Endometrial Cancer-related Deaths Research Articles

Analysis of Risk Factors for Secondary Endometrial Cancer-Related Death: A SEER-Based Study.

The aim of this study was to analyze the survival of patients with endometrial cancer diagnosed after a prior cancer and identify risk factors of endometrial cancer death in this population. Totally 1371 women diagnosed with second primary endometrial cancer (SPEC) between 2004 and 2015 were identified using the SEER database. Clinicopathological characteristics were collected, and Fine and Gray regression model was employed to assess the impact of treatment for the first primary cancer (FPC) and SPEC on the mortality of endometrial cancer patients. After propensity score matching (PSM), patients diagnosed with single primary endometrial cancer and SPEC between 2004 and 2015 were included as the second cohort. Kaplan-Meier and Cox survival risk models were used to assess the influence of previous cancer history on survival. Patients previously diagnosed as lung cancer exhibited the lowest overall survival (OS). A diagnostic interval of ≥3 years was significantly associated with higher mortality from SPEC compared with that <3 years. Surgical treatment for SPEC was linked to a reduced risk of endometrial cancer-specific mortality (ECSM) and non-ECSM. Conversely, radiotherapy and chemotherapy were associated with an increased risk of ECSM. The 1-, 3-, and 5-year OS rates of patients with SPEC were significantly lower than those with single primary endometrial cancer whether before or after PSM. Univariate and multivariate analyses further demonstrated that endometrial cancer, either as FPC or SPEC, was independently associated with an increased risk for endometrial cancer-specific survival (ECSS) and OS. Chemotherapy and radiotherapy for SPEC can elevate the risk of ECSM. Whether as FPC or SPEC, endometrial cancer is demonstrated to be a significant independent risk factor for ECSS and OS.

Promising Therapeutic Impact of Immune Checkpoint Inhibitors in Type II Endometrial Cancer Patients with Deficient Mismatch Repair Status.

Type II endometrial cancer (EC) is responsible for most endometrial cancer-related deaths due to its aggressive nature, late-stage detection, and high tolerance to standard therapies. Thus, novel treatment strategies for type II EC are imperative. For patients with mismatch repair-deficient (dMMR) tumors, immunotherapy with immune checkpoint inhibitors represents a promising therapeutic strategy. However, the prevalence of dMMR tumors in type II EC patients remains unclear. In this study, using immunohistochemistry, we evaluated the expression of mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1) in 60 patients with type II EC (16, 5, 17, and 22 were endometrioid G3, serous, de-differentiated, and carcinosarcoma cases, respectively) to investigate the therapeutic effect of immune checkpoint inhibitors. Approximately 24 cases (40%) had a loss of MMR protein expression. The positivity rate of CD8+ (p = 0.0072) and PD-L1 (p = 0.0061) expression was significantly associated with the dMMR group. These results suggest immune checkpoint inhibitors (anti-PD-L1/PD-1 antibodies) could effectively treat type II EC with dMMR. The presence of dMMR might be a biomarker for a positive response to PD-1/PD-L1 immunotherapy in type II EC.

Phase II trial of maintenance niraparib in patients with stage III,stage IV or platinum-sensitive recurrent uterine serous carcinoma (330)

