TY - JOUR
T1 - Molecular subtypes of pulmonary large-cell neuroendocrine carcinoma predict chemotherapy treatment outcome
AU - Derks, Jules L.
AU - Leblay, Noémie
AU - Thunnissen, Erik
AU - van Suylen, Robert Jan
AU - den Bakker, Michael
AU - Groen, Harry J. M.
AU - Smit, Egbert F.
AU - Damhuis, Ronald
AU - van den Broek, Esther C.
AU - Charbrier, Amélie
AU - Foll, Matthieu
AU - McKay, James D.
AU - Fernandez-Cuesta, Lynnette
AU - Speel, Ernst-Jan M.
AU - Dingemans, Anne-Marie C.
AU - Arensman, L.
AU - Bellot, F. E.
AU - Broers, J. E.
AU - van Dish, C. M.
AU - Duthoi, K. E. S.
AU - Flens, M. J.
AU - Grefte, J. M. M.
AU - Hogenes, M. C. H.
AU - Natté, R.
AU - van Hamel, A. F.
AU - Klinkhamer, P. J. J. M.
AU - Meijer, J. W. R.
AU - van der Meij, J. C. C.
AU - van Nederveen, F. H.
AU - Nijhuis, E. W. P.
AU - van Oosterhout, M. F. M.
AU - Sastrowijoto, S. H.
AU - Schelfout, K.
AU - Sietsma, J.
AU - Smedts, F. M. M.
AU - Smits, M. M.
AU - Stavast, J.
AU - Timens, W.
AU - van Velthuysen, M. L.
AU - Vink, A.
AU - Wauters, C. C. A. P.
AU - Wouda, S.
AU - PALGA-Group
N1 - ©2017 American Association for Cancer Research.
PY - 2018
Y1 - 2018
N2 - Purpose: Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the RB1 mutated (mostly comutated with TP53) and the RB1 wild-type groups. We assessed whether these subtypes have a predictive value on chemotherapy outcome. Experimental Design: Clinical data and tumor specimens were retrospectively obtained from Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for TP53, RB1, STK11, and KEAP1 genes, as well as IHC for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression-free survival (PFS), stratifying for non-small cell lung cancer type chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). Results: RB1 mutation and protein loss were detected in 47% (n = 37) and 72% (n = 78) of the cases, respectively. Patients with RB1 wild-type LCNEC treated with NSCLC-GEM/TAX had a significantly longer OS [9.6; 95% confidence interval (CI), 7.7-11.6 months] than those treated with SCLC-PE [5.8 (5.5-6.1); P = 0.026]. Similar results were obtained for patients expressing RB1 in their tumors (P = 0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an RB1 mutation or lost RB1 protein. Conclusions: Patients with LCNEC tumors that carry a wild-type RB1 gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for RB1 mutated or with lost protein expression.
AB - Purpose: Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the RB1 mutated (mostly comutated with TP53) and the RB1 wild-type groups. We assessed whether these subtypes have a predictive value on chemotherapy outcome. Experimental Design: Clinical data and tumor specimens were retrospectively obtained from Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for TP53, RB1, STK11, and KEAP1 genes, as well as IHC for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression-free survival (PFS), stratifying for non-small cell lung cancer type chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). Results: RB1 mutation and protein loss were detected in 47% (n = 37) and 72% (n = 78) of the cases, respectively. Patients with RB1 wild-type LCNEC treated with NSCLC-GEM/TAX had a significantly longer OS [9.6; 95% confidence interval (CI), 7.7-11.6 months] than those treated with SCLC-PE [5.8 (5.5-6.1); P = 0.026]. Similar results were obtained for patients expressing RB1 in their tumors (P = 0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an RB1 mutation or lost RB1 protein. Conclusions: Patients with LCNEC tumors that carry a wild-type RB1 gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for RB1 mutated or with lost protein expression.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85038878566&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29066508
U2 - 10.1158/1078-0432.CCR-17-1921
DO - 10.1158/1078-0432.CCR-17-1921
M3 - Article
C2 - 29066508
VL - 24
SP - 33
EP - 42
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 1
ER -