High-intermediate Risk Endometrial Cancer Research Articles

Preliminary results of adjuvant image-guided vaginal brachytherapy alone for early stage endometrial carcinoma

ObjectiveThis retrospective study evaluated the preliminary outcomes of image-guided vaginal brachytherapy (IG-VBT) in the adjuvant treatment of high intermediate risk endometrial cancer. Materials and MethodsData were collected from 48 patients who underwent adjuvant IG-VBT between 2019 and 2022 at the Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University. The vaginal cuff clinical target volume (CTV-VC) is composed of a 4-mm-thick band around vaginal cylinder at the upper 3 cm of the vaginal cuff. A total dose of 21 Gy in three fractions was delivered to the CTV-VC, and the dose to the bladder and rectum were evaluated. Treatment details, patient characteristics, and outcomes were analyzed. Descriptive statistics were used for analysis, and Kaplan-Meier method was employed for survival analysis. ResultsThe mean age was 62 years, with mainly endometrioid carcinoma pathology (96 %). All patients were at stage I, with 87.5 % receiving complete surgical staging. Mean total treatment time was 10 days with mean D90 of CTV-VC was 29.7 Gy, and D2cc of bladder, rectum, and sigmoid were 24.6 Gy, 21.0 Gy, and 7.7 Gy, respectively. At a median follow-up of 37 months, 3-year local control, disease-free survival, and overall survival rates were 100 %, 100 %, and 97.9 %. respectively. Two patients (4.2 %) experienced grade 1–2 gastrointestinal toxicity, while no genitourinary toxicity or serious adverse events were observed. ConclusionsThe preliminary results of IG-VBT in endometrial cancer demonstrated favorable outcomes in terms of vaginal control and toxicity. Further studies with larger cohorts and longer follow-up durations are warranted.

Nodal staging in high and high-intermediate risk endometrial cancer surgery: Which role in the molecular classification era?

ObjectivesNodal staging contributes to risk group definition and the indication to adjuvant treatment in endometrial cancer (EC) patients. However, the role of nodal assessment evolved and requires redefinition.Primary outcome of the study was to assess the impact of surgical nodal staging in defining high-risk (HR) EC. Secondary outcome was to evaluate the contribution of nodal assessment to the decision for adjuvant treatment in both high-risk and high-intermediate risk (HIR) patients submitted to surgery. MethodsClinical stage I-II EC patients with postoperative diagnosis of HR and HIR disease were included. The contribution of nodal staging in prognostic groups allocation was assessed by reviewing HR patients to identify those without any other feature of such class (non-endometrioid histology, p53abn immunohistochemistry, post-operative T3-T4 disease) and HIR cases to assess how nodal staging affected adjuvant treatment indication. Descriptive statistics were conducted to describe the two populations. ResultsFifty-seven patients were included, 46 with HR and 11 with HIR disease. Chemotherapy and external-beam radiotherapy (EBRT) were proposed in 40 HR patients. Considering histology, immunohistochemical profile and FIGO stage, high risk classification was exclusively relied on nodal involvement in 2/46 cases (4.3 %). Omitting retroperitoneal staging, one of them would have been classified in the intermediate risk group and the other as HIR: without nodal staging, chemotherapy and EBRT would have been omitted in 1/40 (2.5 %) case.Among HIR patients, chemotherapy was proposed in 7/11 cases and EBRT in all cases. Adjuvant chemotherapy was indicated in 5/6 (83.3 %) and omitted in 1/6 (16.7 %) pN0 patient (stage Ib G2, substantial LVSI). In HIRpN0 patients, omitting nodal staging could have changed adjuvant treatment indication in 1/6 (16.7 %) case. In HIRpNx patients, adjuvant chemotherapy was omitted in one patient (stage II, grade 2 and LVSI negative): nodal staging unavailability might have changed indication to chemotherapy in 1/5 (20 %) case, without changing indication to EBRT.Unavailable nodal staging could globally be related to omission of chemotherapy in 2/57 (3.5 %) patients and of EBRT in 1/57 (1.8 %) patient. ConclusionsIn this series, nodal staging had limited impact on definition of HR class and on the choice of adjuvant treatment in HR and HIR EC patients.

Prognostic impact and causality of age on oncological outcomes in women with endometrial cancer: a multimethod analysis of the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials

Numerous studies have shown that older women with endometrial cancer have a higher risk of recurrence and cancer-related death. However, it remains unclear whether older age is a causal prognostic factor, or whether other risk factors become increasingly common with age. We aimed to address this question with a unique multimethod study design using state-of-the-art statistical and causal inference techniques on datasets of three large, randomised trials. In this multimethod analysis, data from 1801 women participating in the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk endometrial cancer, 427 patients with high-intermediate risk endometrial cancer, and 660 patients with high-risk endometrial cancer. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable, a deep learning causal inference model called AutoCI was used. Median follow-up as estimated using the reversed Kaplan-Meier method was 12·3 years (95% CI 11·9-12·6) for PORTEC-1, 10·5 years (10·2-10·7) for PORTEC-2, and 6·1 years (5·9-6·3) for PORTEC-3. Both overall recurrence and endometrial cancer-specific death significantly increased with age. Moreover, older women had a higher frequency of deep myometrial invasion, serous tumour histology, and p53-abnormal tumours. Age was an independent risk factor for both overall recurrence (hazard ratio [HR] 1·02 per year, 95% CI 1·01-1·04; p=0·0012) and endometrial cancer-specific death (HR 1·03 per year, 1·01-1·05; p=0·0012) and was identified as a significant causal variable. This study showed that advanced age was associated with more aggressive tumour features in women with endometrial cancer, and was independently and causally related to worse oncological outcomes. Therefore, our findings suggest that older women with endometrial cancer should not be excluded from diagnostic assessments, molecular testing, and adjuvant therapy based on their age alone. None.

