Clear Cell Endometrial Cancer Research Articles

Endometrial Clear Cell Carcinoma with Non-Gestational Uterine Choriocarcinoma Differentiation.

Choriocarcinoma is a rare and highly malignant tumor that primarily occurs in women of reproductive age. Choriocarcinoma can be classified as gestational or nongestational, based on its pathogenetic origin. Although primary nongestational choriocarcinoma has been described in the ovaries, it is very rare in the uterus, especially in postmenopausal women. It is crucial to differentiate between gestational and non-gestational choriocarcinoma, as it affects the choice of treatment and prognosis. Endometrial clear cell carcinoma is an aggressive subtype of endometrial cancer, accounting for less than 10% of all uterine carcinomas. Trophoblastic differentiation in uterine cancer is unusual and very rare, with only three examples of the subtype of clear cell endometrial cancer with gestational choriocarcinoma reported in the literature, including only one with nongestational choriocarcinoma. Here, we present an example of clear cell carcinoma with nongestational uterine choriocarcinoma differentiation in a postmenopausal woman.

Unveiling the unique identity of clear-cell endometrial cancer (CCEC): A comprehensive comparative analysis with ovarian counterpart and other endometrial subtypes.

Unveiling the unique identity of clear-cell endometrial cancer (CCEC): A comprehensive comparative analysis with ovarian counterpart and other endometrial subtypes.

Statement of the Uterus Commission of the Gynecological Oncology Working Group (AGO) on the Use of Primary Chemoimmunotherapy to Treat Patients with Locally Advanced or Recurrent Endometrial Cancer.

The publication of two large randomized studies - the ENGOT-EN-6-NSGO/GOG-3031/RUBY trial and the NRG-GY018 trial - which investigated combining chemotherapy with immunotherapy to treat patients with primary advanced or recurrent endometrial cancer (EC) has transformed the clinical study landscape in terms of first-line therapy for affected patients and has set a new standard of therapy. In the ENGOT-EN-6-NSGO/GOG-3031/RUBY trial, the addition of dostarlimab to standard chemotherapy with carboplatin and paclitaxel resulted in a significant and clinically relevant improvement of progression-free survival and overall survival in the overall population, a significant and clinically relevant improvement of progression-free survival and overall survival in the subgroup with dMMR/MSI-high tumors, and a significant and clinically relevant improvement of progression-free survival in the subgroup with pMMR/MSI-low tumors. In the NRG-GY018 trial, the addition of pembrolizumab to standard chemotherapy with carboplatin and paclitaxel resulted in a significant and clinically relevant improvement of progression-free survival in the group with dMMR tumors, and a significant and clinically relevant improvement of progression-free survival in the group with pMMR tumors. As expected, the effect in both trials was much more pronounced in the group of patients with dMMR/MSI-high tumors. According to the assessment of the Uterus Organ Commission of the AGO, all patients with dMMR/MSI-high tumors should receive chemoimmunotherapy and all patients with pMMR/MSI-low tumors who meet the inclusion criteria of the two trials discussed here may have chemoimmunotherapy. For dostarlimab this means: patients with EC recurrence who will not undergo surgery or radiotherapy, patients with stage IIIA, IIIB or IIIC1 disease and a measurable lesion postoperatively, patients with stage IIIA, IIIB or IIIC1 disease with histological findings of serous EC, clear-cell EC or carcinosarcoma with or without a measurable lesion postoperatively, and patients with stage IIIC2 or IV disease with or without a measurable lesion postoperatively. For pembrolizumab this means: patients with EC recurrence (except carcinosarcoma) who will not undergo surgery or radiotherapy, and patients with stage III or IVA disease (except carcinosarcoma) and a measurable lesion postoperatively or with stage IVB disease with or without a measurable lesion.

