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-β, 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–activity relationship of fucoidan from the most promising seaweed species.

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.

The treatment of recurrent endometrial cancer is a challenge. Because of earlier treatments and the site of locoregional recurrence, in the vaginal vault or pelvis, morbidity can be high. A total of about 4 to 20% of the patients with endometrial cancer develop a locoregional recurrence, mostly among patients with locally advanced disease. The treatment options are dependent on previous treatments and the site of recurrence. Local and locoregional recurrences can be treated curatively with surgery or (chemo)radiotherapy with acceptable toxicity and control rates. Distant recurrences can be treated with palliative systemic therapy, i.e., first-line chemotherapy or hormonal therapy. Based on the tumor characteristics and molecular profile, there can be a role for immunotherapy. The evidence on targeted therapy is limited, with no approved treatment in the current guidelines. In selected cases, there might be an indication for local treatment in oligometastatic disease. Because of the novel techniques in radiotherapy, disease control can often be achieved at limited toxicity. Further studies are warranted to analyze the survival outcome and toxicity of newer treatment strategies. Patient selection is very important in deciding which treatment is of most benefit, and better prediction models based on the patient- and tumor characteristics are necessary.

Background: Fifteen percent of patients with endometrial cancer (EC) have advanced stage disease or develop a recurrence. Progestins have been applied as systemic treatment for decades, but there is limited evidence on response prediction with biomarkers and toxicity.Objectives: To review the response and toxicity of progestin therapy and stratify response to progesterone receptor (PR) expression and tumour grade.Search strategy: We used the search terms ‘Endometrial cancer’, ‘Progestins’, ‘Disease progression’, ‘Recurrence’ and related terms in Pubmed, Embase and Cochrane databases.Selection criteria: Studies on patients with advanced stage or recurrent EC treated with progestin monotherapy were included. Studies on adjuvant therapy, with fewer than ten cases and with sarcoma histology were excluded.Data collection and analysis: Evaluation for bias was performed with the Revised Cochrane RoB2 tool for randomised studies and the ROBINS‐I tool for non‐randomised studies. A random effects meta‐analysis was performed with the overall response rate (ORR), clinical benefit rate and toxicity as primary outcome measures.Main results: Twenty‐six studies (1639 patients) were included. The ORR of progestin therapy was 30% (95% CI 25–36), the clinical benefit rate was 52% (95% CI 42–61). In PR‐positive EC, the ORR was 55%, compared with 12% in PR‐negative disease (risk difference 43%, 95% CI 15–71). Severe toxicity occurred in 6.5%.Conclusions: Progestin therapy is a viable treatment option in patients with advanced stage and recurrent EC with low toxicity and high ORR in PR‐positive disease. The role of PR expression in relation to progression‐free survival and overall survival is unclear.

Around 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. To improve efficacy of hormonal therapy by relating immunohistochemical expression of estrogen (ER) and progesterone receptor (PR) and ER pathway activity scores to response to hormonal therapy. Patients with advanced or recurrent endometrial cancer and available biopsies taken prior to start of hormonal therapy, were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer (ENITEC) and the Dutch Gynecologic Oncology Group (DGOG). Tumor tissue was analyzed for ER and PR expression and ER pathway activity using a qPCR-based mRNA model to measure the activity of ER-related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using RECIST criteria. Secondary endpoints were clinical benefit rate and progression free survival. Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. All patients with a response (n=22/81, 27.2%) had ER and PR expression>50%, resulting in a response rate of 32.3% (95%-CI: 20.9-43.7%) for ER-expresion>50% and 50.0% (95%-CI: 35.2-64.8%) for PR-expression>50%. Clinical benefit rate was 56.9% for ER-expression>50% (95%-CI: 44.9-68.9%) and 75.0% (95%-CI: 62.2-87.8%) for PR-expression>50%. Application of the ER pathway test to cases with PR-expression>50%, resulted in a response rate of 57.6% (95%-CI: 42.1-73.1%). After 2 years of follow-up, 34.3% (95%-CI: 20-48%) of cases with PR-expression >50% and 35.8% (95%-CI: 20-52%) of cases with ER pathway activity score >15 had not progressed. Prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cut-off level for PR-IHC and by applying a sequential test algorithm using PR-IHC and ER pathway activity scores. Results need to be validated in the PROMOTE-prospective study.