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, C M Stallinga9, G M Roemen9, E J M Speel9, A-M C Dingemans10. 1. Department of Pulmonary Diseases, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands. 2. Department of Pathology, VU University Medical Centre, P.O. Box 7057, 1007 MB, Amsterdam, the Netherlands. 3. Pathology-DNA, location Jeroen Bosch Hospital, P.O. Box 90153, 5200 ME s', Hertogenbosch, the Netherlands. 4. Department of Pathology, Maasstad hospital, P.O. Box 9100, 3007 AC, Rotterdam, the Netherlands; Department of Pathology, Erasmus MC, P.O.Box 2040, 3000 CA, Rotterdam, the Netherlands. 5. Department of Pulmonary Diseases, University of Groningen and University Medical Centre, P.O. Box 30.001, 9700 RB, Groningen, the Netherlands. 6. Department of Thoracic Oncology, Netherlands Cancer Institute, P.O. Box 90203, 1006 BE, Amsterdam, the Netherlands. 7. Department Research, Comprehensive Cancer Association, P.O. Box 19079, 3501 DB, Utrecht, the Netherlands. 8. PALGA Foundation, P.O. Box 4001, 3502 HA, Utrecht, the Netherlands. 9. Department of Pathology, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands. 10. Department of Pulmonary Diseases, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands. Electronic address: a.dingemans@mumc.nl.
Abstract
BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare tumor with high mutational burden. Two subtypes of LCNEC are recognized, the co-mutated TP53 and RB1 group and the TP53 and STK11/KEAP1 group. We investigated PD-L1 and CD8 expression in a well characterized stage IV LCNEC cohort and compared expression in the two subtypes. METHODS: Immunohistochemical (IHC) analysis for PD-L1 and CD8 was performed on pathological reviewed pretreatment tumor samples for 148 stage IV LCNEC. Data about targeted next generation sequencing (TNGS) (TP53, RB1, STK11, KEAP1) and IHC for RB1 were available for most tumors. IHC staining for PD-L1 (DAKO 28-8) was performed and scored positive if tumors showed ≥1% membranous staining. CD8 was scored for intra-tumor T-cells and stromal cells. RESULTS: PD-L1 IHC expression data could be generated in 98/148 confirmed LCNEC samples along with RB1 IHC (n = 97) of which 77 passed quality control for TNGS. PD-L1 expression was positive in 16/98 cases (16%); 5 (5%) with ≥50%. PD-L1 expression was equal in RB1 mutated and RB1 wildtype tumors. None of STK11 mutated tumors (n = 7) expressed PD-L1. PD-L1 expression was correlated with superior overall survival (OS), hazard ratio 0.55 ((95% Confidence Interval 0.31-0.96), p = 0.038). Intra-tumor CD8 was associated with PD-L1 expression (p = 0.021) and stromal and intra-tumor CD8 were correlated with improved OS (p = 0.037 and p = 0.026 respectively). CONCLUSIONS: PD-L1 expression was positive in 16% of stage IV LCNEC tumors. This was independent of molecular subtype but associated with CD8 expression. In LCNEC patients with PD-L1 and/or CD8 expression superior OS was observed.
BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare tumor with high mutational burden. Two subtypes of LCNEC are recognized, the co-mutated TP53 and RB1 group and the TP53 and STK11/KEAP1 group. We investigated PD-L1 and CD8 expression in a well characterized stage IV LCNEC cohort and compared expression in the two subtypes. METHODS: Immunohistochemical (IHC) analysis for PD-L1 and CD8 was performed on pathological reviewed pretreatment tumor samples for 148 stage IV LCNEC. Data about targeted next generation sequencing (TNGS) (TP53, RB1, STK11, KEAP1) and IHC for RB1 were available for most tumors. IHC staining for PD-L1 (DAKO 28-8) was performed and scored positive if tumors showed ≥1% membranous staining. CD8 was scored for intra-tumor T-cells and stromal cells. RESULTS:PD-L1 IHC expression data could be generated in 98/148 confirmed LCNEC samples along with RB1 IHC (n = 97) of which 77 passed quality control for TNGS. PD-L1 expression was positive in 16/98 cases (16%); 5 (5%) with ≥50%. PD-L1 expression was equal in RB1 mutated and RB1 wildtype tumors. None of STK11 mutated tumors (n = 7) expressed PD-L1. PD-L1 expression was correlated with superior overall survival (OS), hazard ratio 0.55 ((95% Confidence Interval 0.31-0.96), p = 0.038). Intra-tumorCD8 was associated with PD-L1 expression (p = 0.021) and stromal and intra-tumorCD8 were correlated with improved OS (p = 0.037 and p = 0.026 respectively). CONCLUSIONS:PD-L1 expression was positive in 16% of stage IV LCNEC tumors. This was independent of molecular subtype but associated with CD8 expression. In LCNEC patients with PD-L1 and/or CD8 expression superior OS was observed.
Authors: Elizabeth Dudnik; Samuel Kareff; Mor Moskovitz; Chul Kim; Stephen V Liu; Anastasiya Lobachov; Teodor Gottfried; Damien Urban; Alona Zer; Ofer Rotem; Amir Onn; Mira Wollner; Jair Bar Journal: J Immunother Cancer Date: 2021-02 Impact factor: 13.751