Low-grade Endometrioid Endometrial Cancer Research Articles

Tailoring postoperative management through sentinel lymph node biopsy in low- and intermediate-risk endometrial cancer - the SENTRY clinical trial.

While total hysterectomy and bilateral salpingo-oophorectomy without lymph node staging are standard for low- and intermediate-risk endometrial cancer, certain histopathologic factors revealed after surgery can necessitate additional interventions. Our study assessed the influence of sentinel lymph node biopsy on postoperative decision-making. In the SENTRY trial (July 2021 - February 2023), we enrolled patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IA-IB low-grade endometrioid endometrial cancer. Laparoscopic sentinel lymph node mapping using indocyanine green was performed alongside total hysterectomy with bilateral salpingo-oophorectomy. Subsequent management changes based on sentinel lymph node biopsy results were evaluated. The trial was registered at ClinicalTrials.gov (NCT04972682). Of the 100 enrolled participants, a bilateral detection rate of 91% was observed with a median detection time of 10 min (interquartile range 8-13 min). Sentinel lymph node metastases were found in 8% (N = 8) of participants. Postoperative FIGO staging increased in 15% (N = 15) and decreased in 5% (N = 5) of patients. Sentinel lymph node biopsy results altered the adjuvant treatment plan for 20% (N = 20): external beam radiotherapy was omitted in 12% (N = 12) while 6% (N = 6) had external beam radiotherapy +/- systemic chemotherapy added due to sentinel lymph node metastases. In 2% (N = 2), the external beam radiotherapy field was expanded with the paraaortic region. No intraoperative complications were reported and no 30-day major morbidity and mortality occurred. Throughout a median follow-up of 14 (95% CI 12-15 months, neither patient-reported lymphedema nor pelvic recurrence surfaced in the cohort. Sentinel lymph node biopsy using indocyanine green is a safe procedure and allows tailoring adjuvant therapy in presumed low- and intermediate-risk endometrial cancer. It assists in avoiding external beam radiotherapy overtreatment and introducing additional modalities when necessary.

Abstract 4126: The inhibitory effect of statins on distant metastasis and recurrence of endometrial cancer

Abstract Endometrial cancer (EC) is the most common gynecologic malignancy. The most common histological type is endometrioid endometrial cancer (EEC). While the majority of patients present with early-stage and low-grade EEC and have an excellent prognosis, a subset develops distant recurrence derived from EEC after initial treatment of the primary. However, the exact mechanism of distant metastasis and recurrence from EEC is still unclear. In addition, the lack of suitable pre-clinical models is a significant barrier to research for distant metastasis and recurrent cancer derived from EEC. Our preclinical EEC model, the ablation of both Mig-6 and Pten in the uterus (Pgrcre/+Mig-6f/fPtenf/f; Mig-6d/dPtend/d), dramatically accelerates the development of EEC compared to single ablation of either gene. The ablation of both Mig-6 and Pten in the uterus (Pgrcre/+Mig-6f/f Ptenf/f; Mig-6d/dPtend/d mice) displayed distant metastases into the ovary, diaphragmatic skeletal muscle, lymph node, and lung. However, the Ptend/d mice exhibited endometrial cancer without distant metastases. After hysterectomy of EEC confined to uterus, Mig-6d/dPtend/d mice exhibited recurrent EEC in abdomen and lung. To identify prognostic factors for distant metastatic and recurrent EEC, we performed transcriptomic analysis in endometrial hyperplasia, a precancerous condition, from Ptend/d and Mig-6d/dPtend/d mice. Our transcriptomic analysis identified that cholesterol biosynthesis was the most significantly activated pathway in Mig-6d/dPtend/d mice compared to Ptend/d mice. Statins, also known as HMG-CoA reductase inhibitors, are the most common cholesterol-lowering drugs. We evaluated the effect of atorvastatin on tumorigenesis and recurrence of EEC. Mig-6d/dPtend/d mice treated with atorvastatin displayed significant reduction of tumor size compared to vehicle treated group. For vehicle-treated group, our pathological analysis revealed EEC outside the uterus, therefore EEC had disseminated to involve the ovary, diaphragmatic skeletal muscle, lymph node, and lung. However, EEC was confined to the uterus in the atorvastatin treated group. Furthermore, atorvastatin treatment reduced the rate of recurrent EEC development. This data demonstrated that atorvastatin has a remarkable inhibitory effect on metastasis and recurrence of EEC in Mig-6d/d Ptend/d mice. Our results suggest that statins suppress development of distant metastasis and recurrence in mouse models of EEC with Pten and Mig-6 deficiency by inhibiting cholesterol biosynthesis. Citation Format: Keun Cheon Kim, Jung Yoon Yoo, Russell R Broaddus, Eunhee M Jeong, Mark I Hunter, Tae Hoon Kim, Jae-Wook Jeong. The inhibitory effect of statins on distant metastasis and recurrence of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4126.