Symptomatic Lymphocele After Robot-Assisted Pelvic Lymphadenectomy as Part of the Primary Surgical Treatment for Cervical and Endometrial Cancer: A Retrospective Cohort Study

Pelvic lymph node dissection (PLND) is part of the primary treatment for early-stage cervical cancer and high-intermediate risk or high-risk endometrial cancer. Pelvic lymphocele is a postoperative complication of PLND and when symptomatic, lymphoceles necessitate treatment. The aim of this study was to investigate the incidence and risk factors of symptomatic lymphocele after robot-assisted laparoscopic PLND in cervical and endometrial cancer. Retrospective cohort study. Single-center academic hospital. Two hundred and fifty-eight patients with cervical cancer and one hundred and twenty-nine patients with endometrial cancer. Pelvic lymphadenectomy by robot-assisted laparoscopic surgery. We retrospectively included all patients with early-stage cervical cancer and high- intermediate risk or high-risk endometrial cancer who underwent pelvic lymphadenectomy by robot-assisted laparoscopic surgery between 2008 and 2022. Medical records were reviewed for the occurrence of a symptomatic lymphocele. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for developing a symptomatic lymphocele. In total 387 patients, 258 with cervical cancer and 129 with endometrial cancer, were included in the study. The overall incidence of symptomatic lymphoceles was 9.6% with a median follow-up of 47 months [IQR 23-61]. For the entire cohort, smoking was the only significant risk factor for symptomatic lymphoceles identified in univariate (OR 2.47, 95% CI 1.19-5.11) and multivariate analysis (OR 2.42, 95% CI 1.16-5.07). For cervical cancer, BMI (OR 1.09, 95% CI 1.00-1.17) and prior abdominal surgery (OR 2.75, 95% CI 1.22-6.17) were also identified as significant independent risk factors. For endometrial cancer, age was identified as significant independent risk factor (OR 0.90, 95% CI 0.83-0.97). This single-center cohort study demonstrated an incidence of almost 10% of symptomatic lymphoceles after robot-assisted laparoscopic PLND for cervical cancer and endometrial cancer, with a higher risk observed among patients who smoke at the time of diagnosis. Furthermore, risk factors differ between the two populations, necessitating further studies to establish risk models.

Cost-effectiveness of POLE testing for high intermediate risk endometrial cancer (2242)

Cost-effectiveness of POLE testing for high intermediate risk endometrial cancer (2242)

Radiotherapy in Adjuvant Therapy in High-intermediate Risk and High Risk Endometrial Cancer: A Review Article

Radiotherapy in Adjuvant Therapy in High-intermediate Risk and High Risk Endometrial Cancer: A Review Article

Changes in receipt of adjuvant brachytherapy for endometrial cancer patients before and after affordable care act: The impact of Medicaid expansion.

For patients with high-intermediate risk (HIR) endometrial cancer, adjuvant radiation (RT) reduces the risk of recurrence, but many patients do not receive RT. Under the Affordable Care Act (ACA), most states expanded Medicaid coverage. Our hypothesis was patients would be more likely to receive indicated adjuvant RT in states that expanded Medicaid compared with patients in states that did not expand Medicaid. National Cancer Database (NCDB) was used to identify patients aged 40-64 years with HIR endometrial adenocarcinoma, stage IA and grade 3 or stage IB and grade 1 or 2, diagnosed from 2010-2018. We conducted a difference-in-differences (DID) cross-sectional retrospective analysis comparing receipt of adjuvant RT among patients residing in Medicaid expansion and non-expansion states before and after ACA implementation (January 2014). Expansion states had higher rates of adjuvant RT prior to January 2014 compared with non-expansion states (49.21% vs. 36.46%), and the proportion of patients who received adjuvant RT increased over the study period across both Medicaid expansion and non-expansion states. After Medicaid expansion, the non-expansion states had a larger absolute increase in adjuvant radiation resulting in a non-significant change in the difference in adjuvant radiation rates compared with baseline (crude increase: 9.63% vs. 7.45%, adjusted DID: -2.68 [95% CI: -7.12-1.75], p = 0.236). Medicaid expansion is likely not the most significant factor affecting access or receipt of adjuvant RT for HIR endometrial cancer patients. Further study could help inform policy and efforts to ensure all patients have access to guideline-recommended RT.

