Oral nano-formulations for endocrine therapy of endometrioid adenocarcinomas.

Endometrial cancer is one of the three major malignant tumors of the reproductive system that threaten women's lives and health. The incidence of this disease is on the rise globally. Most cases of endometrial cancer comprise endometrioid adenocarcinomas, whose treatment is challenged by factors such as their high recurrence rate and the need to preserve fertility among young patients. Thus, oral endocrine therapy has become the main treatment modality. The main drugs used in oral endocrine therapy are progestins, selective estrogen receptor antagonists, and aromatase inhibitors. However, their clinical use is hindered by their low solubility and low oral utilization. The rapid development of nanotechnology allows the combination of these drugs with oral nano-formulations to create a good carrier. Such nanocarriers, including nanospheres, nanocapsules, and micelles can protect the drug against clearance and increase the site specificity of drug delivery. This paper reviews the pathogenesis of endometrioid endometrial cancer (EEC) and oral nano-formulations for endocrine therapy.

Preclinical evaluation of avutometinib and defactinib in high-grade endometrioid endometrial cancer.

BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts. METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage. RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts. CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

Stage IC grade 1 endometrioid adenocarcinoma of the ovary: assessment of post-operative chemotherapy de-escalation.

OBJECTIVE: Given limited real-world practice data evaluating the National Comprehensive Cancer Network clinical practice guidelines for possible post-operative chemotherapy omission as a treatment option for patients with stage IC grade 1 endometrioid ovarian carcinoma, this population-based study examined the association between post-operative chemotherapy and overall survival in this tumor group. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results program was retrospectively queried. The study population was 1207 patients with stage IC grade 1-3 endometrioid ovarian carcinoma who received primary cancer-directed surgery from 2007 to 2020. Overall survival was assessed with multivariable Cox proportional hazard regression model. RESULTS: The median age was 52, 54, and 55 years for grade 1, 2, and 3 groups, respectively (p=0.02). Grade 1 and 2 tumors were more common than grade 3 tumors (n=508 (42.1%), n=493 (40.8%), and n=206 (17.1%), respectively). Chemotherapy use rate for grade 1 tumors was lower compared with grade 2-3 tumors (67.9%, 76.5%, and 78.6%, respectively, p<0.001). When nodal evaluation was performed for grade 1 tumors, among patients who did not receive post-operative chemotherapy and among those who did, 5-year overall survival rate exceeded 90% (93.3% and 96.0%, respectively), with statistically non-significant hazard estimates (adjusted hazard ratio (aHR) 1.54, 95% CI 0.63 to 3.73). In contrast, post-operative chemotherapy omission for patients who did not undergo nodal evaluation was associated with decreased overall survival (5-year rates 82.3% vs 96.0%, aHR 5.41, 95% CI 1.95 to 15.06). Results were similar for node-evaluated grade 2 tumors (5-year overall survival rates, 94.6% and 94.4% for node-evaluated post-operative chemotherapy omission and administration, respectively), but not in grade 3 tumors. CONCLUSION: The results of this population-based study may partially support the current clinical practice guidelines for post-operative chemotherapy omission as a possible option for patients with stage IC grade 1 endometrioid adenocarcinoma of the ovary for those who had lymph node evaluation. Observed data were also supportive for node-evaluated grade 2 tumors, warranting further evaluation.

Update on the oncologic and obstetric outcomes of medroxyprogesterone acetate treatment for atypical endometrial hyperplasia and endometrial cancer.

AIMS: To evaluate the safety and effectiveness of high-dose oral medroxyprogesterone acetate (MPA) therapy as a fertility-sparing treatment for patients diagnosed with atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1 without myometrial invasion (G1EC). Particular attention was given to the extended administration and readministration of MPA for patients with persistent disease following initial treatment and those with recurrence. METHODS: We conducted a retrospective analysis of data from 79 patients who underwent daily oral MPA treatment between 2005 and 2024 at Nagoya University Hospital. Patient characteristics, treatment outcomes, factors contributing to recurrence, and post-MPA therapy pregnancies were examined. RESULTS: MPA therapy achieved a remarkable complete response (CR) rate of 91.1%. The median time to achieve CR was 26.0 and 40.0 weeks for AEH and G1EC patients, respectively. Importantly, 27 patients (39.7%) attained CR after more than 6 months of treatment, including 8 patients (11.8%) who achieved CR after more than a year of treatment. The recurrence rates were 52.9% for AEH and 64.7% for G1EC. Twenty eight patients resumed MPA treatment, and 23 achieved second CR. Notably, recurrence was not associated with clinical factors such as age, body mass index, or post-CR pregnancy. Among patients who attempted pregnancy after achieving CR, 22 live births were successfully achieved. CONCLUSIONS: High-dose oral MPA therapy demonstrated both safety and efficacy for preserving fertility in patients with AEH and G1EC, resulting in a high CR rate. MPA extension and readministration proved to be beneficial strategies for managing patients with recurrence and persistent disease following initial treatment.

Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer.

OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.

Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

Predicting Progestin Therapy Response With PTEN, PAX2, and ß-Catenin in Patients With Endometrioid Precancer.

This study investigates the predictive value of biomarkers PTEN, PAX2, and ß-catenin for therapeutic outcomes in patients with atypical endometrial hyperplasia or endometrioid intraepithelial neoplasia undergoing progestin therapy. In a retrospective study of 128 patients, we analyzed a total of 351 endometrial biopsy samples and categorized outcomes into responders (absence of residual disease) and nonresponders (presence of residual disease). We found aberrant biomarker expression in pretreatment cases: 48% for PTEN, 65% for PAX2, and 36% for ß-catenin. Approximately 77.3% of patients responded to progestin treatment, with nonresponders showing significantly higher initial PTEN loss (75.86% vs 39.79%, P < 0.001). Nonresponders also demonstrated significant PTEN loss (53.33% vs 20.55%, P < 0.001), PAX2 loss (57.33% vs 41.22%, P < 0.05), and ß-catenin nuclear staining (53.45% vs 27.91%, P < 0.01) in follow-up samples. In addition, nonresponders exhibited lower recovery of intact PTEN and PAX2, along with higher ß-catenin aberrancy in cases initially showing normal ß-catenin levels. We conclude that persistent aberrant PTEN and PAX2 expression, coupled with emerging aberrant ß-catenin in follow-ups, indicates a greater likelihood of treatment failure. Conversely, the absence of these aberrations suggests successful progestin therapy. Our findings highlight the utility of this 3-marker panel in assessing residual disease status and predicting progestin treatment outcomes, thus offering critical insights for patient management.

The promise of combining CDK4/6 inhibition with hormonal therapy in the first-line treatment setting for metastatic or recurrent endometrial adenocarcinoma.

Metastatic or recurrent endometrioid adenocarcinoma of the uterine corpus is often incurable with limited treatment options. First-line treatment often includes cytotoxic chemotherapy, which incurs significant toxicities for many patients. Endometrial cancer, specifically endometrioid cancer, is a hormone-sensitive disease and, while single-agent hormonal therapies have demonstrated clinical benefit, resistance to these agents often leads to the use of chemotherapy. There is a lack of approved endocrine treatment options in the metastatic setting for most recurrent endometrial cancers, representing an unmet clinical need. Emerging evidence suggests that hormonal therapy in combination with other targeted treatments, such as cyclin dependent kinase (CDK)4/6 inhibitors, is well tolerated and effective in select patient populations. We discuss the clinical evidence suggesting that the combination of CDK4/6 inhibitors and hormonal therapy has the potential to represent an important addition to the first-line treatment options for patients with low-grade advanced or recurrent endometrial cancer.

Endometrioid adenocarcinoma of the rectovaginal septum: A case report. / é˜´é“ç›´è‚ éš”å­å®«å† è†œæ ·è ºç™Œ1例.

Primary endometrioid adenocarcinoma of the rectovaginal septum is rare. Its pathogenesis is not clear and there is no standard treatment. One patient with endometrioid adenocarcinoma of the rectovaginal septum arising from deep infiltrative endometriosis was admitted to Qingdao Municipal Hospital. The patient presented with incessant menstruation and abdominal distension. She had bilateral ovarian endometriotic cystectomy 6 years ago. Imaging findings suggested a pelvic mass which might invade the rectovaginal septum. Pathological results of primary surgery confirmed endometrioid carcinoma of the pelvic mass arising from the rectovaginal septum. Then she had a comprehensive staged surgery. Postoperative chemotherapy was given 6 times. No recurrence or metastasis was found during the 2-year follow-up. The possibility of deep infiltrating endometriosis and its malignant transformation should be considered in the differential diagnosis of a new extragonadal pelvic lesion in a patient with a history of endometriosis, which would avoid misdiagnosis and missed diagnosis.