Mixed clear cell/endometrioid and clear cell/serous carcinoma of the uterus are clinicopathologically similar to pure clear cell carcinoma: An NRG Oncology/Gynecologic Oncology Group (GOG-210) study of 311 women

ObjectivesClear cell carcinoma is a high-risk subtype of endometrial cancer. Some patients have a mixture of clear cell carcinoma with other histologic types (endometrioid or serous) or cannot be neatly assigned to one of these types. Protocol GOG-8032 within GOG-210 was designed to determine whether these tumors differ from pure clear cell carcinoma in stage at diagnosis, initial pattern of spread, or patient survival. MethodsThe term “mixed” was applied to tumors with multiple identifiable components, and “indeterminate” was applied to tumors with features intermediate between different histologic types. Three hundred eleven women with pure, mixed, or indeterminate clear cell carcinoma were identified in a larger cohort of patients undergoing hysterectomy for endometrial cancer in GOG-210. Histologic slides were centrally reviewed by expert pathologists. Baseline and follow-up data were analyzed. ResultsOne hundred thirty-six patients had pure clear cell carcinoma and 175 had a mixed or indeterminate clear cell pattern. Baseline clinicopathologic characteristics were similar except for a small difference in age at presentation. Univariate survival analysis confirmed the significance of typical endometrial cancer prognostic factors. Patients in the mixed categories had disease-free and overall survival similar to pure clear cell carcinoma, but the indeterminate clear cell/endometrioid group had longer survival. ConclusionIn clear cell endometrial cancer, the presence of a definite admixed endometrioid or serous component did not correlate with a significant difference in prognosis. Patients whose tumors had indeterminate clear cell features had better prognosis. Some of these tumors may be endometrioid tumors mimicking clear cell carcinoma.

Abstract CT162: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts

Abstract Background: Dual checkpoint inhibition with anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be efficacious in numerous malignancies. This study presents the first results of ipilimumab and nivolumab in the clear cell gynecologic cancer cohorts of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg IV every 6wk) plus nivolumab (240mg IV every 2wk). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed CR and PR); progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity are secondary endpoints. Results: Evaluable patients were as follows: clear cell ovarian cancer (N=19); clear cell endometrial cancer (N=8); clear cell cervical (N=5) (median ages, 53, 66, and 59 years; cohorts 46, 45, and 42, respectively) In the clear cell ovarian cancer cohort, ORR was 21.1% [CR, 15.8%, n=3; PR, 5.3%, n=1]; clinical benefit rate (CBR) (includes stable disease ≥6 months) was 31.6% (6/19 patients). Among three patients with confirmed CR, two patients showed 100% regression (with ongoing response at 36+ months and 37+ months respectively), and the other patient showed 67% regression (due to lymph node < 1.0cm), but eventually progressed after 722 days. One confirmed PR patient achieved 75% regression (ongoing response at 53+ months). Of note, three patients achieved unconfirmed PR; one showed 34% regression (5 months); another, 38% (51.5+ months); and another, 58% regression (5 months). The ORR when including unconfirmed PR is 36.8% (7/19). Median PFS was 3.7 months (95% confidence interval (CI); 1.7-∞). Median OS was 21.7 months (6.4-∞). In the clear cell endometrial cancer cohort, ORR was 0%; CBR, 25% (2/8 patients). Of note, one patient achieved unconfirmed PR with 69% regression (4 months). The ORR when including unconfirmed PR is 12.5% (1/8). Median PFS was 2.0 months (95% confidence interval; 1.8-na). Median OS was 4.3 months (4.2-na). In the clear cell cervical cancer cohort, ORR was 0%; CBR, 20.0% (1/5 patients). Median PFS was 2.2 months (95% CI; 1.9-na). Median OS was 23.6 months (95% CI; 15.3-na). The most common adverse events, in the three cohorts combined, were nausea (37.5%, n=12), fatigue (34.4%, n=11), anorexia (31.2%, n=10), hypothyroidism (31.2%, n=10), and pruritus (28.1%, n=9). Grade 3-4 adverse events were reported in 17 cases (53.1%) with no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in 19 clear cell ovarian cancer patients resulted in an ORR of 21.1% and CBR of 31.6%, with two durable CRs ongoing at 3+ years; CBR was 25% and 20%, respectively, in clear cell endometrial and cervical cohorts, with no objective responses, albeit with only 8 and 5 patients per cohort. Correlative studies to determine response/resistance markers are ongoing. Further prospective studies in rare gynecologic malignancies are warranted. Citation Format: Young Kwang Chae, Christopher W. Ryan, Naing Aung, William R. Robinson, Megan Othus, Elad Sharon, David M. O'Malley, Floortje J. Backes, Charles D. Blanke, Ramez N. Eskander, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT162.