Incidence of sentinel lymph node metastases in apparent early-stage endometrial cancer: a multicenter observational study

ObjectiveUltrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected...

Aberrant nuclear β-catenin distribution does not prognosticate recurrences of endometrioid endometrial cancers – A retrospective single-institutional study

ObjectiveAberrant β-catenin distribution has been theorized as a predictive biomarker for recurrence in early stage, low grade endometrioid endometrial cancer. MethodsThis retrospective single-institution cohort study reviewed 410 patients with endometrial cancer from May 2018 to May 2022. Only endometrioid histology was included. Demographic and clinicopathological data were collected from the medical records. Univariate and multivariate logistic regressions, and sensitivity analyses for early stage, low grade and no specific molecular profile (NSMP) tumors were performed. Results297 patients were included for analysis. Most patients were over 60 years old, White, and with a BMI >30 and early stage low grade disease. Aberrant β-catenin distribution was found in 135 patients (45.5%) and wild type membranous β-catenin distribution in 162 (54.5%). While TP53 mutation correlated with endometrial cancer recurrence in this cohort (OR = 4.78), aberrant β-catenin distribution did not correlate in the overall population (OR = 0.75), the early stage low grade cancers (OR = 0.84), or the NSMP group (OR = 1.41) on univariate or multivariate analysis. No correlation between β-catenin distribution and local (OR = 0.61) or distant recurrences (OR = 0.90) was detected. ConclusionsAberrant β-catenin distribution did not significantly correlate with recurrence in endometrioid endometrial cancer, nor in the early stage, low grade and NSMP sub-cohorts.

Abstract 2470: ARG1 is potential prognostic biomarker for development of distant metastatic endometrial cancer in mice with Pten deficiency

Abstract Endometrial cancer is the most common gynecologic malignancy. The most common histological type is endometrioid endometrial cancer (EEC). While the majority of patients present with early-stage and low-grade EEC and have an excellent prognosis, a subset has metastatic disease at presentation, or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EEC is a critical barrier. We have developed a genetically engineered mouse model for metastatic EEC that implicates coexistent Pten and Mig-6 mutations in EEC. Pten mutation in the uterus is not sufficient for distant metastasis, but mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers including ovarian carcinoma, colorectal cancer, and neuroblastoma. In the present study, ARG1 expression was evaluated with immunohistochemistry in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. Our immunostaining analysis revealed that the expression of ARG1 in early stage of EEC from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. High levels of ARG1 are associated with distant metastatic endometrial cancer. The results demonstrate that a high level of ARG1 is associated with poor prognosis in association with EEC of mouse. ARG1 has the potential to identify patients that require additional treatment at an early stage of endometrial cancer. Citation Format: Jae-Wook Jeong, Dinh Tran, Valery Rozen, Tae Hoon Kim, Jung-Yoon Yoo. ARG1 is potential prognostic biomarker for development of distant metastatic endometrial cancer in mice with Pten deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2470.

Can the microcystic, elongated and fragmented pattern of invasion influence the evaluation of the depth of myometrial invasion in low-grade endometrioid endometrial cancer using imaging techniques?

