Rojo Federico, Corassa Marcelo, Mavroudis Dimitrios, Öz Aysim Büge, Biesma Bonne, Brcic Luka, Pauwels Patrick, Sailer Verena, Gosney John, Miljkovic Darko, Hader Carlos, Wu Meijing, Almarez Todd, Penault-Llorca Frédérique
Hospital Universitario Fundación Jiménez Díaz CIBERONC, Madrid, Spain.
A.C. Camargo Cancer Center, São Paulo, Brazil.
Lung Cancer. 2020 Sep;147:237-243. doi: 10.1016/j.lungcan.2020.07.026. Epub 2020 Jul 27.
Expression of the Notch-family ligand delta-like protein 3 (DLL3), a potential therapeutic target in small cell lung cancer (SCLC), has not been assessed in the real-world setting. To identify the real-world utility of DLL3 as an SCLC therapeutic target, we performed the largest retrospective international noninterventional study to date to evaluate DLL3 prevalence in SCLC patients.
DLL3 expression was assessed using immunohistochemistry in archived histological and cytological specimens (independent and paired) and correlated to patient demographics, clinical disease characteristics, and survival. The primary endpoint was the proportion of patients with DLL3 expression in ≥25 % of tumor cells. DLL3 expression concordance was assessed in paired specimens.
Independent tumor specimens were collected from 1073 patients. The mean age at biopsy was 66 years (SD, 10); 682 (64 %) patients were male. Paired specimens were collected from 36 patients. The mean age at biopsy was 62 years (SD, 11); 16 (44 %) patients were male. Most patients had ECOG performance status of 0-1, were smokers/ex-smokers, and received ≥1 prior therapy. Positive DLL3 expression (defined as ≥25 % of tumor cells) was identified in 895/1050 (85 %) patients with 1 specimen and evaluable DLL3 expression; 719/1050 (68 %) patients had high DLL3 expression (defined as ≥75 % of tumor cells). DLL3 expression concordance was 88 % between paired specimens (n = 17; Cohen's kappa P value, .9412). There was no significant difference in median overall survival from SCLC diagnosis for evaluable patients with nonmissing data based on DLL3 expression (negative DLL3 expression [n = 139], 9.5 months; positive DLL3 expression [n = 747], 9.5 months; all evaluable patients [n = 893, 9.5 months).
These real-world epidemiologic findings indicate that DLL3 is robustly expressed across SCLC disease stages and remains stable despite treatment, consistent with available clinical trial data. There was no prognostic role for DLL3 observed in this study for overall survival.
Notch家族配体δ样蛋白3（DLL3）是小细胞肺癌（SCLC）的一个潜在治疗靶点，尚未在现实环境中进行评估。为了确定DLL3作为SCLC治疗靶点的实际效用，我们开展了迄今为止最大规模的回顾性国际非干预性研究，以评估SCLC患者中DLL3的患病率。
使用免疫组织化学方法在存档的组织学和细胞学标本（独立标本和配对标本）中评估DLL3表达，并将其与患者人口统计学特征、临床疾病特征和生存率相关联。主要终点是肿瘤细胞中DLL3表达≥25%的患者比例。在配对标本中评估DLL3表达的一致性。
从1073例患者中收集了独立肿瘤标本。活检时的平均年龄为66岁（标准差10）；682例（64%）患者为男性。从36例患者中收集了配对标本。活检时的平均年龄为62岁（标准差11）；16例（44%）患者为男性。大多数患者的ECOG体能状态为0-1，为吸烟者/既往吸烟者，且接受过≥1次既往治疗。在895/1050例（85%）有1份标本且DLL3表达可评估的患者中鉴定出DLL3阳性表达（定义为肿瘤细胞≥25%）；719/1050例（68%）患者有高DLL3表达（定义为肿瘤细胞≥75%）。配对标本之间的DLL3表达一致性为88%（n = 17；科恩kappa P值，0.9412）。对于基于DLL3表达且无缺失数据的可评估患者，从SCLC诊断开始的中位总生存期无显著差异（DLL3阴性表达[n = 139]，9.5个月；DLL3阳性表达[n = 747]，9.5个月；所有可评估患者[n = 893]，9.5个月）。
这些现实世界的流行病学研究结果表明，DLL3在SCLC疾病各阶段均有强烈表达，且尽管接受了治疗仍保持稳定，这与现有临床试验数据一致。在本研究中未观察到DLL3对总生存期有预后作用。
