Identification of EML4-ALK Rearrangement and MET Exon 14 R988C Mutation in a Patient with High-Grade Neuroendocrine Lung Carcinoma Who Experienced a Lazarus Response to Crizotinib
Authors: Biagio Ricciuti, Luca Marcomigni, Giulio Metro, Guido Bellezza, Emanuele Caselli, Sara Baglivo, Rita Chiari
Journal: Journal of Thoracic Oncology (2018)

ALK receptor tyrosine kinase gene (ALK) rearrangements identify a subset of molecularly defined NSCLCs that display exquisite sensitivity to ALK receptor tyrosine kinase tyrosine kinase inhibitors.1Ricciuti B. De Giglio A. Mecca C. et al.Precision medicine against ALK-positive non-small cell lung cancer: beyond crizotinib.Med Oncol. 2018; 35: 72Google Scholar High-grade neuroendocrine carcinomas (HGNECs) have anecdotally been associated with ALK rearrangements, which makes the predictive role of such driver mutations in these patients still largely unknown.2Omachi N. Shimizu S. Kawaguchi T. et al.A case of large-cell neuroendocrine carcinoma harboring an EML4-ALK rearrangement with resistance to the ALK inhibitor crizotinib.J Thorac Oncol. 2014; 9: e40-e42Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 3Hayashi N. Fujita A. Saikai T. et al.Large cell neuroendocrine carcinoma harboring an anaplastic lymphoma kinase (ALK) rearrangement with response to alectinib.Intern Med. 2018; 57: 713-716Crossref PubMed Scopus (29) Google Scholar Here we report what, to the best of our knowledge, is the first case of ALK-rearranged and MNNG HOS Transforming gene (MET)-mutant large cell neuroendocrine carcinoma (LCNEC) of the lung in which the patient experienced a Lazarus response to crizotinib. A 58-year-old female never-smoker presented in December 2017 with neurological symptoms. The diagnosis was advanced LCNEC (Ki67 level 70%) of the lung with multiple brain, liver, and lymph node metastases (cT2N2M1b). She received dexamethasone and whole brain radiotherapy and started taking first-line platinum-etoposide chemotherapy with extracranial disease progression. Her clinical condition rapidly worsened because of acute-onset of type I respiratory failure and liver failure, making any second-line cytotoxic treatment unfeasible. Fortunately, in light of the patient's never-smoker status, a molecular work-up for potential actionable mutations was performed and revealed the presence of ALK rearrangement on the basis of immunohistochemistry (score 2+); this rearrangement was confirmed by fluorescent in situ hybridization (Fig. 1A–D) and next-generation sequencing for fusion transcripts. Of note, next-generation sequencing also revealed coexistence of an echinoderm microtubule associated protein like 4 gene (EML4)-ALK transcript of a MET exon 14 R988C mutation (Fig. 1E). Immediately upon documentation of ALK rearrangement, the patient started taking crizotinib, 250 mg twice daily, with marked improvement of her clinical condition within a few days, tapering of oxygen therapy until suspension, and progressive normalization of her liver function within 60 days (Fig. 2A). A positron emission tomography/computed tomography scan performed 28 days after the patient had started taking crizotinib showed a dramatic response to treatment (Fig. 2B). Currently, the patient is still receiving crizotinib with no evidence of disease progression. To the best of our knowledge, this is the first report of a patient with LCNEC of the lung coharboring an ALK-rearrangement and MET exon 14 R988C mutation. Chemotherapy still represents the standard of care of HGNEC, albeit with still unsatisfying survival rates. Because of the extremely low likelihood of finding a targetable genetic alteration, patients with HGNEC are not candidates for molecular testing according to current guidelines unless they present with unusual clinical characteristics that can hide an oncogene addiction, such as never-smoker status and young age. In fact, HGNECs are widely recognized to be strictly related with a heavy smoking habit and to share molecular features, including high expression of Ki-67, Bcl-2, p21, and telomerase activity, as well as abnormal p53 level and absent Rb.4Rekhtman N. Pietanza M.C. Hellmann M.D. et al.Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets.Clin Cancer Res. 2016; 22: 3618Crossref PubMed Scopus (298) Google Scholar Moreover, in roughly 1% to 2 % of cases, oncogene-addicted NSCLCs undergo histological transformation to HGNECs whereas de novo presentation of HGNECs with actionable molecular targets is exceedingly rare.5Oser M.G. Niederst M.J. Sequist L.V. Engelman J.A. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin.Lancet Oncol. 2015; 16: e165-e172Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar Importantly, our patient experienced a Lazarus-like response to crizotinib that reversed a life-threatening disease progression, suggesting that oncogene addiction rather than histologic type is predictive for response in such cases. Moreover, along with ALK gene rearrangement, our patient also carried a MET exon 14 R988C mutation, the predictive role of which for in vivo sensitivity to crizotinib (which also works as a MET inhibitor) is still debated. Our findings underline the need for testing for actionable genetic alterations in those patients with HGNEC of the lung who harbor clinical characteristics suggestive of an underlying targetable genetic mutation.