Abstract 2202P
Background
LCNEC is a rare high-grade neuroendocrine tumor with poor prognosis. pRb subclassifies LCNEC into SCLC-like and NSCLC-like. NEUROD1, ASCL1, POU2F3, and YAP1 (NAPY) subtyping has been identified in SCLC. These subtypes might be present in LCNEC and may correlate with pRb. DLL3, expressed in high-grade neuroendocrine tumors such as SCLC and LCNEC, allows for potential DLL3 targeted therapy. We aimed to define LCNEC subtypes, based on immunohistochemical (IHC) expression of NEUROD1, ASCL1, POU2F3, YAP1, pRb and DLL3.
Methods
Tissue microarrays were made from 133 stage I-III resected LCNEC cases, revised by 2 pathologists, stained for NAPY, pRb and DLL3 and scored using H-scores. An H-score >10 was considered positive (+). The NAPY marker with the highest H-score was considered dominant. Unsupervised clustering of the NAPY markers was performed. Disease free survival (DFS) and overall survival (OS) data were obtained from the Dutch cancer registration.
Results
IHC evaluation demonstrated 100 (75%) cases with pRb loss and 88 (66%) DLL3+ cases. The distribution of NAPY is shown in the table. NEUROD1 was dominant in 30% of cases and ASCL1 in 37%. An association was observed between NEUROD1 and ASCL1, and between NEUROD1 and POU2F3. Unsupervised clustering identified 5 clusters: NEUROD1HIGH/ASCLHIGH/DLLHIGH, ASCL1HIGH/DLL3HIGH, POU2F3HIGH, YAP1HIGH, and NAPYLOW. The clusters ASCL1HIGH/DLL3HIGH, POU2F3HIGH and NAPYLOW were mainly pRb-. The DFS and OS for the different clusters is shown in the table. The ASCL1HIGH/DLL3HIGH cluster had the lowest median OS (24 months) and DFS (13 months). The NAPYLOW cluster had the highest median OS (74 months) and the POU2F3 cluster the highest median DFS (54 months). Table: 2202P
pRb- (%) | DLL3+ (%) | |||
NEUROD1-NEUROD1+ | 52 (52) 48 (48) | 41 (47) 47 (53) | ||
ASCL1- ASCL1+ | 44 (44) 56 (56) | 27 (31) 61 (69) | ||
POU2F3-POU2F3+ | 93 (94) 6 (6) | 85 (99) 1 (1) | ||
YAP1- YAP1+ | 84 (84) 16 (16) | 75 (85) 13 (15) | ||
NAPY- | 15 (88) | 8 (47) | ||
Cluster | Median OS (months) | Median DFS (months) | pRb-(%) | DLL3+ (%) |
NEUROD1 HIGH /ASCL HIGH /DLL HIGH (N = 13) | 58 | 25 | 54 | 92 |
ASCL1 HIGH /DLL3 HIGH (N = 28) | 24 | 13 | 89 | 96 |
POU2F3 HIGH (N = 7) | 61 | 54 | 57 | 0 |
YAP1 HIGH (N = 15) | 56 | 32 | 47 | 47 |
NAPY LOW (N = 66) | 74 | 31 | 82 | 61 |
Conclusions
NAPY-subtyping differentiates subtypes in LCNEC. Difference in survival was seen between the newly identified clusters. 3 out of 5 clusters were mainly pRb-. Clinical significance of these clusters remains to be studied. YAP1 is more frequently expressed in LCNEC, than in SCLC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Amgen.
Disclosure
A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Sanofi, amgen, Bayer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: Takeda, Lilly, Jansen, Pfizer, AstraZeneca, Lilly, Amgen, Daiichi, Roche, Roche, JNJ, Mirati; Financial Interests, Institutional, Research Grant: Amgen; Non-Financial Interests, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Member: IASCL, ASCO, AACR. J. von der Thüsen: Financial Interests, Personal, Invited Speaker: Eli Lilly, MSD, Pfizer, Roche; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Financial Interests, Institutional, Funding: Roche Diagnostics; Non-Financial Interests, Advisory Role: ESP, EORTC, IASLC; Non-Financial Interests, Leadership Role: BDIAP. All other authors have declared no conflicts of interest.
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