Endocrine Abstracts

Background: BCL-2 is an anti-apoptotic protein associated with resistance to tumor cell death and is a histopathologic marker of neuroendocrine differentiation. We characterized the transcriptomic profile of BCL2 expression in NENs and its association with site, immune infiltration, and overall survival (OS).

Methods: Next-generation sequencing of both DNA (592-gene panel or whole exome) and RNA (whole transcriptome) was performed on NENs of pancreatic (P-NENs, n =230), small bowel (SB-NENs, n =149), colorectal (CR-NENs, n =136), and lung (L-NENs; n =121) origin at Caris Life Sciences (Phoenix, AZ). Comparisons were perfomed against non-NENs; Colorectal Carcinoma (n =15,422), Non-small cell lung cancer (n =21,565), Pancreatic cancer (n = 5,484) and Small Bowel Cancer (n =470). BCL2- or MKI67 -High (H) and -Low (L) cohorts were defined based on the top and bottom quartile expression (transcripts/million [TPM]) of these genes, respectively. Gene expression profiles were analyzed for a transcriptomic signature predictive of response to immunotherapy (T-cell inflamed score). Mann-Whitney U and χ² tests were applied with p-values adjusted for multiple comparisons (p < 0.05). OS data was obtained from insurance claims, and Kaplan-Meier estimates were calculated.

Results: NENs had significantly higher expression of BCL2 (TPM) compared to non-NEN counterparts (CR-NENs 4.22 vs 1.55; L-NEN 4.14 vs 1.90 P-NEN 1.90 vs 1.52; p < 0.01 all) except for SB-NENs (1.82 vs 1.53, P =0.07). BCL2 expression (TPM) was significantly higher in MKI67-H vs -L tumors (CR-NEN 5.7 vs 1.9; L-NENs: 6.9 vs 2.2; P-NENs: 2.7 vs 1.4 all p < 0.05), except in SB-NENs (2.5 vs 1.6, P =0.074). In P-NENs, there was a higher prevalence of RB1 mutations in BCL2-H vs -L (40 vs 4.9%, p < 0.005). BCL2-H tumors were more frequently T-cell inflamed across all investigated NENs (CR-NENs: 29 vs 8%, L-NENs: 37 vs 3%, P-NENs: 31 vs 3%, SB-NEN: 32 vs 5%, all p < 0.05). BCL2-H was associated with decreased OS as compared to BCL2-L in all tumor types (CR-NENs: HR 1.58, P =0.14; L-NENs: HR 1.75, P =0.188; P-NENs: HR 1.94, P =0.047; SB-NENs: HR 1.059, P =0.902).

Conclusion: NENs have increased expression of BCL2 vs. non-NENs of the same site. BCL2-H co-related with high MKI67 expression. BCL2-H tumors were more inflamed/immunogenic and there was a trend towards worsening OS compared to BCL2-L within each type of NEN. The BCL-2 pathway is of interest for therapeutic investigation in aggressive NENs

Abstract ID 23650