Higher Expression of Estrogen Response Genes in the Primary Tumor is Associated with a Greater Risk for Late Recurrence in Patients with ER+/HER2-breast Cancer

Background: In patients with ER+ breast cancer, 50% of recurrences occur > 5 years after diagnosis (i.e. late recurrence). Clinical trials report contradicting results on the effect of extended endocrine therapy > 5 years to reduce late recurrence risk. Using publically available breast cancer gene expression profiles, we aimed to gain insight into the biology that increases the risk for late recurrences. Methods: Gene expression profiles of primary ER+/HER2- tumors of breast cancer patients were collected with disease-free survival (DFS) data, defined as time of diagnosis to local recurrence or distant metastasis. We defined (i) a group containing all patients (n = 2,231), (ii) a group that received 5 years of endocrine therapy only (n = 591), and (iii) a group that received no systemic therapy (n = 497). For each group, genes were ranked on their association with DFS as determined by multivariate Cox regression with age, tumor size, grade, lymph node status, and therapy as covariates. Gene set enrichment analysis (GSEA) was performed on these gene lists with the Hallmark collection from the Molecular Signatures Database. Within each group, associations with early recurrence were studied in all patients with censoring at 5 years if no event occurred < 5 years after diagnosis (set I). To study associations with late recurrence, a second set was defined that contained only patients with a follow-up ≥ 5 years and no event < 5 years after diagnosis (set II). Results: Within all patients and the group that received 5 years of endocrine treatment only, higher expression of genes belonging to the Hallmark ‘estrogen response late’ was associated with longer DFS in set I and shorter DFS in set II. This Hallmark contains estrogen responsive genes identified in estradiol treated ER+ breast cancer cell lines. However, in patients who received no systemic treatment, higher expression of these genes was associated with shorter DFS in both set I and II. Conclusions: Higher expression of estrogen response genes is associated with a greater risk for late recurrence in patients with ER+/HER2- breast cancer. Potentially, patients with ER+ tumors with high expression of these genes might benefit most from extended endocrine therapy. Legal entity responsible for the study: R.S.N. Fehrmann Funding: Dutch Cancer Society grants RUG 2010-4739 and RUG 2013-5960, NWO-VENI grant (916-16025) and a Mandema Stipendium. Disclosure: All authors have declared no conflicts of interest.