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.
Highlights
Lung cancer is the leading cause of cancer-related mortality worldwide and non-small cell lung cancer (NSCLC) accounts for more than 80% of all diagnosed cases (1, 2)
The anaplastic lymphoma kinase (ALK) fusion patterns were characterized using comprehensive genomic profiling (CGP), with 43 patients being sequenced at diagnosis and 55 patients being sequenced at progressive disease (PD) after crizotinib treatment (Supplementary Figure 1)
Since the time of sampling makes little difference on the frequency of various ALK fusion patterns (Supplementary Figure 2A vs. 2B), we combined all the CGP analysis and used it to divide all 98 ALK-positive patients into 3 groups (Supplementary Figure 2B): 1) 53 patients (54.1%) had only the canonical Echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions; 2) 19 patients (19.4%) carried only the non-canonical ALK fusions; 3) 26 patients (26.5%) who harbored both canonical and non-canonical ALK fusions were classified as the complex ALK fusion group
Summary
Lung cancer is the leading cause of cancer-related mortality worldwide and non-small cell lung cancer (NSCLC) accounts for more than 80% of all diagnosed cases (1, 2). Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the canonical and most common ALK gene arrangement found in NSCLC, by which multiple EML4 breakpoints fuse in frame with the kinase domain of ALK (5). More than 15 different EML4-ALK fusion variants have been reported in NSCLC, with v1, v2, and v3a/b being the most abundant variants (6). Crizotinib, showed improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in ALK-positive NSCLC patients compared with chemotherapy (12–14). There are limited data about the TKI clinical response for canonical (EML4-ALK) versus noncanonical (non-EML4-ALK) fusions in NSCLC. Echinoderm 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). Studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking
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