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.
Highlights
Oncogenic fusion of anaplastic lymphoma kinase (ALK) with echinoderm microtubule-associated proteinlike 4 resulting from genetic rearrangement is observed in 5% of patients with lung adenocarcinoma (Ad-LC), who tend to be younger and never or light smokers and exhibit aggressive invasion [1]
There were no significant differences in age and sex between patients with ALK-rearranged squamous cell lung carcinoma (Sq-LC) and Ad-LC
All patients with ALK-rearranged Sq-LC had previously undergone standard chemotherapy for Sq-LC prior to treatment with crizotinib and switched regimens when ALK rearrangement was detected, when they were diagnosed with progressive disease (PD) during ongoing chemotherapy, or when they showed severe adverse effects after detection of ALK rearrangement
Summary
Oncogenic fusion of anaplastic lymphoma kinase (ALK) with echinoderm microtubule-associated proteinlike 4 resulting from genetic rearrangement is observed in 5% of patients with lung adenocarcinoma (Ad-LC), who tend to be younger and never or light smokers and exhibit aggressive invasion [1]. ALK-rearranged Sq-LC is extremely rare, and has been reported only i nisolated cases; in these studies, the rearrangements were identified and responses to firstgeneration ALK inhibitors were reported. It is unknown whether ALK inhibitors are effective in patients with ALK-rearranged Sq-LC; the on- and offtarget resistance mechanisms of ALK inhibitors remain unclear. On-target resistance to crizotinib has been observed in approximately one-third of patients with ALK-rearranged Ad-LC [11, 12]. We reviewed previous case reports of ALK-rearranged Sq-LCs as well as two representative cases of responders and non-responders to three ALK inhibitors, including information from rebiopsies that were performed when the patients acquired resistance to previously administered ALK inhibitors
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