A Case Report of Spontaneous Regression of grade 3 Clear Cell Endometrial Cancer

Spontaneous remission of cancer (SR) is a rare, defined as a complete or partial, temporary, or permanent disappearance of all or at least some relevant parameters of a soundly diagnosed malignant disease without any medical treatment or with treatment that is considered inadequate to produce the resulting regression. We present the case of a 43-year-old woman who initially received a diagnosis of high- grade squamous intraepithelial lesion (HSIL) on a Pap smear, further examination and MVA (Manual Vacuum Aspiration) curettage biopsy revealing poorly differentiated clear cell adenocarcinoma of the endometrium, stage 1a3 and subclinical hypothyroidism. The patient was prescribed thyroid tablet replacement but chose not to pursue any cancer treatment. Following two consecutive MVA curettage procedures, she returned for a hysteroscopic examination and the third MVA curettage biopsy, the histological report indicated the absence of any malignancy. Throughout the course of her illness, the patient underwent a total of ten sessions of MVA endometrial curettage and received thyroid replacement therapy for her subclinical hypothyroidism. Despite our initial reservations, we continue to provide care and support to her throughout whole course of this illness. We demonstrated that a patient's autonomy in refusing medical treatment is a fundamental ethical and legal principle in healthcare. Conclusion: We report the 8 cases of spontaneous remission (SR) in endometrial cancer. Given the infrequent occurrence of such cases, it is imperative to involve in a comprehensive and in-depth discussion.

Abstract 3065: Establishment and characterization of a platform of endometrial cancer organoids

Abstract Background: Endometrial cancer is the most commonly diagnosed gynecologic cancer in the US; the incidence is rising, and survival rates for this cancer are decreasing. There is a paucity of effective treatment for recurrent endometrial cancer, especially high grade endometrial cancers (HGEC) which include serous, carcinosarcoma, endometrioid, and clear cell histologies. Models that mimic the clinical and molecular characteristics of HGEC are lacking. To support the development of next generation therapeutics for endometrial cancer, we report on the establishment of 3D endometrial patient-derived organoids (PDOs) from HGEC. Methods: 26 Tumors from 21 different patients with HGEC (Serous, Carcinosarcoma, Clear Cell and High-grade Endometrioid subtypes) who underwent surgical resection (n= 13), biopsy (n = 7), paracentesis (n = 3) or thoracentesis (n = 3) were passaged as 3D organoid cultures in Matrigel in an optimized media. Robust models (defined by average days to passage <14 days) were viably banked. 3 frozen models were also thawed and re-cultured to assess the viability post freezing. PDOs were collected for H&E staining and their histology was compared to the original diagnosis. DNA replication rate and the effect of replication stress on organoid growth were assessed by the DNA Fiber Assay and immunofluorescence (IF). Finally, an established clear cell endometrial cancer organoid model was engrafted in mice to generate a Patient-Derived Xenograft (PDX) model. Results: Endometrial PDOs were successfully developed from 19 of 26 original samples for an overall success rate of 73.1%. Successful PDOs were developed from multiple histologies, including 8 carcinosarcoma, 6 uterine serous, 2 endometrioid, 2 clear cell and 1 mixed uterine serous and endometrioid. Though biopsy samples had initially fewer viable cells, our overall success rate was similar at 85.7% compared to 84.6% for surgical resections and higher than 66.7% for paracenteses. Samples obtained via thoracentesis did not form PDOs. Endometrial PDOs were histologically validated to match the primary patient tumor. Freeze thawing had no effect on morphology and growth characteristics. DNA fiber assays could be successfully conducted in PDOs, with a reduction in replication rate observed in PDO models treated with ATR or WEE1 inhibitors, with concurrent increase in y-H2AX and decrease in pRPA2 observed by IF. We also successfully generated a validated PDX model from organoids. Studies to determine molecular fidelity between the original patient tumor and established organoids are ongoing. Conclusions: We describe the successful establishment of 19 endometrial PDO models which retain original tumor morphology and demonstrate sensitivity to drug-induced DNA damage. 3D endometrial organoids can therefore be used for further target discovery and validation as well as biomarker studies to advance targeted therapies for high-grade endometrial cancer. Citation Format: Aisha L. Saldanha, Ha V. Vo, Kevin Vasquez, Kenneth Ngo, Shrabasti Roychoudhury, Carina Feeney, Courtney H. Qi, Swati Narayan, Jennifer D. Curtis, Prafulla C. Gokhale, Dipanjan Chowdhury, Cloud P. Paweletz, Marisa R. Nucci, Ursula A. Matulonis, Elena Ivanova, Joyce F. Liu. Establishment and characterization of a platform of endometrial cancer organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3065.

