Predictive value of ribonucleotide reductase regulatory subunit M1 (RRM1) and excision cross-complementing-1 (ERCC1) in advanced urothelial carcinoma (UC) treated with first-line gemcitabine (G) and platinum (P)-based chemotherapy (CT).

Abstract

e15614 Background: Preclinical and clinical studies suggested that RRM1 and ERCC1 expression are associated with resistance to G and P, respectively. However, data which correlated RRM1 and ERCC1 status with tumor response to G + P in advanced US is lacking. We evaluated the significance of RRM1 and ERCC1 to predict tumor response to G + P and survival in advanced UC. Methods: We retrospectively collected tumor samples and reviewed clinical data of 55 patients (pts) with unresectable or metastatic UC, who were treated with 1st line G + P from Jan. 2006 to Dec. 2011. RRM1 and ERCC1 expression were measured by immunohistochemistry and scored using a semiquantitative H-score based on staining intensity and proportion. Results: The study population was predominantly male (80%) and had a median age of 66 years (range: 28-88). The primary sites of UC were bladder (61%), renal pelvis (27.3%) and ureter (10.9%). The RRM1 and ERCC1 expression were positive in 21.8% (12/55) and 25.4% (14/55), respectively. Thirty (69.8%) among 43 pts with low RRM1 expression achieved clinical responses (complete responses + partial responses), but three (25%) among 12 pts with high RRM1 expression achieved clinical responses after G + P (P=0.008). Twenty-three (56.1%) among 41 pts with low ERCC1 expression achieved clinical responses, but ten (71.4%) among 14 pts with high ERCC1 expression achieved clinical responses after G + P (P=0.361). In multivariate analysis, high RRM1 expression independently predicted for poorer tumor response to G + P (OR=10.04, 95% CI=1.74~57.93, P=0.010). High RRM1 expression were associated with shorter progression free survival (PFS) (P=0.005). Multivariate analysis confirmed that pts with high RRM1 expression had a significantly greater risk of progression than those with low RRM1 expression (OR=3.66, 95% CI=1.60~8.36, P=0.002). ERCC1 status was not statistically significant in terms of PFS. Conclusions: In advanced UC, RRM1 expression was predictive of clinical responses from 1st-line G + P. Large prospective validation trials of the clinical value of RRM1 are warranted.