Evolving treatment paradigms in metastatic or recurrent low-grade endometrial cancer: When is hormonal-based therapy the preferred option?

Endometrial cancer is the most common gynecologic malignancy in developed countries, with increasing incidence and mortality rates worldwide. While most cases are successfully treated with surgery, first-line treatment options for metastatic or recurrent endometrial cancer involve significant toxicities. Imprecise classification of heterogeneous subgroups further complicates treatment decisions and interpretation of clinical trial results. Recent advances in molecular classification are guiding treatment decisions for metastatic or recurrent endometrial cancers. Integrating molecular characteristics with traditional clinicopathology can both reduce overtreatment or undertreatment and help guide the appropriate choice of therapies and effective design of future studies. Here we discuss the treatment of metastatic or recurrent low-grade endometrioid adenocarcinoma of the uterine corpus, which is distinct from high-grade tumors histologically, molecularly, and in treatment response.

A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283.

OBJECTIVE: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. METHODS: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. RESULTS: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. CONCLUSIONS: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.

LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer.

Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in the regulation of HR repair in endometrioid epithelial ovarian cancer (eEOC) model. We show that DNA damage leads to direct interaction of LCK with the HR repair proteins RAD51 and BRCA1 in a kinase dependent manner RAD51 and BRCA1 stabilization. LCK expression is induced and activated in the nucleus in response to DNA damage insult. Disruption of LCK expression attenuates RAD51, BRCA1, and BRCA2 protein expression by hampering there stability and results in inhibition of HR-mediated DNA repair including suppression of RAD51 foci formation, and augmentation of γH2AX foci formation. In contrast LCK overexpression leads to increased RAD51 and BRCA1 expression with a concomitant increase in HR DNA damage repair. Importantly, attenuation of LCK sensitizes HR-proficient eEOC cells to PARP inhibitor in cells and pre-clinical mouse studies. Collectively, our findings identify a novel therapeutic strategy to expand the utility of PARP targeted therapy in HR proficient ovarian cancer.

The survival impact of adjuvant radiotherapy and chemotherapy in patients with non-endometrioid endometrial carcinomas: a PSM-IPTW analysis based on SEER database.

PURPOSE: To investigate outcomes of adjuvant treatments for non-endometrioid endometrial carcinomas (NEEC), as previous studies are limited by its rarity and heterogeneity. PATIENTS AND METHODS: Patients with endometrial serous carcinoma (SC), clear cell carcinoma (CCC) and carcinosarcoma were identified between 2004 and 2018 from SEER database. Propensity score matching (PSM) along with inverse probability treatment weighting (IPTW) technique were employed to balance confounding factors. Multivariate, exploratory subgroup and sensitivity analyses were conducted to evaluate the impact of adjuvant treatment on overall survival (OS) and cause-specific survival (CSS). RESULTS: The cohort comprised 5577 serous, 977 clear cell, and 959 carcinosarcomas. Combined chemotherapy and radiotherapy (CRT), chemotherapy alone, and radiotherapy alone were respectively administered in 42.21%, 47.27% and 10.58% of the whole cohort. Prior to adjusting, chemotherapy plus brachytherapy yielded the most beneficial effect among various strategies. After PSM-IPTW adjustment, CRT still demonstrated beneficial effect on OS and CSS. Subgroup analysis indicated CRT improved survival among various TNM stages, particularly with uterine carcinosarcoma. In the sensitivity analyses for serous histology, brachytherapy with or without chemotherapy appeared to benefit stage I-II patients. In stage III-IV SC patients, chemotherapy plus brachytherapy was still associated with improved survival outcomes. When nodal metastases were identified, additional external beam radiotherapy (EBRT) to CT was more utilized with survival improvement. CONCLUSION: In NEEC patients, combined CRT yielded beneficial effects than any single mode. Both chemotherapy and brachytherapy promoted survival in early stage SC patients. Late stage SC patients may benefit from chemotherapy plus either EBRT or brachytherapy.

Microenvironmental elements singularity synergistically regulate the behavior and chemosensitivity of endometrioid carcinoma.

