Department of Medical Oncology, The Mater Hospital, Dublin, Ireland.
Eur Urol. 2011 Aug;60(2):344-9. doi: 10.1016/j.eururo.2011.05.034. Epub 2011 May 25.
Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond.
To identify predictors of response to sunitinib.
DESIGN, SETTING, AND PARTICIPANTS: Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib.
BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria.
Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3/4 hypertension compared with grade 0. Response was associated with low HIF-1α expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 × 10(-9)), and vascular endothelial growth factor receptor 2 and HIF-1α (p = 0.008). Results are limited by small numbers.
Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC.
舒尼替尼对转移性尿路上皮癌（UC）患者具有活性，但大多数患者没有反应。
确定舒尼替尼反应的预测因子。
设计、地点和参与者：在一家机构中，77 名晚期 UC 患者接受了两种方案之一的舒尼替尼治疗。对血压（BP）、免疫组织化学（IHC）和药代动力学（PK）结果与舒尼替尼的反应进行了相关性分析。
在每个周期的第 1 天和第 28 天以及第 1 周期的第 14 天评估 BP。使用哺乳动物雷帕霉素靶蛋白和缺氧诱导因子（HIF）通路标志物抗体对 38 例中的 55 例样本进行 IHC。从 15 名患者的三个时间点采集用于 PK 分析的血样。使用实体瘤反应评估标准评估反应。
舒尼替尼诱导的高血压在将高血压分类为离散变量（p = 0.02）或连续变量（p = 0.005 [收缩压]和 p = 0.007 [舒张压]）时预测反应改善。与 0 级相比，3/4 级高血压的反应优势比为 12.5（95%置信区间，1.95-246.8）。原发性组织中低 HIF-1α 表达与反应相关（p = 0.07）。药物浓度与最佳反应之间存在非统计学显著趋势。还鉴定了同一途径内表达标志物之间的相关性，磷酸化-4EBP1 和磷酸化-S6（p = 6.5×10（-9））和血管内皮生长因子受体 2 和 HIF-1α（p = 0.008）。结果受到数量有限的限制。
舒尼替尼反应的临床和分子生物标志物可能具有临床相关性，需要前瞻性验证。迫切需要预测性生物标志物来指导 UC 的管理。
