Comparison of Prognostic Signatures in Node-Negative Tamoxifen-Treated Breast Cancer Patients.

Abstract

Abstract Background: A number of molecular signatures have been published to aid breast cancer prognosis and therapy response prediction. A 76-gene signature has been developed in a node-negative patient cohort that did not receive systemic therapy.1 Another prognostic 97-gene signature measures predominantly proliferation-associated genes.2 Finally, a 21-gene signature has been developed for node-negative and estrogen receptor–positive breast cancer patients treated with tamoxifen in the adjuvant setting.3 Here we compare the prognostic performance of all three published algorithms in a cohort of 189 node-negative breast cancer patients treated with tamoxifen.Materials and Methods: Fresh-frozen tumors from node-negative patients were profiled on HG-U133a arrays. In addition, HG-U133a datasets with clinical annotation were downloaded from GEO (http://www.ncbi.nlm.nih.gov/geo/). All patients received tamoxifen only as adjuvant treatment after surgery. We determined the molecular subclass on the basis of ESR1 and ERBB2 mRNA expression; only ESR1-positive and ERBB2-negative tumors were considered for further analysis, leaving 141 in-house and 48 public datasets. After mapping of the gene signatures to the HG-U133a platform, we performed Cox regression and ROC curve analysis with distant metastasis as endpoint.Results: Cox regression analysis yielded a significant outcome association for all three gene signatures (76-gene signature: P = 0.0018; 97-gene signature: P = 0.0294; 21-gene signature: P = 0.0025) in the whole ESR1+/ERBB2– cohort. However, the 97-gene signature did not yield a significant result by ROC analysis for distant metastasis at 5 years (76-gene signature: AUC = 0.645, CI = 0.505–0.785; 97-gene signature: AUC = 0.608, CI = 0.462–0.754; 21-gene signature: AUC = 0.744, CI = 0.633–0.854). In addition, when the analysis was restricted to grade 2 tumors (n = 114), only the 21-gene signature remained prognostic by Cox regression (76-gene signature: P = 0.2405; 97-gene signature: P = 0.9001; 21-gene signature: P = 0.047) as well as by ROC curve analysis at 5 years (76-gene signature: AUC = 0.575, CI = 0.398–0.751; 97-gene signature: AUC = 0.532, CI = 0.347–0.717; 21-gene signature: AUC = 0.699, CI = 0.549–0.849).Discussion: While all three gene signatures reveal a significant outcome association in our whole patient cohort by Cox regression analysis, only the 21-gene signature remains significant in a subset analysis of grade 2 tumors. Since this group is clinically particularly challenging, further comparison between prognostic gene signatures in homogeneously treated patient cohorts is needed. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 104.