Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.
Cancer Sci. 2021 Jan;112(1):369-379. doi: 10.1111/cas.14711. Epub 2020 Nov 12.
The standard treatment for locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by anti-programmed cell death-ligand 1 (anti-PD-L1) treatment. BIM deletion polymorphism induces the suppression of apoptosis resulting from epidermal growth factor (EGFR)-tyrosine kinase inhibitors in EGFR-mutated NSCLC patients. We aimed to examine the effects of BIM polymorphism on CRT and anti-PD-L1/PD-1 treatment in NSCLC patients. In this retrospective study of 1312 patients with unresectable NSCLC treated at Higashi-Hiroshima Medical Center and Hiroshima University Hospital between April 1994 and October 2019, we enrolled those who underwent CRT or chemotherapy using carboplatin + paclitaxel or cisplatin + vinorelbine, or anti-PD-L1/PD-1 treatment. Of 1312 patients, 88, 80, and 74 underwent CRT, chemotherapy, and anti-PD-L1/PD-1 treatment, respectively, and 17.0%, 15.2% and 17.6% of these patients showed BIM polymorphism. Among patients receiving CRT, the progression-free survival was significantly shorter in those with BIM deletion than in those without. In the multivariate analyses, BIM polymorphism was an independent factor of poor anti-tumor effects. These results were not observed in the chemotherapy and anti-PD-L1/PD-1 treatment groups. In in vitro experiments, BIM expression suppression using small interfering RNA in NSCLC cell lines showed a significantly suppressed anti-tumor effect and apoptosis after irradiation but not chemotherapy. In conclusion, we showed that BIM polymorphism was a poor-predictive factor for anti-tumor effects in NSCLC patients who underwent CRT, specifically radiotherapy. In the implementation of CRT in patients with BIM polymorphism, we should consider subsequent treatment, keeping in mind that CRT may be insufficient.
局部晚期非小细胞肺癌（NSCLC）的标准治疗方法是放化疗（CRT）后再使用抗程序性细胞死亡配体 1（anti-PD-L1）治疗。BIM 缺失多态性可诱导表皮生长因子（EGFR）-酪氨酸激酶抑制剂在 EGFR 突变型 NSCLC 患者中诱导的细胞凋亡抑制。我们旨在研究 BIM 多态性对 NSCLC 患者 CRT 和抗 PD-L1/PD-1 治疗的影响。在这项回顾性研究中，纳入了 1994 年 4 月至 2019 年 10 月在东广岛医疗中心和广岛大学医院接受不可切除 NSCLC 治疗的 1312 例患者，这些患者接受了 CRT 或卡铂+紫杉醇或顺铂+长春瑞滨化疗，或抗 PD-L1/PD-1 治疗。在这 1312 例患者中，分别有 88、80 和 74 例患者接受了 CRT、化疗和抗 PD-L1/PD-1 治疗，分别有 17.0%、15.2%和 17.6%的患者存在 BIM 多态性。在接受 CRT 的患者中，存在 BIM 缺失的患者无进展生存期显著更短。多变量分析显示，BIM 多态性是抗肿瘤效果差的独立因素。在化疗和抗 PD-L1/PD-1 治疗组中未观察到这些结果。在体外实验中，在 NSCLC 细胞系中使用小干扰 RNA 抑制 BIM 表达可显著抑制放疗后而非化疗后的抗肿瘤作用和细胞凋亡。总之，我们表明 BIM 多态性是接受 CRT（尤其是放疗）的 NSCLC 患者抗肿瘤效果的不良预测因素。在存在 BIM 多态性的患者中实施 CRT 时，应考虑后续治疗，因为 CRT 可能不足。
