Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer

Inhibidores de la aromatasa; Terapia de progestinaAromatase inhibitors; Progestin therapyInhibidors de l'aromatasa; Teràpia amb progestinaBackground Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy. Objective This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy. Study Design Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction–based messenger RNA model to measure the activity of estrogen receptor–related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival. Results Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9–43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2–64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9–68.9) and 75.0% (95% confidence interval, 62.2–87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1–73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20–48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20–52) with an estrogen receptor pathway activity score of >15 had not progressed. Conclusion The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study

Anti-estrogen Treatment in Endometrial Cancer: A Systematic Review

Introduction: Hormonal therapy in endometrial cancer (EC) is used for patients who wish to preserve fertility and for patients with advanced or recurrent disease in a palliative setting. First line hormonal therapy consists of treatment with progestins, which has a response rate of 25% in an unselected population. Treatment with anti-estrogens is an alternative hormonal therapy option, but there is limited data on the effect and side-effects of anti-estrogens in EC. Therefore, we performed a systematic review to investigate the response rate and toxicity of anti-estrogenic therapy in patients with endometrial cancer.Methods: A systematic search in electronic databases was performed to identify studies on selective estrogen receptor modulators (SERM) and down-regulators (SERD) and aromatase inhibitors that reported on response rates (RR) among EC patients. Outcome in estrogen receptor (ER) positive and negative disease was assessed independently.Results: Sixteen studies on advanced stage and recurrent EC were included. Ten studies investigated anti-estrogen monotherapy and seven investigated a combination of anti-estrogenic drugs with either progestin or targeted treatment. Due to heterogeneity in patient population, no meta-analysis was performed. The median age of the patients in the included studies ranged from 61 to 71 years and the proportion of low grade tumors ranged from 38 to 80%. The RR for tamoxifen ranged from 10 to 53%, for other SERMs and SERDs 9–31%, for aromatase inhibitors from 8 to 9%, for combined tamoxifen/progestin treatment 19–58%, for combined chemo- and hormonal therapy 43% and for combination of anti-estrogenic treatment with mammalian target of rapamycin (mTOR) inhibitors 14–31%. Toxicity consisted mainly of nausea and thrombotic events and was higher in combination therapy of chemotherapy and hormonal therapy and hormonal therapy and mTOR inhibitors compared to other therapies.Conclusion: Tamoxifen or a combination of tamoxifen and progestin should be the preferred choice when selecting second line hormonal treatment because the RRs are similar to first line progestin treatment and the toxicity is low. The response can be optimized by selecting patients with endometrioid tumors and positive estrogen receptor status, which should be based on a pretreatment biopsy

Impact of body mass index and fat distribution on sex steroid levels in endometrial carcinoma: A retrospective study

Background Obesity is an important cause of multiple cancer types, amongst which endometrial cancer (EC). The relation between obesity and cancer is complicated and involves alterations in insulin metabolism, response to inflammation and alterations in estradiol metabolism. Visceral obesity is assumed to play the most important role in the first two mechanisms, but its role in estradiol metabolism is unclear. Therefore, this retrospective study explores the relationship of body mass index (BMI), visceral fat volume (VAV) and subcutaneous fat volume (SAV) and serum levels of sex steroids and lipids in patients with endometrial cancer. Methods Thirty-nine postmenopausal EC patients with available BMI, blood serum and Computed Tomography (CT) scans were included. Serum was analyzed for estradiol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, cholesterol, triglycerides and high (HDL), low (LDL) and non-high density (NHDL) lipoprotein. VAV and SAV were quantified on abdominal CT scan images. Findings were interpreted using pearson correlation coefficient and linear regression with commonality analysis. Results Serum estradiol is moderately correlated with BMI (r = 0.62) and VAV (r = 0.58) and strongly correlated with SAV (r = 0.74) (p < 0.001 for all). SAV contributes more to estradiol levels than VAV (10.3% for SAV, 1.4% for VAV, 35.9% for SAV and VAV, p = 0.01). Other sex steroids and lipids have weak and moderate correlations with VAV or SAV. Conclusions This study shows that serum estradiol is correlated with BMI and other fat-distribution measures in postmenopausal endometrial cancer patients. Subcutaneous fat tissue contributes more to the estradiol levels indicating that subcutaneous fat might be relevant in endometrial cancer carcinogenesis.publishedVersio

Immunohistochemical biomarkers are prognostic relevant in addition to the ESMO-ESGO-ESTRO risk classification in endometrial cancer

