Jin Kang1, Xu-Chao Zhang1,2,3, Hua-Jun Chen1, Wen-Zhao Zhong1, Yang Xu4, Jian Su1, Qing Zhou1, Hai-Yan Tu1, Zhen Wang1, Chong-Rui Xu1, Xue-Ning Yang1, Zhi-Hong Chen1, Xue Wu4, Xian Zhang5, Yang Shao5,6, Yi-Long Wu1,7, Jin-Ji Yang1. 1. Division of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. 2. Medical Research Center, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China. 3. Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China. 4. Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, ON, Canada. 5. Nanjing Geneseeq Technology Inc., Nanjing, China. 6. School of Public Health, Nanjing Medical University, Nanjing, China. 7. Medical Research Center, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
Abstract
BACKGROUND: 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). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking. METHODS: Ninety-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. RESULTS: 54.1% 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. CONCLUSION: Our 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.
BACKGROUND: 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). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking. METHODS: Ninety-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. RESULTS: 54.1% 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. CONCLUSION: Our 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.
Authors: Jason N Rosenbaum; Ryan Bloom; Jason T Forys; Jeff Hiken; Jon R Armstrong; Julie Branson; Samantha McNulty; Priya D Velu; Kymberlie Pepin; Haley Abel; Catherine E Cottrell; John D Pfeifer; Shashikant Kulkarni; Ramaswamy Govindan; Eric Q Konnick; Christina M Lockwood; Eric J Duncavage Journal: Mod Pathol Date: 2018-01-12 Impact factor: 7.842
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