Bhavana Konda | PubMed Health

PubMed2026

Novel genomic score predicts survival with immune checkpoint inhibition in neuroendocrine neoplasms.

BACKGROUND: Immune checkpoint inhibition (ICI) has activity in Grade 3 (G3) neuroendocrine neoplasms (NENs), but predictive biomarkers of long-term overall survival (OS) are currently lacking. METHODS: We derived a genomic scoring system using a retrospective cohort of 54 NEN patients treated with nivolumab and/or ipilimumab, alongside a chemotherapy-only control (n = 15) and pan-cancer validation cohort (n = 1661). An overall genomic score (GS-O) combining positive (GS-P) and negative response genes (GS-N) was calculated. RESULTS: In the ICI cohort, patients with GS-O ≥ 2 had significantly better outcomes: median OS was not reached, compared to 3.9 months for low scores (HR = 0.007, P < .001). After multivariate adjustment, GS-P was independently associated with improved OS while GS-N showed a trend towards worsened OS. Importantly, GS-O ≥ 2 did not predict survival in the chemotherapy-alone cohort but was validated as independently predictive in the pan-cancer validation dataset (HR = 0.92, P < .001). CONCLUSION: This study establishes a novel genomic score to predict OS in NENs treated with ICI with important pan-cancer implications.

Humans↗

PubMed2025

Targeting anti-apoptosis as a therapeutic strategy in neuroendocrine neoplasms.

BCL-2 is an anti-apoptotic protein expressed by aggressive neuroendocrine neoplasms (NENs). We report a case of a patient with a pancreatic neuroendocrine tumor (pNET) who received venetoclax, a BCL-2-targeting drug for the treatment of chronic lymphocytic leukemia. We further characterized BCL2 expression in NENs from a large multi-institutional patient cohort. Clinical data were abstracted from the records of a patient with a pNET. Next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) was performed on 636 NENs of pancreatic (P-NENs), small bowel (SB-NENs), colorectal (CR-NENs), and lung (L-NENs) origin by Caris Life Sciences. Comparisons were performed against site-matched non-NEN cancers. BCL2- or MKI67- high and low cohorts were defined based on the top and bottom quartiles of gene expression. The patient with a pNET who received venetoclax had a partial response in the primary tumor that lasted 30 months. CR-, L-, and P-NENs had significantly higher expression of BCL2 compared to non-NEN counterparts. BCL2 expression was significantly higher in MKI67-high tumors among all NEN subtypes. In P-NENs, there was a higher prevalence of RB1 mutations in BCL2-high vs BCL2-low (40 vs 4.9%, P < 0.005). Patients with BCL2-high P-NENs had significantly decreased overall survival (HR 1.94, 95% CI 1.0-3.76, P = 0.047). Immune checkpoint gene expression and T cells were enriched in BCL2-high tumors across all subtypes. In summary, we report the first known case of a pancreatic NET with response to venetoclax. BCL2 expression correlated with high MKI67 expression, worse survival, and a highly immune-enriched microenvironment.

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