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.

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.

Postchemotherapy Endometrioid to Gastrointestinal Histotype Shift in Recurrent Endometrial Carcinoma.

Herein, we report a case of low-grade endometrial endometrioid carcinoma recurred on the vaginal stump, which showed a complete histotype shift toward a gastrointestinal-type carcinoma after chemotherapy. The recurrent tumor increased in volume during chemotherapy. Postchemotherapy histologic examination showed a pure mucinous signet-ring cell pattern with positivity for cytokeratin 20 and CDX2, focal SATB2 expression and negativity for cytokeratin 7 and estrogen and progesterone receptors. Such features led to consider a diagnosis of metastasis from a primary carcinoma of the gastrointestinal tract. The accurate exclusion of any primary lesions of gastrointestinal and of other sites allowed identifying the tumor as the recurrent endometrial carcinoma. Our case highlights that chemotherapy may induce a histotype shift from endometrioid carcinoma to gastrointestinal-type carcinoma; such occurrence might be a mechanism of resistance and might provide new insights on the sensitiveness of different histotypes to systemic therapies. Considering the possibility of a shift from endometrioid to gastrointestinal-type carcinoma may be useful for a correct diagnosis and an appropriate patient management.

Real-life data on treatment and outcomes in advanced ovarian cancer: An observational, multinational cohort study (RESPONSE trial).

BACKGROUND: This study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer (OC). METHODS: This observational study collected real-world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III-IV) high-grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for ≥20 months. RESULTS: Of the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician-assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first-line chemotherapy after surgery. After ≥20 months of follow-up, 32.9% of the patients were disease-free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42-0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression-free survival (HR, 0.60; 95% CI, 0.41-0.84; p < .01). CONCLUSIONS: Women with advanced high-grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real-world population. LAY SUMMARY: Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high-grade serous or endometrioid OC could potentially be eligible for first-line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first-line PARPi maintenance treatment.

Adjuvant treatment in early-stage endometrial cancer: context-dependent impact of somatic CTNNB1 mutation on recurrence-free survival.

OBJECTIVE: The primary objective of this study was to determine whether women whose tumors harbor a somatic CTNNB1 mutation have longer recurrence-free survival if they receive traditional adjuvant therapy strategies compared with those who do not. METHODS: A retrospective, stage I endometrial cancer cohort from MD Anderson Cancer Center was assessed. Clinical and pathological characteristics and type of adjuvant therapy (cuff brachytherapy, pelvic radiation, chemotherapy) were obtained by review of medical records. CTNNB1 exon 3 sequencing was performed. Summary statistics were calculated, and recurrence-free survival was measured using the Kaplan-Meier product-limit estimator. RESULTS: The analysis included 253 patients, 245 with information regarding adjuvant therapy. Most patients had tumors of endometrioid histology (210/253, 83%) with superficial myometrial invasion (197/250, 79%) and no lymphatic/vascular space invasion (168/247, 68%). Tumor CTNNB1 mutations were present in 45 (18%) patients. Patients receiving adjuvant therapy were more likely to have higher-grade tumors, non-endometrioid histology, deep myometrial invasion, and lymphatic/vascular invasion. For patients with low-risk features not receiving adjuvant therapy, the presence of CTNNB1 mutation did not significantly impact recurrence-free survival (11.3 years wild-type vs 8.1 years mutant, p=0.65). The cohort was then limited to intermediate-risk tumors, defined as endometrioid histology of any grade with deep myometrial invasion and/or lymphatic/vascular space invasion. When recurrence-free survival was stratified by CTNNB1 mutation status and adjuvant therapy, patients with CTNNB1 mutations and no adjuvant therapy had the shortest recurrence-free survival at 1.6 years, followed by patients with CTNNB1 mutations who received adjuvant therapy (4.0 years), and wild-type CTNNB1 with and without adjuvant therapy (8.5 and 7.2 years, respectively) (comparison for all four groups, p=0.01). CONCLUSION: In patients with intermediate-risk endometrioid endometrial cancers, the use of adjuvant therapy was associated with an improvement in recurrence-free survival for patients with tumor mutations in CTNNB1.

Hormonal therapy or chemotherapy for early-stage, low-grade endometrial cancer with malignant peritoneal cytology: A comparative effectiveness study.