<b>Objectives:</b> Uterine serous carcinoma (USC) accounts for up to 40% of endometrial cancer-related deaths. Patients with USC share many genomic and clinical characteristics with serous ovarian cancer patients. This study aims to determine the efficacy of Niraparib in women with advanced or platinum-sensitive recurrent USC. We also aim to describe the safety profile of this regimen. We hypothesize that Niraparib maintenance will be a well-tolerated treatment and show a significant response in patients with USC. <b>Methods:</b> We are conducting a Phase II prospective non-randomized cohort study recruiting 45 patients with newly diagnosed stage III, IV, or platinum-sensitive recurrent USC who will receive 300 mg of Niraparib daily for one year or until disease progression. Dose reductions to 200 mg and 100 mg will be allowed based on treatment side effects. Newly diagnosed patients receive standard platinumbased treatment +/- radiation followed by Niraparib maintenance. Women with recurrent USC will receive platinum-based therapy followed by Niraparib maintenance. Platinum sensitivity is defined as achieving a complete or partial response and disease progression >6 months after completion of their last dose of platinum-based chemotherapy. Patients must have achieved a partial, stable, or complete tumor response following the last chemotherapy, minimal of 3 cycles, and physician choice of platinum-based regimen. Patients must be recruited within 12 weeks of completing chemotherapy or 14 weeks if they are receiving adjuvant radiation therapy. The primary outcome will be progression-free survival (PFS) at one year. Secondary outcomes include PFS at three years, treatment-related adverse events, quality of life measures using Functional Assessment of Cancer Therapy and EQ-5D-5L Euroqol, overall survival (OS), and overall response rate at 2 and 3 years. Mutational burden and loss of heterozygosity will be evaluated for all patients using FoundationOne testing. This trial will employ a Simon two-stage minimax design to test the null hypothesis that the one-year response rate is <20% (which would not be clinically meaningful) versus the alternative hypothesis that the one-year response rate is ≥40%. A treatment "success" will be defined as the patient being alive and progressionfree at one-year post-treatment. This design corresponds to testing the null hypothesis that the true objective response rate is 20% or less versus the alternative hypothesis that the true response rate is 40% or greater, with alpha=0.05 and power=0.90. To date, we have recruited six patients at Northwell and are opening additional sites for recruitment.

In Vivo and In Vitro Efficacy of Enhertu in Uterine Serous Carcinoma (047)

Objectives: Uterine serous carcinoma (USC) is an aggressive subtype of epithelial endometrial cancer, comprising approximately 40% of endometrial cancer-related deaths. HER2 overexpression is detected in about 35% of patients with USC. Enhertu is a novel humanized monoclonal anti-HER2 antibody (trastuzumab) linked to the topoisomerase I inhibitor payload deruxtecan by a cleavable linker. Enhertu is FDA-approved for HER2-expressing metastatic breast and gastric cancers; however, its efficacy has not been tested in endometrial cancer. The objective of this study was to study the in vitro and in vivo efficacy of Enhertu in USC. Methods: HER2 expression was analyzed with flow cytometry in primary USC cell lines: ARK2, ARK4, ARK7, and ARK20. Cell lines were treated with 0.05, 0.010, 0.025, 0.05, 0.2 μg/ml of Enhertu or Control antibody-drug conjugate (Control ADC). The inhibitory concentration 50 (IC50) was assessed by counting the viable cells using a flow cytometer. Apoptosis and necrosis were assessed with Annexin V and propidium iodide (PI) staining. GFP-expressing ARK4 (ARK4-GFP) cells were co-cultured with ARK2 cells for the bystander effect assay. For in vivo experiments, eight million ARK2 cells were injected subcutaneously into SCID mice. Animals were randomized to intravenous injection of PBS (n=5), control ADC (4 mg/kg, n=6) or Enhertu (4 mg/kg, n=5) treatment. Kruskal Wallis, Friedman, and Log Rank tests were used for statistical analysis. Graphical Abstract View Large Image Figure Viewer Download Hi-res image Graphical Abstract View Large Image Figure Viewer Download Hi-res image Conclusions: Enhertu showed significant preclinical efficacy against HER2 overexpressing uterine serous carcinoma cell lines. Further clinical trials in USC are warranted. Objectives: Uterine serous carcinoma (USC) is an aggressive subtype of epithelial endometrial cancer, comprising approximately 40% of endometrial cancer-related deaths. HER2 overexpression is detected in about 35% of patients with USC. Enhertu is a novel humanized monoclonal anti-HER2 antibody (trastuzumab) linked to the topoisomerase I inhibitor payload deruxtecan by a cleavable linker. Enhertu is FDA-approved for HER2-expressing metastatic breast and gastric cancers; however, its efficacy has not been tested in endometrial cancer. The objective of this study was to study the in vitro and in vivo efficacy of Enhertu in USC. Methods: HER2 expression was analyzed with flow cytometry in primary USC cell lines: ARK2, ARK4, ARK7, and ARK20. Cell lines were treated with 0.05, 0.010, 0.025, 0.05, 0.2 μg/ml of Enhertu or Control antibody-drug conjugate (Control ADC). The inhibitory concentration 50 (IC50) was assessed by counting the viable cells using a flow cytometer. Apoptosis and necrosis were assessed with Annexin V and propidium iodide (PI) staining. GFP-expressing ARK4 (ARK4-GFP) cells were co-cultured with ARK2 cells for the bystander effect assay. For in vivo experiments, eight million ARK2 cells were injected subcutaneously into SCID mice. Animals were randomized to intravenous injection of PBS (n=5), control ADC (4 mg/kg, n=6) or Enhertu (4 mg/kg, n=5) treatment. Kruskal Wallis, Friedman, and Log Rank tests were used for statistical analysis. Conclusions: Enhertu showed significant preclinical efficacy against HER2 overexpressing uterine serous carcinoma cell lines. Further clinical trials in USC are warranted.

