Young age, increased tumor proliferation and FOXM1 expression predict early metastatic relapse only for endocrine-dependent breast cancers.

It is unclear if earlier onset (<40 years) and greater proliferative capacity confer an equally poor prognosis to endocrine-dependent and endocrine-independent breast cancers. Available outcome (distant metastasis-free survival, DMFS) and expression microarray data from 621 adjuvant treatment-naïve, node-negative primary breast cancers were pooled for prognostic evaluation of age-at-diagnosis (< 40 years vs. ≥ 40 years) and tumor proliferative capacity relative to estrogen receptor status (n = 400 ER-positive, n = 221 ER-negative). Transcriptome measures of proliferative capacity included a proliferation score (PS) based on a 61-gene proliferation signature and the single gene surrogate, FOXM1. Kaplan-Meier analyses revealed no significant difference in DMFS between ER-positive and ER-negative cases >5 years after diagnosis. In contrast, younger age and higher proliferative capacity resulted in significantly more metastatic events cumulated over 15 years, but only in ER-positive breast cancers where positive correlations between age and proliferation were observed. While strongly correlated, FOXM1 and PS did not appear equivalent in relation to age and prognosis. The poor prognosis associated with breast cancer arising before age 40 or with higher proliferative capacity pertains only to endocrine-dependent (ER-positive) breast cancer, indicating that different biological processes drive the metastatic potential of ER-negative breast cancer.