The molecular detection and clinical significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK targeted therapy

• Published in: PloS one 2014-01, Vol.9 (1), p.e84501-e84501
• Main Authors: Zhang, Ning-Ning, Liu, Yu-Tao, Ma, Li, Wang, Lin, Hao, Xue-Zhi, Yuan, Zheng, Lin, Dong-Mei, Li, Dan, Zhou, Yu-Jie, Lin, Hua, Han, Xiao-Hong, Sun, Yan, Shi, Yuankai
• Format: Article
• Language: English
• Subjects: Aberration; Adult; Aged; Anaplastic Lymphoma Kinase; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Care and treatment; Cell survival; Clinical outcomes; Clinical significance; Clinical trials; Crizotinib; Cytogenetics; Data processing; Drugs; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Fluorescence; Fluorescence in situ hybridization; Gene Expression; Genetic aspects; Genotype; Humans; Immunohistochemistry; Kinases; Laboratories; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Lymphoma; Lymphomas; Male; Medicine; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Staging; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncology; Pathology; Patients; Polymerase chain reaction; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Recombination, Genetic; Risk Factors; Small cell lung cancer; Smoking; Survival; Therapy; Treatment Outcome
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084501

This study aimed to elucidate clinical significance of anaplastic lymphoma kinase (ALK) rearrangement in selected advanced non-small cell lung cancer (NSCLC), to compare the application of different ALK detection methods, and especially evaluate a possible association between ALK expression and clinical outcomes in crizotinib-treated patients. ALK status was assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) in 173 selected advanced NSCLC patients. Clinicopathologic data, genotype status and survival outcomes were analyzed. Moreover, the association of ALK expression with clinical outcomes was evaluated in ALK FISH-positive crizotinib-treated patients including two patients with concurrent epidermal growth factor receptor (EGFR) mutation. The positivity detection rate of ALK rearrangement by FISH, IHC and qRT-PCR was 35.5% (59/166), 35.7% (61/171), and 27.9% (34/122), respectively. ALK rearrangement was observed predominantly in young patients, never or light smokers, and adenocarcinomas, especially with signet ring cell features and poor differentiation. Median progression-free survival (PFS) of crizotinib-treated patients was 7.6 months. The overall survival (OS) of these patients was longer compared with that of crizotinib-naive or wild-type cohorts, but there was no significant difference in OS compared with patients with EGFR mutation. ALK expression did not associate with PFS; but, when ALK expression was analyzed as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P = 0.026). The two patients with concomitant EGFR and ALK alterations showed difference in ALK expression, response to EGFR and ALK inhibitors, and overall survival. Selective enrichment according to clinicopathologic features in NSCLC patients could highly improve the positivity detection rate of ALK rearrangement for ALK-targeted therapy. IHC could provide more clues for clinical trial design and therapeutic strategies for ALK-positive NSCLC patients including patients with double genetic aberration of ALK and EGFR.