Epidermal Growth Factor Receptor and Ki-67 as Predictive Biomarkers Identify Patients Who Will Be More Sensitive to Intravesical Instillations for the Prevention of Bladder Cancer Recurrence after Radical Nephroureterectomy

Background
To date, prophylactic intravesical chemotherapy after radical nephroureterectomy is one of the few available treatments that effectively prevent secondary bladder cancer. However, treating all patients with prophylactic intravesical chemotherapy is excessive for patients who are at a low risk or insensitive to the treatment. Thus, to guide individualized clinical treatment, in addition to identifying patients who are at risk of bladder cancer recurrence, it is equally necessary to identify the patients who will benefit the most from prophylactic, postoperative intravesical instillation therapy.
Methods
Epidermal growth factor receptor (EGFR) and Ki-67 expression levels were measured using immunohistochemical staining samples from 320 patients with upper urinary tract urothelial carcinoma (UTUC) from 2004 to 2012. Although no patients received intravesical chemotherapy after RNU before 2008, this method began to be used in 2008 to prevent bladder cancer recurrence. To identify the patients who would most benefit from intravesical chemotherapy, we assessed biological interactions between intravesical chemotherapy and clinicopathological factors or biomarkers.
Results
The incidence rates of bladder UTUC recurrence decreased after intravesical chemotherapy, and the decrease was greater in patients with low Ki-67 levels, negative EGFR staining and preoperative positive urine cytology. Biological interactions were observed between intravesical chemotherapy, low-level Ki-67 and EGFR negativity. The multivariate analysis showed that after balancing a variety of factors, intravesical chemotherapy is a protective factor for preventing intravesical recurrence in the negative EGFR, low-level Ki-67 and preoperative positive urine cytology sub-groups but not in their corresponding sub-groups. Additionally, the multivariate analysis revealed that preoperative positive urine cytology and Ki-67 were not but that EGFR positivity was an independent risk factor for recurrence after intravesical chemotherapy.
Conclusions
Patients with low Ki-67 levels, negative EGFR staining and preoperative positive urine cytology appear to be more sensitive to intravesical instillations for bladder recurrence prevention after RNU.

背景
截至目前，根治性肾输尿管切除术（radical nephroureterectomy, RNU）后的预防性膀胱内化疗是为数不多可有效预防继发性膀胱癌的临床治疗手段之一。然而，对于膀胱癌复发低风险或对该治疗不敏感的患者而言，对所有患者均实施预防性膀胱内化疗则存在过度治疗之嫌。因此，为指导个体化临床诊疗，除需甄别存在膀胱癌复发风险的患者外，精准识别可从术后预防性膀胱灌注治疗中获益最大的人群亦同等重要。

方法
本研究纳入2004年至2012年间收治的320例上尿路上皮癌（upper urinary tract urothelial carcinoma, UTUC）患者，通过免疫组织化学染色检测其表皮生长因子受体（epidermal growth factor receptor, EGFR）及Ki-67的表达水平。2008年前，无患者在接受根治性肾输尿管切除术后接受膀胱内化疗；自2008年起，该疗法开始被用于预防膀胱癌复发。为甄别可从膀胱内化疗中获益最大的患者，本研究分析了膀胱内化疗与临床病理因素、生物标志物之间的生物学交互作用。

结果
膀胱内化疗实施后，膀胱癌复发发生率有所下降，且在Ki-67低表达、EGFR染色阴性以及术前尿细胞学检查阳性的患者中，复发率下降更为显著。研究观察到膀胱内化疗与Ki-67低表达、EGFR阴性状态之间存在生物学交互作用。多因素分析结果显示，在平衡各类混杂因素后，膀胱内化疗可作为EGFR阴性、Ki-67低表达及术前尿细胞学阳性亚组患者预防膀胱内复发的保护因素，但在其对应亚组中未观察到该保护效应。此外，多因素分析表明，术前尿细胞学阳性与Ki-67表达并非膀胱内化疗后复发的独立危险因素，而EGFR阳性则为该类复发的独立危险因素。

结论
Ki-67低表达、EGFR染色阴性且术前尿细胞学检查阳性的患者，在接受根治性肾输尿管切除术后，对用于预防膀胱复发的膀胱灌注治疗更为敏感。