Division of Medical Oncology, Department of Oncology, Mayo Clinic Rochester, MN, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA.
Lung Cancer. 2019 Sep;135:73-79. doi: 10.1016/j.lungcan.2019.07.016. Epub 2019 Jul 17.
Delta-like protein 3 (DLL3), an inhibitory Notch ligand, is the target for rovalpituzumab tesirine in development for the treatment of small cell lung cancer (SCLC). We studied the expression of DLL3, its reproducibility and prognostic role in pulmonary neuroendocrine tumors.
Institutional pathology files were searched for resected pulmonary neuroendocrine tumors (1995-2017). Expression of DLL3 (clone SP347) was categorized as high (≥50% of tumor cells) or low (<50%). Interobserver agreement among 5 thoracic pathologists was measured by Krippendorff's α coefficient. Staging (N = 148) was performed according to the 8th AJCC.
Our study included 157 patients with a median age of 62.2 years (range 23.2-88.1) including 59 men (37.6%). Tumors included 44 (28.0%) SCLC, 46 (29.3%) atypical and 67 (42.7%) typical carcinoid tumors at stages I (N = 83, 56.1%), II (N = 28, 18.9%), and III/IV (N = 37, 25.0%). Interobserver agreement for high vs low DLL3 expression (N = 70) was 82.9% (α = 0.79, substantial). High DLL3 expression was observed in 35 (79.5%) SCLC, 17 (37.0%) atypical and 22 (32.8%) typical carcinoid tumors. High DLL3 was associated with SCLC morphology (p < 0.0001). During a median follow-up of 4.2 years (range, 2 days-20.3 years), 70 patients died; 19 died from disease. High DLL3 expression was associated with better overall survival in SCLC (p = 0.049) but not after adjusting for age, tumor size and stage.
DLL3 expression is reliably quantifiable by pathologists and is highly expressed in the majority of SCLC and a subset of carcinoid tumors, making it an attractive target for anti-DLL3 treatment.
Delta-like 蛋白 3（DLL3）是一种抑制性 Notch 配体，是正在开发用于治疗小细胞肺癌（SCLC）的罗瓦匹妥单抗 tesirine 的靶点。我们研究了 DLL3 的表达、可重复性及其在肺神经内分泌肿瘤中的预后作用。
检索机构病理学档案，寻找切除的肺神经内分泌肿瘤（1995-2017 年）。DLL3（克隆 SP347）的表达分为高（≥50%的肿瘤细胞）或低（<50%）。5 位胸病理学家之间的观察者间一致性通过 Krippendorff 的α系数来衡量。根据第 8 版 AJCC 进行分期（N=148）。
我们的研究包括 157 名中位年龄为 62.2 岁（范围 23.2-88.1）的患者，其中 59 名男性（37.6%）。肿瘤包括 44 例（28.0%）SCLC、46 例（29.3%）非典型和 67 例（42.7%）典型类癌肿瘤，分期为 I（N=83，56.1%）、II（N=28，18.9%）和 III/IV（N=37，25.0%）。高 vs 低 DLL3 表达（N=70）的观察者间一致性为 82.9%（α=0.79，中等）。在 35 例（79.5%）SCLC、17 例（37.0%）非典型和 22 例（32.8%）典型类癌肿瘤中观察到高 DLL3 表达。高 DLL3 与 SCLC 形态学相关（p<0.0001）。在中位随访 4.2 年（范围 2 天-20.3 年）期间，70 例患者死亡；19 例死于疾病。高 DLL3 表达与 SCLC 的总生存相关（p=0.049），但在校正年龄、肿瘤大小和分期后无统计学意义。
DLL3 表达可由病理学家可靠地定量，在大多数 SCLC 和一部分类癌肿瘤中高度表达，使其成为抗-DLL3 治疗的有吸引力的靶点。