GSOR21 Presentation Time: 12:10 PM: Racial, Ethnic, and Regional Disparities in the Utilization of Vaginal Brachytherapy in Patients Meeting PORTEC-2 Criteria: A SEER Analysis

<h3>Purpose</h3> Brachytherapy remains a critical component of locoregional therapy for many women with gynecologic cancers. Other groups have demonstrated racial disparities in the utilization of brachytherapy. Specifically, black women with locally advanced cervical cancer are less likely to receive brachytherapy compared to non-black women. We hypothesized that similar disparities may exist for the utilization of vaginal brachytherapy (VBT) for women who meet PORTEC-2 criteria for high-intermediate risk (HIR) endometrial cancer. <h3>Materials and Methods</h3> Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified patients who were diagnosed with endometrial cancer between 2011 to 2018, who met PORTEC-2 criteria for HIR disease (age 60 or greater with 1) FIGO stage IC (1988) and grade 1-2 disease or 2) FIGO stage IB (1988) and grade 3 disease). We limited our analysis to the year following the initial PORTEC-2 publication (2010) and beyond in order to allow for adoption into routine clinical practice. The impact of race and ethnicity on utilization of VBT versus external beam radiation therapy (EBRT) was analyzed on univariate and multivariate analyses (binary logistic regression, with significance assumed if p≤0.05), as was the impact of marital status, United States (U.S.) Census Bureau region, and whether or not a lymph node dissection was performed. <h3>Results</h3> A total of 2,182 patients were included in the analysis with a median age of 68 (range 60-97). The majority of patients were White (77.3%), married (50.8%), resided in the Western U.S. (45.1%), diagnosed with adenocarcinoma (97.2%), underwent lymph node dissection (84.7%), and received VBT (75.5%). On UVA, patients who were Hispanic (HR 1.58, CI 95% 1.15-2.16, p=0.005) and Asian or Pacific Islanders (HR 1.47, CI 95% 1.01-2.15, p=0.046) were less likely to receive VBT compared to White patients. There was a non-significant trend for Black patients (HR 1.43, 95% CI 0.98-2.08, p=0.066). Patients in the Southern (HR 1.69, CI 95% 1.24-2.31, p=0.001), Western (HR 1.7, CI 95% 1.31-2.20, p<0.001), and Pacific (HR 2.89, CI 95% 1.09-7.64, p=0.032) U.S. Census regions were less likely to receive VBT compared to the Northeast. Those who were divorced were more likely to receive VBT (HR 0.65, 95% CI 0.43-0.98, p=0.038). Finally, those patients who underwent lymph node dissection were more likely to receive VBT on UVA (HR 0.28, CI 95% 0.22-0.36, p<0.001). On MVA, patients who were Hispanic (HR 1.43, CI 95% 1.01-2.03, p=0.046), lived in the Southern (HR 1.82, CI 95% 1.30-2.55, p=0.001), Western (HR 1.61, CI 95% 1.21-2.14, p=0.001), or Pacific regions (HR 3.04, CI 95% 1.05-8.78, p=0.04) were less likely to receive VBT. Although it did not meet statistical significance, there was a trend for decreased utilization of VBT for Asian or Pacific Islanders (HR 1.45, CI 95% 0.94-2.25, p=0.094) and Black patients (HR 1.42, CI 95% 0.94-2.15, p=0.099), potentially a reflection of small patient numbers. Lastly, patients who underwent lymph node dissection were more likely to receive VBT on MVA (HR 0.27, CI 95% 0.21-0.35, p<0.001). <h3>Conclusions</h3> Brachytherapy remains a critical component of locoregional therapy for many women with endometrial cancer. VBT provides a significant improvement in local control in the pelvis with an improved toxicity profile compared to EBRT. Efforts should be made to make VBT available to those women in which it is clinically indicated, with apparent disparities based on the patient's race, ethnicity, and/or their geographic location within the U.S. in the setting of HIR disease. These disparities may have been further exacerbated during the ongoing COVID-19 pandemic, which has been shown in other settings to widen many pre-existing healthcare disparities.

Racial Disparity in Accessibility and Outcomes of Adjuvant Radiotherapy in Stage I High Intermediate Risk Endometrial Adenocarcinoma: A National Database Study

<h3>Purpose/Objective(s)</h3> Based on PORTEC-2 study in 2010, vaginal brachytherapy (VB) was found to be non-inferior to whole pelvic radiation (WPRT) in terms of survival and loco-regional control with a more favorable toxicity Profile. VB is now the preferred choice of adjuvant treatment in patients with high-intermediate risk (HIR) endometrial cancer, especially those with negative Lymphovascular space invasion. In this study we assessed the accessibility and outcomes of this recommended regimen in the different groups of race/ethnicity. <h3>Materials/Methods</h3> The Surveillance, Epidemiologic, and End Results (SEER) database was used to identify patients who met PORTEC-2 inclusion criteria. All patients underwent surgery followed by either vaginal brachytherapy (VB) or whole pelvic radiation (WPRT). Patients with stage I disease, grade 1 with ≥ 50% myometrial invasion (MI), grade 2 with any invasion, and grade 3 with < 50% MI were included in the analysis. Patients were excluded if any lymph nodes were examined or involved, if they received any chemotherapy. Lymphovascular space invasion was not available in the database. HIR endometrial adenocarcinoma was defined as the presence of 2 of the following: age>60, grade 3, and ≥50% myometrial invasion. Radiation status was extracted from the SEER Radiation/Chemotherapy database. Race/ethnicity was defined as non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic and others/unknown. Cox regression analysis was performed to calculate hazard of cancer specific death and overall death both before and after counting for race/ethnicity with following variables in the model: grade, radiation status, myometrial invasion. <h3>Results</h3> Between 2005- 2015, 571 patients met PORTEC-2 inclusion criteria of whom 349 (61.1%) and 222 (38.9%) received WPRT and VB, respectively. Rate of VB was 38.9% overall, 41.1% in NHW however 29.0% in H and only 27.0% in NHB (p<0.05). There was no difference in grade and myometrial invasion between the study groups nor within categories of race/ethnicity (p=0.21 and 0.89, respectively). Cox regression analysis revealed an overall 66% decrease in the hazard of cancer specific death in the VB group as compared to WPRT group (HR=0.34, 95% CI: 0.16-0.73, p<0.01); this decrease was 67% in non-Hispanic White subjects (HR=0.33, 95% CI: 0.12-0.86, p<0.05) however no significant change was noted in NHB (HR=0.55, 95% CI: 0.11-2.67, p=0.45). Moreover, after adjusting for confounding variables, hazard of cancer specific death in NHB was 2.62 times higher than NHW (HR=2.62, 95% CI: 1.22-5.62, p=0.01). <h3>Conclusion</h3> Administration of VB following surgery has become significantly more popular after publication of the PORTEC-2 results however racial disparity exists against both accessibility to and outcomes of this treatment modality. Being a NHB is a risk factor for lack of accessibility as well as failure to respond to PORTEC-2 regimen; future studies on genetic predispositions are recommended.

