Evaluation of drug-specific multigene markers to predict aromatase inhibitor efficacy in advanced breast cancer: a cohort study from Danish Breast Cancer Cooperative Group

Abstract

Background Even with positive oestrogen receptor (ER+) status some advanced breast cancer (ABC) patients fail to benefit from endocrine therapy (ET). A method that previously predicted other drugs in various cancers was evaluated. Here multigene markers based on aromatase inhibitor (AI) effect in vitro were used for prediction of AI benefit in ER+ ABC patients. Simultaneously effects of long-term ET on predictive efficacy was evaluated. Methods The Drug Response Predictors (DRPs) are based on correlations between baseline gene expression and growth inhibition patterns of exemestane, anastrozole and letrozole, respectively, in the National Cancer Institute 60 cell lines. The genes were controlled for expression in 3,500 tumours. In a Danish Breast Cancer Cooperative Group cohort of 695 ABC patients with complete gene expression and time-to-progression (TTP) data, 414 received an AI as monotherapy. Hereof, 57 received anastrozole, 166 received exemestane, and 327 received letrozole. mRNA was isolated from archival formalin-fixed paraffin embedded tumour tissue and run on microarray and 60% of the tumours were from time of primary diagnosis. Medical records of the patients were assessed for TTP for all treatments given for ABC. Results The DRPs were tested in subsets 1) with no adjuvant ET and 2) with adjuvant ET. In 1) the anastrozole DRP predicted benefit of anastrozole (hazard ratio (HR) was 0.21 upper 95%-confidence interval limit (CI) 0.76, p=0.023) but not in 2). Dichotomised by a DRP of 50, the anastrozole DRP did predict benefit (HR=0.16, upper 95%-CI 0.75, p=0.026). Only in 1) the exemestane DRP predicted benefit of exemestane (HR=0.57, upper 95%-CI 1.00, p=0.0497). The letrozole DRP had no predictive value. Additionally, we tested each DRPs ability to predict other AIs. Only the anastrozole DRP predicted benefit of overall AI treatment, in 1)with an HR of 0.76 (upper 95%-CI 0.99, p=0.044) and in 2) with an HR of 0.71 (upper 95%-CI 0.92, p=0.015). The anastrozole DRP did though not predict benefit of letrozole. All tests are one-sided, alpha=5%. Conclusions Among the DRPs for AIs, the anastrozole DRP was strongest with clinically relevant prediction of TTP in AI treated ER+ ABC patients. Trial registration: ClinicalTrials.gov NCT01861496. BackgroundApproximately 70% of women with advanced breast cancer (ABC) have oestrogen-receptor positive