Objectives: The microcystic, elongated and fragmented pattern of invasion can be associated with an underestimation of the depth of myometrial invasion by imaging techniques. We aimed to evaluate the influence of microcystic, elongated and fragmented pattern of invasion in the diagnostic performance of transvaginal ultrasound scan and magnetic resonance imaging for the prediction of the depth of myometrial invasion in low-grade endometrioid endometrial carcinomas. Methods: Prospective and consecutive study including all low-grade (G1-G2) endometrioid endometrial carcinomas diagnosed between October 2013 and July 2018 in a tertiary hospital. Preoperative staging was performed with transvaginal ultrasound scan and/or magnetic resonance imaging followed by surgical staging. Final histology was considered as the reference standard. Sensitivity, specificity and diagnostic accuracy for the prediction of depth of myometrial invasion was calculated for both imaging techniques. The STARD 2015 guidelines were used. Results: A total of 136 patients were consecutively included. Transvaginal ultrasound scan was performed in 132 patients and magnetic resonance imaging in 119 patients. The diagnostic accuracy of transvaginal ultrasound scan for the prediction of depth of myometrial invasion in the microcystic, elongated and fragmented negative group (82% (95% confidence interval = 73–88)) was higher compared to the microcystic, elongated and fragmented positive group (61% (95% confidence interval = 36–83)). The diagnostic accuracy of magnetic resonance imaging was also higher in the microcystic, elongated and fragmented negative group (80% (95% confidence interval = 71–87)) compared to the microcystic, elongated and fragmented positive (47% (95% confidence interval = 21–73)). Conclusions: In low-grade endometrioid endometrial carcinomas with a positive microcystic, elongated and fragmented pattern of invasion, the evaluation of the depth of myometrial invasion using transvaginal ultrasound scan and magnetic resonance imaging may be underestimated.

The impact of lymphovascular space invasion on survival in early stage low-grade endometrioid endometrial cancer

BackgroundThe lymphovascular space invasion (LVSI) is suggested as a prognostic factor for endometrial cancer in many studies, but it has not yet been employed in FIGO staging system. The present study was aimed to evaluate the impact of LVSI on survival in patients with early stage endometrioid endometrial cancer.MethodsThis retrospective cohort was conducted on early stage endometrial cancer patients who underwent surgical staging [total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO)] and omental biopsy at Referral Teaching Hospitals of Tehran from 2005 to 2021. Patient’s age, menopause status, tumor grade, tumor size, depth of myometrial invasion, LVSI and lower segment involvement were recorded. Data were analyzed with SPSS 22.Results415 patients with stage I and grade 1–2, endometrioid endometrial cancer were analyzed. 100 patients (24.1%) were LVSI-positive. 3-year and 5-year survival rates were 97.1% and 88.9%, respectively. Recurrence occurred in 53 patients (12.8%). 3-year overall survival rates in LVSI-negative and LVSI-positive were 98.7% and 92%. These rates for 5-year survival were 92.1% and 79%, respectively. Recurrence rates in LVSI-negative were 8.9% while it was 25% in LVSI-positive cases. Multivariate analysis showed that LVSI has significant correlation with 3-year and 5-year overall survival rates.ConclusionsLVSI in early stage endometrial cancer significantly and independently influences 3-year and 5-year survival rates and acts as a strong prognostic factor in these patients. LVSI should be implemented in endometrial cancer staging systems due to its significant correlation with cancer recurrence rates and 5-year survival rates.

Evidence-based guidelines increase uptake and decrease racial disparities in endometrioid endometrial cancer patients electing ovarian preservation (573)

