Coexistence of a novel CCNY-ALK and ATIC-ALK double-fusion in one patient with ALK-positive NSCLC and response to crizotinib: a case report

Abstract

Anaplastic lymphoma kinase (ALK) rearrangement, one of the common oncogene rearrangements in the mutational history of lung adenocarcinoma, occurs in approximately 5% of non-small cell lung cancer (NSCLC) patients who could be effectively treated with ALK tyrosine kinase inhibitors (TKIs). The earlier phase III PROFILE 1014 study has shown that crizotinib, a first-generation ALK-TKI, significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. Thus, clinicians must screen potential candidates for this driver alteration to guide ALK inhibitor therapy with a molecular testing platform capable of capturing all ALK fusions. Echinoderm microtubule-associated proteins, including the EML4 gene, are the most common ALK rearrangement partner. With the widespread use of the next-generation sequencing (NGS) techniques, which could approach enable the simultaneous screening of multiple genetic alterations, increasingly ALK rearrangement partners have been documented. However, the concurrent two ALK rearrangements within the same patient have rarely previously been reported. Here, we describe a novel CCNY-ALK (C1:A20) and ATIC-ALK (A7:A20), coexisting in the same case with poorly differentiated NSCLC and providing evidence of its sensitivity to ALK inhibitors. The newly identified rearrangement partners can be added to the list of ALK rearrangements that occurred in ALK-positive NSCLC, as it could lead to prolonged disease control. Also, while different ALK rearrangement variants might bring differing clinical outcomes, we discuss the impact of the co-mutations of these two ALK rearrangements on the sensitivity to ALK inhibitors. However, the impact of co-mutations on the pathogenesis of NSCLC should be further studied to supply more theoretical insight that co-mutations present for personalized anti-cancer therapy.

Long-Term Survival After Salvage Thoracic Surgery on a Patient with ALK-Rearranged Metastatic Lung Adenocarcinoma After Progression on Targeted Therapy

“…To the best of our knowledge, only a few of cases have been documented in the literature, which reveal that patients with NSCLC who harbor double ALK fusion (such as NLRC4-ALK and EML4-ALK, CDK15-ALK and EML4-ALK, CCNY-ALK and ATIC-ALK, PRKCB-ALK and EML4-ALK, BCL11A-ALK and EML4-ALK) could benefit from ALK-TKI crizotinib. [9][10][11][12][13] In the present work, the patient is the first reported case that harbors concurrent TAC1-ALK (Tintergenic: A20) and EML4-ALK fusion. We also found that this patient achieved durable response to crizotinib plus radiotherapy with a PFS of 14 months.…”

A novel FSHR-ALK and EML4-ALK double fusion variant in advanced lung adenocarcinoma: A case report

“…Jiangming et al described a patient with the double ALK fusion EML4-ALK and BIRC6-ALK who received alectinib treatment for 3 months and did not exhibit adverse drug reactions [5]. In addition, some reports also confirmed that patients with double ALK fusions may be sensitive to crizotinib [2,[14][15][16][17][18]. However, not all lung adenocarcinomas with ALK fusion may benefit from treatment with ALK-TKIs.…”

Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer

“…Few investigations have focused on the concomitance of double ALK rearrangements because of the low incidence ( Table 5 ). According to our literature search results, only eleven cases have been previously reported, including CCNY-ALK and ATIC-ALK [ 104 ], NLRC4-ALK and EML4-ALK [ 105 ], PRKCB-ALK and EML4-ALK [ 106 ], EML4-ALK and BCL11A-ALK [ 107 ], EML6-ALK and FBXO11-ALK [ 108 ], DYSF-ALK and ITGAV-ALK [ 109 ], ALK-SSH2 and EML4-ALK [ 110 ], ARID2-ALK and EML4-ALK [ 110 ], EML4-ALK and CDK15-ALK [ 111 ], PDK1-ALK and STRN-ALK [ 68 ], as well as ALK-GCA and EML4-ALK [ 112 ], etc. Previous reports confirmed that patients with double ALK fusion may respond to ALK-TKIs.…”