Comparison of rates of vaginal brachytherapy vs. external beam radiation post-hysterectomy for endometrial cancer patients in rural vs. urban settings (459)

<b>Objectives:</b> The GOG-99 trial published in 2004 demonstrated that patients with high-intermediate risk endometrial cancer benefit from adjuvant external beam radiation therapy (EBRT) post-hysterectomy to decrease the risk of recurrence. The PORTEC-2 trial was then published in 2010, which was an open-label, non-inferiority randomized control trial that compared vaginal brachytherapy (VBT) to EBRT for patients with high-intermediate risk endometrial cancer. This trial demonstrated non-inferiority of VBT compared to EBRT with no significant difference in vaginal or locoregional recurrence, overall survival, and disease-free survival. However, it did show a significant decrease in grade 1-2 gastrointestinal toxicities in the VBT group. VBT is now the standard of care given its decreased toxicity but is also notably less time-consuming for patients. Our objective was to identify if there was a difference in the administration of VBT versus EBRT for endometrial cancer patients post-hysterectomy in rural versus urban locations. <b>Methods:</b> This is a retrospective cohort study based on the SEER 18 dataset of the US National Cancer Institute. Women with localized endometrial cancer post-hysterectomy were included in this study. The SEER dataset defines a localized tumor as a tumor confined to the organ of origin without extending beyond the primary organ. Data were collected from 2011 to 2018, given that PORTEC-2 was published in 2010. Urban versus rural population was defined by the rural-urban continuum codes. Women were excluded if they received both VBT and EBRT or if a rural-urban continuum code was not provided. Statistical analysis was completed with relative risk and confidence interval calculation. <b>Results:</b> In total, 10,840 women were included. There were 9813 women identified in metropolitan counties; 22% (<i>n</i>=2136) received EBRT post-hysterectomy for localized endometrial cancer, whereas 78% underwent VBT. There were 1027 women identified in nonmetropolitan counties, 22% (<i>n</i>=230) received EBRT and 78% (<i>n</i>=797) received VBT. When comparing metropolitan versus nonmetropolitan counties, there was no statistical difference between rates of EBRT versus VBT, with a relative risk of 1.16 (95% CI: 0.91-1.16, p=0.64). There were 125 women identified in completely rural counties, 21% (<i>n</i>=26) received EBRT and 79% (<i>n</i>=99) received VBT. There was no statistical difference in rates of radiation therapy between completely rural and metropolitan counties, with a relative risk of 0.95 (95% CI: 0.67-1.34, p=0.77). <b>Conclusions:</b> Living in a nonmetropolitan county or even a completely rural county was not associated with a difference in receiving EBRT versus VBT in patients with localized endometrial cancer status post-hysterectomy compared to rates in metropolitan counties. It could be inferred that even though rural counties may have fewer medical resources, patients are still receiving the standard of care in regard to radiation therapy for endometrial cancer.

664 Laparoscopic sentinel lymph node dissection in patients with high-intermediate risk endometrial cancer and serious comorbidity

Introduction and aims of the study: Sentinel lymph node dissection (SLND) is an alternative procedure in surgical staging of patients with intermediate risk endometrial cancer. Data about use of this technique in patients with high-intermediate risk endometrial cancer and serious comorbidity is insufficient. Methods: The retrospective study included 24 patients with high intermediate risk endometrial cancer (endometrioid adenocarcinoma FIGO stage IA, grade 3 (n=15) and stage IA, grade 1-2, LVSI+ (n=9).

High-intermediate risk endometrial cancer: moving toward a molecularly based risk assessment profile.

In the USA, endometrial cancer (EMCA) incidence is increasing as the risk factors of obesity, diabetes, and hypertension become more prevalent. Although most EMCA is detected at an early stage and surgical intervention is curative, a subset of patients termed 'high-intermediate risk' (H-IR) experience an increased rate of recurrence. Unfortunately, adjuvant therapies in patients with H-IR EMCA have yet to increase overall survival. Historically, stratification of these patients from their low-risk counterparts incorporated clinical and pathologic findings. However, due to developments in molecular testing and genomic sequencing, tumor biomarkers are now being incorporated into the risk-assessment criteria in the hope of finding molecular profile(s) that could highlight treatment regimens that will increase patient survival. Since modern research aims to accurately identify patients with a higher risk of recurrence and develop effective interventions to improve patient survival, these molecular-based analyses could allow for an enhanced understanding of a patient's true risk of recurrence to facilitate the rise of personalized medicine. This review summarizes key clinical trials and recent advances in molecular and genomic profiles that have influenced current treatment regimens for patients with H-IR EMCA and laid the foundation for subsequent research.