Objectives: To evaluate trends over time and identify demographic factors associated with the pursuit of ovarian preservation before and after implementing evidence-based guidelines among endometrioid endometrial cancer patients aged ≤50 years, treated at a single institution. Methods: In December 2018, evidence-based institutional guidelines were introduced detailing when to offer ovarian preservation for low-grade endometrioid endometrial cancer patients. The guidelines included patients aged 50 or younger, patients who desire to preserve hormonal function, normal-appearing ovaries on preoperative imaging, no family history of hereditary breast and ovarian cancer syndrome, and no personal history of hormone receptor-positive malignancy. Trends in ovarian preservation over time were examined, with the Cochran-Armitage trend test p-value was reported. Associations between choosing ovarian preservation and age, body mass index classification (normal, overweight, obese), race/ethnicity, marital status, and insurance type, before and after guideline implementation, were compared using the Wilcoxon rank-sum and Fisher’s exact tests. Results: From January 2010, 420 women aged <50 years underwent staging surgery for endometrioid endometrial cancer, and 355 (85%) met the criteria for ovarian preservation; 267 before and 88 after guideline introduction. Patients qualifying for ovarian preservation were significantly more likely to choose ovarian preservation after guideline implementation (43%) versus before guideline implementation (18%) (p<0.001, Figure 1). Before guideline introduction, 12% (17/144) of White women elected ovarian preservation compared with 28% (23/82) of non-White women (p=0.003). Similarly, 13% (25/196) of women aged >40 years elected ovarian preservation compared with 44% (31/71) of women aged <40 years (p<0.001). There were no differences in ovarian preservation rates by obesity status (p=0.68), marital status (p=0.86), or insurance type (p=0.53). After guideline introduction, 36% of White (14/39) and 50% of non-White (15/30) women chose ovarian preservation (p=0.33). Eighteen of 56 (32%) women aged >40 years elected ovarian preservation compared with 24/32 (75%) women aged <40 years (p<0.001). There were no differences in ovarian preservation rates by obesity status (p=0.19), marital status (p=0.45), or insurance type (p>0.99). Conclusions: Implementation of ovarian preservation guidelines for women with endometrial cancer aged <50 years increased rates of ovarian preservation over time. After guideline implementation, there were fewer demographic differences in patients electing ovarian preservation. Objectives: To evaluate trends over time and identify demographic factors associated with the pursuit of ovarian preservation before and after implementing evidence-based guidelines among endometrioid endometrial cancer patients aged ≤50 years, treated at a single institution. Methods: In December 2018, evidence-based institutional guidelines were introduced detailing when to offer ovarian preservation for low-grade endometrioid endometrial cancer patients. The guidelines included patients aged 50 or younger, patients who desire to preserve hormonal function, normal-appearing ovaries on preoperative imaging, no family history of hereditary breast and ovarian cancer syndrome, and no personal history of hormone receptor-positive malignancy. Trends in ovarian preservation over time were examined, with the Cochran-Armitage trend test p-value was reported. Associations between choosing ovarian preservation and age, body mass index classification (normal, overweight, obese), race/ethnicity, marital status, and insurance type, before and after guideline implementation, were compared using the Wilcoxon rank-sum and Fisher’s exact tests. Results: From January 2010, 420 women aged <50 years underwent staging surgery for endometrioid endometrial cancer, and 355 (85%) met the criteria for ovarian preservation; 267 before and 88 after guideline introduction. Patients qualifying for ovarian preservation were significantly more likely to choose ovarian preservation after guideline implementation (43%) versus before guideline implementation (18%) (p<0.001, Figure 1). Before guideline introduction, 12% (17/144) of White women elected ovarian preservation compared with 28% (23/82) of non-White women (p=0.003). Similarly, 13% (25/196) of women aged >40 years elected ovarian preservation compared with 44% (31/71) of women aged <40 years (p<0.001). There were no differences in ovarian preservation rates by obesity status (p=0.68), marital status (p=0.86), or insurance type (p=0.53). After guideline introduction, 36% of White (14/39) and 50% of non-White (15/30) women chose ovarian preservation (p=0.33). Eighteen of 56 (32%) women aged >40 years elected ovarian preservation compared with 24/32 (75%) women aged <40 years (p<0.001). There were no differences in ovarian preservation rates by obesity status (p=0.19), marital status (p=0.45), or insurance type (p>0.99). Conclusions: Implementation of ovarian preservation guidelines for women with endometrial cancer aged <50 years increased rates of ovarian preservation over time. After guideline implementation, there were fewer demographic differences in patients electing ovarian preservation.

Demographic shifts associated with implementation of evidence-based guidelines for ovarian conservation in patients with endometrioid endometrial cancer

ObjectiveIn 2018, evidence-based surgical guidelines were introduced to identify appropriate patients with low-grade endometrioid endometrial cancer for ovarian conservation. We sought to identify trends and demographic shifts associated with guideline...

Delayed time to surgery with hormonal treatment does not adversely impact outcomes in women with low-grade endometrioid endometrial cancer

