INTRODUCTION: Early stage estrogen receptor (ER)-positive breast cancer may be 
treated with chemotherapy in addition to hormone therapy. Currently available 
molecular signatures assess the risk of recurrence and the benefit of 
chemotherapy; however, these tests may have large intermediate risk groups, 
limiting their usefulness.
METHODS: The EarlyR prognostic score was developed using integrative analysis of 
microarray data sets and formalin-fixed, paraffin-embedded-based quantitative 
real-time PCR assay and validated in Affymetrix data sets and METABRIC cohort 
using Cox proportional hazards models and Kaplan-Meier survival analysis. 
Concordance index was used to measure the probability of prognostic score 
agreement with outcome.
RESULTS: The EarlyR score and categorical risk strata (EarlyR-Low, EarlyR-Int, 
EarlyR-High) derived from expression of ESPL1, MKI67, SPAG5, PLK1 and PGR was 
prognostic of 8-year distant recurrence-free interval in Affymetrix (categorical 
P = 3.5 × 10-14; continuous P = 8.8 × 10-15) and METABRIC (categorical P < 2.2 × 
10-16; continuous P < 10-16) data sets of ER+ breast cancer. Similar results 
were observed for the breast cancer-free interval end point. At most 13% of 
patients were intermediate risk and at least 66% patients were low risk in both 
ER+ cohorts. The EarlyR score was significantly prognostic (distant 
recurrence-free interval; P < .001) in both lymph node-negative and lymph 
node-positive patients and was independent from clinical factors. EarlyR and 
surrogates of current molecular signatures were comparable in prognostic 
significance by concordance index.
CONCLUSION: The 5-gene EarlyR score is a robust prognostic assay that identified 
significantly fewer patients as intermediate risk and more as low risk than 
currently available assays. Further validation of the assay in clinical 
trial-derived cohorts is ongoing.