Department of Thoracic Surgery, Hyogo Cancer Center, Akashi, Japan.
Department of Pathology, Hyogo Cancer Center, Akashi, Japan.
Thorac Cancer. 2020 Sep;11(9):2561-2569. doi: 10.1111/1759-7714.13574. Epub 2020 Jul 21.
The mammalian Notch family ligands delta-like 3 (DLL3) is reported to be a potential therapeutic target for large cell neuroendocrine carcinomas (LCNEC). The effect of DLL3 expression on LCNEC prognosis has not yet been elucidated.
We reviewed the medical records of 70 LCNEC patients undergoing surgical resection between 2001 and 2015 using a prospectively maintained database. We performed immunohistochemistry for DLL3 and investigated the correlation between the sensitivity of LCNEC to platinum-based adjuvant chemotherapy.
DLL3 expression was positive in 26 (37.1%) LCNEC patients. A total of 23 patients (32.9%) received platinum-based adjuvant chemotherapy. Among patients with DLL3 expression-positive tumors, no difference was found in the five-year overall survival (OS) or recurrence-free survival (RFS) between patients with and without adjuvant chemotherapy (surgery + chemotherapy vs. surgery alone, five-year OS: 58.3% vs. 35.7% P = 0.36, five-year RFS: 41.7% vs. 35.7% P = 0.74). In contrast, among patients with DLL3-negative tumors, significantly greater five-year OS and RFS rates were observed for patients with adjuvant chemotherapy than for those without it (surgery + chemotherapy vs. surgery alone: five-year OS: 90.0% vs. 26.9% P<0.01, five-year RFS: 80.0% vs. 21.7% P < 0.01). A multivariate analysis for the RFS revealed that adjuvant chemotherapy was a significant independent prognostic factor among patients with DLL3-negative tumors (hazard ratio [HR]: 0.05, 95% confidence interval [CI]: 0.01-0.41, P < 0.01), although it was not a factor among patients with DLL3-positive tumors (HR: 0.73, 95% CI: 0.23-2.27, P = 0.58).
Our results revealed that DLL3 is a predictive marker of sensitivity to platinum-based adjuvant chemotherapy for LCNEC.
SIGNIFICANT FINDINGS OF THE STUDY: DLL3 was a predictive marker of sensitivity to platinum-based adjuvant chemotherapy for LCNEC. Among patients with DLL3 expression-negative LCNEC, platinum-based adjuvant chemotherapy significantly improved the OS and RFS, although it did not do so among patients with DLL3 expression-positive LCNEC.
Our results suggest that DLL3 expression-positive LCNEC may be better treated with other types of adjuvant chemotherapy, such as the anti-DLL3 therapies if these effects are confirmed by ongoing clinical research.
哺乳动物 Notch 家族配体 delta-like 3（DLL3）被报道为大细胞神经内分泌癌（LCNEC）的潜在治疗靶点。DLL3 表达对 LCNEC 预后的影响尚未阐明。
我们使用前瞻性维护的数据库回顾了 2001 年至 2015 年间接受手术切除的 70 例 LCNEC 患者的病历。我们对 DLL3 进行了免疫组织化学染色，并研究了 LCNEC 对铂类辅助化疗敏感性的相关性。
26 例（37.1%）LCNEC 患者 DLL3 表达阳性。共有 23 例（32.9%）患者接受了铂类辅助化疗。在 DLL3 表达阳性肿瘤患者中，接受化疗与未接受化疗的患者 5 年总生存率（OS）或无复发生存率（RFS）无差异（手术+化疗 vs. 单纯手术，5 年 OS：58.3% vs. 35.7% P=0.36，5 年 RFS：41.7% vs. 35.7% P=0.74）。相比之下，在 DLL3 阴性肿瘤患者中，接受辅助化疗的患者 5 年 OS 和 RFS 率明显更高，而未接受化疗的患者则较低（手术+化疗 vs. 单纯手术：5 年 OS：90.0% vs. 26.9% P<0.01，5 年 RFS：80.0% vs. 21.7% P<0.01）。多变量 RFS 分析显示，辅助化疗是 DLL3 阴性肿瘤患者的独立预后因素（HR：0.05，95%CI：0.01-0.41，P<0.01），而不是 DLL3 阳性肿瘤患者的因素（HR：0.73，95%CI：0.23-2.27，P=0.58）。
我们的结果表明，DLL3 是 LCNEC 对铂类辅助化疗敏感性的预测标志物。在 DLL3 表达阴性的 LCNEC 患者中，铂类辅助化疗显著改善了 OS 和 RFS，而在 DLL3 表达阳性的 LCNEC 患者中则没有。
研究的重要发现：DLL3 是 LCNEC 对铂类辅助化疗敏感性的预测标志物。在 DLL3 表达阴性的 LCNEC 患者中，接受铂类辅助化疗可显著提高 OS 和 RFS，而在 DLL3 表达阳性的 LCNEC 患者中则不然。如果这些结果得到正在进行的临床研究的证实，我们的研究结果提示 DLL3 阳性的 LCNEC 可能更适合接受其他类型的辅助化疗，如抗-DLL3 治疗。
