Predictive value of RRM1 and ERCC1 protein levels in a prospective community-based trial of gemcitabine/carboplatin (GC) vs gemcitabine (G) alone

Abstract

8033 Background: RRM1 and ERCC1 mRNA and/or protein levels are molecular predictors of G and C efficacy. Prior studies had been performed under highly controlled conditions in tertiary referral centers. We prospectively assessed if RRM1 and ERCC1 protein levels are predictive of response in a community-based randomized phase III trial of GC vs G. Patients and Methods: 170 pts with NSCLC were enrolled from 3/04–12/06. All had IIIB/IV, PS 2, and no prior therapy. Routine diagnostic pretreatment tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression by an automated quantitative immunofluorescence-based technology (AQUA, HistoRx). Full section specimens were analyzed individually, and expression data were adjusted by using a standardized control TMA that was included in each analysis. Results: Tumor specimens were received from 91 pts. 69 were of sufficient quality for expression analysis (76% of specimens, 41% of all pts). These pts included 34 treated with GC, 35 with G; 34 women, 35 men; age 49–85 y; 5 stage IIIB, 64 stage IV; 43 adeno-, 13 squamous, 13 other cas. Adjusted RRM1 values ranged from 5.3- 105.6 (median 34.1). Adjusted ERCC1 values ranged from 10.4 -262.6 (median 69.4). RRM1 and ERCC1 expression levels were significantly correlated (p=0.001, r=0.39). They were marginally associated with pts’ age (p=0.05 and p=0.11). Neither was significantly associated with gender (p=0.73 and p=0.39) or histology (p=0.77 and p=0.91). RRM1 and ERCC1 protein values were significantly and inversely correlated with disease response (p=0.001, r=0.41 for RRM1; p=0.003, r=0.39 for ERCC1) in all pts; i.e., response was better for pts with low levels of expression. There was no significant interaction between either RRM1 or ERCC1 and best response by treatment arm. Conclusion: Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens from pts with advanced NSCLC is possible in most cases in a community setting. RRM1 and ERCC1 expression are predictive of response to G and GC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly Eli Lilly, sanofi-aventis