Adjuvant therapy in early uterine serous carcinoma (324)

<b>Objectives:</b> Uterine serous carcinomas represent approximately 10% of all endometrial cancers but are responsible for nearly 40% of all endometrial cancer-related deaths. Given the relatively low incidence of this disease, there are limited prospective data to guide adjuvant treatment decisions in early-stage disease. The purpose of this study was to evaluate the impact of adjuvant therapy on recurrence-free and overall survival in women with stage I-II pure uterine serous carcinoma. <b>Methods:</b> IRB approval was obtained. Using an institutional pathology database, we retrospectively identified all patients with 2009 FIGO stage I and II pure uterine serous carcinoma treated at a single institution from January 2006 to December 2019. Demographic, clinical-pathologic, treatment, and outcome data were collected using the electronic medical record. Serous histology was confirmed by a gynecologic pathologist, and only cases of pure uterine serous histology were included. Data were compared using descriptive statistics. Survival analyses were performed using Kaplan-Meier and Cox proportional hazard methods. <b>Results:</b> Ninety-four patients meeting inclusion criteria were identified with a median follow-up time of 33.5 months. The median age was 68 years (range: 49-87), the majority of patients were White (<i>n</i>=78, 83.0%), and the median BMI was 30.7 (range: 14.2-57.3). The minimally-invasive surgical staging was performed in 59.6% of cases (<i>n</i>=56). Most patients had stage IA disease (<i>n</i>=70, 74.5%), and lymphadenectomy was performed in 90.4% of cases (<i>n</i>=85). Most patients (<i>n</i>=79, 84.0%) received adjuvant therapy, and a majority of patients received a combination of systemic chemotherapy and radiation therapy (<i>n</i>=55, 58.5%), with the most common combination being chemotherapy plus vaginal brachytherapy (<i>n</i>=42, 44.7%). Most patients (<i>n</i>=77, 81.9%) remained without evidence of recurrent disease at the most recent follow-up, while 17 patients (18.1%) had experienced recurrence. Patients who received six cycles of adjuvant chemotherapy experienced improved overall survival (p=0.004) and improved recurrence-free survival (p=0.02) compared to those who received no adjuvant chemotherapy. <b>Conclusions:</b> Patients with surgically staged early pure serous uterine carcinoma who received six cycles of adjuvant chemotherapy had significantly improved overall and recurrence-free survival compared to those who did not receive adjuvant chemotherapy.

PLK3 amplification and tumor immune microenvironment of metastatic tumors are linked to adjuvant treatment outcomes in uterine serous cancer.