The importance of the microenvironment is widely recognized as it regulates not only malignant cell behavior but also drug sensitivity. The cancer cell microenvironment is composed of biological, physical and chemical elements, and simultaneous reproduction of these three elements are important conditions investigated in cancer research. In the present study, we focused on the epidemiological and anatomical specificities of endometrioid carcinoma, obesity (biological), fluid flow (physical) and anticancer agents (chemical) to target the specific microenvironmental elements of endometrioid carcinoma. To elucidate the individual effects of these elements on endometrioid carcinoma and to investigate the relationships between these factors, we developed an adipose tissue fragments (ATFs)-embedded cell disc under a rotational culture method to generate carcinoma-stroma interactions and to create fluid flow. ATFs and fluid flow individually or synergistically influenced proliferative cellular behavior and the morphological changes underlying endometrioid carcinoma. ATFs and fluid flow also governed the expression of extracellular signal-regulated kinase and p38 signaling synergistically or individually, depending on the endometrioid carcinoma cell type. Adipose tissue induced chemoresistance to cis-diamminedichloro-platinum (CDDP) in endometrioid cancer, but the resistance effect was abolished by fluid flow. Thus, a simple reconstructed model was established to investigate three elements of the microenvironment of endometrioid carcinoma in vitro. This culture model unequivocally demonstrated the individual and synergistic effects of the three elements on endometrioid carcinoma. This new culture model is a promising tool for elucidating the mechanisms underlying endometrioid carcinoma and for developing further treatment strategies.

Clinical outcomes of levonorgestrel-releasing intrauterine device present during controlled ovarian stimulation in patients with early stage endometrioid adenocarcinoma and atypical endometrial hyperplasia after fertility-sparing treatments: 10-year experience in one tertiary hospital in China.

BACKGROUND: To evaluate the oncologic and pregnancy outcomes of patients with early stage endometrioid adenocarcinoma (EMC) and atypical endometrial hyperplasia (AEH) treated with controlled ovarian stimulation (COS) with or without levonorgestrel-releasing intrauterine device (LNG-IUD) after fertility-sparing treatment (FSTs). METHODS: A total of 67 patients with EMC or AEH who achieved complete response after FSTs and underwent COS between January 2010 and December 2019 were retrospectively reviewed. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for recurrence after COS. RESULTS: The average age was 32.9 ± 3.46 years. 23.9 % of these patients relapsed after COS during the follow-up period. The 2-year cumulative recurrence rate was 14.9 % (9.1 % and 20.6 % in the LNG-IUD and control groups, respectively). Compared with the control group, the recurrence rate was lower in patients with LNG-IUDs present during COS (12.1 % vs 35.5 %, p = 0.027). The clinical pregnancy (42.4 % vs 52.9 %, p = 0.392) and live birth (21.2 % vs 29.4 %, p = 0.444) rates were similar between the LNG-IUD and control groups. Age, body mass index (BMI), histology, FST type and time to complete response were not related to prognosis after COS. After adjusting for age and BMI in a multivariate Cox regression model, the use of LNG-IUD during COS was a favorable factor for better oncologic outcomes after COS (HR 0.263, 95 %CI 0.084-0.822, p = 0.022). CONCLUSIONS: Patients with early stage EMC and AEH treated with assisted reproductive technology after FSTs might benefit from LNG-IUDs present during COS.

Quantification of Women Who Could Benefit from Hormone Therapy after Endometrial Cancer Treatment: An Analysis of SEER Data.

Our primary aim was to estimate the magnitude of stage I endometrial cancer (EC) survivors that could benefit from hormonal therapy (HT). Our secondary aims were to assess EC incidence in women below 50 and below 60 over the years, and analyze the overall survival and any influencing factors. We analyzed the endometrioid EC data from the Surveillance, Epidemiology, and End Results (SEER) program according to women's age, tumor stage, and grade. We analyzed the proportions of EC survivors below 50 and below 60 years of age and stratified those age groups by race. For age distribution and survival analysis SEER, 18 registries' research data (2000-2018) were analyzed. We analyzed the SEER 12 registries' research data (1992-2019) for incidence time trends. Our investigation found a 14% and 40% cumulative prevalence of stage I EC that occurs in women below 50 or 60 years, respectively. EC's prevalence has progressively risen in recent decades, but cancer-specific mortality remains low. The increasing number of women affected by EC in premenopause or early postmenopause face an 18 years-survival rate of 96.86% and 95.73%, respectively. A significant proportion of low-grade EC survivors can potentially benefit from HT treatment, and this requires awareness of other aspects of their health or quality of life, in addition to cancer treatments.

Chemotherapy plus radiotherapy vs. radiotherapy alone in high-risk endometrioid endometrial carcinoma.