Is Substantial Lymphovascular Space Invasion Prognostic for Clinical Outcomes in Type II Endometrial Cancer?

AimsSubstantial lymphovascular space invasion (LVSI) compared with none or focal LVSI is predictive of lymph node involvement and worse clinical outcomes in endometrioid-type endometrial carcinoma. We aimed to quantify the incidence of substantial LVSI in type II (clear cell and serous) endometrial cancer and correlate the extent of LVSI with clinical outcomes. Materials and methodsA retrospective review was conducted on type II endometrial cancer patients who underwent surgical management from July 2017 to December 2019 using the three-tier LVSI scoring system. Binary logistic regression and Cox regression were used to analyse predictors of lymph node involvement or survival outcomes, respectively. The Kaplan–Meier method and Log-rank test were used to analyse differences in locoregional disease-free survival (LR-DFS), distant metastasis disease-free survival (DM-DFS) and overall survival between patients with substantial versus none/focal LVSI. ResultsIn 79 patients with type II endometrial carcinoma, no LVSI, focal LVSI and substantial LVSI was present in 48.1%, 15.2% and 36.7% of patients, respectively. Lymph nodes were involved in 0.0% with no LVSI, 20.0% with focal LVSI and 60.0% with substantial LVSI (P < 0.001). The median follow-up was 22.2 months. In patients with none/focal versus substantial LVSI, the 2-year LR-DFS and DM-DFS rates were 91.5% versus 71.4% (P = 0.01) and 90.2% versus 63.8% (P = 0.005), respectively. On univariate analysis, myometrial invasion ≥50%, tumour size ≥3.6 cm, substantial versus none/focal LVSI, lymph node involvement and omission of adjuvant radiotherapy were significant predictors for worse LR-DFS and DM-DFS (P < 0.05). DiscussionSubstantial LVSI has a high incidence in type II pathology at our institution and predicts for lymph node involvement and worse clinical outcomes.

Adjuvant brachytherapy for FIGO stage I serous or clear cell endometrial cancer

ObjectivesOptimal adjuvant treatment for early-stage clear cell and serous endometrial cancer remains unclear. We report outcomes for women with surgically staged International Federation of Gynecology and Obstetrics (FIGO) stage I...