Quality of life and sexual functioning among endometrial cancer patients treated with one week adjuvant high-dose-rate vaginal brachytherapy schedule.

PurposeTo examine quality of life (QOL) and sexual functioning in a series of patients with intermediate- and high-intermediate risk endometrial cancer, treated with exclusive adjuvant one week high-dose-rate (HDR) vaginal brachytherapy (VBT) schedule.Material and methodsBetween July 2008 and October 2013, 55 patients with diagnosis of endometrial cancer were treated with adjuvant exclusive VBT. All patients had undergone surgical treatment with a laparotomy approach before VBT. Post-operative VBT was administered 6-8 weeks after surgery. Treatment was delivered to vaginal vault using Nucletron HDR unit with iridium-192 source at a dose of 21 Gy/3 fractions of 7 Gy each, three times a week, every other day, prescribed at 0.5 cm depth of vaginal wall, and 3 cm in length from the apex. QOL was assessed using European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire Core-30 (QLQ-C30), and EORTC cancer-specific quality of life questionnaire (QLQ-CX24).ResultsMedian follow-up time was 92 months (range, 42-162 months). Questionnaires were carried out respectively at 1, 3, 6, 12, 24, 36, 48, and 60 months after the end of BT. Response rate to questionnaires was 100% (n = 55). Nineteen patients (35%) answered all the questions of surveys, while 36 patients (65%) completed the surveys, except for questions on sex activity, vaginal function, and sex enjoyment. Longitudinal analysis during 5-year follow-up period showed a statistically significant trend towards worsening of fatigue, constipation, and diarrhea. Overall physical functioning and role functioning was not impaired after VBT. Over the time, sex enjoyment improved, except for elderly patients. For emotional functioning, sex worry and social functioning presented no significant time-related effect.ConclusionsOne week brachytherapy schedule to vaginal cuff is generally well-tolerated. QOL does not worsen after applying vaginal brachytherapy.

Identifying a molecular profile to predict the risk of recurrence in high-intermediate risk endometrial cancer.

BackgroundPatients with high‐intermediate risk endometrial cancer (H‐IR EMCA) have an elevated risk of recurrence compared to low‐risk counterparts. Many H‐IR EMCA patients are treated with radiation or chemotherapy, but their overall survival is not significantly impacted by treatment. The objective of this study was to compare molecular profiles of H‐IR EMCA patients with disease recurrence to those without to identify characteristics that could better predict patient outcomes.MethodsTissue was acquired from H‐IR EMCA patients with disease recurrence (n=15) and without disease recurrence (n=15) who had not received adjuvant therapy and performed DNA and RNA analyses.ResultsIn recurrent population, 5 patients had matchingrecurrent and initial tumor tissues. Of note, 5/7 (71%) African Americanpatients had disease recurrence compared to 10/23 (43%) White patients. Inaddition, several new mutations were found in individual patient’s recurrentcompared to initial tumors.ConclusionsCurrently the treatment ofendometrial cancer is rapidly changing with molecular profiling becoming partof the standard of care. Additionally, it and is being incorporated intoclinical trials in this group of patients. The specific gene mutations and RNAexpression signatures that were observed in our small cohort need to bevalidated in larger cohorts to determine their impact.

Effect of mismatch repair protein status on outcomes in high intermediate risk endometrial cancer

<h3>Objectives:</h3> To compare recurrence rates between patients with mismatch repair proficient (pMMR) and MMR deficient (dMMR) high intermediate risk (HIR) endometrial cancer <h3>Methods:</h3> Adult women with HIR endometrial cancer diagnosed between January 1, 2016, and December 31, 2018, were identified from UC San Diego and Kaiser Southern California. Patient and disease characteristics were collected by chart review. Cases were limited to those who underwent hysterectomy with endometrioid histology and stage 1 disease. HIR disease was defined as the presence of three risk factors if age < 50 years, two risk factors if age ≥50 and <70 years, and one risk factor if age ≥70 years. Risk factors included tumor grade 2 or 3, the presence of lymphovascular space invasion (LVSI), and ≥50% myometrial invasion as outlined in GOG protocol 249. Categorical variables were compared using Chi-square tests, and continuous variables were compared using Student's t-test. The Kaplan-Meier method was used to evaluate time to recurrence. Assuming a two-sided alpha error of 0.05, power calculation identified a sample size of 174 would be needed to detect a 0.15 difference in recurrence rates between cohorts with 80% power. <h3>Results:</h3> Two hundred forty-four patients with HIR endometrial cancer were identified during the study period. One hundred fifty-eight patients (65%) were pMMR by immunohistochemical staining, and 86 patients (35%) were dMMR. There were no differences in mean age, mean body mass index (BMI), race, grade, mean follow-up time, or type of adjuvant treatment received between the pMMR versus dMMR cohorts. In total, 40 (16%) patients experienced cancer recurrence, and there were 11 (4.5%) cancer-related deaths during the study period. There was no statistically significant difference in recurrence rates between the pMMR and dMMR cohorts (15% versus 19%, p=0.49). The lack of association between MMR status and recurrence persisted after controlling for depth of myometrial invasion and LVSI in logistic regression multivariable analysis. pMMR tumors were more likely to exhibit ≥50% myometrial invasion than patients with dMMR tumors (p=0.03). dMMR tumors were significantly more likely to exhibit LVSI than pMMR tumors (p<0.001). There was no statistically significant association between the type of adjuvant treatment received and MMR status among those who recurred (p=0.58). Among patients who recurred, site of first recurrence (local vs distant) was not associated with MMR status (p=.90). The mean time to recurrence was 531 days in the pMMR cohort (n=24) and 473 days in the dMMR cohort (n=16), which was not significantly different (p=0.28). <h3>Conclusions:</h3> Our analysis represents one of the largest recurrence rate analyses of HIR endometrial cancer as stratified by MMR status. Although our pMMR and dMMR patient cohorts with HIR did not differ with respect to patient characteristics, dMMR tumors were significantly more likely to have <50% myometrial invasion and to exhibit LVSI. Despite these differences, we observed no difference in recurrence rates or time to recurrence between the two groups, which is in contrast to previously published reports of better prognosis among patients with pMMR tumors. Further study is ongoing to evaluate the effect of mismatch repair status on treatment selection and patient outcomes.

