C G Woo1, S Seo2, S W Kim3, S J Jang4, K S Park5, J Y Song6, B Lee7, M W Richards8, R Bayliss8, D H Lee9, J Choi10. 1. Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Gyeonggi-do, South Korea. 2. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 3. Department of Surgery, Seoul National University College of Medicine, Daehak-ro 101, Jongno-gu, Seoul, South Korea. 4. Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, South Korea. 5. Department of Biomedical Science, College of Life Science, CHA University, Seoul, South Korea. 6. Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 7. Division of Surgical Oncology, Department of Surgery, City of Hope, Duarte, California, USA. 8. Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK. 9. Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, South Korea. 10. epartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Abstract
Background: Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. Patients and methods: By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Results: Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Conclusion: Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.
Background: Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. Patients and methods: By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Results: Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Conclusion: Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.
Authors: Petros Christopoulos; Martina Kirchner; Volker Endris; Albrecht Stenzinger; Michael Thomas Journal: J Thorac Dis Date: 2018-06 Impact factor: 2.895
Authors: Marissa S Mattar; Jason Chang; Ryma Benayed; Darragh Halpenny; Astin Powers; David E Kleiner; Alexander Drilon; Mark G Kris Journal: Clin Lung Cancer Date: 2019-10-13 Impact factor: 4.785
Authors: Jessica J Lin; Viola W Zhu; Satoshi Yoda; Beow Y Yeap; Alexa B Schrock; Ibiayi Dagogo-Jack; Nicholas A Jessop; Ginger Y Jiang; Long P Le; Kyle Gowen; Philip J Stephens; Jeffrey S Ross; Siraj M Ali; Vincent A Miller; Melissa L Johnson; Christine M Lovly; Aaron N Hata; Justin F Gainor; Anthony J Iafrate; Alice T Shaw; Sai-Hong Ignatius Ou Journal: J Clin Oncol Date: 2018-01-26 Impact factor: 44.544