Boisen Mogens K, Dehlendorff Christian, Linnemann Dorte, Nielsen Boye S, Larsen Jim S, Osterlind Kell, Nielsen Svend E, Tarpgaard Line S, Qvortrup Camilla, Pfeiffer Per, Holländer Niels H, Keldsen Nina, Hansen Torben F, Jensen Brita B, Høgdall Estrid V S, Jensen Benny V, Johansen Julia S
Department of Oncology, Herlev University Hospital, Herlev, Denmark.
Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark.
PLoS One. 2014 Oct 15;9(10):e109430. doi: 10.1371/journal.pone.0109430. eCollection 2014.
We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC).
Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs.
In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts.
We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.
我们检验了以下假设，即癌症组织中微小RNA（miRNA）的表达可以预测贝伐单抗联合卡培他滨和奥沙利铂（CAPEOX）治疗转移性结直肠癌（mCRC）患者的疗效。
回顾性确定接受一线CAPEOX和贝伐单抗（CAPEOXBEV）治疗的mCRC患者：筛查队列（n = 212）和验证队列（n = 121），或仅接受CAPEOX治疗的患者：对照队列（n = 127），并收集存档的原发性肿瘤样本。使用聚合酶链反应（PCR）阵列分析筛查队列中754种miRNA的表达，并将表达水平与疾病进展时间（TTP）和总生存期（OS）相关联。使用定制PCR阵列在所有三个队列中分析筛查研究中具有显著意义的miRNA。对选定的miRNA进行原位杂交（ISH）。
在筛查研究中，26种miRNA在多变量分析中与结局显著相关。选择了22种miRNA进行进一步研究。较高的miR-664-3p表达和较低的miR-455-5p表达可预测CAPEOXBEV队列的结局改善，并显示与贝伐单抗疗效有显著相互作用。对OS的影响最强。两种miRNA在基质细胞中均高表达且。无论贝伐单抗治疗如何，较高的miR-196b-5p和miR-592表达均预测结局改善，在所有三个队列中的效应估计相似。
我们已经确定了贝伐单抗疗效的潜在预测性miRNA，以及可能与mCRC患者化疗疗效或预后相关的其他miRNA。我们的研究结果需要在大型队列中进一步验证，最好来自已完成的随机试验。
