AUTHOR=Kang Jin , Zhang Xu-Chao , Chen Hua-Jun , Zhong Wen-Zhao , Xu Yang , Su Jian , Zhou Qing , Tu Hai-Yan , Wang Zhen , Xu Chong-Rui , Yang Xue-Ning , Chen Zhi-Hong , Wu Xue , Zhang Xian , Shao Yang , Wu Yi-Long , Yang Jin-Ji 

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

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.596937

DOI=10.3389/fonc.2020.596937

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Echinoderm microtubule-associated protein-like 4 (<italic>EML4</italic>) is the canonical anaplastic lymphoma kinase (<italic>ALK</italic>) fusion partner in non-small cell lung cancer (NSCLC), and <italic>ALK</italic>-positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different <italic>ALK</italic> fusion patterns are still lacking.</p></sec><sec><title>Methods</title><p>Ninety-eight <italic>ALK</italic>-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 <italic>ALK</italic> fusion patterns. Non-canonical <italic>ALK</italic> fusions were validated using RNA-sequencing.</p></sec><sec><title>Results</title><p>54.1% of patients had pure canonical <italic>EML4-ALK</italic> fusions, 19.4% carried only non-canonical <italic>ALK</italic> fusions, and 26.5% harbored complex <italic>ALK</italic> fusions with coexisting canonical and non-canonical <italic>ALK</italic> fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex <italic>ALK</italic> fusion group. Notably, patients with complex <italic>ALK</italic> fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical <italic>EML4-ALK</italic> fusion group (p = 0.010). The complex <italic>ALK</italic> fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical <italic>ALK</italic> fusions were likely to be expressed in tumors, and some of them formed canonical <italic>EML4-ALK</italic> transcripts during mRNA maturation.</p></sec><sec><title>Conclusion</title><p>Our results suggest NSCLC patients with complex <italic>ALK</italic> fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel <italic>ALK</italic> fusions and predict prognosis.</p></sec>