Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer

Abstract

BackgroundEchinoderm microtubule-associated protein-like 4 (EML4) is the canonical anaplastic lymphoma kinase (ALK) fusion partner in non-small cell lung cancer (NSCLC), and ALK-positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking.MethodsNinety-eight ALK-positive patients with advanced NSCLC were retrospectively studied for their response to crizotinib and subsequent treatments. Comprehensive genomic profiling (CGP) was conducted to divide patients into different groups based on their ALK fusion patterns. Non-canonical ALK fusions were validated using RNA-sequencing.Results54.1% of patients had pure canonical EML4-ALK fusions, 19.4% carried only non-canonical ALK fusions, and 26.5% harbored complex ALK fusions with coexisting canonical and non-canonical ALK fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex ALK fusion group. Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical EML4-ALK fusion group (p = 0.010). The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.ConclusionOur results suggest NSCLC patients with complex ALK fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis.

Novel MRPS9-ALK Fusion Mutation in a Lung Adenocarcinoma Patient: A Case Report

“…According to the characteristics of ALK fusion, one reasonable explanation is that different variations at the N-terminus of the ALK fusions affects its subcellular localization and the properties of resulting protein, such as stability and activity, and then further leads to the impact of ALK TKIs on downstream signaling. It has also been demonstrated that patients harboring complex ALK fusions (coexisting canonical and non-canonical ALK fusions) are associated with better treatment outcomes in ALK TKI therapy ( 20 ). For clinicians, to better serve clinical decision-making, it is vital to determine the mutational status of the ALK kinase domain, as well as the therapeutic implications of the partner involved in the fusion.…”

Identification of a Novel SLC8A1-ALK Fusion and Non-Canonical Expression Significantly Responding to ALK-TKIs in Lung Adenocarcinoma: A Case Report

“…The response of TKI treatments for ALK-rearrangement patients largely depends on whether the ALK domain is expressed entirely and at high levels driven by the rearranged-partner genes, which are influenced by complex rearrangement structures and RNA splicing mechanisms, and sometimes disaccord on DNA levels and RNA levels. 9 Therefore, RT-PCR and Sanger sequencing were performed to validate the transcription pattern of the fusion gene and confirm the sequences around the breaking point. Notably, the RT-PCR sequencing demonstrated a different type of ALK fusion transcript (ie BCL11A exon 3-ALK exon 20 fusion) in this patient ( Figure 3 ).…”

“… 9 , 14–16 Notably, some coexistent gene mutations, such as TP53 mutations, also impair the efficacy of ALK-TKI treatment. 9 …”

“…8 In addition, approximately half of ALK fusions are non-canonical or complex, which have been associated with poor clinical response to ALK-TKI therapy, accounting for 10-40% of ALK rearrangement events. 9 Fusions that upregulate the expression of the entire ALK domain, such as rearrangements with EMAP like 4 (EML4), nucleophosmin (NPM), tropomyosin 3 (TPM3), trafficking from ER to golgi regulator (TFG), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), clathrin heavy chain (CLTC), etc, have been linked to good responses to ALK-TKI therapy. [3][4][5]8,9 Thus, the clinical outcomes of therapy with ALK-TKIs vary depending on the type of fusion.…”

Predicting the difference in treatment response and survival time of lung adenocarcinoma patients based on a prognostic risk model of glycolysis-related genes

“…LUAD is a pathological type of lung malignancy and can be further divided into different therapeutic subtypes and prognostic subtypes according to the status of multiple genes. For instance, LUAD patients with EGFR mutations and ALK fusion mutations have better treatment options available and higher survival rates than patients without these mutations [27][28][29][30] . Moreover, as immunotherapies have been developed, researchers have found that only some patients with LUAD bene t from these treatments 31 .…”