Research Papers:

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

Junko Watanabe, Shinsaku Togo _, Issei Sumiyoshi1, Yukiko Namba, Kentaro Suina, Takafumi Mizuno, Kotaro Kadoya, Hiroaki Motomura1, Moe Iwai, Tetsutaro Nagaoka, Shinichi Sasaki, Takuo Hayashi, Toshimasa Uekusa, Kanae Abe, Yasuo Urata, Fuminori Sakurai, Hiroyuki Mizuguchi, Shunsuke Kato and Kazuhisa Takahashi

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Oncotarget. 2018; 9:24000-24013. https://doi.org/10.18632/oncotarget.25257

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Junko Watanabe1,2, Shinsaku Togo1,2, Issei Sumiyoshi1, Yukiko Namba3, Kentaro Suina1, Takafumi Mizuno4, Kotaro Kadoya1, Hiroaki Motomura1, Moe Iwai1,2,5, Tetsutaro Nagaoka1,2, Shinichi Sasaki3, Takuo Hayashi6, Toshimasa Uekusa7, Kanae Abe8, Yasuo Urata8, Fuminori Sakurai9, Hiroyuki Mizuguchi9, Shunsuke Kato10 and Kazuhisa Takahashi1,2

1Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan

2Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan

3Department of Respiratory Medicine, Juntendo University Urayasu Hospital, Chiba 279-0001, Japan

4Junior Resident of Juntendo University Hospital, Tokyo 113-8431, Japan

5Department of Pharmacy, Juntendo University School of Medicine, Tokyo 113-8431, Japan

6Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8431, Japan

7Department of Pathology, Labor Health and Welfare Organization Kanto Rosai Hospital, Kanagawa 211-8510, Japan

8Oncolys BioPharma, Inc, Minato-ku, Tokyo 105-0001 Japan

9Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan

10Department of Medical Oncology, Juntendo University School of Medicine, Tokyo 113-8431, Japan

Correspondence to:

Shinsaku Togo, email: [email protected]

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


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.

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