Adjuvant Vaginal Brachytherapy in the Treatment of Surgically Staged, FIGO Stage I Papillary Serous or Clear Cell Endometrial Cancer

Adjuvant Vaginal Brachytherapy in the Treatment of Surgically Staged, FIGO Stage I Papillary Serous or Clear Cell Endometrial Cancer

Malignant peritoneal cytology and increased mortality risk in stage I non-endometrioid endometrial cancer

ObjectiveTo examine the survival of women with stage I non-endometrioid endometrial cancer with malignant peritoneal cytology. MethodsA retrospective observational cohort study was conducted to examine the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2010 to 2016. Women with stage I serous, clear cell, carcinosarcoma, undifferentiated, and mixed endometrial cancer with known peritoneal cytology results at hysterectomy were examined (N = 4506). Propensity score inverse probability of treatment weighting was used to balance the measured covariates, and survival outcomes were assessed according to peritoneal cytology results. ResultsMalignant peritoneal cytology was reported in 401 (8.9%) women. In multivariable analysis, older age, serous histology, and large tumors were associated with an increased likelihood of malignant peritoneal cytology (all, P < 0.05). In a propensity score weighted model, malignant peritoneal cytology was associated with a nearly two-fold increase in all-cause mortality risk compared to negative peritoneal cytology (5-year rates, 63.4% versus 80.2%, hazard ratio 2.18, 95% confidence interval 1.78–2.66). In sensitivity analyses, malignant peritoneal cytology was associated with decreased overall survival in old and young age groups, serous, clear cell, carcinosarcoma, and mixed histology groups, stage T1a disease, and staged and unstaged cases, but not for stage T1b disease. Difference in 5-year overall survival rates between the malignant and negative peritoneal cytology groups was particularly large among those with clear cell histology (24.0%), stage T1a disease (19.4%), aged >78 years (18.2%), and serous tumors (17.6%). ConclusionMalignant peritoneal cytology can be prevalent in stage I non-endometrioid endometrial cancer. Our study suggests that malignant peritoneal cytology is a prognostic factor for decreased survival in stage I non-endometrioid endometrial cancer.

High-grade endometrial cancer survival (endometrioid to non-endometrioid histology comparison)

Purpose of Investigation: To analyze overall survival (OS) and disease-free survival (DFS) in a retrospective series of 125 patients with serous, clear cell, and high-grade endometrioid carcinoma having undergone complete treatment (primary surgery, oncology treatments, and follow up) at the present institution. Materials and Methods: All women with high-grade endometrial cancer having undergone surgery (1998-2012) and postoperatively treated and monitored at Split University Hospital Center, whose tissue samples were stored at Department of Pathology, Split University Hospital Center, were included in the study. Survival time was analyzed with Kaplan-Meier method and the log-rank test was used to assess between-group differences. Cox proportional hazard regression model was used on multivariate survival analysis. Patients were followed from the time of primary surgery until death or last follow up in December 2015. Results: Women with serous and clear cell endometrial cancer had similar survival compared to those with high-grade endometrioid endometrial cancer. On multivariate analysis, only earlier stage was an independent predictor of improved survival. Conclusions: The present findings suggest that serous and clear cell endometrial carcinomas have a similar prognosis compared to high-grade endometrioid carcinoma of the uterus.

Cause-specific mortality according to adjuvant therapy of serous and clear cell endometrial cancers: A population-based analysis

Objective: Serous and clear cell carcinomas represent a minority of patients in recent clinical trials investigating adjuvant therapy of higher-risk endometrial cancers (PORTEC-3, GOG-249, GOG-258), and national guidelines such as the National Comprehensive Cancer Network permit substantial variations in treatment. To help address this gap in knowledge, we analyzed outcomes of patients in the NCT's Suveillance, Epidemiology and End Results (SEER) registry-Medicare database, given its large sample size, national representation of real-life practice patterns, and availability of radiation and chemotherapy data.

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 .