<h3>Objectives:</h3> Longer wait times from diagnosis of low grade endometrioid endometrial cancer to treatment is associated with decreased overall survival. LNG-IUD therapy or systemic progesterone therapy can be reasonable options for conservative management of early-grade, uterus confined endometrial cancer in patients who wish to delay definitive surgical management. We sought to determine if delaying surgical treatment with progestin therapy adversely affected grade and stage of cancer at time of surgery. <h3>Methods:</h3> The Tumor Registries at a county and university hospital were used to perform a retrospective chart review of patients diagnosed with endometrial cancer from 2009 to 2017. Those with grade 1 or grade 2 endometrioid endometrial adenocarcinoma on EMB or D&C were included. Exclusion criteria included cervical involvement, imaging suggestive of metastatic disease, or completed surgical treatment prior to presentation for care. Patients were grouped into four cohorts: surgery within 42 days of diagnosis (S, n=65), surgery after 42 days (DS, n=52), delayed surgery after progestin therapy (DS+H, n=20), and progestin therapy alone (H, n=21). A one-way ANOVA test and two-tailed t-test were performed to determine whether cohorts differed demographically or in regard to grades and stages. <h3>Results:</h3> 158 patients met inclusion criteria. In total, average age at diagnosis was 55.30 years, average BMI was 39.22, and average Charlton Comorbidity Index (CCI) was 3.97. There was a difference in average age between the S v DS+H (p=0.002, 58.4 v 46.8) and DS v DS+H (p=0.009, 56.6 vs 46.8) cohorts. There was a difference in average BMI between the S vs DS+H (p=0.005, 35.9 vs 42.7) and S v H (p=0.01, 35.9 vs 46.4) cohorts. There were no differences in CCI scores between groups (p=0.25) (Figure 1). There were no differences between the cohorts in regard to initial grade (p=0.36), grade at surgery (p=0.75), grade change between initial diagnosis and surgical specimen (p=0.47), or surgical stage (p=0.52). <h3>Conclusions:</h3> Delayed time to surgery with progestin treatment does not result in stage progression or change in grade. Patients treated with hormones tended to be younger and with higher BMIs. Temporary progestin therapy should be considered if delaying surgical treatment for women with corpus confined low grade endometrioid endometrial cancer.

Effect of progestin therapy on steroid receptor status and cellular proliferation in low-grade endometrial adenocarcinoma

<h3>Objectives:</h3> Low grade endometrioid endometrial cancer is a hormone sensitive disease however little is known about the role of steroid receptors in the development or treatment of disease. Our objective was to determine if steroid receptor status, or change in receptor status, predicts response to progesterone therapy in women with early stage, low grade endometrial cancer. <h3>Methods:</h3> A retrospective cohort of women was identified who underwent primary progesterone therapy for treatment of grade 1 endometrial adenocarcinoma. Steroid receptor (SR) status as well as Ki-67 expression was assessed with immunohistochemistry on pre- and post-treatment formalin fixed paraffin embedded biopsy specimens. Automated image analysis on digitized immunostained slides was performed. Estrogen Receptor (ER), Progesterone Receptor (PR), Androgen Receptor (AR) and Glucocorticoid Receptor (GR) were scored with an H-score and Ki-67 was reported as percent positive. Clinical and pathologic variables, including response to progesterone therapy were collected. SR levels and clinical characteristics were compared using paired t- and Fischer exact tests. <h3>Results:</h3> Fourteen women were included in this analysis, the majority of whom (13/14) had a progestin IUD for treatment of their carcinoma and the majority (9/14) were non-surgical candidates due to medical co-morbidities. Eight women had resolution of adenocarcinoma and six women did not have a response to therapy. Median treatment duration was 4.8 months (range 3.3 – 9.3). Responders were more likely to be younger and pre-menopausal. Two patients had mismatch repair deficient tumors, neither responded to progestin therapy. Both ER and PR declined significantly after progestin treatment (median H-score pre vs post for ER 183 vs 104, p=0.013; PR 110 vs 40, p<.001). GR levels increased (23 vs 47, p=0.003). AR demonstrated variable response. Neither pre-treatment, post-treatment, nor change in SR levels were associated with response to progestin therapy. Women with a response to therapy had lower Ki-67 levels prior to treatment compared to women who did not respond to therapy (26% vs 39%, p=0.033). <h3>Conclusions:</h3> Both ER and PR levels declined during progestin treatment in primary low grade endometrial adenocarcinoma suggesting a negative feedback loop from PR to ER signaling at the level of protein expression. Neither pre-treatment SR levels, nor change in SR receptor status predicted a response to progestin therapy which suggests more complex context-specific interactions of SRs and their ligands. Pre-treatment cellular proliferation as a biomarker for response to hormonal therapy warrants further study.

Change in practice in gynecologic oncology during the COVID-19 pandemic: a social media survey.

