Enterprise Interest. Pfizer, Roche, BMS, MSD, Novartis
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1 Enterprise Interest Pfizer, Roche, BMS, MSD, Novartis
2 Beyond the WHO 2015 classification of lung neuroendocrine tumours Genomics of lung NETs & identification of biomarkers for prognosis and therapy Prof. dr. Ernst-Jan Speel Department of Pathology
3 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 3 Summary 3 Recent genomic studies in carcinoid and LCNEC Study Samples Tissue Normal tissue Techniques Fernandez-Cuesta TC (59) AC (9) NOS CA (6) Frozen Yes WES/WGS/RNA-seq Simbolo TC (53), AC (35), LCNEC (27), SCLC (33) Frozen/FFPE Yes WES / NGS custom panel Rekhtman LCNEC (45) FFPE Yes NGS custom panel George LCNEC (75)* Frozen Yes WES/WGS/RNA-seq Miyoshi LCNEC (78)** FFPE Yes NGS custom panel Karlsson LCNEC (17) FFPE Yes NGS custom panel Rekhtman CCR 2016 Miyoshi CCR 2016 Simbolo J path George (abstract AACR 2016) Karlsson CCR 2016
4 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 4 Summary4 Molecular characteristics of carcinoids: Few mutations (0.4 /MB) not related to smoking (such as SCLC) Fernandez-Cuesta et al. Nature com. 2014
5 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 5 Summary5 Chromatin remodeling mutations recurrent mutations in MEN1/PSIP1, ARID1A and EIF1AX Fernandez-Cuesta et al. Nature com. 2014
6 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 6 Summary6 Chromatin remodeling mutations recurrent mutations in MEN1, TP53 Tp53 MEN1 Simbolo et al J Path.
7 Fernandez-Cuesta et al. Nature com Simbolo et al. J Path Genomics of lung NETs Identification of biomarkers for prognosis and therapy 7 Summary 7 Chromothripsis/hypermutation/large chromosomal alterations relevant for aggressive biological behavior of carcinoid? Hyper mutation profile prognostic? Therapeutic?
8 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 8 Summary8 SCLC characterized by 100% inactivation of RB1 and TP53 Aangepast van George J. et al. Nature 2015
9 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 9 Summary9 Molecular characteristics of LCNEC Multiple mutations (10.7/MB) related to smoking (such as SCLC) LCNEC Fernandez-Cuesta et al. IASLC oral WCLC 2016
10 Genomics JL. Derks of lung Afdeling NETs Longziekten, GROW School Identification for Oncology of and biomarkers Developmental for prognosis Biology and therapy 10 Summary 10 Molecular characteristics of LCNEC: Less RB1 mutations than SCLC, STK11/KEAP1 mutations as in NSCLC? But no prognostic value Fernandez-Cuesta et al. IASLC oral WCLC 2016
11 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 11 Summary 11 Confirmation of LCNEC subtypes: LCNEC-SCLC (TP53-RB1) vs. LCNEC-NSCLC (STK11/KRAS, but not KEAP1) Rekhtman CCR 2016
12 Genomics JL. Derks of lung Afdeling NETs Longziekten, GROW School Identification for Oncology of and biomarkers Developmental for prognosis Biology and therapy 12 Summary 12 Few targetable mutations in LCNEC Mutually exclusive MYC family genes? -> related to progression? Few targetable alt. EGFR <1%, FGFR1 amp. Fewer RB1 mutations Miyoshi et al. CCR 2016
13 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 13 Summary 13 Summary of molecular alterations found in carcinoids, LCNEC and SCLC Derks et al. unpublished
14 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 14 Summary 14 Yes! To distinguish Carcinoids tending to metastasize from those with less aggressive behaviour (Swarts, Rindi and Pelosi et al.) LCNEC from SCLC (Bari et al. and Derks et al. unpublished)
15 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 15 Summary 15 Are there molecular markers available that may help to increase prognostic prediction in carcinoids? Marker Good prognosis Validated? Ki-67 Low Varying criteria OTP/CD44 Positive staining Yes SSRT2 Positive staining Yes ERCC1 Positive staining No KLF4/P21 Positive staining No IMP3 Lost staining No MEN1 Lost expression/mutated No Chromosomal alterations 11q deletions No Pubmed search: Prognosis AND (carcinoid OR neuroendocrine tumor) AND (lung OR pulmonary) AND marker AND (histology OR molecular) NOT case report NOT (FDG OR PET/CT)
16 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 16 Summary 16 Results from a (small) questionnaire during the yearly Dutch Pathology conference (2017) (n=30) Neuroendocrine lung tumours should be classified as gastrointestinal neuroendocrine tumours (GEP-NET) (with Ki-67) Yes 61% No 39%