The role of adjuvant therapy in stage IA serous and clear cell uterine cancer: A multi-institutional pooled analysis

ObjectiveAs the optimal adjuvant management of stage IA serous or clear cell endometrial cancer is controversial, a multi-institutional review was conducted with the objective of evaluating the appropriateness of various strategies including observation. MethodsRetrospective chart reviews for 414 consecutive patients who underwent hysterectomy for FIGO stage IA endometrial cancer with serous, clear cell or mixed histology between 2004 and 2015 were conducted in 6 North American centers. Time-to-event outcomes were analyzed by Kaplan-Meier estimates, log-rank test, univariable and multivariable cox proportional hazard regression models. ResultsPost-operative management included observation (50%), chemotherapy and radiotherapy (RT) (27%), RT only (16%) and chemotherapy only (7%). The 178 RT patients received external beam (EBRT, 16%), vaginal vault brachytherapy (VVB, 56%) or both (28%). Among patients without any adjuvant treatment, 5-year local control (LC), disease free survival (DFS) and cancer-specific survival (CSS) were 82% (95% confidence interval: 74–88), 70% (62–78) and 90% (82–94), respectively. CSS in patients without adjuvant treatment was improved with adequate surgical staging (100% vs. 87% (77–92), log-rank p=0.022). Adjuvant VVB was associated with improved LC (5-year 96% (91–99) vs. 84% (76–89), log-rank p=0.007) and DFS (5-year 79% (66–88) vs. 71% (63–77), log-rank p=0.033). Adjuvant chemotherapy was associated with better LC (5-year 96% (90–98) vs. 84% (77–89), log-rank p=0.014) and DFS (5-year 84% (74–91) vs. 69% (61–76), log-rank p=0.009). On multivariable analysis, adjuvant chemotherapy and VVB were associated with improved LC while adjuvant chemotherapy and age were significant for DFS. ConclusionsIn stage IA serous or clear cell uterine cancer, adjuvant RT and chemotherapy were associated with better LC and DFS. Observation may be appropriate in patients who have had adequate surgical staging.

Ornithine decarboxylase as a therapeutic target for endometrial cancer.

Ornithine Decarboxylase (ODC) a key enzyme in polyamine biosynthesis is often overexpressed in cancers and contributes to polyamine-induced cell proliferation. We noted ubiquitous expression of ODC1 in our published endometrial cancer gene array data and confirmed this in the cancer genome atlas (TCGA) with highest expression in non-endometrioid, high grade, and copy number high cancers, which have the worst clinical outcomes. ODC1 expression was associated with worse overall survival and increased recurrence in three endometrial cancer gene expression datasets. Importantly, we confirmed these findings using quantitative real-time polymerase chain reaction (qRT-PCR) in a validation cohort of 60 endometrial cancers and found that endometrial cancers with elevated ODC1 had significantly shorter recurrence-free intervals (KM log-rank p = 0.0312, Wald test p = 5.59e-05). Difluoromethylornithine (DFMO) a specific inhibitor of ODC significantly reduced cell proliferation, cell viability, and colony formation in cell line models derived from undifferentiated, endometrioid, serous, carcinosarcoma (mixed mesodermal tumor; MMT) and clear cell endometrial cancers. DFMO also significantly reduced human endometrial cancer ACI-98 tumor burden in mice compared to controls (p = 0.0023). ODC-regulated polyamines (putrescine [Put] and/or spermidine [Spd]) known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p = 0.0006), [Spd] (p<0.0001)) and blood plasma ([Put] (p<0.0001), [Spd] (p = 0.0049)) of treated mice. Our study indicates that some endometrial cancers appear particularly sensitive to DFMO and that the polyamine pathway in endometrial cancers in general and specifically those most likely to suffer adverse clinical outcomes could be targeted for effective treatment, chemoprevention or chemoprevention of recurrence.

Folate receptor-α targeted near-infrared fluorescence imaging in high-risk endometrial cancer patients: a tissue microarray and clinical feasibility study.