Uterine serous carcinoma (USC), an aggressive variant of endometrial cancer representing approximately 10% of endometrial cancer diagnoses, accounts for ∼39% of endometrial cancer-related deaths. We examined the role of genomic alterations in advanced-stage USC associated with outcome using paired primary-metastatic tumors (n = 29) treated with adjuvant platinum and taxane chemotherapy. Comparative genomic analysis of paired primary-metastatic patient tumors included whole exome sequencing and targeted gene expression. Both PLK3 amplification and the tumor immune microenvironment (TIME) in metastatic tumors were linked to time-to-recurrence (TTR) risk without any such association observed with primary tumors. TP53 loss was significantly more frequent in metastatic tumors of platinum-resistant versus platinum-sensitive patients and was also associated with increased recurrence and mortality risk. Increased levels of chr1 breakpoints in USC metastatic versus primary tumors co-occur with PLK3 amplification. PLK3 and the TIME are potential targets for improving outcomes in USC adjuvant therapy.

Metabolomic Analysis Points to Bioactive Lipid Species and Acireductone Dioxygenase 1 (ADI1) as Potential Therapeutic Targets in Poor Prognosis Endometrial Cancer.

Simple SummaryUterine serous carcinoma is considered a rare and aggressive variant of endometrial cancer that accounts for 10% of all endometrial cancers diagnosed but is responsible for 40% of endometrial cancer-related deaths. Unfortunately, current treatments for serous endometrial carcinoma are ineffective. Therefore, there is a need to find new therapeutic targets. The aim of this study was to analyse the metabolic profile of serous cancer in order to identify new molecules and thereby define potential therapeutic targets. We observed that most of the differential metabolites are lipid species (suggesting the important role of the lipid metabolism). In addition, we found an increase in 2-Oxo-4-methylthiobutanoic acid (synthesised by the ADI1 enzyme) in serous carcinomas. Using public database analysis and immunohistochemistry, we established a correlation between elevated ADI1 levels and serous carcinoma. Furthermore, the ectopic modification of ADI1 expression in vitro revealed the ability of ADI1 to induce pathological cell migration and invasion capabilities.Metabolomic profiling analysis has the potential to highlight new molecules and cellular pathways that may serve as potential therapeutic targets for disease treatment. In this study, we used an LC-MS/MS platform to define, for the first time, the specific metabolomic signature of uterine serous carcinoma (SC), a relatively rare and aggressive variant of endometrial cancer (EC) responsible for 40% of all endometrial cancer-related deaths. A metabolomic analysis of 31 ECs (20 endometrial endometrioid carcinomas (EECs) and 11 SCs) was performed. Following multivariate statistical analysis, we identified 232 statistically different metabolites among the SC and EEC patient samples. Notably, most of the metabolites identified (89.2%) were lipid species and showed lower levels in SCs when compared to EECs. In addition to lipids, we also documented metabolites belonging to amino acids and purine nucleotides (such as 2-Oxo-4-methylthiobutanoic acid, synthesised by acireductone dioxygenase 1 (ADI1) enzyme), which showed higher levels in SCs. To further investigate the role of ADI1 in SC, we analysed the expression protein levels of ADI1 in 96 ECs (67 EECs and 29 SCs), proving that the levels of ADI1 were higher in SCs compared to EECs. We also found that ADI1 mRNA levels were higher in p53 abnormal ECs compared to p53 wild type tumours. Furthermore, elevated ADI1 mRNA levels showed a statistically significant negative correlation with overall survival and progression-free survival among EEC patients. Finally, we tested the ability of ADI1 to induce migration and invasion capabilities in EC cell lines. Altogether, these results suggest that ADI1 could be a potential therapeutic target in poor-prognosis SCs and other Ecs with abnormal p53 expression.

