Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, 71003, Heraklion, Crete, Greece.
Department of Medical Oncology, University General Hospital of Heraklion, 1352 PO BOX, 711 10, Heraklion, Crete, Greece.
Breast Cancer Res. 2018 Jul 11;20(1):72. doi: 10.1186/s13058-018-1001-3.
In primary breast cancer metastases frequently arise from a state of dormancy that may persist for extended periods of time. We investigated the efficacy of plasma micro-RNA (miR)-21, miR-23b, miR-190, miR-200b and miR-200c, related to dormancy and metastasis, to predict the outcome of patients with early breast cancer.
miRNAs were evaluated by RT-qPCR in plasma obtained before adjuvant chemotherapy. miRNA expression, classified as high or low according to median values, correlated with relapse and survival. Receiver operating characteristic (ROC) curves were constructed to determine miRNA sensitivity and specificity.
miR-21 (p < 0.001), miR-23b (p = 0.028) and miR-200c (p < 0.001) expression were higher and miR-190 was lower (p = 0.013) in relapsed (n = 49), compared to non-relapsed patients (n = 84). Interestingly, miR-190 was lower (p = 0.0032) in patients with early relapse (at < 3 years; n = 23) compared to those without early relapse (n = 110). On the other hand, miR-21 and miR-200c were higher (p = 0.015 and p < 0.001, respectively) in patients with late relapse (relapse at ≥ 5 years; n = 20) as compared to non-relapsed patients. High miR-200c was associated with shorter disease-free survival (DFS) (p = 0.005) and high miR-21 with both shorter DFS and overall survival (OS) (p < 0.001 and p = 0.033, respectively) compared to low expression. ROC curve analysis revealed that miR-21, miR-23b, miR-190 and miR-200c discriminated relapsed from non-relapsed patients. A combination of of miR-21, miR-23b and miR-190 showed higher sensitivity and specificity in ROC analyses compared to each miRNA alone; accuracy was further improved by adding lymph node infiltration and tumor grade to the panel of three miRs (AUC 0.873). Furthermore, the combination of miR-200c, lymph node infiltration, tumor grade and estrogen receptor predicted late relapse (AUC 0.890).
Circulating miRNAs are differentially expressed among relapsed and non-relapsed patients with early breast cancer and predict recurrence many years before its clinical detection. Our results suggest that miRNAs represent potential circulating biomarkers in early breast cancer.
在原发性乳腺癌转移中，经常会出现从休眠状态中出现的转移，这种休眠状态可能会持续很长时间。我们研究了与休眠和转移相关的血浆微小 RNA（miR）-21、miR-23b、miR-190、miR-200b 和 miR-200c，以预测早期乳腺癌患者的预后。
采用 RT-qPCR 法检测辅助化疗前血浆中 miRNA 的表达。根据中位数将 miRNA 表达分类为高或低，并与复发和生存相关联。构建受试者工作特征（ROC）曲线以确定 miRNA 的敏感性和特异性。
与无复发（n=84）患者相比，复发（n=49）患者的 miR-21（p<0.001）、miR-23b（p=0.028）和 miR-200c（p<0.001）表达较高，而 miR-190 表达较低（p=0.013）。有趣的是，与无早期复发（n=110）患者相比，早期复发（<3 年；n=23）患者的 miR-190 表达较低（p=0.0032）。另一方面，与无复发患者相比，晚期复发（≥5 年；n=20）患者的 miR-21 和 miR-200c 表达较高（p=0.015 和 p<0.001）。与低表达相比，高 miR-200c 与较短的无病生存（DFS）（p=0.005）和较短的总生存（OS）（p<0.001 和 p=0.033）相关，而高 miR-21 与较短的 DFS 和 OS 相关（p<0.001 和 p=0.033）。ROC 曲线分析显示，miR-21、miR-23b、miR-190 和 miR-200c 可区分复发与无复发患者。miR-21、miR-23b 和 miR-190 的组合在 ROC 分析中的敏感性和特异性高于每种 miRNA 单独使用；通过将淋巴结浸润和肿瘤分级添加到三个 miRs 的面板中，准确性进一步提高（AUC 0.873）。此外，miR-200c、淋巴结浸润、肿瘤分级和雌激素受体的组合预测晚期复发（AUC 0.890）。
早期乳腺癌患者中，复发和无复发患者的循环 miRNA 表达存在差异，并在其临床检测多年前预测复发。我们的研究结果表明，miRNA 可能是早期乳腺癌潜在的循环生物标志物。