Endometrial carcinoma; Immunohistochemistry; OutcomeCarcinoma de endometrio; Inmunohistoquímica; ResultadoCarcinoma d'endometri; Immunohistoquímica; ResultatObjective Pre-operative immunohistochemical (IHC) biomarkers are not incorporated in endometrial cancer (EC) risk classification. We aim to investigate the added prognostic relevance of IHC biomarkers to the ESMO-ESGO-ESTRO risk classification and lymph node (LN) status in EC. Methods Retrospective multicenter study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), analyzing pre-operative IHC expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER) and progesterone receptor (PR), and relate to ESMO-ESGO-ESTRO risk groups, LN status and outcome. Results A total of 763 EC patients were included with a median follow-up of 5.5-years. Abnormal IHC expression was present for p53 in 112 (14.7%), L1CAM in 79 (10.4%), ER- in 76 (10.0%), and PR- in 138 (18.1%) patients. Abnormal expression of p53/L1CAM/ER/PR was significantly related with higher risk classification groups, and combined associated with the worst outcome within the ‘high and advanced/metastatic’ risk group. In multivariate analysis p53-abn, ER/PR- and ESMO-ESGO-ESTRO ‘high and advanced/metastatic’ were independently associated with reduced disease-specific survival (DSS). Patients with abnormal IHC expression and lymph node metastasis (LNM) had the worst outcome. Patients with LNM and normal IHC expression had comparable outcome with patients without LNM and abnormal IHC expression. Conclusion The use of pre-operative IHC biomarkers has important prognostic relevance in addition to the ESMO-ESGO-ESTRO risk classification and in addition to LN status. For daily clinical practice, p53/L1CAM/ER/PR expression could serve as indicator for surgical staging and refine selective adjuvant treatment by incorporation into the ESMO-ESGO-ESTRO risk classification

Poor outcome in hypoxic endometrial carcinoma is related to vascular density

Background Identification of endometrial carcinoma (EC) patients at high risk of recurrence is lacking. In this study, the prognostic role of hypoxia and angiogenesis was investigated in EC patients. Methods Tumour slides from EC patients were stained by immunofluorescence for carbonic anhydrase IX (CAIX) as hypoxic marker and CD34 for assessment of microvessel density (MVD). CAIX expression was determined in epithelial tumour cells, with a cut-off of 1%. MVD was assessed according to the Weidner method. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Kaplan–Meier curves and Cox regression analysis. Results Sixty-three (16.4%) of 385 ECs showed positive CAIX expression with high vascular density. These ECs had a reduced DSS compared to tumours with either hypoxia or high vascular density (log-rank p = 0.002). Multivariable analysis showed that hypoxic tumours with high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002), DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). Conclusions This study has shown that adverse outcome in hypoxic ECs is seen in the presence of high vascular density, suggesting an important role of angiogenesis in the metastatic process of hypoxic EC. Differential adjuvant treatment might be indicated for these patients.publishedVersio

Fucoidan Structure and Activity in Relation to Anti-Cancer Mechanisms

Fucoidan is a natural derived compound found in different species of brown algae and in some animals, that has gained attention for its anticancer properties. However, the exact mechanism of action is currently unknown. Therefore, this review will address fucoidans structure, the bioavailability, and all known different pathways affected by fucoidan, in order to formulate fucoidans structure and activity in relation to its anti-cancer mechanisms. The general bioactivity of fucoidan is difficult to establish due to factors like species-related structural diversity, growth conditions, and the extraction method. The main pathways influenced by fucoidan are the PI3K/AKT, the MAPK pathway, and the caspase pathway. PTEN seems to be important in the fucoidan-mediated effect on the AKT pathway. Furthermore, the interaction with VEGF, BMP, TGF-&beta;, and estrogen receptors are discussed. Also, fucoidan as an adjunct seems to have beneficial effects, for both the enhanced effectiveness of chemotherapy and reduced toxicity in healthy cells. In conclusion, the multipotent character of fucoidan is promising in future anti-cancer treatment. However, there is a need for more specified studies of the structure&ndash;activity relationship of fucoidan from the most promising seaweed species

Trends over time in the incidence and use of hormonal therapy in endometrial cancer:a population-based study in the Netherlands

Item does not contain fulltextINTRODUCTION: According to current guidelines, hormonal therapy may be applied in endometrioid type endometrial cancer as an alternative to surgery for fertility preservation and in medically unfit patients. Since it is unknown how often hormonal therapy is applied, the objective of this study was to investigate trends over time in hormonal therapy use in the background of the overall incidence of endometrial cancer. METHODS: All patients with endometrial cancer (n=48 222) registered in the Netherlands Cancer Registry in the period 1989-2018 were included. European age-standardized incidence rates with corresponding estimated annual percentage change were calculated to describe trends in the incidence of endometrial cancer. The use of hormonal therapy was analyzed in the three periods 1989-1998, 1999-2008, and 2009-2018 for the following sub-groups: primary and adjuvant therapy, International Federation of Gynecology and Oncology (FIGO) stage I-II and III-IV, and by age group. RESULTS: The European age-standardized incidence rate of endometrioid endometrial cancer peaked in 2004 with a significant increase from 1989 to 2004 (annual percentage change 0.55; 95% CI 0.10 to 0.99, p=0.020) and a subsequent decrease from 2005 to 2018 (annual percentage change -1.79; 95% CI -2.28 to -1.31, p<0.001). The incidence rate of non-endometrioid type endometrial cancer increased significantly in the study period. Hormonal therapy was used in 1482 (3.5%) patients with endometrioid endometrial cancer. Among patients with FIGO stage I aged ≤40 years, hormonal therapy increased from 0% in 1989-1998 to 27% in 2009-2018. Primary hormonal treatment increased from 175 patients (5.5%) to 329 patients (7.8%) in those aged ≥75 years. Adjuvant hormonal treatment was mostly used in advanced stage endometrial cancer. CONCLUSIONS: The use of primary hormonal therapy in endometrioid type endometrial cancer increased over time in patients aged ≤40 years and among elderly patients. The observed trends in the current use of hormonal therapy support the need to study the effect of hormonal treatment in elderly patients and as adjuvant treatment in advanced stage endometrial cancer