Effect of surgical approach on risk of recurrence after vaginal brachytherapy in early-stage high-intermediate risk endometrial cancer

Objectives: The objective was to determine if surgical approach affects time to recurrence in early-stage high-intermediate risk endometrial cancer (HIR-EC) treated with adjuvant vaginal brachytherapy (VBT). Methods: In this retrospective cohort study, HIR-EC patients treated with VBT between 2005-2017 were identified and those who received open or minimally invasive hysterectomies (MIS) were included. Clinical and surgical variables were analyzed and time to recurrence was compared between surgical groups. Results: We identified 494 patients, of which 363 had MIS hysterectomies, 92.5% had endometrioid histology, 45.7% were stage IA and 48.0% stage IB. Open hysterectomy patients had higher BMIs (p=0.007), lower rates of lymph node sampling (p<0.001) and lymphovascular space invasion (LVSI) (p=0.036), however in patients who recurred, no differences were noted between groups. Overall, 65 patients (13.2%) recurred, 14 in the open group (10.7%) and 51 in the MIS group (14.0%) (p=0.58), while vaginal recurrences were noted in 4.6% and 6.1% respectively. When compared to the open group, the MIS group had a significantly shorter time to any recurrence (p=0.022), to pelvic (p=0.05) and locoregional recurrence (p=0.021) and to death from any cause (p=0.039). After adjusting for age, BMI, grade, LVSI and surgery date, the MIS group had a higher risk of any recurrence (HR 2.29 (1.07-4.92), p=0.034) and locoregional recurrence (HR 4.18 (1.44-12.1), p=0.008). Conclusions: Patients with HIR-EC treated with VBT after MIS hysterectomy have a shorter time to recurrence and higher risk of recurrence when compared to open hysterectomy patients. Further studies into the safety of MIS in high-intermediate risk patients are required. The objective was to determine if surgical approach affects time to recurrence in early-stage high-intermediate risk endometrial cancer (HIR-EC) treated with adjuvant vaginal brachytherapy (VBT). In this retrospective cohort study, HIR-EC patients treated with VBT between 2005-2017 were identified and those who received open or minimally invasive hysterectomies (MIS) were included. Clinical and surgical variables were analyzed and time to recurrence was compared between surgical groups. We identified 494 patients, of which 363 had MIS hysterectomies, 92.5% had endometrioid histology, 45.7% were stage IA and 48.0% stage IB. Open hysterectomy patients had higher BMIs (p=0.007), lower rates of lymph node sampling (p<0.001) and lymphovascular space invasion (LVSI) (p=0.036), however in patients who recurred, no differences were noted between groups. Overall, 65 patients (13.2%) recurred, 14 in the open group (10.7%) and 51 in the MIS group (14.0%) (p=0.58), while vaginal recurrences were noted in 4.6% and 6.1% respectively. When compared to the open group, the MIS group had a significantly shorter time to any recurrence (p=0.022), to pelvic (p=0.05) and locoregional recurrence (p=0.021) and to death from any cause (p=0.039). After adjusting for age, BMI, grade, LVSI and surgery date, the MIS group had a higher risk of any recurrence (HR 2.29 (1.07-4.92), p=0.034) and locoregional recurrence (HR 4.18 (1.44-12.1), p=0.008). Patients with HIR-EC treated with VBT after MIS hysterectomy have a shorter time to recurrence and higher risk of recurrence when compared to open hysterectomy patients. Further studies into the safety of MIS in high-intermediate risk patients are required.