17 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 17 Summary 17 GEP-NET 2010 criteria do not allow a proper classification in lung NET Lung NETs, diagnosed by WHO 2004 (2015) Lung NETs, diagnosed by WHO GEP-NET 2010 Rindi et al. ERC 2014
18 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 18 Summary 18 Proposed classification including mitosis, necrosis AND Ki-67; neglected by the WHO 2015 classification Grade Mitoses Ki-67 Necrosis 1 2 <4 None 2 > % 3 >47 >25 >10% At least 2 categories needed to classify Rindi et al. ERC 2014
19 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 19 Summary 19 Why? Argued that there was insufficient homogeneity among Ki-67 results 2 ( ) 10 (0.7-20) 40 (25-60) 60 (29-87) Pelosi et al. JTO 2014
20 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 20 Summary 20 Molecular markers based on tumor behavior better? (i.e. poor vs. good prognosis) Orthopedia Homeobox (OTP) & CD44? After surgical removal of early stage carcinoids No progression Progression (<5 years) n=301 lung NETs OTP (+) & CD44 (+) CD44 OTP (+) of CD44 (+) OTP OTP (-) & CD44 (-) OTP tested on>500 (neuro-endocriene) tumors/carcinomas Sensitivity: 80% Specificity: 99% Swarts et al. CCR 2013 Nanoka et al. Endoc Path 2017
21 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 21 Summary 21 Independent, external validation OTP/CD44 (n=96 carcinoids) OTP/CD44 markers OTP & CD44+ No progression! WHO 2015 classification Papaxoinis et al. Endocr Pathol 2017
22 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 22 Summary 22 OTP and Ki-67 maybe helpful in cases without a consensus typical/atypical carcinoid diagnosis No consensus OTP (+) no consensus Ki-67 <5% vs. >5% Swarts et al. AJSP 2014
23 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 23 Summary 23 OTP/CD44 and Ki-67 also applicable in presented case Lytic tumor tissue: 3-6 mitoses in10 HPF Ki-67: 10% CD44 negative OTP positive
24 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 24 Summary 24 Yes! To distinguish Carcinoids tending to metastasize from those with less aggressive behaviour (Swarts, Rindi and Pelosi et al.) LCNEC from SCLC (Bari et al. and Derks et al. unpublished)
25 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 25 Summary 25 LCNEC-NSCLC (RB1 wt ) retains expression of RB1 protein, lost in LCNEC-SCLC type Rekhtman CCR 2016
26 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 26 Summary 26 Does the LCNEC subtype require different (chemotherapy) treatment? LCNEC-NSCLC(RB1 wt ) possibly more resistant to SCLC type (platinum-etoposide) chemotherapy) Rekhtman CCR 2016
27 Genomics of lung NETs Identification of biomarkers for prognosis and therapy Summary 27 JL. Derks Afdeling Longziekten, GROW School for Oncology and Developmental Biology 27 LCNEC with RB1 wild-type may respond better to platinumgemcitabine/taxane chemotherapy vs. etoposide Stage IV LCNEC, first line chemotherapy. NGS profiles in collaboration with Fernandez Cuesta et al. RB1 mutated in 47% Derks et al. ASCO J Clin Oncol 35, 2017 (suppl; abstr 9061)
28 Dowlati Ann Oncol 2016 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 28 Summary 28 RB1 wildtype: less response to platinum-etoposide (SCLC) chemotherapy??
29 Genomics of lung NETs Identification of biomarkers for prognosis and therapy 29Summary Summary Lung carcinoids have few mutations, mainly MEN1 and other chromatin remodeling genes LCNEC and SCLC >90% TP53 mutated Difference in RB1 gene alterations SCLC (100%) and LCNEC (40%) Ki-67 useful markers to separate carcinoids from LCNEC/SCLC OTP/CD44 possibly future markers useful for prognosis and follow-up in carcinoids RB1 mutation possibly has clinical consequences for choice of chemotherapy in high grade neuroendocrine carcinomas
30 Maastricht University Medical Centre A-M. C. Dingemans, MD, PhD E.F. Wouters, MD, PhD M. Henfling D. Swarts, PhD (VUMC) F. Ramaekers, PhD Pathologie DNA Locatie Jeroen Bosch Hospital R.J. van Suylen, MD, PhD Locatie Antonius Hospital M. Van Oosterhout, MD, PhD Erasmus University Medical Centre/ Maasstad Hospital M.A. den Bakker, MD, PhD VU University Medical Centre E. Thunnissen, MD, PhD E.F. Smit, MD, PhD University of Groningen and University Medical Centre H.J.M. Groen, MD, PhD Comprehensive Cancer Centre R.A. Damhuis, MD, PhD University of Turin M. Volante, MD, PhD PALGA, Netherlands Pathology Registry L. Overbeek, PhD E. van den Broek, PhD International Agency on Research of Cancer Genetic cancer susceptibility group J.D. McKay, PhD L. Fernandez-Cuesta, PhD N. Leblay A. Chabrier M. Foll, PhD
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