OBJECTIVE: To examine trends, characteristics, and outcomes related to hormonal therapy (HT) or chemotherapy (CT) use for early-stage, low-grade endometrial cancer with malignant peritoneal cytology (MPC). METHODS: This is a comparative effectiveness study querying the National Cancer Database from 2010 to 2017. Study population was 2730 women with stage I grade 1-2 endometrioid endometrial cancer who had MPC at primary hysterectomy. Patients were stratified based on postoperative therapy as: CT (n = 348, 12.7%), HT (n = 112, 4.1%), and neither two (n = 2270, 83.2%). Outcome measures included (i) trends and characteristics related to adjuvant therapy, assessed with a multivariable logistic regression model, and (ii) overall survival (OS) assessed with a multivariable Cox proportional hazards regression model. RESULTS: The number of women who received HT (2.7% to 4.5%) or no adjuvant systemic therapy (81.8% to 84.4%) increased while CT use decreased (15.5% to 11.1%)(P = 0.04). In a multivariable analysis, HT use was associated with older age, more recent year of diagnosis, grade 1 lesions, treatment at academic/research facilities, performance of minimally invasive surgery, no lympho-vascular space invasion, and absence of radiotherapy compared to CT use (P < 0.05). Neither HT (adjusted-hazard ratio [aHR] 0.61, 95% confidence interval [CI] 0.27-1.40) nor CT (aHR 1.33, 95% CI 0.92-1.93) were associated with OS compared to no adjuvant systemic therapy. In the low-risk group (stage IA, grade 1-2 tumors, and no lympho-vascular space invasion; n = 1453), 69 (4.7%) women received HT and 117 (8.1%) received CT. OS was similar across the three groups (P = 0.89). CONCLUSION: There was an increasing utilization of HT and decreasing utilization of CT as adjuvant therapy for early-stage, low-grade endometrial cancer with MPC. These two adjuvant therapies were not associated with short-term OS compared to neither two.

Fertility sparing treatment in patients with endometrial cancer (FERT-ENC): a multicentric retrospective study from the Spanish Investigational Network Gynecologic Oncology Group (SPAIN-GOG).

OBJECTIVE: The primary objective was to evaluate the response rate of conservative treatment for endometrial cancer, and the secondary objective was to assess oncological, fertility and obstetric outcomes in patients who underwent fertility preservation treatment. MATERIAL AND METHODS: This multicentre, observational, retrospective study evaluated endometrial cancer patients who underwent fertility-sparing treatment in Spanish centres between January 2010 and January 2020. Seventy-three patients with stage IA endometrioid adenocarcinoma of the uterus were included in the study. RESULTS: The levonorgestrel intrauterine device (LNG-IUD) was the most common fertility-sparing treatment (53.4%), followed by megestrol acetate (20.5%) and medroxyprogesterone acetate (16.4%). During the 24-month follow-up period, the rate of complete response to fertility-sparing management was 74% (n = 54), and 8.2% (n = 6) of patients presented a partial response. Additionally, 13 (17.8%) patients presented with persistent disease and six (8.2%) relapsed after response. The LNG-IUD was associated with a higher complete response rate than the other methods (87.2 vs. 58.8%; p = 0.01). Surgical treatment (at least hysterectomy) was performed in 44 (60.3%) patients as the end of fertility-sparing treatment. Four (5.5%) patients presented relapse after surgery, associated with final FIGO stage III (p = 0.036), myometrial invasion > 50% (p = 0.018) and final tumour grade 2-3 (p = 0.018). The mean follow-up period was 57.8 (range 6-159) months. The 5-year relapse-free survival and overall survival rates were 92.6% [95% CI (81.3, 97.2)] and 93.5% [95% CI (80.7, 97.9)], respectively. During follow-up, three patients (4.1%) died of the disease after completion of surgical treatment. Up to 50.7% of patients included in the study attempted to get pregnant. Of these, the rate of pregnancy was 81.1% (n = 30/37), and reproductive techniques were used for this purpose in 78.4% of cases. CONCLUSIONS: Fertility-sparing management presented a high response rate in patients with endometrial cancer. LNG-IUD was associated with a better response rate compared to the other treatment options. Moreover, in patients using this management method, pregnancy could be achieved using reproductive techniques.

Survey on Reporting of Endometrial Biopsies From Women on Progestogen Therapy for Endometrial Atypical Hyperplasia/Endometrioid Carcinoma.

Histologic assessment of response to progestogen therapy is a cornerstone of nonsurgical management of atypical hyperplasia/low-grade endometrioid carcinoma. Pathologists are required to assess whether there is ongoing preneoplastic or neoplastic change in the biopsies (often multiple) taken during therapy. There have been few studies documenting the specific histologic changes induced by therapeutic progestogens and currently there are no guidelines on terminology used in this scenario. Given the need for uniformity in reporting and the lack of guidance in the current literature, we initiated an online survey (including questions, categories of reporting, and scanned slides for assessment) which was sent to all members of British Association of Gynaecological Pathologists (BAGP) and the International Society of Gynecological Pathologists (ISGyP) with the aim to assess the variability among pathologists in reporting these specimens and to come up with a consensus-based terminology for reporting of endometrial biopsies from women on progestogen therapy for endometrial atypical hyperplasia/endometrioid carcinoma. In total, 95 pathologists participated in this survey. This manuscript elaborates on the results of the survey with recommendations aimed at promoting uniform terminology in reporting these biopsies.