Clinical features of squamous cell lung cancer with anaplastic lymphoma kinase (ALK)-rearrangement: a retrospective analysis and review

// Junko Watanabe 1, 2 , Shinsaku Togo 1, 2 , Issei Sumiyoshi 1 , Yukiko Namba 3 , Kentaro Suina 1 , Takafumi Mizuno 4 , Kotaro Kadoya 1 , Hiroaki Motomura 1 , Moe Iwai 1, 2, 5 , Tetsutaro Nagaoka 1, 2 , Shinichi Sasaki 3 , Takuo Hayashi 6 , Toshimasa Uekusa 7 , Kanae Abe 8 , Yasuo Urata 8 , Fuminori Sakurai 9 , Hiroyuki Mizuguchi 9 , Shunsuke Kato 10 and Kazuhisa Takahashi 1, 2 1 Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan 2 Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan 3 Department of Respiratory Medicine, Juntendo University Urayasu Hospital, Chiba 279-0001, Japan 4 Junior Resident of Juntendo University Hospital, Tokyo 113-8431, Japan 5 Department of Pharmacy, Juntendo University School of Medicine, Tokyo 113-8431, Japan 6 Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8431, Japan 7 Department of Pathology, Labor Health and Welfare Organization Kanto Rosai Hospital, Kanagawa 211-8510, Japan 8 Oncolys BioPharma, Inc, Minato-ku, Tokyo 105-0001 Japan 9 Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan 10 Department of Medical Oncology, Juntendo University School of Medicine, Tokyo 113-8431, Japan Correspondence to: Shinsaku Togo, email: shinsaku@juntendo.ac.jp Keywords: anaplastic lymphoma kinase rearrangement; circulating tumor cells; epithelial-mesenchymal transition; squamous cell lung cancer; TelomeScan Received: October 27, 2017      Accepted: April 06, 2018      Published: May 08,2018 ABSTRACT Anti-anaplastic lymphoma kinase (ALK)-targeted therapy dramatically improves therapeutic responses in patients with ALK-rearranged lung adenocarcinoma (Ad-LC). A few cases of squamous cell lung carcinoma (Sq-LC) with ALK rearrangement have been reported; however, the clinicopathological features and clinical outcomes following treatment with ALK inhibitors are unknown. We addressed this in the present study by retrospectively comparing the clinical characteristics of five patients with ALK-rearranged Sq-LC with those of patients with ALK-rearranged Ad-LC and by evaluating representative cases of ALK inhibitor responders and non-responders. The prevalence of ALK rearrangement in Sq-LCs was 1.36%. Progression-free survival (PFS) after initial treatment with crizotinib was significantly shorter in Sq-LC than in Ad-LC with ALK rearrangement ( p = 0.033). Two ALK rearrangements assayed by fluorescence in situ hybridization (FISH)-positive/immunohistochemistry-negative cases did not respond to crizotinb, and PFS decreased following alectinib treatment of ALK-rearranged Sq-LC ( p = 0.045). A rebiopsy revealed that responders to ceritinib harbored the L1196M mutation, which causes resistance to other ALK inhibitors. However, non-responders were resistant to all ALK inhibitors, despite the presence of ALK rearrangement in FISH-positive circulating tumor cells and circulating free DNA and absence of the ALK inhibitor resistance mutation. These results indicate that ALK inhibitors remain a reasonable therapeutic option for ALK-rearranged Sq-LC patients who have worse outcomes than ALK-rearranged Ad-LC patients and that resistance mechanisms are heterogeneous. Additionally, oncologists should be aware of the possibility of ALK-rearranged Sq-LC based on clinicopathological features, and plan second-line therapeutic strategies based on rebiopsy results in order to improve patient outcome.