983P - Risk of cancer associated death in younger vs older patients with FIGO stage I endometrial cancer

Background: Although age is considered a traditional risk factor for relapse in stage I endometrial cancer, whether it impacts endometrial cancer-related death is unclear. We aimed to assess disease risk factors, overall survival (OS), disease-free survival (DFS), and cancer-specific survival, in patients > =70 (OP) vs. <70 (YP) years of age with or without adjuvant therapy. Methods: We reviewed medical records of all patients who underwent surgery for stage I endometrial cancer between 2000 and 2013 in British Columbia, Canada. Descriptive, logistic regression, multivariate Cox regression and competing risks analyses were used to evaluate patient outcomes. Results: 365 OP and 1063 YP were included (n = 1428). No significant differences were found between OP and YP with regards to disease risk factors such as stage IB disease and lymphovascular invasion (LVI). However, OP had higher odds of non-endometrioid histology (OR 1.88, p < 0.001). 22 (6%) OP and 78 (7.3%) YP received adjuvant chemotherapy (CT); 120 (32.9%) OP and 290 (27.3%) YP received adjuvant radiotherapy (RT). When adjusted for histology, LVI and grade, YP were more likely to receive CT (OR 2.10, p = 0.009); no significant difference in odds of receiving RT was found between YP and OP (OR 0.86, p = 0.33). OP experienced higher odds of relapse (OR 1.95, p = 0.001) and worse OS (HR 4.12, p < 0.001) and DFS (HR 2.18, p < 0.001) than YP after adjusting for risk factors. 10-year OS (endometrioid: 61.9 vs 89.2%; non-endometrioid: 46.1 vs 85.8%, p < 0.001) and DFS (endometrioid: 86.7 vs 91.9%; non-endometrioid: 69.6 vs 84.5%, p < 0.001) were worse for OP. Controlling for risk factors, OP experienced a higher incidence of endometrial cancer-related death than YP (HR = 2.09, p < 0.001). Conclusions: In patients with stage I endometrial cancer, patients > =70 years had higher odds of having non-endometrioid histology as well as relapse and death due to endometrial cancer, yet were less likely to receive adjuvant CT. Appropriate adjuvant therapy should be considered regardless of age, as recurrent disease is still a significant cause of mortality in older patients with stage I endometrial cancer. Legal entity responsible for the study: BC Cancer. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late.

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

The Effect of Adenomyosis in Myometrial Invasion and Overall Survival in Endometrial Cancer.

The aim of this study was to evaluate whether adenomyosis had an effect on myometrial tumor invasion, stage of the disease, and survival in endometrial cancer. Endometrial cancer patients encountered between 2007 and 2016 were identified from pathology records. Patients who underwent suboptimal surgical or medical treatment or with insufficient clinical or surgical data were excluded. Patients diagnosed as having concurrent adenomyosis constituted the study group. Control group patients were randomly selected in a paired design according to the tumor grades in the study group, and for each tumor grade, 4 times as many as patients were included. Tumor stage, histologic type and grade, myometrial invasion, lymphovascular space invasion, presence and location of the adenomyosis in myometrial wall, distance from endometrial line, tumor in adenomyosis, adjuvant treatment, and relapse were primary outcomes.Age, body mass index, medical comorbidities, and type of operation were also recorded. Univariate and multivariate Cox proportional hazards regression models were performed for overall survival. Of those 1242 endometrial cancer patients, 80 with concurrent adenomyosis were identified and compared with 320 patients without adenomyosis following a paired selection based on tumor grade. Higher rates of myometrial invasion, lymphovascular space invasion, tumor diameter, and adjuvant treatments were found in the nonadenomyosis group compared with adenomyosis group (P ≤ 0.001). In patients with adenomyosis, rates of early-stage disease and overall survival were significantly higher compared with the control group (P = 0.001 and 0.01, respectively). Our results showed that adenomyosis is significantly associated with lower stage in endometrial cancer that may suggest a possible limiting effect on endometrial cancer spread. In addition, despite similar rates in disease-free survival and endometrial cancer-related death, overall survival rate was significantly higher in the presence of adenomyosis and might be considered as a good prognostic factor for endometrial cancer.

Final results of the international randomized PORTEC-3 trial of adjuvant chemotherapy and radiation therapy (RT) versus RT alone for women with high-risk endometrial cancer.

