Large miRNA survival analysis reveals a prognostic four-biomarker signature for triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is currently the only major breast tumor subtype without effective targeted therapy and, as a consequence, usually presents a poor outcome. Due to its more aggressive phenotype, there is an urgent clinical need to identify novel biomarkers that discriminate individuals with poor prognosis. We hypothesize that miRNAs can be used to this end because they are involved in the initiation and progression of tumors by altering the expression of their target genes. To identify a prognostic biomarker in TNBC, we analyzed the miRNA expression of a cohort composed of 185 patients diagnosed with TNBC using penalized Cox regression models. We identified a four-biomarker signature based on miR-221, miR-1305, miR-4708, and RMDN2 expression levels that allowed for the subdivision of TNBC into high- or low-risk groups (Hazard Ratio – HR = 0.32; 95% Confidence Interval - CI = 0.11–0.91; p = 0.03) and are also statistically associated with survival outcome in subgroups of postmenopausal status (HR = 0.19; 95% CI = 0.04–0.90; p= 0.016), node negative status (HR = 0.12; 95% CI = 0.01–1.04; p = 0.026), and tumors larger than 2cm (HR = 0.21; 95% CI = 0.05–0.81; p = 0.021). This four-biomarker signature was significantly associated with TNBC as an independent prognostic factor for survival.

摘要 三阴性乳腺癌（Triple negative breast cancer, TNBC）是目前唯一尚无有效靶向治疗方案的主要乳腺肿瘤亚型，因此通常预后不佳。由于其侵袭性更强的表型，临床上亟需识别可区分不良预后患者的新型生物标志物。我们提出假说：微小RNA（microRNA, miRNA）可用于该目标，因为它们通过调控靶基因的表达参与肿瘤的发生与进展。为识别三阴性乳腺癌的预后生物标志物，我们采用惩罚性Cox回归模型，对185例确诊三阴性乳腺癌患者的队列进行了miRNA表达谱分析。我们基于miR-221、miR-1305、miR-4708以及RMDN2的表达水平，构建了四标志物标签，该标签可将三阴性乳腺癌患者划分为高风险组与低风险组（风险比（Hazard Ratio, HR）= 0.32；95%置信区间（Confidence Interval, CI）= 0.11–0.91；p = 0.03），并且在绝经后亚组（HR = 0.19；95% CI = 0.04–0.90；p= 0.016）、淋巴结阴性亚组（HR = 0.12；95% CI = 0.01–1.04；p = 0.026）以及肿瘤直径大于2cm的亚组（HR = 0.21；95% CI = 0.05–0.81；p = 0.021）中，该标签均与生存结局存在统计学关联。该四标志物标签可作为独立的生存预后因素，与三阴性乳腺癌显著相关。