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

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.

ALK‐rearranged squamous cell carcinoma of the lung

“…The DCR was 90.1% (10/11) and 25.0% (1/4), respectively ( p = 0.01). Four patients in which ALK rearrangement was assayed by IHC (−)/FISH (+) or IHC (+)/FISH (−) did not respond to crizotinib, and the duration time of treatment decreased sharply from one to four months ( p = 0.001) 26,27 …”

Transformation from adenocarcinoma to squamous cell lung carcinoma with MET amplification after lorlatinib resistance: A case report

“…In the case reported here, there was no smoking history, basal ALK translocation was maintained, and MET amplification was found in addition to squamous cell transformation. Progression‐free survival of patients treated with crizotinib has been previously reported to be significantly shorter in squamous cell lung carcinoma with ALK rearrangement than in adenocarcinoma with ALK rearrangement 15 . This suggests that squamous cell histology can be related to resistance to ALK inhibitors.…”

Different driver gene mutations in patients with synchronous multiple primary lung cancers: a case report

“…Crizotinib exhibited high response rates in advanced patients with ALK-positive NSCLC, especially brain metastasis [ 12 ]. In spite of the remarkable responses have been observed by some researchers [ 13 , 14 ], it is still controversy about the efficacy of ALK inhibitor in ALK-rearranged squamous cell carcinoma [ 9 ]. A recent study indicated that the RAS-RAF-MEK-ERK signaling pathway determines the ALK inhibitor response in ALK-positive lung cancer, but still needs further investigation [ 15 ].…”