Sukrithan Vineeth, Ahmed Uzair, Krause Harris, Gandhi Nishant, Elliott Andrew, Hinton Andrew, Walker Phillip, Vanderwalde Ari, Zhou Ye, Patel Dipen C, Lou Emil, Soares Heloisa P, Rogers Kerry A, Konda Bhavana
Endocr Relat Cancer. 2025 Jun 21;32(7). doi: 10.1530/ERC-24-0341. Print 2025 Jul 1.
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.
BCL-2是一种由侵袭性神经内分泌肿瘤（NENs）表达的抗凋亡蛋白。我们报告了一例胰腺神经内分泌肿瘤（pNET）患者，该患者接受了维奈克拉治疗，维奈克拉是一种用于治疗慢性淋巴细胞白血病的靶向BCL-2的药物。我们进一步对来自一个大型多机构患者队列的NENs中的BCL2表达进行了特征分析。临床数据取自一名pNET患者的记录。Caris生命科学公司对636例胰腺（P-NENs）、小肠（SB-NENs）、结直肠（CR-NENs）和肺（L-NENs）来源的NENs进行了DNA（592基因panel或全外显子组）和RNA（全转录组）的二代测序。与部位匹配的非NEN癌症进行了比较。根据基因表达的上四分位数和下四分位数定义了BCL2或MKI67高和低队列。接受维奈克拉治疗的pNET患者的原发肿瘤出现部分缓解，持续30个月。与非NEN对应物相比，CR-NENs、L-NENs和P-NENs的BCL2表达显著更高。在所有NEN亚型中，MKI67高的肿瘤中BCL2表达显著更高。在P-NENs中，BCL2高表达组与BCL2低表达组相比，RB1突变的发生率更高（40%对4.9%，P<0.005）。BCL2高表达的P-NENs患者的总生存期显著降低（HR 1.94，95%CI 1.0-3.76，P=0.047）。在所有亚型中，免疫检查点基因表达和T细胞在BCL2高表达的肿瘤中富集。总之，我们报告了首例已知对维奈克拉有反应的胰腺NET。BCL2表达与高MKI67表达、较差的生存率和高度免疫富集的微环境相关。