OBJECTIVE: Adding chemotherapy to radiotherapy in patients with high-risk endometrioid endometrial cancer (EEC) remains controversial, particularly in stages I-II. We aimed to investigate the effect of treatment modalities on survival in high-risk EEC patients. PATIENTS AND METHODS: Patients with high-risk EEC were evaluated retrospectively between 2010 and 2019. Patients who did not receive adjuvant treatment were excluded. We included seventy patients and formed two groups: patients who received radiotherapy (RT) alone and those who received chemotherapy and radiotherapy (CT and RT). RESULTS: The median follow-up time was 60.3 months (8.0-143.5). 38.5% of the patients had relapsed. Recurrence-free survival (RFS) rates were 97. 1%, 68.3% , and 60.8% at 12-, 36-, and 60-month, respectively. Overall survival rates were 97.1%, 80.6%, and 72.6% at 12-, 36-, and 60-month, respectively. Hematological adverse events and neuropathy were more common in the CT and RT group than in the RT group. Multivariate Cox regression analysis for RFS revealed that the FIGO stage and treatment modalities were statistically independent factors (p=0.031 and p=0.040, respectively). Stage stratified log-rank test revealed that adding chemotherapy improved RFS in patients with stage III (p=0.020) but not in stage I-II disease (p=0.725). The number of chemotherapy cycles administered (≤4 vs. >4) did not affect survival in all patients and stage III disease (p=0.497, and p=0.436, respectively). CONCLUSIONS: Adding chemotherapy to radiotherapy may be considered in high-risk stage III EEC. Further studies are needed to determine the optimal duration of chemotherapy.

Characterization of HCI-EC-23 a novel estrogen- and progesterone-responsive endometrial cancer cell line.

Most endometrial cancers express the hormone receptor estrogen receptor alpha (ER) and are driven by excess estrogen signaling. However, evaluation of the estrogen response in endometrial cancer cells has been limited by the availability of hormonally responsive in vitro models, with one cell line, Ishikawa, being used in most studies. Here, we describe a novel, adherent endometrioid endometrial cancer (EEC) cell line model, HCI-EC-23. We show that HCI-EC-23 retains ER expression and that ER functionally responds to estrogen induction over a range of passages. We also demonstrate that this cell line retains paradoxical activation of ER by tamoxifen, which is also observed in Ishikawa and is consistent with clinical data. The mutational landscape shows that HCI-EC-23 is mutated at many of the commonly altered genes in EEC, has relatively few copy-number alterations, and is microsatellite instable high (MSI-high). In vitro proliferation of HCI-EC-23 is strongly reduced upon combination estrogen and progesterone treatment. HCI-EC-23 exhibits strong estrogen dependence for tumor growth in vivo and tumor size is reduced by combination estrogen and progesterone treatment. Molecular characterization of estrogen induction in HCI-EC-23 revealed hundreds of estrogen-responsive genes that significantly overlapped with those regulated in Ishikawa. Analysis of ER genome binding identified similar patterns in HCI-EC-23 and Ishikawa, although ER exhibited more bound sites in Ishikawa. This study demonstrates that HCI-EC-23 is an estrogen- and progesterone-responsive cell line model that can be used to study the hormonal aspects of endometrial cancer.

The present status of metformin in fertility-preserving treatment in atypical endometrial hyperplasia and endometrioid endometrial cancer.

Progestin therapy is the main fertility-sparing treatment for women with endometrial cancer (EC) and atypical endometrial hyperplasia (AEH). However, still 15-25% of these women failed to achieve complete response (CR) and then lost their fertility after definitive surgery. Metformin has been demonstrated to play an anti-cancer role in multiple cancers including EC. Several studies also suggested metformin had potential benefit in improving the therapeutic outcome of fertility-preserving treatment alongside with progestin. This review has discussed existed evidence regarding the effect of metformin combined with progestin for women with AEH and EC who desire childbearing. Nevertheless, the therapeutic effect of metformin varied in different studies due to the high heterogeneity in the patient's characteristics, the inconsistency in dose and treatment duration of metformin, the combined use of hysteroscopy, the insufficient sample size and underpowered study-design. Therefore, care should be taken when interpreting the current results on this issue. Till now, there is still no strong evidence supporting the use of metformin in fertility-preserving treatment in AEH and EEC patients. Further research is needed to provide high-quality data to validate the role of metformin as adjunctive therapy alongside with progestin to preserve fertility for AEH and EEC patients.