Heimes Anne-Sophie, Almstedt Katrin, Krajnak Slavomir, Runkel Anne, Droste Annika, Schwab Roxana, Stewen Kathrin, Lebrecht Antje, Battista Marco J, Brenner Walburgis, Hasenburg Annette, Gehrmann Mathias, Hengstler Jan G, Schmidt Marcus
Department of Gynecology and Obstetrics, University Medical Center Mainz, 55131 Mainz, Germany.
Bayer AG, 42113 Wuppertal, Germany.
Biomedicines. 2022 Oct 21;10(10):2656. doi: 10.3390/biomedicines10102656.
Background: Monoclonal antibodies against PD-1 or PD-L1 have been established in clinical practice for the treatment of both early and advanced/metastatic triple-negative breast cancer. Beyond the established immune checkpoints (ICPs) (PD-1 and CTLA-4), additional ICPs, such as lymphocyte activation gene-3 (LAG-3), are subject of current research. In the present retrospective gene-expression analysis, we evaluated the prognostic significance of LAG-3 in 461 patients with early breast cancer. In addition, we examined whether there was a correlation between the different ICP and CD8 expressions. Methods: Using microarray-based gene-expression analysis, we examined the prognostic significance of LAG-3 mRNA expression for metastasis-free survival (MFS) in the whole cohort of 461 breast cancer patients and among different molecular subtypes. Correlations were analyzed using Spearman’s rho correlation coefficient. Results: In the whole cohort, LAG-3 expression had no significant impact on MFS (p = 0.712, log-rank). In the subgroup analyses, there was a trend that a higher LAG-3 expression was associated with a favorable outcome in the luminal B (p = 0.217), basal-like (p = 0.370) and HER2 (p = 0.089) subtypes, although significance was not reached. In contrast, in a multivariate Cox regression analysis, adjusted for age, tumor size, axillary nodal status, histological grade of differentiation and proliferation marker Ki-67, LAG-3 showed a significant influence on MFS (HR 0.574; 95% CI 0.369−0.894; p = 0.014). High LAG-3 significantly correlated with CD8 (ρ = 0.571; p < 0.001). Conclusions: LAG-3 expression had an independent impact on MFS. In addition to PD-1 and PD-L1, further immune checkpoints, such as LAG-3, could serve as therapeutic targets in breast cancer.
抗PD-1或PD-L1单克隆抗体已在临床实践中用于治疗早期以及晚期/转移性三阴性乳腺癌。除了已确定的免疫检查点（ICPs）（PD-1和CTLA-4）外，其他免疫检查点，如淋巴细胞激活基因-3（LAG-3），也是当前研究的对象。在本回顾性基因表达分析中，我们评估了LAG-3在461例早期乳腺癌患者中的预后意义。此外，我们研究了不同免疫检查点与CD8表达之间是否存在相关性。方法：使用基于微阵列的基因表达分析，我们在461例乳腺癌患者的整个队列以及不同分子亚型中，研究了LAG-3 mRNA表达对无转移生存期（MFS）的预后意义。使用Spearman等级相关系数分析相关性。结果：在整个队列中，LAG-3表达对MFS没有显著影响（p = 0.712，对数秩检验）。在亚组分析中，尽管未达到显著性，但有一个趋势，即较高的LAG-3表达与管腔B型（p = 0.217）、基底样型（p = 0.370）和HER2型（p = 0.089）亚型的良好预后相关。相反，在多变量Cox回归分析中，校正年龄、肿瘤大小、腋窝淋巴结状态、组织学分化程度和增殖标志物Ki-67后，LAG-3对MFS有显著影响（HR 0.574；95% CI 0.369−0.894；p = 0.014）。高LAG-3与CD8显著相关（ρ = 0.571；p < 0.001）。结论：LAG-3表达对MFS有独立影响。除了PD-1和PD-L1外，其他免疫检查点，如LAG-3，可作为乳腺癌的治疗靶点。
