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      Pulmonary Adenocarcinoma, Harboring Both an EGFR Mutation and ALK Rearrangement, Presenting a Stable Disease to Erlotinib and a Partial Response to Alectinib

      case-report

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          Abstract

          A 63-year-old woman with pulmonary adenocarcinoma (stage IIIB) that was positive for an epidermal growth factor receptor ( EGFR) mutation and an anaplastic lymphoma kinase ( ALK) rearrangement was treated with erlotinib as the first-line treatment, resulting in a stable disease. Due to skin rashes, fatigue and anorexia, erlotinib was suspended on erlotinib day 44. Alectinib was administered as the second-line treatment, exhibiting a partial response. On alectinib day 56, drug-induced lung injury forced suspension of alectinib, which was cured with corticosteroid therapy. ALK-tyrosine kinase inhibitors may be more effective for patients positive for both EGFR mutation and ALK rearrangement than other agents.

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          Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.

          Hisayuki Shigematsu, Li. Lin, Takao Takahashi … (2005)
          Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P < .001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers.
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            Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

            Alice Shaw, Beow Yeap, Mari Mino-Kenudson … (2009)
            The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
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              Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.

              Toyoaki Hida, Hiroshi Nokihara, Masashi Kondo … (2017)
              Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Intern Med
                Journal ID (iso-abbrev): Intern. Med
                Title: Internal Medicine
                Publisher: The Japanese Society of Internal Medicine
                ISSN (Print): 0918-2918
                ISSN (Electronic): 1349-7235
                Publication date (Electronic): 9 March 2018
                Publication date (Print): 15 August 2018
                Volume: 57
                Issue: 16
                Pages: 2377-2382
                Affiliations
                [1 ]Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Japan
                [2 ]Department of Respiratory Medicine, Graduated School of Medicine, The University of Tokyo, Japan
                [3 ]Department of Pathology, National Hospital Organization Tokyo National Hospital, Japan
                Author notes

                Correspondence to Dr.　Akira Yokoyama, ayokoyama-tki@ 123456umin.ac.jp

                Article
                DOI: 10.2169/internalmedicine.0383-17
                PMC ID: 6148164
                PubMed ID: 29526950
                SO-VID: d5cf16ab-9c6e-457c-86a0-8a8e4212cc74
                Copyright © Copyright © 2018 by The Japanese Society of Internal Medicine
                License:

                The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 20 October 2017
                Date accepted : 19 December 2017
                Categories
                Subject: Case Report

                Keywords: non-small cell lung cancer,egfr mutation,alk rearrangement
                Data availability:
                Keywords: non-small cell lung cancer, egfr mutation, alk rearrangement

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