ObjectiveDetection and resection of all malignant lesions is pivotal in staging and cytoreductive surgery (CRS) of endometrial cancer (EC). Intraoperative EC detection could be enhanced using OTL-38, a fluorescent-labelled folate receptor-α (FRα) targeted imaging agent. The objectives of this study were to investigate which subgroups of high-risk EC patients express FRα and assess feasibility of intraoperative EC detection using OTL-38.ResultsFRα expression on TMA was significantly correlated with tumor type (p < 0.01). Eighty-two percent of serous and clear cell carcinomas showed FRα expression. Four patients were enrolled in the clinical study. Using fluorescence imaging all omental (n = 3) and lymph node (LN) metastases (n = 16) could be clearly identified, including one otherwise undetected omental metastasis. However, false-positive fluorescence was identified in 17/50 non-metastatic LNs, caused by OTL-38 targeting of FRβ, expressed by tumor-associated activated macrophages.ConclusionsThis study describes high FRα expression in serous and clear cell EC and demonstrates the first experience of intraoperative FRα-targeted tumor detection in patients with these subtypes of EC. Although all metastases could be clearly identified using OTL-38, the role of tumor-associated macrophages should be further evaluated.MethodsImmunohistochemical (IHC) staining of FRα expression was performed on tissue micro arrays (TMA) of 116 patients with high-risk EC features. Patients with either serous or clear cell EC, planned for staging or CRS, were eligible for inclusion in the clinical study and received an intravenous dose of 0.0125 mg/kg OTL-38, 2-3 hours prior to surgery. Resected lesions, identified by standard-of-care and/or fluorescence imaging, were histopathologically assessed for FRα and tumor status.

Abstract 1242: Ornithine decarboxylase as a therapeutic target in endometrial cancer

Abstract Endometrial cancer is the 4th most common cancer and the 6th deadliest cancer in US women. The American Cancer Society estimates there will be 60,050 new endometrial cancers in 2016, an increase of more than 10% from the previous year highlighting the need for more effective treatments and prevention. Ornithine Decarboxylase (ODC) a key enzyme in polyamine synthesis is often overexpressed in cancers and contributes to cell proliferation and tumor growth. Therefore, ODC and the polyamine pathway are considered rational targets for cancer treatment or prevention. We noted ubiquitous expression of ODC1 in our previously published endometrial cancer gene array data and confirmed this in the cancer genome atlas (TCGA), finding expression in all four molecular sub-types with highest expression in copy number high cancers which have the worst clinical outcomes. Therefore, we explored the association of ODC1 gene expression with clinical outcomes of overall survival (OS) and recurrence in the TCGA cohort and noted that elevated ODC1 was significantly related to OS (Wald test p=0.001) and recurrence (p=0.01). Importantly, we confirmed these observations using QRT-PCR in a validation cohort of 60 endometrial cancers and found that endometrial cancers with elevated ODC1 had significantly shorter recurrence-free intervals (p=5.59x10-5) and elevated hazard ratio=3.72. Similar to TCGA data we also noted a strong trend to worse OS ( p=0.00014) with elevated hazard ratio 3.81. Numerous studies including clinical trials have examined the chemopreventive and anti-tumor effects of difluoromethylornithine (DFMO), a specific inhibitor of ODC. We found that DFMO treatment significantly reduced cell proliferation, cell viability, and colony formation in human cell line models derived from undifferentiated, endometrioid, serous, MMT and clear cell endometrial cancers. In contrast, immortalized uterine endometrial epithelial cells (EM E6/E7 TERT1) were less sensitive to DFMO. To confirm the significant effects of DFMO in vitro we performed an in vivo study with human endometrial cancer (ACI-98) tumor-bearing athymic nude mice. Xenografted mice were either treated with 2% (w/v) DFMO supplied in drinking water or water only (n=10/group). DFMO significantly reduced the tumor burden in mice compared to controls (p=0.0023). ODC-regulated polyamines (putrescine [Put] and spermidine [Spd]) known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p=0.0006), [Spd] (p&amp;lt;0.0001)) and blood plasma ([Put] (p&amp;lt;0.0001), [Spd] (p=0.0049)) of treated mice. Results of these studies indicate that some endometrial cancers appear particularly sensitive to DFMO. Our findings indicate that the polyamine pathway in endometrial cancers in general and specifically those most clinically relevant endometrial cancers could be targeted for effective treatment, chemoprevention or chemoprevention of recurrence. Citation Format: Hong Im Kim, Chad R. Schultz, Andrea L. Buras, Elizabeth Friedman, Alyssa M. Fedorko, Leigh G. Seamon, Gadisetti Chandramouli, André S. Bachmann, John I. Risinger. Ornithine decarboxylase as a therapeutic target in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2017-1242

