背景:先前的研究表明循环,基于血液的microRNAs(miRNAs)可以作为微创前列腺癌的生物标志物,然而,来自前瞻性临床试验的数据有限.这里,我们探讨了候选血浆miRNAs作为潜在生物标志物在SWOG0925新的转移性激素敏感型前列腺癌患者中的作用,该研究是在雄激素剥夺联合西克苏木单抗与单用雄激素剥夺的对照研究.
方法:相关生物标本,包括用于miRNA分析的循环肿瘤细胞(CTC)和血浆,在基线和治疗12周后,从参加SWOG0925的50名患者中收集。使用实时RT-PCR微小RNA阵列定量循环微小RNA,该阵列允许对先前鉴定的候选miRNA(miR-141,miR-200a,miR-200b,miR-210和miR-375)以及发现分析以鉴定新的候选miRNA。miRNA水平与先前使用CellSearch®(Veridex)报告的CTC计数相关,并与28周PSA反应的主要研究结果相关(≤0.2、0.2至≤4.0或>4.0ng/mL),先前显示与总生存率相关。
结果:我们观察到基线循环miR-141,miR-200a,和miR-375水平与基线CTC。基线miR-375水平与28周PSA反应相关(≤0.2、0.2至≤4.0或>4.0ng/mL,P=0.007)。采用ROC曲线分析,基线miR-375和基线CTC在预测28周PSA应答方面无显著差异(≤0.2vs>0.2ng/mL).为了发现新的候选miRNA,我们分析了365种miRNA与28周PSA应答终点的相关性,并鉴定了新的候选miRNA以及现有候选miR-375和miR-200b(分别为P=0.0012,P=0.0046.
结论:基线血浆miR-141,miR-200a,miR-375水平与基线CTC计数相关。基线miR-375也与28周PSA反应的试验终点相关。我们的结果提供了证据,表明循环miRNA生物标志物可能具有作为预后生物标志物的价值,并需要在更大的前瞻性临床试验中进一步研究。
BACKGROUND: Previous studies suggest circulating, blood-based microRNAs (miRNAs) may serve as minimally invasive prostate cancer biomarkers, however there is limited data from prospective clinical trials. Here, we explore the role of candidate plasma miRNAs as potential biomarkers in the SWOG 0925 randomized phase II
study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer.
METHODS: Correlative biospecimens, including circulating tumor cells (CTCs) and plasma for miRNA analysis, were collected at baseline and after 12 weeks on treatment from 50 patients enrolled on SWOG 0925. Circulating microRNAs were quantified using real-time RT-PCR microRNA array that allowed specific analysis of previously identified candidate miRNAs (miR-141, miR-200a, miR-200b, miR-210, and miR-375) as well as discovery analysis to identify new candidate miRNAs. MiRNA levels were correlated to previously reported CTC counts using CellSearch® (Veridex) and with the primary
study outcome of 28-week PSA response (≤0.2, 0.2 to ≤4.0, or >4.0 ng/mL), previously shown to correlate with overall survival.
RESULTS: We observed a correlation between baseline circulating miR-141, miR-200a, and miR-375 levels with baseline CTCs. Baseline miR-375 levels were associated with 28-week PSA response (≤0.2, 0.2 to ≤4.0, or >4.0 ng/mL, P = 0.007). Using ROC curve analysis, there was no significant difference between baseline miR-375 and baseline CTC in predicting 28-week PSA response (≤0.2 vs >0.2 ng/mL). To discover novel candidate miRNAs, we analyzed 365 miRNAs for association with the 28-week PSA response endpoint and identified new candidate miRNAs along with the existing candidates miR-375 and miR-200b (P = 0.0012, P = 0.0046, respectively.
CONCLUSIONS: Baseline plasma miR-141, miR-200a, and miR-375 levels are associated with baseline CTC count. Baseline miR-375 was also associated with the
trial endpoint of 28-week PSA response. Our results provide evidence that circulating miRNA biomarkers may have value as prognostic biomarkers and warrant further
study in larger prospective clinical trials.