Custom Gene Capture and Next-Generation Sequencing to Resolve Discordant ALK Status by FISH and IHC in Lung Adenocarcinoma

Jang, Jin Sung; Wang, Xiaoke; Vedell, Peter T.; Wen, Ji; Zhang, Jinghui; Ellison, David W.; Evans, Jared M.; Johnson, Sarah H.; Yang, Ping; Sukov, William R.; Oliveira, André M.; Vasmatzis, George; Sun, Zhifu; Jen, Jin; Yi, Eunhee S.

doi:10.1016/j.jtho.2016.06.001

Cited by 37 publications

(29 citation statements)

References 36 publications

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“…14 No morphologic parameter could be identified that correlated with the presence of V3 in tumor biopsies of ALK 1 NSCLC patients. 18,31,32 Upfront NGS testing in particular is a time-efficient and material-sparing strategy for parallel detection of actionable genetic alterations in NSCLC with failure rates of approximately 10%, 18 which is considerably lower than the 32%-50% drop-out rate in the detection of ALK fusion variants observed in the current and other studies after serial application of different methods on the limited material obtained from small biopsies. These methods, however, are not part of the current diagnostic guidelines, which prioritize ALK IHC and FISH.…”

Section: Cancer Therapy and Preventionmentioning

confidence: 68%

EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK⁺ non‐small cell lung cancer

Christopoulos

Endris

Bozorgmehr

et al. 2018

Intl Journal of Cancer

103

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In order to identify anaplastic lymphoma kinase-driven non-small cell lung cancer (ALK NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants V1, V2 and V3 as detected by next-generation sequencing or reverse transcription-polymerase chain reaction (n = 67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4-ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3-driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p = 0.005), which suggests increased disease aggressiveness. Furthermore, V3-positive status was associated with earlier failure after treatment with first and second-generation ALK TKI (median progression-free survival [PFS] by RECIST in the first line 7.3 vs. 39.3 months, p = 0.01), platinum-based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p = 0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first-line treatment, p = 0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p = 0.017). Thus, EML4-ALK fusion variant V3 is a high-risk feature for ALK NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies.

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Section: Cancer Therapy and Preventionmentioning

confidence: 68%

EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK⁺ non‐small cell lung cancer

Christopoulos

Endris

Bozorgmehr

et al. 2018

Intl Journal of Cancer

103

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“…The authors identified false‐negative FISH samples and concluded that ALK testing should initially be based on IHC and/or NGS‐based methods instead of FISH testing . Finally, Jang et al conducted a similar study and found that ALK FISH results were false‐positive in three out of four FISH‐positive/IHC‐negative cases and confirmed that NGS approach was most effective in detection of ALK rearrangements …”

Section: Discussionmentioning

confidence: 95%

Targeted RNA‐sequencing assays: a step forward compared to FISH and IHC techniques?

et al. 2019

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Introduction ALK and ROS1 rearrangements are molecular targets of several tyrosine kinase inhibitors. RNA‐sequencing approaches are regarded as the new standard for fusion gene detection, representing an alternative to standard immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques. Patients and Methods We aimed to compare two recent amplicon‐based RNA‐sequencing techniques: FusionPlex® Alk Ret Ros1 v2 Kit (Archer®) with FHS‐003Z‐12—Human Lung Cancer Panel (Qiagen®) and assessed the accuracy of the data for therapy management. Thirty‐seven formalin‐fixed paraffin‐embedded non‐small cell carcinoma (NSCC) lesions initially explored by IHC and FISH were selected for RNA‐sequencing analysis. Results Qiagen® and Archer® kits produced similar results and correctly identified 85.1% (23/27) and 81.5% (22/27) of IHC/FISH ALK‐ and ROS1‐positive samples, respectively, and 100% (6/6) of the negative samples. With regard to the ambiguous IHC‐positive/FISH‐negative cases, RNA‐sequencing confirmed 75% (3/4) of the FISH conclusion. Although not statistically significant, patients with common EML4‐ALK variants presented shorter overall survival and progression‐free survival compared with patients harboring rare variants. Conclusion Our findings assessed the implementation of RNA‐sequencing approaches to explore ALK and ROS1 rearrangements from formalin‐fixed paraffin‐embedded samples. We highlighted the similarities between Qiagen® and Archer® kits in terms of handling time, cost, and outcomes. We confirmed the feasibility of molecular testing in routine organization and its possible use not only as an alternative for standard IHC and FISH techniques, but as a supplementary technique helping to classify discrepant cases.

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“…As mentioned earlier, this case probably represents a false positive ALK FISH result. It has been shown recently that NGS studies might be of help in resolving discordant ALK status cases …”

Section: Discussionmentioning

confidence: 99%

“…5 Other methods for detection of ALK rearrangement status reported extensively in the literature include immunohistochemistry (IHC), [6][7][8][9][10][11][12][13] reverse transcription-polymerase chain reaction (RT-PCR) 14,15 and, more recently, next-generation sequencing. 10,16,17 In 2013, the College of American Pathologists (CAP), the Association for Molecular Pathology (AMP) and the International Association for the Study of Lung Cancer (IASLC) guideline for molecular testing in lung adenocarcinoma recommended ALK FISH testing as a standard method for detection of ALK rearrangements. 5 The same guideline suggests ALK IHC as an alternative method for the screening of ALK rearrangement status.…”

Section: Introductionmentioning

confidence: 99%

A comparison of ALK gene rearrangement and ALK protein expression in primary lung carcinoma and matched metastasis

et al. 2017

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Custom Gene Capture and Next-Generation Sequencing to Resolve Discordant ALK Status by FISH and IHC in Lung Adenocarcinoma

Abstract: Background-We performed a genomic study in lung adenocarcinoma cases with discordant anaplastic lymphoma kinase (ALK) status by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC).

Cited by 37 publications

References 36 publications

EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK⁺ non‐small cell lung cancer

EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK⁺ non‐small cell lung cancer

Targeted RNA‐sequencing assays: a step forward compared to FISH and IHC techniques?

A comparison of ALK gene rearrangement and ALK protein expression in primary lung carcinoma and matched metastasis

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Custom Gene Capture and Next-Generation Sequencing to Resolve Discordant ALK Status by FISH and IHC in Lung Adenocarcinoma

Abstract: Background-We performed a genomic study in lung adenocarcinoma cases with discordant anaplastic lymphoma kinase (ALK) status by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC).

Cited by 37 publications

References 36 publications

EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non‐small cell lung cancer

EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non‐small cell lung cancer

Targeted RNA‐sequencing assays: a step forward compared to FISH and IHC techniques?

A comparison of ALK gene rearrangement and ALK protein expression in primary lung carcinoma and matched metastasis

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EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK⁺ non‐small cell lung cancer

EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK⁺ non‐small cell lung cancer