HE4 is superior to CA125 in the detection of recurrent disease in high-risk endometrial cancer patients.

OBJECTIVE: To date, biomarkers are not routinely used in endometrial cancer diagnosis, prognosis, and follow-up. The purpose of this study was to evaluate whether serum HE4 was related to clinicopathological risk factors and outcome. Second, the role of serum HE4 and CA125 was assessed as indicator for recurrent disease during follow-up. METHODS: A total of 174 patients with endometrial cancer between 1999 and 2009 were selected for this retrospective study. Serum HE4 and CA125 were analyzed at primary diagnosis, during follow-up, and at the time of recurrence. Correlations with clinicopathological factors were studied by univariate and multivariate survival analyses. Lead time was calculated in order to determine which serum marker was elevated prior to clinical detection of recurrent disease. RESULTS: Serum levels of HE4 and CA125 were significantly associated with high tumor grade, myometrial invasion, lymph node involvement, and advanced stage (p < 0.01). HE4 was an independent prognostic factor for reduced disease-free survival and overall survival with hazard ratios of 2.96 (95% confidence interval: 1.18-7.99) and 3.27 (95% confidence interval: 1.18-9.02), respectively. At recurrence, 75% of the patients had an elevated HE4 compared to 54% with an elevated CA125. HE4 levels were more frequently elevated in patients with distant metastasis compared to local recurrences, 67% and 37%, respectively. Serum HE4 detected a recurrence with a median of 126 days earlier than clinical confirmation. CONCLUSION: Elevated serum HE4 is an independent risk factor for reduced disease-free survival and overall survival. HE4 seems to be superior to CA125 in the detection of recurrent disease during follow-up, mainly in high-risk endometrial cancer patients who are more prone to distant metastasis.

ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands.

We used ChIP-Seq to map ERalpha-binding sites and to profile changes in RNA polymerase II (RNAPII) occupancy in MCF-7 cells in response to estradiol (E2), tamoxifen or fulvestrant. We identify 10 205 high confidence ERalpha-binding sites in response to E2 of which 68% contain an estrogen response element (ERE) and only 7% contain a FOXA1 motif. Remarkably, 596 genes change significantly in RNAPII occupancy (59% up and 41% down) already after 1 h of E2 exposure. Although promoter proximal enrichment of RNAPII (PPEP) occurs frequently in MCF-7 cells (17%), it is only observed on a minority of E2-regulated genes (4%). Tamoxifen and fulvestrant partially reduce ERalpha DNA binding and prevent RNAPII loading on the promoter and coding body on E2-upregulated genes. Both ligands act differently on E2-downregulated genes: tamoxifen acts as an agonist thus downregulating these genes, whereas fulvestrant antagonizes E2-induced repression and often increases RNAPII occupancy. Furthermore, our data identify genes preferentially regulated by tamoxifen but not by E2 or fulvestrant. Thus (partial) antagonist loaded ERalpha acts mechanistically different on E2-activated and E2-repressed genes.

Downregulation of matrix Gla protein is a biomarker for tamoxifen-resistant and radioresistant breast cancer.

Aim: To establish downregulated biomarkers for cross-resistance for radiotherapy (RT) in tamoxifen (TAM)-resistant breast cancer cells. Materials & methods: RNA sequencing was performed on TAM and RT-resistant breast cancer cells. Breast cancer patient cohorts were queried in silico for associations between genes of interest and outcome after TAM treatment or irradiation. Results: 20 genes showed decreased expression in both TAM-resistant and RT-resistant breast cancer cells. Only matrix Gla protein in the primary tumor was associated with outcome after TAM treatment or RT in breast cancer patients. Conclusion: Matrix Gla protein is a biomarker for therapy sensitivity in breast cancer.