Cirugía oncológica ginecológica mediante puerto único y endoscopia operatoria por orificios naturales empleando equipamiento convencional

ObjectiveTo describe and assess the feasibility of combining natural orifice transluminal endoscopic surgery (NOTES) and laparoendoscopic single-site surgery in gynaecological cancer using only conventional laparoscopic equipment. Material and methodsA retrospective review of 30 patients with gynaecological cancer, managed by either laparoendoscopic single-site surgery or hybrid natural orifice transluminal endoscopic surgery technique, from June 2012 to June 2014. Only conventional trocars, grasping forceps and sealing devices were used, similar to multiport laparoscopic surgery. ResultsTwenty-one (70%) patients were managed by umbilical laparoendoscopic single-site surgery, while 8 (30%) patients underwent a hybrid natural orifice transluminal endoscopic surgery. One patient underwent a double retroperitoneal and transperitoneal single-site approach. Hysterectomy was performed in 10 cases of endometrial cancer and 2 of cervical cancer, while hysterectomy plus pelvic lymphadenectomy or sentinel node biopsy was conducted in 6 cases of endometrial cancer. Hysterectomy plus pelvic and para-aortic lymphadenectomy was performed in 3 patients with endometrial cancer. Transperitoneal pelvic and para-aortic lymphadenectomy was conducted in one case for cervical cancer staging. Staging was also performed in 3 patients with borderline ovarian cancer and in 2 cases of infiltrating cervical carcinoma. Single-port laparoscopic debulking surgery was performed in the remaining 3 cases. Additional 5-mm ports were used in 5 (16.66%) cases to perform para-aortic lymphadenectomy, but no conversion to laparotomy was needed. There were no intraoperative complications, with minor postoperative complications observed in only 5 cases. There was one postoperative major complication: Heart failure in a 72-year-old female patient with clear cell endometrial cancer stage IAG3, who needed to be referred to the cardiology department during her hospitalisation. ConclusionCombined laparoendoscopic single-site surgery and natural orifice transluminal endoscopic surgery is a safe and feasible procedure in the surgical treatment of gynaecological cancer.

Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing

The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome-wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases. We conducted whole exome sequencing of paired tumor-normal DNAs from 16 cases of CCEC (12 CCECs and the CCEC components of 4 mixed histology tumors). Twenty-two genes-of-interest were Sanger-sequenced from another 47 cases of CCEC. Microsatellite instability (MSI) and microsatellite stability (MSS) were determined by genotyping 5 mononucleotide repeats. Two tumor exomes had relatively high mutational loads and MSI. The other 14 tumor exomes were MSS and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein-encoding genes. Among the 63 cases of CCEC in this study, we identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%). Five of 8 mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included 2 recurrently mutated residues. Based on patterns of MSI and mutations in 7 genes, CCEC subsets molecularly resembled serous endometrial cancer (SEC) or endometrioid endometrial cancer (EEC). Our findings demonstrate molecular similarities between CCEC and SEC and EEC and implicate TAF1 as a novel candidate CCEC driver gene. Cancer 2017;123:3261-8. © 2017 American Cancer Society.