A Genomic Predictor Developed From Breast Cancer Cell Lines Predicts Both Disease-Free Survival And Overall Survival In Breast Cancer Patients Treated With Doxorubicin And Cyclophosphamide: A Collaborative Project Of The Nsabp And Precision Therapeutics

Abstract Background: A cell line-derived multigene predictor of tumor response to doxorubicin + cyclophosphamide (MGP-AC) has been shown to predict the pathological complete response (pCR) in breast cancer patients from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-27. However, a cell line-derived MPG for doxorubicin + cyclophosphamide + docetaxel (MGP-ACT) was not predictive in patients from B-27. The purpose of this study was to further assess the performance of these predictors on disease-free survival (DFS) and overall survival (OS) in the same patient populations. Methods: NSABP B-27 was a 3-arm trial of 2411 early-stage breast cancer patients randomized to receive 4 cycles of preoperative doxorubicin+cyclophosphamide (AC) or 4 cycles of AC followed by 4 cycles of docetaxel either pre-op (AC+T) or post-op (AC→T). MGPs for AC and ACT were developed based on the in vitro assay and microarray genomic profiles of 40 breast cancer cell lines. A higher MGP score indicates lower chemoresponse sensitivity. Results: 322 patients with available microarray data were included for this analysis (103 treated with AC, 102 with AC+T, and 117 with AC→T). For patients treated with AC, a higher MGP-AC score was significantly associated with increased risk of disease progression (standardized hazard ratio [HR] [SD set to 1]=1.48, 95% confidence interval [CI]=1.02−2.15, p=0.043) or death (standardized HR=1.66, 95% CI=1.06−2.62, p=0.028) after adjusting for clinical covariates (ER status, clinical tumor size, lymph node status, and age). The addition of MGP-AC to the clinical model improves the accuracy in predicting five-year DFS: the area under the ROC curve improved from 63% to 72%. For patients treated with AC+T or AC→T, MGP-ACT was not predictive of either DFS (standardized HR=1.03, 95% CI=0.78−1.37, p=0.818) or OS (standardized HR=1.05, 95% CI=0.73−1.51, p=0.8). Conclusions: A cell line-derived MGP for AC that was predictive of pCR was also predictive of DFS and OS in breast cancer patients treated with neoadjuvant AC. The MGP for ACT, which was not predictive for pCR, was not predictive of either DFS or OS in patients who received docetaxel after AC. The B-27 study was funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U24-CA-114732, and received additional support from sanofi-aventis. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-15.