Estradiol metabolites as biomarkers of endometrial cancer prognosis after surgery

Abstract

Endometrial cancer (EC) is the most common gynecologic malignancy prevailing after menopause. Defining steroid profiles may help predict the risk of recurrence after hysterectomy, which remains limited due to the lack of reliable markers. Adrenal precursors, androgens, parent estrogens and catechol estrogen metabolites were measured by mass spectrometry (MS) in preoperative serums and those collected one month after hysterectomy from 246 newly diagnosed postmenopausal EC cases. We also examined the associations between steroid hormones and EC status by including 110 healthy postmenopausal women. Steroid concentrations were analyzed in relation to clinicopathological features, recurrence and overall survival (OS). The mean follow-up time was 65.5 months and 26 patients experienced relapse after surgery for a recurrence incidence of 10.6% (6.4% Type I and 29.5% Type II). Recurrence and OS were related to a more aggressive disease but not linked to body mass index. Preoperative levels of estriol (E) and estrone-sulfate (E-S) were inversely associated with recurrence in a multivariate logistic regression analysis (Hazard ratios (HRs) of 0.31, P=0.039 and 3.01, P=0.024; respectively). All circulating steroids declined considerably after surgery almost reaching those of healthy women, except 4-methoxy-E (4MeO-E) for which postoperative levels increased by 35% and were associated to a 68% decreased risk of recurrence (HR=0.32, P=0.015). Women diagnosed with both histological types of EC present significantly higher levels of steroids, in support of their mitogenic effects. The estrogen precursor E-S, the anticancer metabolite 4MeO-E, and E that exert mixed antagonist and agonist estrogenic activities and immunological effects, are potential independent prognostic factors.

Identification of metabolomic biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women

“…These have been associated with EC and breast cancer progression, supporting the role of bradykinin in tumors originating from steroid sensitive tissues (39,40). Sulfated androgens were also higher in type I EC cases, consistent with the reported implication of sulfated steroids in this histotype (8,(41)(42)(43)(44). Furthermore, our data identified heme as a putative biomarker of type II EC and highlighted modifications in pathways closely related to heme synthesis, namely the tetrahydrofolate-serine/glycine pathway (45).…”

“…Bile acids contribute to cholesterol homeostasis, a precursor of the steroids that drive the development and progression of this histological type of EC (10). Recently, we showed that higher levels of circulating steroids are linked to an increased risk of recurrence (43). Numerous enzymatic pathways are involved in the conversion of both bile acids and steroids, including reduction by aldo-keto reductases (49), conjugation by uridine diphospho-glucuronosyltransferases (50), sulfotransferases (51), and sulfatase (52).…”

Identification of Metabolomic Biomarkers for Endometrial Cancer and Its Recurrence after Surgery in Postmenopausal Women

“…Bile acids contribute to cholesterol homeostasis, a precursor of the steroids that drive the development and progression of this histological type of EC ( 10 ). Recently, we showed that higher levels of circulating steroids are linked to an increased risk of recurrence ( 43 ). Numerous enzymatic pathways are involved in the conversion of both bile acids and steroids, including reduction by aldo-keto reductases ( 49 ), conjugation by uridine diphospho-glucuronosyltransferases ( 50 ), sulfotransferases ( 51 ), and sulfatase ( 52 ).…”

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

“…Overall, EC has a good prognosis with 78% of patients achieving 10-year survival [ 1 ]. Currently, our only methods of determining which patients are more likely to suffer poor outcomes include clinicopathological features such as tumour grade, histological subtype and clinical stage [ 2 ]. Hysterectomy with or without adjuvant radiotherapy is curative for most patients.…”

“…Hysterectomy with or without adjuvant radiotherapy is curative for most patients. However, a small subset of patients will develop a disease recurrence that fails to respond to chemotherapy and thus experience shorter survival [ 2 ]. This group has proven difficult to identify at diagnosis, therefore a novel prognostic marker may be of particular benefit for these patients.…”