Utility of microRNA to Predict Bladder Recurrence after Nephroureterectomy for Upper Tract Urothelial Carcinoma
Alison Levy, MD1; Travis Sullivan, PhD1, Kristian Stensland, MD1; Eric Burks, MD1; Brendan Browne, MD1; Chintan Patel, MD1; Joshua Warrick, MD2; Jay Raman, MD2; David Canes, MD1; Kimberly Rieger-Christ, PhD1
1Lahey Hospital, Burlington, MA; 2Penn State Health, Hershey, PA
Introduction and Objective
Upper tract urothelial carcinoma (UTUC) is a rare but aggressive urologic malignancy. Nephroureterectomy (NU) can be curative for organ confined disease. However, 30-50% of patients will develop intravesical recurrence, which is associated with higher cancer specific and overall mortality. Bladder surveillance is costly and time consuming. Single dose intravesical therapy at the time of NU decreases bladder recurrences but has potential toxicity so targeting those at highest risk would be useful. MicroRNA (miRNA) are biomarkers with potential to differentiate behavior of cancers. Identification of miRNA associated with intravesical recurrence could improve screening and treatment algorithms after NU. We sought to identify miRNA associated with intravesical recurrence after NU for UTUC.
Total RNA was extracted from formalin-fixed, paraffin-embedded NU samples from 2005 to 2013 under a multi-institutional IRB-approved study. Patients were excluded if they had history of or synchronous diagnosis of bladder cancer. Samples were categorized as either having a bladder recurrence after NU or not having a bladder recurrence within 12 months of NU. Samples from each group were profiled via miRNA RT-qPCR array.
Eleven samples from the recurrence group and 13 from the no-recurrence group underwent array analysis. Demographics and baseline characteristics were similar between groups. Array analysis of 752 miRNA identified 11 miRNA with ≥2 fold differential expression between the recurrence and no-recurrence groups. A combination of two miRNA predicted recurrence with a sensitivity of 82% and a specificity of 85%, for an AUC=0.846. Several of the miRNA we identified have been previously implicated in other types of cancer. One of the top performing miRNA had a strong association with median overall survival (p<0.001).
MiRNA expression profiles are able to differentiate patients with or without subsequent intravesical urothelial cancer recurrence after NU for UTUC. This study is among the first to identify molecular biomarkers that correlate with intravesical recurrence after NU. This miRNA profile needs to be validated in a larger cohort. Patients with this miRNA profile may merit receipt of single dose intravesical therapy, and/or shorter screening cystoscopy intervals after NU.
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