A 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories.

The goal of this study was to assess the prognostic value of a 3-gene (TOP2A, FOXM1, and MKI67) proliferation score and use it to risk stratify grade-2, estrogen receptor (ER)-positive breast cancers into low- and high-risk groups. We used 4 different breast cancer gene expression datasets including two cohorts of patients who received no systemic adjuvant therapy (Mainz: n = 206, TRANSBIG: n = 134) and two other cohorts that received adjuvant tamoxifen (JBI: n = 227, MDACC/SET: n = 192). We compared individual and combined expression values of the 3 genes between grade 1, 2, and 3 tumors and plotted distant metastasis-free survival (DMFS) curves by the 3-gene score for grade-2 cancers. We compared the prognostic value of the 3-gene score to the Genomic Grade Index (GGI). The individual and combined expression of TOP2A, FOXM1, and MKI67 were significantly different between the 3 histological grade groups with the highest expression in grade-3 and the lowest in grade-1 cancers. Expression levels were variable in grade-2 cancers. Grade-2 tumors with high expression of the 3 genes (>median) showed significantly worse DMFS in one prognostic and one tamoxifen-treated set and showed a similar but non-significant trend for worse survival in the remaining two datasets. The 3-gene score performed equally well in risk stratification as the GGI. A 3-gene proliferation score shows similar prognostic value as the GGI in ER-positive, grade-2 cancers and may serve as basis for a PCR-based assay that could aid prognostic prediction for clinically intermediate-risk cancers.