Abstract
BackgroundThis 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.MethodsALK 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.ResultsThe 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.ConclusionsSelective 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.
Highlights
Progress in molecular techniques provides better identification and understanding of molecular markers that may have prognostic value and can drive therapeutic decision making for non-small cell lung cancer (NSCLC)
In 2007, a fusion gene of anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein like 4 (EML4) in NSCLC was first identified by Soda et al [2], and soon became a novel molecular target for lung cancer treatment
ALK Detection Results One hundred and thirty-two resected and forty one biopsied specimens were analyzed both by IHC and fluorescent in situ hybridization (FISH); no interpretable IHC results were obtained for two patients and no interpretable FISH results for seven patients
Summary
Progress in molecular techniques provides better identification and understanding of molecular markers that may have prognostic value and can drive therapeutic decision making for non-small cell lung cancer (NSCLC). In 2007, a fusion gene of anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein like 4 (EML4) in NSCLC was first identified by Soda et al [2], and soon became a novel molecular target for lung cancer treatment. Crizotinib (ALK/MET/ROS1 inhibitor) was the first clinically available agent that showed remarkable antitumor activity in ALK-positive advanced NSCLC patients. 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
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