Validation of NAD(P)H quinone oxidoreductase (NQO1) expression as a predictive factor for adjuvant chemotherapy benefit in patients with early breast cancer.

Abstract

1091 Background: NAD(P)H:quinone oxidoreductase-1 (NQO1) has important antioxidant functions by stabilizing p53 from proteasomal degradation. NQO1 knockdown is associated with higher susceptibility to oxidative stress. Polymorphisms suppressing NQO1 are predictors of poor survival in patients with breast cancer (BC) treated with anthracyclines. BC cell lines with impaired NQO1 function showed resistance to epirubicin chemotherapy (CT) independently of p53 status suggesting NQO1 as predictive factor for anthracycline benefit. In this study we hypothesized that lack of NQO1 could predict resistance to anthracycline-containing CT in patients with early breast cancer (EBC). Methods: Patients were identified from two French multicentric trials that randomized patients with EBC to adjuvant anthracycline-based CT vs no CT between 1988 and 1995. NQO1 was determined in TMAs by automated quantitative assessment of immunofluorescence (On-Q-ity Inc, Waltham). Cut-off for positivity was the median value of NQO1 expression. Univariate and multivariate Cox regression models were performed. Treatment effect was assessed on long term overall survival (OS). Results: NQO1 expression was assessed in 600 patients. 75% were postmenopausal, had more often grade II (62%), LN-negative (58%) and ER-positive (67%) BC. Higher NQO1 expression was observed in postmenopausal (P=0.02) patients. No relation with other clinicopathological factors (grade, LN or ER) was observed. Effect of adjuvant CT on death rates was dependant on NQO1 level. Hazard ratio (HR) for treatment efficacy at the four quartiles of NQO1 were 1.07 (95%CI: 0.69-1.7), 0.87 (0.64-1.19), 0.66 (0.45-0.97), 0.46 (0.22-0.95) (interaction test: 0.1). Interaction test was statistically significant (0.02) when NQO1 expression was considered as binary variable with median value taken as cut-off. NQO1 remained predictive among ER+ patients only. HR for OS was 0.61 (0.36-1.02) and 1.25 (0.79-1.99) in patients with high and low NQO1 respectively. Conclusions: This study adds to the existing data suggesting NQO1 expression as an independent predictor of efficacy for adjuvant anthracycline-containing CT.