Clinical Characteristics and Outcomes of Patients with Primary Lung Adenocarcinoma Harboring ALK Rearrangements Detected by FISH, IHC, and RT-PCR

Abstract

EML4-ALK is a new driver gene of non-small cell lung cancer and a target of crizotinib. The objectives of this study were to determine the frequency of ALK rearrangements in a large cohort of patients with primary lung adenocarcinoma and to analyze the association of ALK rearrangements with clinicopathological characteristics and clinical outcomes. The roles of fluorescence in situ hybridization (FISH), Ventana immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR) in the detection of ALK rearrangements were evaluated. The ALK rearrangement was detected in 430 specimens from individual patients with primary lung adenocarcinoma using FISH and Ventana IHC based on tissue microarrays. The EGFR status was detected in all of the specimens through DNA sequencing. An RT-PCR was performed on 200 of the specimens and confirmed by sequencing. Of the 430 patients, 46 (10.7%) harbored ALK rearrangements. The ALK rearrangements were associated with a younger age and the EGFR wild type in comparison with ALK-negative patients. The sensitivity and specificity of the Ventana IHC were 100% and 98.2%, respectively, and the concordance rate between the FISH and the Ventana IHC was 98.4%. The sensitivity and specificity of RT-PCR were 95.5% and 87.0%, respectively, and the concordance rate between the FISH and the RT-PCR was 89.0%. The Cox analysis indicated that an early stage and EGFR-activating mutations were independently associated with a longer OS. This study demonstrated that ALK rearrangements are associated with a younger age and the EGFR wild type rather than with other clinicopathological factors. Although the FISH and Ventana IHC have better concordance, and RT-PCR is a more sensitive method and can identify different variants or partners, the IHC and RT-PCR need to be further evaluated in clinical trials to identify their roles in guiding patients’ targeted therapy using crizotinib.

Novel ALK fusion partners in lung cancer

“…Data on the clinical features of ALK-rearranged tumors are in good agreement with previous findings [33,34]. It is essential to acknowledge that the observed increase of the frequency of ALK translocations in women is entirely attributed to the high proportion of non-smokers in female lung cancer patients, but not to the genuine gender differences.…”

Crizotinib versus platinum‐based double‐agent chemotherapy as the first line treatment in advanced anaplastic lymphoma kinase‐positive lung adenocarcinoma

“…As EGFR mutation is related to clinical and pathological characteristics including Asian, female, non-smoking and adenocarcinoma, ALKpositive is commonly found in young, non-smoking individuals and the solid, adenocarcinoma subtype of signet-ring cell carcinoma. [4][5][6][7][8] In this study, the median age of patients was 52 years with 77.4% non-smokers, with a comparable gender ratio to previous studies. However, the diagnosis of each patient in this study was ultimately confirmed by the examination of bronchoscopy, lung biopsy or embedded sediment of pleural effusion.…”

“…Echinoderm microtubule‐associated protein‐like 4‐anaplastic lymphoma kinase is one of the most important driver genes of lung adenocarcinoma. As EGFR mutation is related to clinical and pathological characteristics including Asian, female, non‐smoking and adenocarcinoma, ALK‐positive is commonly found in young, non‐smoking individuals and the solid, adenocarcinoma subtype of signet‐ring cell carcinoma . In this study, the median age of patients was 52 years with 77.4% non‐smokers, with a comparable gender ratio to previous studies.…”

“…In our hospital, Wang et al . analyzed 430 lung adenocarcinoma cases using FISH, IHC, and RT‐PCR simultaneously . The results indicated that the sensitivity of Ventana IHC was 100% and the specificity was 98.2%, showing 98.4% consistency with the FISH test.…”

ALK‐rearrangement in non‐small‐cell lung cancer (NSCLC)

“…Second, the high sensitivity may lead to a false‐positive result. In a previous study, the sensitivity and specificity of RT‐PCR were 95.5% and 87.0%, respectively, and the concordance rate between FISH and RT‐PCR was 89.0% …”