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Poster session 13

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

Date

21 Oct 2023

Session

Poster session 13

Topics

Tumour Site

Small Cell Lung Cancer;  Neuroendocrine Neoplasms;  Prostate Cancer

Presenters

Anthony Crymes

Citation

Annals of Oncology (2023) 34 (suppl_2): S701-S710. 10.1016/S0923-7534(23)01264-4

Authors

A. Crymes1, M.G. Evans2, A. Elliott3, J.R. Lozada4, E. Heath5, B.A. Carneiro6, E. Lou4, H.P. Soares7, E.S. Antonarakis4, C.J. Ryan4, C. Nabhan8, J. Marks1, H. Beltran9, J.H. Hwang4

Author affiliations

  • 1 Medicine, Keck School of Medicine - University of Southern California USC, 90033 - Los Angeles/US
  • 2 Pathology, Caris Life Sciences - Headquarters, 75039 - Irving/US
  • 3 Clinical And Translational Research, Caris Life Sciences - Headquarters, 75039 - Irving/US
  • 4 Hematology, Oncology And Transplantation Division, University of Minnesota, Masonic Cancer Center, 55455 - Minneapolis/US
  • 5 Oncology, Karmanos Cancer Institute, 48201 - Detroit/US
  • 6 Hematology/oncology Division, Lifespan Cancer Institute - Rhode Island Hospital, 02903 - Providence/US
  • 7 Medicine, University of Utah Health - Huntsman Cancer Institute, 84112 - Salt Lake City/US
  • 8 Precision Oncology Alliance, Caris Life Sciences - Headquarters, 75039 - Irving/US
  • 9 Medical Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US

Resources

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Abstract 1188P

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.

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