5502 Background: Women with high-risk endometrial cancer (HREC) are at increased risk of distant metastasis and endometrial cancer-related death. The randomized PORTEC-3 intergroup trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (CTRT) versus pelvic radiotherapy (RT) alone for women with HREC. Methods: Women with HREC (FIGO stage I grade 3 with deep myometrial invasion and/or LVSI; stage II or III; or serous/clear cell histology) were randomly allocated (1:1) to RT (48.6 Gy in 1.8 Gy fractions) or CTRT (two cycles of cisplatin 50 mg/m² in week 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² at 3-week intervals) with stratification for participating center, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival (OS) and failure-free survival (FFS). The Kaplan-Meier method, log-rank test and Cox regression analysis were used for final analysis according to intention-to-treat. PORTEC-3 is registered with ISRCTN (ISRCTN14387080) and ClinicalTrials.gov (NCT00411138). Results: 686 women were enrolled between 2006 and 2013. 26 women were excluded; 13 withdrew consent early and 13 were ineligible, which left 660 patients in the analysis, with a median follow up time of 60.2 months (IQR 47.1–72.9): 330 CTRT and 330 RT. Three- and five-year OS for CTRT vs. RT was 84.4% versus 83.9%, and 81.8% versus 76.7%; overall HR 0.79 [95% CI 0.57-1.12, p=0.183]. Three-year FFS was 79.7% (CTRT) versus 71.8% (RT), and at 5 years 75.5% versus 68.9%, overall HR for FFS 0.77 [0.58-1.03, p=0.078]. Patients with stage III EC had lower 5-year FFS and OS compared to stage I-II (FFS 63.9% vs 78.9%, p&lt;0.001, and OS 74.3% vs 83.1%, p=0.003). They also had greatest benefit of CTRT: 5-year FFS for stage III was 69.3% for CTRT vs 58.0% for RT [95% CI 0.45-0.97, p=0.032], and 5-year OS for stage III was 78.7 % vs 69.8% (p=0.114). Conclusions: Adjuvant chemotherapy given during and after pelvic radiotherapy for treatment of HREC did not significantly improve 5-year FFS and OS, compared with RT alone. For women with stage III EC FFS was however significantly improved with CTRT by 11% at 5 years. Follow-up will continue to evaluate long-term outcomes. Clinical trial information: NCT00411138.

Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial

About 15% of patients with endometrial cancer have high-risk features and are at increased risk of distant metastases and endometrial cancer-related death. We designed the PORTEC-3 trial to investigate the benefit of adjuvant chemoradiotherapy compared with radiotherapy alone for women with high-risk endometrial cancer. PORTEC-3 was a multicentre, open-label, randomised, international trial. Women with high-risk endometrial cancer were randomly allocated (1:1) to radiotherapy alone (48·6 Gy) in 1·8 Gy fractions five times a week or chemoradiotherapy (two cycles concurrent cisplatin 50 mg/m(2) and four adjuvant cycles of carboplatin area under the curve [AUC] 5 and paclitaxel 175 mg/m(2)) using a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The primary endpoints of the PORTEC-3 trial were overall survival and failure-free survival analysed in the intention-to-treat population. This analysis focuses on 2-year toxicity and health-related quality of life as secondary endpoints; analysis was done according to treatment received. Health-related quality of life was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) the cervix cancer module and chemotherapy and neuropathy subscales of the ovarian cancer module at baseline, after radiotherapy and at 6, 12, 24, 36, and 60 months after randomisation. Adverse events were graded with Common Terminology Criteria for Adverse Events version 3.0. The study was closed on Dec 20, 2013, after achieving complete accrual, and follow-up remains ongoing for the primary outcomes analysis. This trial is registered with ISRCTN.com, number ISRCTN14387080, and with ClinicalTrials.gov, number NCT00411138. Between Sept 15, 2006, and Dec 20, 2013, 686 women were randomly allocated in the PORTEC-3 trial. Of these, 660 met eligibility criteria, and 570 (86%) were evaluable for health-related quality of life. Median follow-up was 42·3 months (IQR 25·8-55·1). At completion of radiotherapy and at 6 months, EORTC QLQ-C30 functioning scales were significantly lower (worse functioning) and health-related quality of life symptom scores higher (worse symptoms) for the chemoradiotherapy group compared with radiotherapy alone, improving with time. At 12 and 24 months, global health or quality of life was similar between groups, whereas physical functioning scores remained slightly lower in patients who received chemoradiotherapy compared with patients who received radiotherapy alone. At 24 months, 48 (25%) of 194 patients in the chemoradiotherapy group reported severe tingling or numbness compared with 11 (6%) of 170 patients in the radiotherapy alone group (p<0·0001). Grade 2 or worse adverse events were found during treatment in 309 (94%) of 327 patients in the chemoradiotherapy group versus 145 (44%) of 326 patients in the radiotherapy alone group, and grade 3 or worse events were found in 198 (61%) of 327 patients in the chemoradiotherapy group versus 42 (13%) of 326 patients in the radiotherapy alone group (p<0·0001), with most of the grade 3 adverse events being haematological (45%). At 12 and 24 months, no significant differences in grade 3 or worse adverse events were found between groups; only grade 2 or higher sensory neuropathy adverse events persisted at 24 months (25 [10%] of 240 patients in the chemoradiotherapy group vs one [<1%] of 247 patients in the radiotherapy alone group; p<0·0001). Despite the increased physician and patient-reported toxicities, this schedule of adjuvant chemotherapy given during and after radiotherapy in patients with high-risk endometrial cancer is feasible, with rapid recovery after treatment, but with persistence of patient-reported sensory neurological symptoms in 25% of patients. We await the analysis of primary endpoints before final conclusions are made. Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and Canadian Cancer Society Research Institute.