ObjectiveCOVID-19 has affected gynecologic cancer management. The goal of this survey was to evaluate changes that occurred in gynecologic oncology practice during the COVID-19 pandemic.MethodsA anonymous survey consisting of 33 questions (https://sites.google.com/view/gyncacovidfmartinelli) regarding interaction between gynecologic cancers and COVID-19 was distributed online via social media from April 9 to April 30, 2020. Basic descriptive statistics were applied. Analytics of survey-diffusion and generated-interest (visualizations, engagement rates, response rate) were analyzed.ResultsThe survey received 20 836 visualizations, generating an average engagement rates by reach of 4.7%. The response rate was 30%. A total of 86% of respondents completed the survey, for a total of 187 physicians surveyed across 49 countries. The majority (143/187; 76%) were gynecologic oncologists, and most were ≤50 years old (146/187; 78%). A total of 49.7% (93/187) were facing the early phase of the COVID-19 pandemic, while 26.7% (50/187) and 23.5% (44/187) were in the peak and plateau phases, respectively. For 97.3% (182/187) of respondents COVID-19 affected or changed their respective clinical practice. Between 16% (27/165) (before surgery) and 25% (26/102) (before medical treatment) did not perform any tests to rule out COVID-19 infection among patients. The majority of respondents did not alter indications of treatment if patients were COVID-19-negative, while treatments were generally postponed in COVID-19-positive patients. Treatments were considered priority for: early stage high-risk uterine cancers (85/187; 45%), newly diagnosed epithelial ovarian cancer (76/187; 41%), and locally advanced cervical cancer (76/187; 41%). Treatment of early stage low-grade endometrioid endometrial cancer was deferred according to 49% (91/187) of respondents, with hormonal treatment as the option of therapy (31%; 56/178). A total of 77% (136/177) of respondents reported no changes in (surgical) treatment for early stage cervical cancer in COVID-19-negative patients, while treatment was postponed by 54% (96/177) of respondent, if the patient tested COVID-19-positive. Neoadjuvant chemotherapy for advanced ovarian cancers was considered by over one-third of respondents as well as hypofractionation of radiation treatment for locally advanced cervical cancers.ConclusionCOVID-19 affected the treatment of gynecologic cancers patients, both in terms of prioritization and identification of strategies to reduce hospital access and length of stay. Social media is a reliable tool to perform fast-tracking, worldwide surveys.

Role of the pathologist in assessing response to treatment of ovarian and endometrial cancers.

Standardisation of pathological evaluation of tissue responses to therapy permits robust stratification of patient outcomes for management decisions and allows comparison of results across clinical trials. In gynaecological pathology there are two major areas where pathological assessment of treatment response is currently used to determine ongoing therapy. High-grade serous carcinoma (HGSC) of tubo-ovarian origin frequently presents as high-stage disease and may be managed by neoadjuvant chemotherapy with debulking surgery. The chemotherapy response score (CRS) is a reproducible, validated three-tiered morphological scoring system to assess the response of HGSC to treatment. Interobserver agreement is shown to be substantial following online training, and women with CRS3 have significantly improved progression-free and overall survival. Low-grade endometrioid endometrial cancer and atypical hyperplasia/endometrioid intraepithelial neoplasia may be managed by progestogenic therapy in women who wish to preserve fertility or for whom medical co-morbidities preclude surgical management. The response to treatment is assessed histologically in successive endometrial biopsies. The histological parameters are well described, but the pathological classification of treatment response is still under development. Pathological assessment of the response to treatment is incorporated into clinical guidelines.

The association between histological subtype of a first primary endometrial cancer and second cancer risk.

To evaluate the risk of a second primary cancer after endometrial cancer according to histological subtype. Using data from the 13 National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries we identified women diagnosed with a primary endometrial cancer between 1992 and 2014. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for second primary cancer risk (all anatomical sites combined and for individual anatomical sites) among patients with endometrial cancer compared with the general population, in the overall study population and according to histological subtype. Among 96 256 women diagnosed with endometrial cancer, 8.4% (n=8083) developed a second primary cancer. The risk of second primary cancer was higher among patients with endometrial cancer than in the general population (SIR=1.05, 95% CI 1.03 to 1.07). We observed significantly higher second primary cancer risk among women with high grade endometrioid (SIR=1.12, 95% CI 1.05 to 1.19), serous (SIR=1.24, 95% CI 1.11 to 1.38), carcinosarcoma (SIR=1.18, 95% CI 1.02 to 1.35), mixed epithelial (SIR=1.22, 95% CI 1.06 to 1.40), and sarcoma (SIR=1.28, 95% CI 1.12 to 1.45) compared with the general population, but not for women with low grade endometrioid (SIR=1.01, 95% CI 0.98 to 1.03) or clear cell (SIR=1.09, 95% CI 0.88 to 1.33) endometrial cancer. Women with low grade endometrioid endometrial cancer had significantly lower second primary cancer risks in the gum and other mouth (SIR=0.57, 95% CI 0.30 to 0.97), lung and bronchus (SIR=0.72, 95% CI 0.66 to 0.77), and lymphocytic leukemia (SIR=0.71, 95% CI 0.54 to 0.93) while women with high risk endometrial cancer histological subtypes experienced significantly higher second primary cancer risk at several anatomical sites. Risk of developing second primary cancersat all anatomic sites combined and at individual anatomical sites varied according to histological subtype. Clinicians should be aware that women with different histological subtypes carry different second primary cancer risks .

