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.