Endometrial cancer in morbidly obese women: Do racial disparities affect surgical or survival outcomes?

ObjectiveEndometrial cancer mortality disproportionately affects black women and whether greater prevalence of obesity plays a role in this disparity is unknown. We examine the effect of race on post-surgical complications, length of stay, and mortality specifically in a morbidly obese population. MethodsBlack and white women with endometrial cancer diagnosed from 1996 to 2012 were identified from the University Pathology Group database in Detroit, Michigan, and records were retrospectively reviewed to obtain clinicopathological, demographic, and surgical information. Analysis was limited to those with a body mass index of 40kg/m2 or greater. Differences in the distribution of variables by race were assessed by chi-squared tests and t-tests. Kaplan–Meier and Cox regression analyses were performed to examine factors associated with mortality. Results97 white and 89 black morbidly obese women were included in this analysis. Black women were more likely to have type II tumors (33.7% versus 15.5% of white women, p-value=0.003). Hypertension was more prevalent in black women (76.4% versus 58.8%, p-value=0.009), and they had longer hospital stays after surgery despite similar rates of open vs minimally invasive procedures and lymph node dissection (mean days=5.4) compared to whites (mean days=3.5, p-value=0.036). Wound infection was the most common complication (16.5% in whites and 14.4% in blacks, p-value=0.888). Blacks were more likely to suffer other complications, but overall the proportions did not differ by race. In univariate analyses, black women had higher risk of endometrial cancer-related death (p-value=0.090). No racial differences were noted in adjusted survival analyses. ConclusionA more complete investigation, incorporating socio-demographic factors, is warranted to understand the effects of morbid obesity and race on endometrial cancer.

Adjuvant radiotherapy for stage I endometrial cancer.

