboring L858R point mutation at the exon 21 of the epidermal growth factor receptor (EGFR). During the maintenance treatment with EGFR-TKI, the patient presented with a right breast mass, which was accompanied by elevated serum neuron specific enolase (NSE) level. The histological examination of biopsies from the breast mass and enlarging lung mass revealed SCLC that was less sensitive to standard SCLC treatment. The breast tumor was positive for thyroid transcription factor-1 (TTF-1), consistent with a lung primary cancer.


          This is the first case report of small cell transformation and metastatic to the breast in a patient with lung adenocarcinoma following EGFR-TKI treatment. Repeat biopsy is important for evaluation of evolving genetic and histologic changes and selection of appropriate treatment. and serum NSE measurement may be useful for detection of small cell transformation in cases with resistance to EGFR-TKI therapy.

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          Most cited references9

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          EGFR mutations in small-cell lung cancers in patients who have never smoked.

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            Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma.

            The epithelial to mesenchymal transition (EMT) may well play a part in determining the sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). However to date, no study has investigated the association between the EMT status and acquired resistance using cancer specimens. Immunohistochemical (IHC) staining was used to analyse the protein expression of epithelial and mesenchymal markers in tumour samples from lung adenocarcinoma patients. Mutations in the EGFR and K-ras gene were also examined. All patients showed a positive expression of epithelial markers in sensitive tumours. Tumour in 4 (44.4%) out of 9 patients showed down-regulation of epithelial markers or up-regulation of mesenchymal markers. The change in the EMT status between pre-and post-treatment was shown in 2 cases each with and without the T790M mutation. EMT plays a role in approximately half of the cases of resistance to EGFR-TKI, independent of T790M mutation.
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              Epidermal growth factor receptor mutations in small cell lung cancer.

              The vast majority of epidermal growth factor receptor (EGFR) mutations occur in lung adenocarcinoma, and even rare cases of other subtypes with this mutation, such as adenosquamous cell carcinoma, are associated with adenocarcinoma histology. According to this adenocarcinoma-specific nature of EGFR mutation, analysis of EGFR mutations with small cell lung cancers (SCLC) may provide a clue to its histogenesis. The mutational status of the EGFR gene was accessed in a cohort of 122 patients with SCLC; all patients were from a single institute. When the EGFR mutated, its gene copy number was also examined. EGFR mutations were detected in five SCLCs (4%). The patients were mainly in the light smoker and histologic combined subtype. All but one of the tumors harbored gene amplifications. Notably, in three tumors of the combined SCLC subtype, both components of adenocarcinoma and SCLC harbored an EGFR mutation, whereas gene amplification was detected only in the adenocarcinoma component. A partial response was achieved in a patient (with an EGFR mutation) who was treated with gefitinib. Although EGFR mutations are rare in SCLC, a combined subtype of SCLC with adenocarcinoma in light smokers may have a chance of harboring EGFR mutations. For patients with an EGFR mutation, EGFR tyrosine kinase inhibitor can be a treatment option. In terms of molecular pathogenesis, it is suggested that some SCLCs may have developed from pre-existing adenocarcinomas with EGFR mutations, but the development may not be simply linear, taking into consideration the discordant distribution of EGFR amplification.

                Author and article information

                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                3 August 2016
                3 August 2016
                : 16
                : 593
                [1 ]Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015 China
                [2 ]Department of Pathology, Yale University School of Medicine, New Haven, Connecticut USA
                [3 ]Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015 China
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                : 7 October 2015
                : 26 July 2016
                Funded by: Project from ZJATCM
                Award ID: 2010ZA084
                Case Report
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                adenocarcinoma,small cell lung cancer,metastatic breast tumor,epidermal growth factor receptor,tyrosine kinase inhibitor


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