DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile

B. C. M. Hermans; J. L. Derks; E. Thunnissen; R. J. van Suylen; M. A. den Bakker; H. J. M. Groen; E. F. Smit; R. A. Damhuis; E. C. van den Broek; A. Ruland; E. J. M. Speel; A. M. C. Dingemans; PALGA Group

doi:10.1016/j.lungcan.2019.10.010

DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile

B. C. M. Hermans, J. L. Derks, E. Thunnissen, R. J. van Suylen, M. A. den Bakker, H. J. M. Groen, E. F. Smit, R. A. Damhuis, E. C. van den Broek, A. Ruland, E. J. M. Speel, A. M. C. Dingemans^*, PALGA Group

^*Corresponding author for this work

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

21 Citations (Web of Science)

Abstract

Objectives: For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics.

Materials and Methods: Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if >= 1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data.

Results: DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0-160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3 + in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3 + in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3 +. Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers.

Conclusion: The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group.

Original language	English
Pages (from-to)	102-108
Number of pages	7
Journal	Lung Cancer
Volume	138
DOIs	https://doi.org/10.1016/j.lungcan.2019.10.010
Publication status	Published - Dec 2019

Keywords

Large cell neuroendocrine carcinoma (LCNEC)
Lung cancer
DLL3
ASCL1
RB1
DELTA-LIKE 3
ANTIBODY-DRUG CONJUGATE
LUNG-CANCER
CHEMOTHERAPY
TESIRINE
THERAPY

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Hermans, B. C. M., Derks, J. L., Thunnissen, E., van Suylen, R. J., den Bakker, M. A., Groen, H. J. M., Smit, E. F., Damhuis, R. A., van den Broek, E. C., Ruland, A., Speel, E. J. M., Dingemans, A. M. C., & PALGA Group (2019). DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung Cancer, 138, 102-108. https://doi.org/10.1016/j.lungcan.2019.10.010

@article{33dd20f337914beb9f03be409193b4fd,

title = "DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile",

abstract = "Objectives: For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics.Materials and Methods: Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if >= 1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data.Results: DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0-160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3 + in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3 + in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3 +. Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers.Conclusion: The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group.",

keywords = "Large cell neuroendocrine carcinoma (LCNEC), Lung cancer, DLL3, ASCL1, RB1, DELTA-LIKE 3, ANTIBODY-DRUG CONJUGATE, LUNG-CANCER, CHEMOTHERAPY, TESIRINE, THERAPY",

author = "Hermans, {B. C. M.} and Derks, {J. L.} and E. Thunnissen and {van Suylen}, {R. J.} and {den Bakker}, {M. A.} and Groen, {H. J. M.} and Smit, {E. F.} and Damhuis, {R. A.} and {van den Broek}, {E. C.} and A. Ruland and Speel, {E. J. M.} and Dingemans, {A. M. C.} and {PALGA Group}",

year = "2019",

month = dec,

doi = "10.1016/j.lungcan.2019.10.010",

language = "English",

volume = "138",

pages = "102--108",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

Hermans, BCM , Derks, JL, Thunnissen, E, van Suylen, RJ, den Bakker, MA, Groen, HJM, Smit, EF, Damhuis, RA, van den Broek, EC, Ruland, A, Speel, EJM, Dingemans, AMC & PALGA Group 2019, 'DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile', Lung Cancer, vol. 138, pp. 102-108. https://doi.org/10.1016/j.lungcan.2019.10.010

TY - JOUR

T1 - DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile

AU - Hermans, B. C. M.

AU - Derks, J. L.

AU - Thunnissen, E.

AU - van Suylen, R. J.

AU - den Bakker, M. A.

AU - Groen, H. J. M.

AU - Smit, E. F.

AU - Damhuis, R. A.

AU - van den Broek, E. C.

AU - Ruland, A.

AU - Speel, E. J. M.

AU - Dingemans, A. M. C.

AU - PALGA Group

PY - 2019/12

Y1 - 2019/12

N2 - Objectives: For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics.Materials and Methods: Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if >= 1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data.Results: DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0-160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3 + in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3 + in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3 +. Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers.Conclusion: The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group.

AB - Objectives: For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics.Materials and Methods: Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if >= 1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data.Results: DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0-160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3 + in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3 + in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3 +. Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers.Conclusion: The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group.

KW - Large cell neuroendocrine carcinoma (LCNEC)

KW - Lung cancer

KW - DLL3

KW - ASCL1

KW - RB1

KW - DELTA-LIKE 3

KW - ANTIBODY-DRUG CONJUGATE

KW - LUNG-CANCER

KW - CHEMOTHERAPY

KW - TESIRINE

KW - THERAPY

U2 - 10.1016/j.lungcan.2019.10.010

DO - 10.1016/j.lungcan.2019.10.010

M3 - Article

C2 - 31678831

VL - 138

SP - 102

EP - 108

JO - Lung Cancer

JF - Lung Cancer

SN - 0169-5002

ER -