ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib

E. Thunnissen; B. Lissenberg-Witte; M. M. van den Heuvel; K. Monkhorst; B. G. Skov; J. B. Sorensen; A. Mellemgaard; A. M. C. Dingemans; E. J. M. Speel; A. J. de Langen; S. M. S. Hashemi; I. Bahce; M. A. van der Drift; M. G. Looijen-Salamon; J. Gosney; P. E. Postmus; S. M. S. Samii; F. Duplaquet; B. Weynand; X. Durando; F. Penault-Llorca; S. Finn; A. O. Grady; B. Oz; N. Akyurek; R. Buettner; J. Wolf; L. Bubendorf; S. Duin; L. Marondel; L. C. Heukamp; W. Timens; E. M. D. Schuuring; P. Pauwels; E. F. Smit

doi:10.1016/j.lungcan.2019.09.023

ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib

E. Thunnissen^*, B. Lissenberg-Witte, M. M. van den Heuvel, K. Monkhorst, B. G. Skov, J. B. Sorensen, A. Mellemgaard, A. M. C. Dingemans, E. J. M. Speel, A. J. de Langen, S. M. S. Hashemi, I. Bahce, M. A. van der Drift, M. G. Looijen-Salamon, J. Gosney, P. E. Postmus, S. M. S. Samii, F. Duplaquet, B. Weynand, X. DurandoF. Penault-Llorca, S. Finn, A. O. Grady, B. Oz, N. Akyurek, R. Buettner, J. Wolf, L. Bubendorf, S. Duin, L. Marondel, L. C. Heukamp, W. Timens, E. M. D. Schuuring, P. Pauwels, E. F. Smit

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	13-18
Number of pages	6
Journal	Lung Cancer
Volume	138
DOIs	https://doi.org/10.1016/j.lungcan.2019.09.023
Publication status	Published - Dec 2019

Keywords

non-small cell lung cancer
alk
immunohistochemistry
fluorescence in situ hybridisation
treatment
prognosis
MOLECULAR TESTING GUIDELINE
KINASE INHIBITORS GUIDELINE
OF-AMERICAN-PATHOLOGISTS
LUNG-CANCER PATIENTS
INTERNATIONAL-ASSOCIATION
COPY NUMBER
REARRANGEMENT
IHC
ADENOCARCINOMA
PREVALENCE

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10.1016/j.lungcan.2019.09.023

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Thunnissen, E., Lissenberg-Witte, B., van den Heuvel, M. M., Monkhorst, K., Skov, B. G., Sorensen, J. B., Mellemgaard, A., Dingemans, A. M. C., Speel, E. J. M., de Langen, A. J., Hashemi, S. M. S., Bahce, I., van der Drift, M. A., Looijen-Salamon, M. G., Gosney, J., Postmus, P. E., Samii, S. M. S., Duplaquet, F., Weynand, B., ... Smit, E. F. (2019). ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib. Lung Cancer, 138, 13-18. https://doi.org/10.1016/j.lungcan.2019.09.023

@article{17c5cd5b3a8d49d4b6d479b706a0f5d3,

title = "ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib",

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.",

keywords = "non-small cell lung cancer, alk, immunohistochemistry, fluorescence in situ hybridisation, treatment, prognosis, MOLECULAR TESTING GUIDELINE, KINASE INHIBITORS GUIDELINE, OF-AMERICAN-PATHOLOGISTS, LUNG-CANCER PATIENTS, INTERNATIONAL-ASSOCIATION, COPY NUMBER, REARRANGEMENT, IHC, ADENOCARCINOMA, PREVALENCE",

author = "E. Thunnissen and B. Lissenberg-Witte and {van den Heuvel}, {M. M.} and K. Monkhorst and Skov, {B. G.} and Sorensen, {J. B.} and A. Mellemgaard and Dingemans, {A. M. C.} and Speel, {E. J. M.} and {de Langen}, {A. J.} and Hashemi, {S. M. S.} and I. Bahce and {van der Drift}, {M. A.} and Looijen-Salamon, {M. G.} and J. Gosney and Postmus, {P. E.} and Samii, {S. M. S.} and F. Duplaquet and B. Weynand and X. Durando and F. Penault-Llorca and S. Finn and Grady, {A. O.} and B. Oz and N. Akyurek and R. Buettner and J. Wolf and L. Bubendorf and S. Duin and L. Marondel and Heukamp, {L. C.} and W. Timens and Schuuring, {E. M. D.} and P. Pauwels and Smit, {E. F.}",

