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

Zhang, Ningning; Liu, Yutao; Ma, Li; Wang, Lin; Hao, Xuezhi; Zheng, Yanfang; Lin, Dongmei; Li, Dan; Zhou, Yujie; Lin, Hua; Han, Xiaohong; Sun, Yan; Shi, Yuankai

doi:10.1371/journal.pone.0084501

Cited by 25 publications

(18 citation statements)

References 37 publications

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“…This observation was consistent with another study, which showed that ALK-positive adenocarcinomas might metastasize to lymph nodes early, despite the small size of the primary tumor (Jokoji et al, 2010;Paik et al, 2012;Takamochi et al, 2013). To date, several small sample studies (Takahashi et al, 2010;Zhang et al, 2014;Toll and Maleki, 2015) have reported that ALK rearrangements were associated with moderate or poor differentiation status; our study further affirmed this finding in a relatively larger sample size.…”

Section: Discussionsupporting

confidence: 93%

“…The incidence of ALK rearrangements was found to be 9.6% (73/763) in NSCLC and 11.0% (54/493) in adenocarcinoma in our study, which was similar to the results previously published in Chinese (Shan et al, 2014;Wang et al, 2014a;Yang et al, 2014) and Asian cohorts (Kim et al, 2014). As previously reported, patients who were ALK-positive were predominantly young women and never/light smokers (Lynch et al, 2004;Rodig et al, 2009;Shaw et al, 2009;Wong et al, 2009;Jokoji et al, 2010;Takahashi et al, 2010;Zhang et al, 2013;Zhang et al, 2014). In our study, young age, female gender, and never-smokers were significantly associated with ALK rearrangement.…”

Section: Discussionsupporting

confidence: 92%

“…Recently many studies have reported the efficacy of Ventana IHC for detecting ALK rearrangements with D5F3 antibodies and have supported that Ventana IHC is a method with excellent sensitivity and specificity to identify ALK rearrangements in paraffin-embedded lung cancer specimens (Takahashi et al, 2010;Zhang et al, 2013;Shan et al, 2014;Wang et al, 2014a;Zhang et al, 2014). The sensitivity and specificity of Ventana IHC were found to be 100 and 98.2%, respectively, and the concordance rate between the fluorescence in situ hybridization (FISH) and the Ventana IHC was 98.4% (Wang et al, 2014a).…”

Section: Discussionmentioning

confidence: 99%

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Clinical characteristics of patients with non-small cell lung cancers harboring anaplastic lymphoma kinase rearrangements and primary lung adenocarcinoma harboring epidermal growth factor receptor mutations

Lei

Wang

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) gene rearrangements and epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been intensively studied. The objective of this study was to determine the clinicopathological characteristics in genotype-specific subsets of patients with NSCLC to help ensure the optimal identification of patients whose tumors harbor these two driver mutations. The incidence of ALK rearrangements was investigated in 763 NSCLC specimens by immunohistochemistry using a D5F3 antibody, and EGFR mutations were assessed by amplification refractory mutation system (ARMS) in 222 patients with lung adenocarcinoma. Of these, 73 (9.6%) were detected as being ALK-positive; this designation was associated with young age, female gender, never-smokers, lymph node metastasis, and poor tumor differentiation, but not with histology. EGFR mutations were identified in 102 (45.9%) of 222 adenocarcinoma samples, and were more frequent in females and never-smokers. No difference in age was observed. Specifically, we identified several cases of complex EGFR mutations, and concomitant EGFR mutations and ALK rearrangements. These results suggest that young women and never-smokers are at risk for ALK rearrangement. We also identified concomitant mutations of EGFR and rearrangements of ALK in this study.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Clinical characteristics of patients with non-small cell lung cancers harboring anaplastic lymphoma kinase rearrangements and primary lung adenocarcinoma harboring epidermal growth factor receptor mutations

Lei

Wang

et al. 2015

Genet. Mol. Res.