Durable response in a woman with recurrent low-grade endometrioid endometrial cancer and a germline BRCA2 mutation treated with a PARP inhibitor

A 42-year-old woman with a germline BRCA2 mutation and recurrent low-grade endometrioid endometrial adenocarcinoma experienced clinical and radiographic response to the poly (ADP ribose) polymerase (PARP) inhibitor, olaparib. Molecular and treatment factors are discussed.

Prognosis and treatment of positive peritoneal cytology in early endometrial cancer: matched cohort analyses from the National Cancer Database

While positive peritoneal cytology is no longer included among the endometrial cancer staging criteria, Federation International de Gynecologie et Obstetrique recommends continued collection of pelvic washings for cytology to produce additional data that may be used to determine the significance of positive cytology for prognosis and treatment of endometrial cancer. The objectives of the study was to validate that positive cytology is a predictor of decreased survival in early endometrial cancer and to test whether adjuvant chemotherapy for positive cytology is associated with increased survival. We performed an observational retrospective cohort analysis of the 2010-2013 National Cancer Database including women with cytology status and Federation International de Gynecologie et Obstetrique stage IA-II endometrial cancer. Overall cohort and matched cohort survival analyses were performed with and without imputation of missing data. We also performed survival analyses of women with positive cytology grouped by chemotherapy exposure. Multivariable Cox proportional-hazards regressions were performed to adjust for possible confounders. A variety of sensitivity analyses, including robustness of results to possible unmeasured confounding, were reported. A total of 16,851 women including 953 with positive cytologywere included. Four-year overall survival was 79.5% (range, 76.2-83.0%) for women with stage I/II with positive cytology vs 92.2% (range, 91.5-92.9%), 83.3% (range, 81.6-84.9%), and 86.8% (range, 85.1-88.5%) for stage IA, IB, and II with negative cytology, respectively (P≤ .001). Positive cytology was associated with decreased survival (hazard ratio [95% confidence interval], 1.85 [range, 1.54-2.21], P<.001). For women with Federation International de Gynecologie et Obstetrique grade 1/2 endometrioid adenocarcinoma, the hazard of death associated with positive cytology was similar (hazard ratio [95% confidence interval], 1.85 [1.28-2.67], P < .001). Use of adjuvant chemotherapy by women with positive cytology was associated with increased survival (hazard ratio [95% confidence interval], 0.62 [0.40-0.95], P= .03). Positive peritoneal cytology was associated with decreased overall survival of women with Federation International de Gynecologie et Obstetrique stage I/II endometrial cancer, including low-grade endometrioid endometrial cancer. Treatment of women with stage I/II endometrial cancer and positive cytology with adjuvant chemotherapy was associated with increased survival.

Exploring Morphologic and Molecular Aspects of Endometrial Cancer Under Progesterone Treatment in the Context of Fertility Preservation.

The standard treatment of early-stage (FIGO [International Federation of Gynecology and Obstetrics] I) endometrioid endometrial cancer (EEC) is hysterectomy with bilateral salpingo-oophorectomy. An alternative approach for younger women with low-grade EEC who wish to preserve fertility may be hormonal treatment. Previous studies have suggested that progesterone may elicit its antitumor effect in EEC by interacting with the Wingless (Wnt) and/or phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Therefore, we explored whether common activating genetic alterations in Wnt and PI3K/Akt signaling correlated with nonresponsiveness to progesterone therapy for low-grade EEC. In addition, we investigated whether benign morphology under progesterone treatment is accompanied by the absence of genetic changes. We analyzed molecular alterations in the Wnt and PI3K/Akt signaling in 84 serial endometrial samples from 11 premenopausal patients with progesterone receptor-positive low-grade EEC conservatively treated with progesterone and correlated these with histological and clinical follow-up. There were 6 responders and 5 nonresponders to progesterone treatment. The response rate to progesterone treatment was 55%, and the relapse rate was 83%. All responders had alterations in both the Wnt and PI3K/Akt pathway before treatment. In the nonresponder group, tumors inconsistently showed alterations in none, 1, or both pathways. Normalization of the endometrium morphology under progesterone treatment is accompanied by the absence of the genetic changes found in the specimen before treatment. We found that activating molecular alterations in either Wnt or PI3K/Akt signaling pathways did not predict resistance to progesterone treatment. It seems that morphological response goes along with disappearance of the established mutations. This exploratory study suggests that Wnt or PI3K/Akt status is unable to predict response to progesterone treatment in patients with EEC.