Clinicopathologic evaluation of CTNNB1 gene mutations in high-intermediate risk endometrial cancer

<h3>Objectives:</h3> <i>CTNNB1</i> mutations convey increased risk of recurrence in low risk endometrioid endometrial cancers. However, sub-analyses of high-intermediate risk (HIR) endometrioid endometrial cancers in other cohorts have not demonstrated a clearly increased recurrence risk and have often been equivocal. The objective of this study is to perform a clinicopathologic evaluation of patients with HIR endometrioid endometrial cancer in relation to <i>CTNNB1</i> mutational status. <h3>Methods:</h3> A single-institution chart review of patients diagnosed with endometrioid endometrial cancer between 2006 and 2018 was undertaken. Patients were classified as HIR according to GOG249 criteria. Mutational status was determined by Sanger sequencing of exon 3 of the <i>CTNNB1</i> gene in primary tumor specimens. Immunohistochemical (IHC) analysis of B-catenin was performed to evaluate for the presence of nuclear staining. Factors associated with recurrence were assessed by logistic regression; recurrence-free (RFS) and overall survival (OS) were assessed by Kaplan-Meier survival analysis. <h3>Results:</h3> 93 cases of HIR endometrioid endometrial cancer were identified, of which 23 (24.7%) were <i>CTNNB1</i> mutant and 70 (75.3%) were wild type. Median follow-up was 59.7 months. Recurrence occurred in 14/93 (15.1%) patients. Recurrence rates were not significantly different between patients with <i>CTNNB1</i> mutant and wild type tumors (13.0% vs. 15.9%, p=0.76). In both univariable and multivariable analyses, RFS and OS were not significantly different (RFS HR 0.88, p=0.85, 95% CI 0.24 - 3.17; OS HR 0.20, p=0.12, 95% CI 0.03 - 1.54). Predicted oncogenic mutations comprised 87% of all identified mutations and were present in 100% of recurrent tumors and 85% of non-recurrent tumors (p=0.47). Nuclear B-catenin expression by IHC demonstrated a sensitivity of 87% and a specificity of 83% for <i>CTNNB1</i> mutations. <h3>Conclusions:</h3> <i>CTNNB1</i> mutations have a prevalence of 25% in HIR endometrioid endometrial cancer. In this single institution retrospective study, there were no differences in RFS or OS in patients with <i>CTNNB1</i> mutant compared to wild-type tumors.

Not all high-intermediate risk endometrial cancers are created equal: recurrence-free survival and cause-specific survival after observation or vaginal brachytherapy in all possible subgroups of early-stage high-intermediate risk endometrial cancer

<h3>Objectives:</h3> Historically, patients with early-stage high-intermediate risk (HIR) endometrioid endometrial cancer (EC) have been known to benefit from improved recurrence-free survival (RFS) with the use of adjuvant therapy. However, specific subgroups of HIR patients may benefit from observation ± vaginal brachytherapy (VB) only. We sought to evaluate RFS and cause-specific survival (CSS) after observation ± VB in the subgroups of early-stage HIR endometrioid EC. <h3>Methods:</h3> We identified patients with early-stage HIR endometrioid EC, who underwent a total hysterectomy, bilateral salpingo-oopho-rectomy, and sentinel lymph node biopsy or pelvic ± paraaortic lymphadenectomy at Mayo Clinic and Cleveland Clinic between 1999 and 2016. HIR group was defined based on revised GOG99 criteria used in the GOG249 trial: age ≥70 with 1 risk factor, age ≥50 with 2 risk factors, or all the 3 risk factors (grade 2-3, ≥50% myometrial invasion, or positive lymphovascular space invasion [LVSI]). HIR subgroups were determined by all possible combinations of risk factors, and 3-year RFS, site-specific RFS, and CSS were estimated. <h3>Results:</h3> Among 1,507 women with stage I or II EC, 447 stage I endometrioid EC patients were identified who fulfilled HIR criteria, and 349 (78.1%) were managed with observation ± VB. Eleven subgroups were defined and evaluated (Table). Among stage IA patients (1-5 subgroups), subgroup 5 (G3 ≥50y LVSI+) had the lowest RFS and CSS of 68.9% (46.6-100.0%) and 86.7% (71.1-100.0%), respectively, whereas the remaining 4 subgroups had 3-year RFS and CSS >90%. In all stage IA subgroups, 3-year lymphatic RFS was >90%; 3-year distant RFS was lowest in subgroup 5 (79.6% [56.9-100.0%] and 97.1% [91.8-100.0%] in subgroup 3 [G2 ≥50y LVSI+]). Additionally, 3-year CSS was <100% in these two subgroups (vs. 100% in subgroups 1, 2, and 4). Among the 6 stage IB subgroups (6-11), 3-year RFS ranged from 68.2% (48.6-95.7%) to 93.6% (87.7-99.9%) and 3-year CSS from 80.0% (58.7-100.0%) to 100.0% (100.0-100.0%). Lymphatic recurrence was observed in subgroup 8 (IB G2 ≥50y LVSI -), but site-specific RFS was >90%. Conversely, all stage IB subgroups experienced distant recurrence; 3-year distant RFS ranged from 73.1% (53.5-99.7%) to 96.5% (91.8-100.0%). 3-year distant RFS lower than 90% was observed in those subgroups with grade 3 or positive LVSI (7, 9, 10, and 11). <h3>Conclusions:</h3> Our results suggest that observation ± VB can be sufficient in some subgroups of stage I endometrioid HIR patients, specifically stage IA endometrioid HIR EC without the concomitant presence of grade 3 and LVSI. Among stage IB endometrioid HIR EC subgroups, particularly those with grade 3 or LVSI, observation ± VB is associated with lower RFS and CSS. Stratifying HIR patients into risk subgroups would alleviate the risk of overtreatment and undertreatment among patients with early-stage endometrioid EC; in this regard, the molecular characterization will provide a further instrument to achieve this objective.

