Parallel FISH and Immunohistochemical Studies of ALK Status in 3244 Non–Small-Cell Lung Cancers Reveal Major Discordances

Cabillic, Florian; Gros, Audrey; Dugay, Frédéric; Bégueret, Hugues; Mesturoux, Laura; Chiforeanu, Dan Cristian; Dufrenot, Leila; Jauffret, Vincent; Dachary, Dominique; Corre, Romain; Lespagnol, Alexandra; Soler, Gwendoline; Dagher, Julien; Catros, Véronique; Calve, Michèle Le; Merlio, Jean-Philippe; Belaud‐Rotureau, Marc‐Antoine

doi:10.1097/jto.0000000000000072

Cited by 149 publications

(142 citation statements)

References 47 publications

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“…For two of these FISH + /IHC − cases, presence of variant 1 was identified by qRT-PCR. Overall, our discordance rate is far from that reported by CABILLIC et al [20]. This previous study, based on the daily practice of two French molecular genetics platforms, reported a very low rate of positive cases by both FISH and IHC (80 (53%) out of 150), reaching 59% (80 out of 135) if noncontributive cases were excluded.…”

Section: Discussioncontrasting

confidence: 52%

“…The present study is the second largest study to date on ALK rearrangements in adenocarcinoma in French Caucasian patients [20]. However, our study does not reflect ALK rearrangement epidemiology or FISH: fluorescence in situ hybridisation; NI: not interpretable; ALK: anaplastic lymphoma kinase; IHC: immunohistochemistry; V: variant; WT: wild type; Abs: antibodies; NA: not available.…”

Section: Discussionmentioning

confidence: 71%

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French multicentric validation ofALKrearrangement diagnostic in 547 lung adenocarcinomas

et al. 2015

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Anaplastic lymphoma kinase (ALK) gene rearrangements in lung adenocarcinoma result in kinase activity targetable by crizotinib. Although fluorescence in situ hybridisation (FISH) is the reference diagnostic technique, immunohistochemistry (IHC) could be useful for pre-screening.Diagnostic yields of ALK IHC, FISH and quantitative reverse transcriptase PCR performed in 14 French pathology/molecular genetics platforms were compared. 547 lung adenocarcinoma specimens were analysed using 5A4 and D5F3 antibodies, two break-apart FISH probes and TaqMan kits. Clinicopathological data were recorded. 140 tumours were ALK rearranged (FISH with ⩾15% of rearranged cells) and 400 were ALK FISH negative (<15%). FISH was not interpretable for seven cases. ALK patients were young (p=0.003), mostly females (p=0.007) and light/nonsmokers (p<0.0001). 13 cases were IHC negative but FISH ⩾15%, including six cases with FISH between 15% and 20%; eight were IHC positive with FISH between 10% and 14%. Sensitivity and specificity for 5A4 and D5F3 were 87% and 92%, and 89% and 76%, respectively. False-negative IHC, observed in 2.4% of cases, dropped to 1.3% for FISH >20%. Variants were undetected in 36% of ALK tumours.Discordances predominated with FISH ranging from 10% to 20% of rearranged cells and were centre dependent. IHC remains a reliable pre-screening method for ALK rearrangement detection. @ERSpublications IHC is useful in pre-screening for ALK rearrangement, with FISH for confirmation of diagnosis

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 71%

French multicentric validation ofALKrearrangement diagnostic in 547 lung adenocarcinomas

et al. 2015

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“…163e165 Importantly, however, clinical outcomes of patients with discrepant FISH and IHC results have not shown a consistent pattern of superiority of one method over the other. 156,166 Although at the time of writing RT-PCR and NGS are not approved by FDA in the United States as first-line methods for determining ALK status in selection of patients for ALK inhibitor therapy, these approaches have shown comparable performance with IHC 163e165 when designed to detect the majority of fusions, and are standard practice in many other countries. 163e165,167 These methods are highly specific for most fusions, 97,168,169 and patients with positive results should be treated with an ALK inhibitor, although patients with negative results may benefit from a more sensitive method to exclude the possibility of a variant fusion.…”

Section: Recommendationmentioning

confidence: 99%

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Aung

Donald

Ellison

et al. 2014

The Journal of Molecular Diagnostics

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Context: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. Objective: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. Design: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. Results: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. Conclusions: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of

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“…Of 3244 cases, 150 were found to be ALK positive by FISH and/or positive by IHC, but only 80 of those samples were found to be positive by both FISH and IHC. They concluded that one-quarter of ALK -positive samples would have been missed had only single FISH or IHC testing been employed [14]. Both these tests are approved for the diagnosis of ALK -positive patients and most institutions use one of the two tests.…”

Section: Testing For Anaplastic Lymphoma Kinase (Alk)mentioning

confidence: 99%

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Qin

Gadgeel

2017

Targ Oncol

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Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

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Parallel FISH and Immunohistochemical Studies of ALK Status in 3244 Non–Small-Cell Lung Cancers Reveal Major Discordances

Cited by 149 publications

References 47 publications

French multicentric validation ofALKrearrangement diagnostic in 547 lung adenocarcinomas

French multicentric validation ofALKrearrangement diagnostic in 547 lung adenocarcinomas

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

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