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Clin Cancer Res. 2018 Jan 1;24(1):33-42. doi: 10.1158/1078-0432.CCR-17-1921. Epub 2017 Oct 24.

Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome.

Author information

1
Department of Pulmonary Diseases, GROW School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
2
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
3
Department of Pathology, VU University Medical Centre, Amsterdam, the Netherlands.
4
Pathology-DNA, Jeroen Bosch Hospital, s' Hertogenbosch, the Netherlands.
5
Department of Pathology, Maasstad hospital, Rotterdam, the Netherlands.
6
Department of Pulmonary Diseases, University of Groningen and University Medical Centre, Groningen, the Netherlands.
7
Department of Pulmonary Diseases, VU medical centre, Amsterdam, the Netherlands.
8
Department Research, Comprehensive Cancer Association, Utrecht, the Netherlands.
9
PALGA Foundation, Houten, the Netherlands.
10
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France. a.dingemans@mumc.nl fernandezcuestal@iarc.fr.
11
Department of Pathology, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
12
Department of Pulmonary Diseases, GROW School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands. a.dingemans@mumc.nl fernandezcuestal@iarc.fr.
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Contributed equally

Abstract

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 the 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. Clin Cancer Res; 24(1); 33-42. ©2017 AACR.

PMID:
29066508
DOI:
10.1158/1078-0432.CCR-17-1921
[Indexed for MEDLINE]
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