Uncovering genomic differences between small and large cell extra-pulmonary neuroendocrine carcinomas

A. Mohamed; E. Teslow; E. Jaeger; M. Stoppler; S.L. Asa; S.H. Tirumani; L. Qiubai; A. Mahipal; D. Bajor; S. Chakrabarti; J.E. Selfridge; M. Conces; M. Lumish; R.S. Hoehn; J. Winter; J. Ammori; J. Hardacre; L.E. Henke; A Dowlati

doi:10.1530/endoabs.108.B18

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Endocrine Abstracts (2024) 108 B18 | DOI: 10.1530/endoabs.108.B18

NANETS2024 17th Annual Multidisciplinary NET Medical Symposium NANETS 2024 Applied Basic Science (13 abstracts)

Uncovering genomic differences between small and large cell extra-pulmonary neuroendocrine carcinomas

A. Mohamed ¹ , E. Teslow ² , E. Jaeger ² , M. Stoppler ² , S.L. Asa ³ , S.H. Tirumani ⁴ , L. Qiubai ⁴ , A. Mahipal ¹ , D. Bajor ¹ , S. Chakrabarti ¹ , J.E. Selfridge ¹ , M. Conces ¹ , M. Lumish ¹ , R.S. Hoehn ⁵ , J. Winter ⁵ , J. Ammori ⁵ , J. Hardacre ⁵ , L.E. Henke ⁶ & A Dowlati ¹

Author affiliations

¹Department of Medicine, Division of Medical Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; ²Tempus AI, Inc., Chicago, IL; ³Department of Pathology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; ⁴Department of Radiology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; ⁵Department of Surgical Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; ⁶Department of Radiation Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH

Background: Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are rare and aggressive cancers that include two morphological subtypes: large cell NEC (LC-NEC) and small cell NEC (SC-NEC). Although they are treated with similar chemotherapy regimens, they are distinct diseases, and their genomic profiles have not been compared. We investigated the genomic profile of the extrapulmonary LC-NEC and SC-NEC to identify mutations that could enable more personalized therapy.

Methods: Patients diagnosed with poorly differentiated extra-pulmonary NECs (LC-NEC and SC-NEC subtypes) were selected from the de-identified Tempus real-world multimodal database. Patient demographic/clinical characteristics and genomic/transcriptomic data were described as N (%) or median (IQR), min, and max and compared between subgroups by Chi-squared/Fisher’s Exact tests or Wilcoxon rank-sum tests, as applicable. The prevalence of somatic mutations (SNVs, CNVs, and Fusions) was described and compared similarly, with a false-discovery rate correction for multiple comparisons. Analyses were two-sided, with statistical significance evaluated at the 0.05 alpha level.

Results: 307 patient samples (121 LC-NECs and 186 SC-NECs) were identified. There was no difference in race and ethnicity between LC and SC NECs. There were no significant differences in median TMB between LC and SC-NECs (3.1 vs 3.4 mut/Mb, P = 0.2, respectively); the majority had low TMB (<10 mut/Mb). LC-NECs had higher frequency of deletions vs SC-NECs in CDKN2A (12% vs 1.6%, q=0.002), CDKN2B (12% vs 1.6%, q=0.002), and MTAP (9.9% vs 1.1%, q=0.002). SC-NECs had more frequent RB1 loss compared to LC-NECs, although not significant after correction for multiple testing (16% vs 7.4%, q=0.2). LC-NECs have more common CCND1, FGF3, FGF4, KDM5A, NOTCH1, and MYC amplifications, but less common SDHC, SLAMF1, FCGR2A, FCGR3A, and NIT1 amplifications compared to SC-NECs. SNVs in APC, KRAS, BRAF, DAXX, NOTCH1, and SMARCA4 mutations were more common in LC-NECs, while RB1, TERT, and FOXA1 mutations were more common in SC-NECs.

Conclusions: Our results demonstrated that EP-NECs display a broad pattern of genomic alterations according to their histological subtypes. These distinct molecular signatures could impact the development of future precision therapeutics for SC-NECs and LC-NECs.

ABSTRACT ID28479