2202P - Large cell neuroendocrine carcinoma (LCNEC) subtyping based on NEUROD1, ASCL1, POU2F3 and YAP1 expression

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: NEUROD1^HIGH/ASCL^HIGH/DLL^HIGH, ASCL1^HIGH/DLL3^HIGH, POU2F3^HIGH, YAP1^HIGH, and NAPY^LOW. The clusters ASCL1^HIGH/DLL3^HIGH, POU2F3^HIGH and NAPY^LOW were mainly pRb-. The DFS and OS for the different clusters is shown in the table. The ASCL1^HIGH/DLL3^HIGH cluster had the lowest median OS (24 months) and DFS (13 months). The NAPY^LOW cluster had the highest median OS (74 months) and the POU2F3 cluster the highest median DFS (54 months). Table: 2202P

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.