B C M Hermans1, J L Derks1, E Thunnissen2, R J van Suylen3, M A den Bakker4, H J M Groen5, E F Smit6, R A Damhuis7, E C van den Broek8, A Ruland9, E J M Speel9, A M C Dingemans10. 1. Department of Pulmonary Diseases, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. 2. Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. 3. Pathology-DNA, location Jeroen Bosch Hospital, s' Hertogenbosch, The Netherlands. 4. Department of Pathology, Maasstad hospital, Rotterdam, The Netherlands; Department of Pathology, Erasmus MC, Rotterdam, The Netherlands. 5. Department of Pulmonary Diseases, University of Groningen and University Medical Centre, Groningen, The Netherlands. 6. Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 7. Department Research, Comprehensive Cancer Association, Utrecht, The Netherlands. 8. PALGA Foundation, Houten, The Netherlands. 9. Department of Pathology, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. 10. Department of Pulmonary Diseases, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address: a.dingemans@erasmusmc.nl.
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.
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.
Authors: Melissa Frizziero; Elaine Kilgour; Kathryn L Simpson; Dominic G Rothwell; David A Moore; Kristopher K Frese; Melanie Galvin; Angela Lamarca; Richard A Hubner; Juan W Valle; Mairéad G McNamara; Caroline Dive Journal: Clin Cancer Res Date: 2022-05-13 Impact factor: 13.801
Authors: Marina K Baine; Min-Shu Hsieh; W Victoria Lai; Jacklynn V Egger; Achim A Jungbluth; Yahya Daneshbod; Amanda Beras; Rowanne Spencer; Jessica Lopardo; Francis Bodd; Joseph Montecalvo; Jennifer L Sauter; Jason C Chang; Darren J Buonocore; William D Travis; Triparna Sen; John T Poirier; Charles M Rudin; Natasha Rekhtman Journal: J Thorac Oncol Date: 2020-10-01 Impact factor: 15.609