Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen

Abstract

Background: ER-positive (ER+) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only.

Methods: Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan-Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance.

Results: All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%-100%).

Conclusions: Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.

Figure 1.

Kaplan–Meier DRFS analysis of intrinsic subtype as determined by PAM50 gene expression measurement (quantitative reverse transcription–PCR and microarray-based) from women with (A) node-negative and (B) node-positive invasive breast carcinoma, treated with adjuvant tamoxifen only. The number of patients and the estimated DRFS at 8.5 years in each group are shown beside each curve's description. DRFS, distant relapse-free survival.

Figure 2.

Comparison of prognostic classifiers and single genes in (A) node-negative and (B) node-positive subjects. The C-index is used to compare accuracy of the prognostic classifiers and single genes. Signatures have been ranked ordered from highest to lowest mean C-index. In node-negative disease, the C-index of the combined model was superior to the C-index of each individual signature in at least 75% of the 200 total estimations.

Figure 3.

Kaplan–Meier DRFS analysis of selected gene signatures within luminal A disease treated with adjuvant tamoxifen only. (A) SET index within node-negative luminal A tumors; (B) PAM50-RORP within node-negative luminal A tumors (Nielsen series included); (C) GHI within node-positive luminal A tumors; (D) PAM50-RORP within node-positive luminal A tumors (Nielsen series included). The complete survival analyses can be found in supplemental Tables S5 and S6, available at Annals of Oncology online. DRFS, distant relapse-free survival.