Evaluating the prognostic significance of JAK2 in distant breast cancer recurrence.

Abstract

e22178 Background: Estrogen, progesterone, and epidermal growth factor receptor ligands stimulate growth in a subset of breast cancers, however recent studies suggest roles for additional factors such as interleukins-6 and 8, prolactin, and erythropoietin. These and other growth factors act upon ligand-specific receptors to activate janus kinase 2 (JAK2), and JAK2 inhibitors are under investigation as a novel targeted therapy. We tested whether erythropoietin receptor (EPOR) or JAK2 mRNA levels are associated with distant breast cancer recurrence. Methods: We used quantitative RT-PCR to measure mRNA levels of JAK2, EPOR and a series of control genes using archival tumors from 112 women who experienced distant breast cancer recurrence (cases) and 112 tumors from women who did not (controls). Cases and controls were matched for tumor size, lymphovascular invasion, nodal status, extra-nodal extension, and ER/PR/HER2. Recurrence risks were evaluated using logistic regression. Associations between mRNA levels (via microarray data) and recurrence-free survival were validated in an independent cohort from the Netherlands Cancer Institute (n=295) using Cox proportional hazards regression. Results: Increasing JAK2 mRNA levels strongly correlated with a reduced risk of distant recurrence in our case control study (univariate p=0.0004, multivariate p=0.003), and with improved recurrence-free survival in the validation cohort (univariate p=0.0009; multivariate p=0.003). Remarkably, in the validation cohort, the ranking of the prognostic significance of JAK2 (top 3.5% of ~25,000 genes) was comparable to the known strong prognostic indicator of recurrence, ESR1 (top 1.3%). Similarly although less prominently, increasing EPORmRNA levels were significantly associated with reduced distant recurrence in our case control study (continuous model: univariate p=0.01, multivariate p=0.05) and with improved recurrence free survival in the validation cohort in univariate (p=0.03) but not multivariate analysis (p=0.35). Conclusions: JAK2 mRNA levels in breast tumors correlate with a reduced risk of recurrence. Understanding the mechanistic basis for this association is important for the rational application of JAK2 inhibitors.