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ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.
Lung Cancer 2019; 138:13-18LC

Abstract

OBJECTIVE

Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases.

MATERIALS AND METHODS

In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH.

RESULTS

Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010.

CONCLUSION

ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Authors+Show Affiliations

Department of Pathology, Amsterdam UMC, Location VU University Medical Center, the Netherlands. Electronic address: e.thunnissen@amsterdamumc.nl.Epidemiology and Biostatistics, Amsterdam UMC, Location VU University Medical Center, the Netherlands.Department of Thoracic Oncology Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.Department of Oncology, Herlev University Hospital, Copenhagen, Denmark.Department of Pulmonary Diseases, Maastricht University Medical Center, Maastricht, the Netherlands.Pathology, Maastricht University Medical Center, Maastricht, the Netherlands.Department of Pulmonary Diseases, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands.Department of Pulmonary Diseases, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands.Department of Pulmonary Diseases, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands.Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom.Department of medical oncology, Clatterbridge Cancer Centre, Bebington, Cheshire, United Kingdom.Department of Pulmonary Diseases, Deventer Hospital, Deventer, the Netherlands.Department of Pneumology, CHU Mont-Godinne, Catholic University of Louvain (UCL), Yvoir, Belgium.Pathology, CHU Mont-Godinne, Catholic University of Louvain (UCL), Yvoir, Belgium.Department of Medical Oncology, Centre Jean Perrin, Clermont-Ferrand, France.Pathology, Centre Jean Perrin, Clermont-Ferrand, France.Department of Pathology, Trinity College Dublin, Dublin, Ireland.Royal College of Surgeons in Ireland, Department of Pathology, Dublin, Ireland.Istanbul University Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey.Department of Pathology, Gazi University Medical Faculty, Ankara, Turkey.Institute for Pathology, University Hospital Cologne, Köln, Germany.Department of Internal Medicine, University of Cologne, Center for Integrated Oncology Köln Bonn, Germany.Institute of Pathology, University Hospital Basel, Basel, Switzerland.Department of Pathology, Amsterdam UMC, Location VU University Medical Center, the Netherlands.Pfizer Innovative Health, Oncology - International Developed Markets, Berlin, Germany.Institute of Haematopathology Hamburg, Hamburg, and Lung Cancer Network NOWEL.org, Oldenburg, Germany.Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.Department of Pathology, Antwerp University Hospital, Edegem, Belgium.Department of Thoracic Oncology Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Department of Pulmonary Diseases, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31630043

Citation

Thunnissen, E, et al. "ALK Immunohistochemistry Positive, FISH Negative NSCLC Is Infrequent, but Associated With Impaired Survival Following Treatment With Crizotinib." Lung Cancer (Amsterdam, Netherlands), vol. 138, 2019, pp. 13-18.
Thunnissen E, Lissenberg-Witte BI, van den Heuvel MM, et al. ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib. Lung Cancer. 2019;138:13-18.
Thunnissen, E., Lissenberg-Witte, B. I., van den Heuvel, M. M., Monkhorst, K., Skov, B. G., Sørensen, J. B., ... Smit, E. F. (2019). ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib. Lung Cancer (Amsterdam, Netherlands), 138, pp. 13-18. doi:10.1016/j.lungcan.2019.09.023.
Thunnissen E, et al. ALK Immunohistochemistry Positive, FISH Negative NSCLC Is Infrequent, but Associated With Impaired Survival Following Treatment With Crizotinib. Lung Cancer. 2019 Oct 3;138:13-18. PubMed PMID: 31630043.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib. AU - Thunnissen,E, AU - Lissenberg-Witte,B I, AU - van den Heuvel,M M, AU - Monkhorst,K, AU - Skov,B G, AU - Sørensen,J B, AU - Mellemgaard,A, AU - Dingemans,A M C, AU - Speel,E J M, AU - de Langen,A J, AU - Hashemi,S M S, AU - Bahce,I, AU - van der Drift,M A, AU - Looijen-Salamon,M G, AU - Gosney,J, AU - Postmus,P E, AU - Samii,S M S, AU - Duplaquet,F, AU - Weynand,B, AU - Durando,X, AU - Penault-Llorca,F, AU - Finn,S, AU - Grady,A O, AU - Oz,B, AU - Akyurek,N, AU - Buettner,R, AU - Wolf,J, AU - Bubendorf,L, AU - Duin,S, AU - Marondel,I, AU - Heukamp,L C, AU - Timens,W, AU - Schuuring,E M D, AU - Pauwels,P, AU - Smit,E F, Y1 - 2019/10/03/ PY - 2019/07/18/received PY - 2019/09/24/revised PY - 2019/09/28/accepted PY - 2019/10/21/pubmed PY - 2019/10/21/medline PY - 2019/10/21/entrez KW - alk KW - fluorescence in situ hybridisation KW - immunohistochemistry KW - non-small cell lung cancer KW - prognosis KW - treatment SP - 13 EP - 18 JF - Lung cancer (Amsterdam, Netherlands) JO - Lung Cancer VL - 138 N2 - OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. CONCLUSION: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines. SN - 1872-8332 UR - https://www.unboundmedicine.com/medline/citation/31630043/ALK_immunohistochemistry_positive,_FISH_negative_NSCLC_is_infrequent,_but_associated_with_impaired_survival_following_treatment_with_crizotinib L2 - https://linkinghub.elsevier.com/retrieve/pii/S0169-5002(19)30668-3 DB - PRIME DP - Unbound Medicine ER -