note = "Funding Information: This work was supported by an {\textquoteleft}investor initiated research{\textquoteright} grant by Pfizer . Funding Information: Dr. De Langen reports grants from AstraZeneca, BMS, MSD, Boehringer, non-financial support from Roche, Merck-Serono, outside the submitted work. Funding Information: Dr. PENAULT-LLORCA reports personal fees and non-financial support from PFIZER, NOVARTIS, grants, personal fees and non-financial support from ROCHE, outside the submitted work. Funding Information: Dr. Gosney reports personal fees, non-financial support from Astra Zeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Merck Sharp and Dome, Roche, grants, personal fees, non-financial support from Pfizer outside the submitted work. Publisher Copyright: {\textcopyright} 2019 Elsevier B.V.",

year = "2019",

month = dec,

doi = "10.1016/j.lungcan.2019.09.023",

language = "English",

volume = "138",

pages = "13--18",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

Thunnissen, E, Lissenberg-Witte, B, van den Heuvel, MM, Monkhorst, K, Skov, BG, Sorensen, JB, Mellemgaard, A, Dingemans, AMC, Speel, EJM, de Langen, AJ, Hashemi, SMS, Bahce, I, van der Drift, MA, Looijen-Salamon, MG, Gosney, J, Postmus, PE, Samii, SMS, Duplaquet, F, Weynand, B, Durando, X, Penault-Llorca, F, Finn, S, Grady, AO, Oz, B, Akyurek, N, Buettner, R, Wolf, J, Bubendorf, L, Duin, S, Marondel, L, Heukamp, LC, Timens, W, Schuuring, EMD, Pauwels, P & Smit, EF 2019, 'ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib', Lung Cancer, vol. 138, pp. 13-18. https://doi.org/10.1016/j.lungcan.2019.09.023

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.

AU - van den Heuvel, M. M.

AU - Monkhorst, K.

AU - Skov, B. G.

AU - Sorensen, 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, L.

AU - Heukamp, L. C.

AU - Timens, W.

AU - Schuuring, E. M. D.

AU - Pauwels, P.

AU - Smit, E. F.

N1 - Funding Information: This work was supported by an ‘investor initiated research’ grant by Pfizer . Funding Information: Dr. De Langen reports grants from AstraZeneca, BMS, MSD, Boehringer, non-financial support from Roche, Merck-Serono, outside the submitted work. Funding Information: Dr. PENAULT-LLORCA reports personal fees and non-financial support from PFIZER, NOVARTIS, grants, personal fees and non-financial support from ROCHE, outside the submitted work. Funding Information: Dr. Gosney reports personal fees, non-financial support from Astra Zeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Merck Sharp and Dome, Roche, grants, personal fees, non-financial support from Pfizer outside the submitted work. Publisher Copyright: © 2019 Elsevier B.V.

PY - 2019/12

Y1 - 2019/12

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.

AB - 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.

KW - non-small cell lung cancer

KW - alk

KW - immunohistochemistry

KW - fluorescence in situ hybridisation

KW - treatment

KW - prognosis

KW - MOLECULAR TESTING GUIDELINE

KW - KINASE INHIBITORS GUIDELINE

KW - OF-AMERICAN-PATHOLOGISTS

KW - LUNG-CANCER PATIENTS

KW - INTERNATIONAL-ASSOCIATION

KW - COPY NUMBER

KW - REARRANGEMENT

KW - IHC

KW - ADENOCARCINOMA

KW - PREVALENCE

U2 - 10.1016/j.lungcan.2019.09.023

DO - 10.1016/j.lungcan.2019.09.023

M3 - Article

C2 - 31630043

SN - 0169-5002

VL - 138

SP - 13

EP - 18

JO - Lung Cancer

JF - Lung Cancer

ER -