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“…The ALKþ translocation confers special clinicopathologic features to the NSCLC cancer sub-type: ALK þ NSCLC patients tend to be diagnosed with lung cancer at a younger age 14,15,19,21,40 , and have a higher risk of developing brain (and other) metastases than patients with other NSCLC sub-types 20,21,41,42 . Brain metastases are known to severely impact a patient's quality-of-life (physical, cognitive, and functional impairments) 24,31,33 , as well as to result in high healthcare resource utilization 37 and substantial clinical 43 , economic 27 , and caregiver 32 burden.…”

Section: Discussionmentioning

confidence: 99%

Brain metastases in patients with ALK+ non-small cell lung cancer: clinical symptoms, treatment patterns and economic burden

Guérin

Sasané

Zhang

et al. 2015

Journal of Medical Economics

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Objective: Brain metastases (BM) are highly prevalent among anaplastic lymphoma kinase positive (ALKþ) non-small cell lung cancer (NSCLC) patients; yet little is known about their real-world treatment patterns and clinical and economic burdens. This study aimed to describe these patients' treatment patterns, symptoms, and costs. Research design and methods:Retrospective study pooling data from three large administrative databases in the US (08/2011-06/2013). ALKþ NSCLC patients with BM and continuous enrollment for ! 60 days before and !30 days after the first observed BM diagnosis were identified by pharmacy records for crizotinib among patients with lung cancer and BM diagnostic codes. Main outcome measures:Treatment patterns, symptoms, healthcare resource utilization, and costs, before and after BM diagnosis. Results:Of the 213 crizotinib patients with BM diagnoses meeting the selection criteria, 23.0% had BM prior to NSCLC diagnosis; 47.4% had BM prior to crizotinib initiation; 19.2% during crizotinib treatment; and 10.3% post-crizotinib treatment. For those diagnosed with BM after NSCLC diagnosis, the median time between the NSCLC and BM diagnoses was 88 days. Following the first observed BM diagnosis, 88.7% used chemotherapy, 63.4% had radiotherapy, and 31.9% had stereotactic radiosurgery. The prevalence of BM-related symptoms substantially increased post-BM-diagnosis: fatigue (from 15% to 39%), headaches (from 5% to 24%), and depression (from 5% to 15%). Monthly costs per patient averaged $5983 before the BM diagnosis and $22,645 after diagnosis. Patients' resource utilization increased significantly post-BM-diagnosis, with a 3-fold increase in OP visits and a 6-fold increase in IP stays. Post-BM-diagnosis costs were driven by pharmacy (42.0%), inpatient (29.6%), and outpatient costs (26.0%). Limitations:The study sample was limited to crizotinib-treated patients. Conclusions:Post-BM-diagnosis, patients experience high symptom burden. Post-BM-diagnosis, treatment is highly variable and costly: average monthly costs per patient almost quadrupled post-BM-diagnosis.312 Burden of brain metastasis in ALKþ lung cancer Gué rin et al.

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“…In spite of recent progresses of chemotherapy and novel therapies, the prognosis of lung cancer remains poor mostly because patients were at advanced stages when diagnosed. Lack of adequate tumor biomarkers for early diagnosis and metastasis identification is still one of the most important challenges in lung cancer therapy [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

AFAP1-AS1, a long noncoding RNA upregulated in lung cancer and promotes invasion and metastasis

et al. 2015

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Long noncoding RNAs (lncRNAs) have emerged as a major regulator of cancer. Significant fraction of lncRNAs is represented on widely used microarray platforms; however, many of which have no known function. To discover novel lung cancer-related lncRNAs, we analyzed the lncRNA expression patterns in five sets of previously published lung cancer gene expression profile data that were represented on Affymetrix HG-U133 Plus 2.0 array, and identified dysregulated lncRNAs in lung cancer. One lncRNA, actin filament associated protein 1 antisense RNA1 (AFAP1-AS1), was the most significantly upregulated in lung cancer and associated with poor prognosis. In vitro experiments demonstrated that AFAP1-AS1 knockdown significantly inhibited the cell invasive and migration capability in lung cancer cells. AFAP1-AS1 knockdown also increased the expression of its antisense protein coding gene, actin filament associated protein 1 (AFAP1), and affected the expression levels of several small GTPase family members and molecules in the actin cytokeratin signaling pathway, which suggested that AFAP1-AS1 promoted cancer cell metastasis via regulation of actin filament integrity. Our findings extend the number of noncoding RNAs functionally implicated in lung cancer progression and highlight the role of AFAP1-AS1 as potential prognostic biomarker and therapeutic target of lung cancer.

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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

Cited by 25 publications

References 37 publications

Clinical characteristics of patients with non-small cell lung cancers harboring anaplastic lymphoma kinase rearrangements and primary lung adenocarcinoma harboring epidermal growth factor receptor mutations

Clinical characteristics of patients with non-small cell lung cancers harboring anaplastic lymphoma kinase rearrangements and primary lung adenocarcinoma harboring epidermal growth factor receptor mutations

Brain metastases in patients with ALK+ non-small cell lung cancer: clinical symptoms, treatment patterns and economic burden

AFAP1-AS1, a long noncoding RNA upregulated in lung cancer and promotes invasion and metastasis

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