A longitudinal study of the adherence to PORTEC-2 based adjuvant radiotherapy in high-intermediate-risk endometrial adenocarcinoma and associated oncologic outcomes.

e17570 Background: In 2010, Nout et al. reported on PORTEC-2, which randomized patients with high intermediate risk (HIR) endometrial cancer to adjuvant vaginal brachytherapy or pelvic radiotherapy or observation, and showed that vaginal brachytherapy was non-inferior in terms of locoregional control and was deemed the adjuvant treatment of choice for these patients. We sought to evaluate the adherence to and the oncologic outcomes of the PORTEC-2 regimen. Methods: We utilized the SEER database to identify patients who met PORTEC-2 inclusion criteria. All patients underwent surgery followed by either vaginal brachytherapy (VBT) or whole pelvic radiotherapy (WPRT). Inclusion criteria were patients with the following characteristics: grade 1 with ≥ 50% myometrial invasion (MI), grade 2 with any invasion, and grade 3 with &lt; 50% MI. Patients were excluded if any lymph nodes were examined or involved, if they received any chemotherapy, or had any missing values for any of the variables. HIR endometrial adenocarcinoma was defined as the presence of 2 of the following: age &gt; 60, grade 3, and ≥50% myometrial invasion. Radiation status was extracted from the SEER Radiation/Chemotherapy database. Outcomes were overall death, cancer specific death and total survival months per SEER’s standard definitions. Variables are reported as median and interquartile range (IQR) or number (%). Mean survival was calculated using Kaplan Meier analysis and Mantel-Cox rank test was done to test for statistical significance between the study groups. Cox regression analysis was performed, and hazard ratios (HR) were calculated. Statistical analysis was performed using SPSS v. 22.0. Results: Between 2005- 2015, 571 patients met PORTEC-2 inclusion criteria of whom 349 (61.1%) and 222 (38.9%) received WPRT and VBT, respectively. We showed that the rate of VBT was significantly increased from 85 (27.4%) between 2005-2010 to 137 (52.5%) between 2011-2015 (p &lt; 0.001). There was no difference in grade and myometrial invasion between the study groups. Kaplan Meier analysis showed a 22.5 and 16.3 month improvement in overall and cancer specific survival in subjects who underwent VBT as compared to WPRT, respectively (p &lt; 0.001 for both). Cox regression analysis revealed a 36% and 66% decrease in the hazard of overall and cancer specific death, respectively, in the VBT group as compared to WPRT group (Overall death: HR = 0.64, 95% CI: 0.45-0.91, p = 0.012; Cancer specific death: HR = 0.34, 95% CI: 0.16-0.73, p = 0.006). Conclusions: Administration of vaginal brachytherapy following surgery has become significantly more popular after publication of the PORTEC-2 results in 2010. Our study shows a significant decrease in both overall and cancer related death and an increase in survival with VBT over WPRT in patients with HIR endometrial cancer.

Abstract PO014: Clinicopathologic evaluation of CTNNB1 gene mutations in high-intermediate risk endometrial cancer

Abstract Background: CTNNB1 mutations convey increased risk of recurrence in low risk endometrioid endometrial cancers. However, sub-analyses of high-intermediate risk (HIR) endometrioid endometrial cancers in other cohorts have not demonstrated a clearly increased recurrence risk and have often been equivocal. The objective of this study is to perform a clinicopathologic evaluation of patients with HIR endometrioid endometrial cancer in relation to CTNNB1 mutational status. Methods: A single-institution chart review of patients diagnosed with endometrioid endometrial cancer between 2006 and 2018 was undertaken. Patients were classified as HIR according to GOG249 criteria. Mutational status was determined by Sanger sequencing of exon 3 of the CTNNB1 gene in primary tumor specimens. Immunohistochemical (IHC) analysis of B-catenin was performed to evaluate for the presence of nuclear staining. Factors associated with recurrence were assessed by logistic regression; recurrence-free (RFS) and overall survival (OS) were assessed by Kaplan-Meier survival analysis. Results: 93 cases of HIR endometrioid endometrial cancer were identified, of which 23 (24.7%) were CTNNB1 mutant and 70 (75.3%) were wild type. Median follow-up was 54.7 months. Recurrence occurred in 14/93 (15.1%) patients. Recurrence rates were not significantly different between patients with CTNNB1 mutant and wild type tumors (13.0% vs. 15.9%, p=0.76). In both univariable and multivariable analyses, RFS and OS were not significantly different (RFS HR 0.88, p=0.85, 95% CI 0.24 – 3.17; OS HR 0.20, p=0.12, 95% CI 0.03 – 1.54). Predicted oncogenic mutations comprised 87% of all identified mutations and were present in 100% of recurrent tumors and 85% of non-recurrent tumors (p=0.47). Nuclear B-catenin expression by IHC demonstrated a sensitivity of 87% and a specificity of 83% for CTNNB1 mutations. Conclusions: CTNNB1 mutations have a prevalence of 25% in HIR endometrioid endometrial cancer. In this single institution retrospective study, there were no differences in RFS or OS in patients with CTNNB1 mutant compared to wild-type tumors. Citation Format: Jennifer G. Haag, Rebecca J. Wolsky, Marisa R. Moroney, Jamie Sheren, Jeanelle Sheeder, Benjamin G. Bitler, Bradley R. Corr. Clinicopathologic evaluation of CTNNB1 gene mutations in high-intermediate risk endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO014.