背景:基于紫杉烷的化疗广泛用于铂类药物和免疫疗法难治性患者,转移性尿路上皮癌(mUC)。结果较差,缺乏与结果相关的生物标志物。我们的目标是确定与接受紫杉醇的患者生存相关的癌症标志。
方法:为参与一项研究紫杉醇和帕唑帕尼在铂类难治性mUC(PLUTO,EudraCT2011-001841-34)。计算基因表达的估计值并将其输入到Almac专有分析流程中,并使用ClaraTV3.0.0计算签名得分。评估了十个关键基因特征:免疫肿瘤学,上皮向间充质转化,血管生成,扩散,细胞死亡,基因组不稳定,能量学,炎症,不朽和逃避增长。使用Cox回归模型计算风险比,并使用Kaplan-Meier方法估计无进展生存期(PFS)和总生存期(OS)。
结果:38和45例患者接受紫杉醇或帕唑帕尼治疗。使用紫杉醇治疗的高基因组不稳定性表达患者的生存率显著提高,PFS和OS的HR为0.29(95%CI:0.14-0.61,p=0.001)和HR0.34(95%CI:0.17-0.69,p=0.003)。分别。同样,紫杉醇治疗的高逃避生长抑制因子表达患者的PFS和OS均得到改善,HR为0.35(95%CI:0.19-0.77,p=0.007)和HR为0.46(95%CI:0.23-0.91,p=0.026),分别。没有其他基因标记对结果有显著影响。在紫杉醇和帕唑帕尼队列中,血管生成激活与较差的PFS和OS相关,而VEGF靶向治疗并未改善结局.
结论:在接受紫杉醇治疗的铂类难治性mUC患者中,高基因组不稳定性和抑制生长抑制生物制剂与生存改善相关。这些可能会完善MUC风险分层,并指导未来的治疗决策。
BACKGROUND: Taxane- based chemotherapy is widely used in patients with platinum- and immunotherapy refractory, metastatic urothelial carcinoma (mUC). Outcomes are poor and biomarkers associated with outcome are lacking. We aim to identify cancer hallmarks associated with survival in patients receiving paclitaxel.
METHODS: Whole-transcriptome profiles were generated for a subset of patients enrolled in a randomised phase II study investigating paclitaxel and pazopanib in platinum refractory mUC (PLUTO, EudraCT 2011-001841-34). Estimates of gene expression were calculated and input into the Almac proprietary analysis pipeline and signature scores were calculated using ClaraT V3.0.0. Ten key gene signatures were assessed: Immuno-Oncology, Epithelial to Mesenchymal Transition, Angiogenesis, Proliferation, Cell Death, Genome Instability, Energetics, Inflammation, Immortality and Evading Growth. Hazard ratios were calculated using Cox regression model and Kaplan-Meier methods were used to estimate progression free survival (PFS) and overall survival (OS).
RESULTS: 38 and 45 patients treated with paclitaxel or pazopanib were included. Patients with high genome instability expression treated with paclitaxel had significantly improved survival with a HR of 0.29 (95% CI: 0.14-0.61, p=0.001) and HR 0.34 (95% CI: 0.17-0.69, p=0.003) for PFS and OS, respectively. Similarly, patients with high evading growth suppressor expression treated with paclitaxel had improved PFS and OS with a HR of 0.35 (95% CI: 0.19-0.77, p=0.007) and HR 0.46 (95% CI: 0.23-0.91, p=0.026), respectively. No other gene signatures had significant impact on outcome. In both paclitaxel and pazopanib cohorts, angiogenesis activation was associated with worse PFS and OS, and VEGF targeted therapy did not improve outcomes.
CONCLUSIONS: High Genome-instability and Evading-growth suppressor biologies are associated with improved survival in patients with platinum refractory mUC receiving paclitaxel. These may refine mUC risk stratification and guide treatment decision in the future.