1188P - Landscape of Delta-like-ligand 3 (DLL3) expression across neuroendocrine neoplasms (NENs)

Background

Delta-like-ligand-3 (DLL3) has emerged as a promising therapeutic target for neuroendocrine neoplasms (NENs), such as small cell lung cancer (SCLC). The spectrum of DLL3 expression and correlation with genomics across NENs remains ill-defined.

Methods

We retrospectively analyzed DNA (592-gene panel or whole exome) and RNA (whole transcriptome) sequencing from 29 distinct NEN sites encompassing 1589 patient samples submitted to Caris Life Sciences (Phoenix, AZ). DLL3-high NENs were defined using a threshold TPM 10x the median expression of DLL3 in prostate NENs. Centralized pathology review was done on NENs from prostate (n = 64), lung (n = 122), and bladder (n = 64). Immune cell fractions were inferred via quanTIseq (Finotello, 2019). Statistical significance was determined using χ² or Fisher’s exact tests, with Benjamini-Hochberg correction for multiple comparisons.

Results

Across NENs, prostate (76%), lung (71%), and bladder (77%) displayed the highest expression of DLL3. High expression of DLL3 was associated with shorter survival in all NENs compared with DLL3-low tumors (HR=1.9, CI=1.65-2.19, p<0.0001), with the most profound association seen in lung (HR=2.5, CI=1.26-5.09, p=0.007). In lung NENs, DLL3 expression increased with higher pathologic grade and was more robust in lung NENs diagnosed as SCLC. DLL3-high NENs harbored greater rates of pathogenic alterations in TP53 (51.2% VS 22.8%, q<0.001), RB1 (41.6% VS 10%, q<0.001), and KRAS (13.6% VS 5.4%, q<0.001), and were more likely to be TMB-high (12.1% VS 4.5%) than DLL3-low cases. Among known neuroendocrine markers, DLL3 expression was positively correlated with ASCL1 and INSM1 (rho=0.7 and 0.5, p<0.001). Lastly, DLL3-high NENs displayed higher fractions of immunomodulatory B cells (5.6% VS 4.5%, q<0.001), dendritic cells (4.6% VS 3.7%, q<0.001), and M1 macrophages (1.6% VS 1.1%, q<0.001).

Conclusions

High DLL3 expression is associated with poor overall survival, advanced pathologic grade, and distinct immune landscape. Further development of DLL3-targeted therapies for high-grade NENs is warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Caris Life Sciences®.

Funding

Has not received any funding.

Disclosure

M.G. Evans, A. Elliott: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. C. Nabhan: Financial Interests, Personal, Full or part-time Employment: Caris life sciences; Financial Interests, Personal, Stocks/Shares: Caris life sciences. All other authors have declared no conflicts of interest.