Prognostic value of p53 expression in early stage low grade endometrioid endometrial cancer.

e16510 Background: Low grade endometrioid EC is the most common subtype and is usually estrogen dependent and associated with mutations in PTEN. Overexpression of p53 correlates with poor prognosis...

Loss of LKB1 in high-grade endometrial carcinoma: LKB1 is a novel transcriptional target of p53.

Liver kinase B1 (LKB1) is a serine/threonine kinase that functions as a tumor suppressor and regulates cell polarity, proliferation, and metabolism. Mutations in LKB1 are associated with Peutz-Jeghers syndrome as well as sporadic cervical and lung cancers. Although LKB1-null mice develop invasive endometrial cancers, the role and regulation of LKB1 in the pathogenesis of human endometrial cancer are not well defined and are the focus of these studies. LKB1 protein and messenger RNA (mRNA) expression levels were evaluated in high-grade and low-grade endometrioid endometrial cancer (EEC) and cell lines by reverse transcriptase-polymerase chain reaction analysis, Western blot analysis, and immunohistochemistry. Mutational and promoter analyses of the LKB1 gene (serine/threonine kinase 11 [STK11]) were performed to identify the mechanisms that contribute to the loss of LKB1 in high-grade EEC. Analysis of the LKB1 gene in low-grade and high-grade EECs revealed no genetic mutations, suggesting that alterations in LKB1 transcription may be responsible for LKB1 protein loss in high-grade EEC. Analysis of the LKB1 promoter revealed 4 putative tumor protein 53 (p53) binding sites. Quantitative chromatin immunoprecipitation demonstrated that p53 bound directly to 1 of these sites and increased LKB1 promoter activity 140-fold. LKB1 promoter activity, mRNA, and protein levels were suppressed after silencing of p53 with small interfering RNA and were elevated in cells that overexpressed p53. Levels of p53 mRNA and protein expression were decreased in high-grade EEC and were positively correlated with LKB1 protein levels (Spearman correlation, r=0.601; P<.001). LKB1 is a direct transcriptional target of p53. The loss of wild-type p53 in high-grade EEC may contribute to the LKB1 loss observed in these more aggressive tumors.

Serum HE4 as a prognostic marker in endometrial cancer — A population based study

ObjectiveHE4 has emerged as a promising biomarker in gynaecological oncology. The purpose of this study was to evaluate serum HE4 as a biomarker for high-risk phenotypes in a population-based endometrial cancer cohort. MethodsPeri-operative serum HE4 and CA125 were measured in 373 patients identified from the prospective Australian National Endometrial Cancer Study (ANECS). HE4 and CA125 were quantified on the ARCHITECT instrument in a clinically accredited laboratory. Receiver operator curves (ROC), Spearman rank correlation coefficient, and chi-squared and Mann–Whitney tests were used for statistical analysis. Survival analysis was performed using Kaplan–Meier and Cox multivariate regression analyses. ResultsMedian CA125 and HE4 levels were higher in stage III and IV tumours (p<0.001) and in tumours with outer-half myometrial invasion (p<0.001). ROC analysis demonstrated that HE4 (area under the curve (AUC)=0.76) was a better predictor of outer-half myometrial invasion than CA125 (AUC=0.65), particularly in patients with low-grade endometrioid tumours (AUC 0.77 vs 0.64 for CA125). Cox multivariate analysis demonstrated that elevated HE4 was an independent predictor of recurrence-free survival (HR=2.40, 95% CI 1.19–4.83, p=0.014) after adjusting for stage and grade of disease, particularly in the endometrioid subtype (HR=2.86, 95% CI 1.25–6.51, p=0.012). ConclusionThese findings demonstrate the utility of serum HE4 as a prognostic biomarker in endometrial cancer in a large, population-based study. In particular they highlight the utility of HE4 for pre-operative risk stratification to identify high-risk patients within low-grade endometrioid endometrial cancer patients who might benefit from lymphadenectomy.