This is an updated version of the original Cochrane review published in Issue 2, 2007. The role of radiotherapy (both pelvic external beam radiotherapy (EBRT) and vaginal intracavity brachytherapy (VBT)) in stage I endometrial cancer following hysterectomy remains controversial. To assess the efficacy of adjuvant radiotherapy following surgery for stage I endometrial cancer. We searched The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Specialised Register to end-2005 for the original review, and extended the search to January 2012 for the update. We included randomised controlled trials (RCTs) that compared post-operative adjuvant radiotherapy (either EBRTor VBT, or both) versus no radiotherapy or VBT in women with stage I endometrial cancer. Two review authors independently assessed trials and extracted data to a specifically designed data collection form. The primary outcome was overall survival. Secondary outcomes were endometrial cancer-related deaths, locoregional recurrence and distant recurrence. Meta-analyses were performed using Cochrane Review Manager Software 5.1. We included eight trials. Seven trials (3628 women) compared EBRT with no EBRT (or VBT), and one trial (645 women) compared VBTwith no additional treatment. We considered six of the eight trials to be of a high quality. Time-to-event data were not available for all trials and all outcomes.EBRT (with or without VBT) compared with no EBRT (or VBT alone) for stage I endometrial carcinoma significantly reduced locoregional recurrence (time-to-event data: five trials, 2965 women; Hazard Ratio (HR) 0.36, 95% Confidence Interval (CI) 0.25 to 0.52; and dichotomous data: seven trials, 3628 women; Risk Ratio (RR) 0.33, 95% CI 0.23 to 0.47). This reduced risk of locoregional recurrence did not translate into improved overall survival (time-to-event data: five trials, 2,965 women; HR 0.99, 95% CI 0.82 to1.20; and dichotomous data: seven trials, 3628 women; RR 0.98, 95% CI 0.83 to 1.15) or improved endometrial cancer-related survival (time-to-event data: five trials, 2965 women; HR 0.96, 95% CI 0.72 to 1.28; and dichotomous data: seven trials, 3628 women; RR 1.02, 95% CI 0.81 to 1.29) or improved distant recurrence rates (dichotomous data: seven trials, 3628 women; RR 1.04, 95% CI 0.80 to 1.35).EBRT did not improve survival outcomes in either the intermediate-risk or high-risk subgroups, although high-risk data were limited, and a benefit of EBRT for high-risk women could not be excluded. One trial (PORTEC-2) compared EBRT with VBT in the high-intermediate risk group and reported that VBT was effective in ensuring vaginal control with a non-significant difference in loco-regional relapse rate compared to EBRT (5.1% versus 2.1%; HR 2.08, 95% CI 0.71 to 6.09; P = 0.17). In the subgroup of low-risk patients (IA/B and grade 1/2), EBRT increased the risk of endometrial carcinoma-related deaths (including treatment-related deaths) (two trials, 517 women; RR 2.64, 95% CI 1.05 to 6.66) but there was a lack of data on overall survival. We considered the evidence for the low-risk subgroup to be of a low quality.EBRT was associated with significantly increased severe acute toxicity (two trials, 1328 patients, RR 4.68, 95% CI 1.35 to 16.16), increased severe late toxicity (six trials, 3501 women; RR 2.58, 95% CI 1.61 to 4.11) and significant reductions in quality of life scores and rectal and bladder function more than 10 years after randomisation (one trial, 351 women) compared with no EBRT.One trial of VBT versus no additional treatment in women with low-risk lesions reported a non-significant reduction in locoregional recurrence in the VBT group compared with the no additional treatment group (RR 0.39, (95% CI 0.14 to 1.09). There were no significant differences in survival outcomes in this trial. EBRT reduces the risk of locoregional recurrence but has no significant impact on cancer-related deaths or overall survival. It is associated with significant morbidity and a reduction in quality of life. There is no demonstrable survival advantage from adjuvant EBRT for high-risk stage I endometrial cancer, however, the meta-analyses of this subgroup were underpowered and also included high-intermediate risk women, therefore we cannot exclude a small benefit in the high-risk subgroup. EBRT may have an adverse effect on endometrial cancer survival when used to treat uncomplicated low-risk (IA/B grade 1/2) endometrial cancer. For the intermediate to high-intermediate risk group, VBT alone appears to be adequate in ensuring vaginal control compared to EBRT. Further research is needed to guide practice for lesions that are truly high risk. In addition, the definitions of risk should be standardised.

A Pilot Study of Microsatellite Instability and Endometrial Cancer Survival in White and African American Women

Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States and can be classified on the basis of various pathologic, molecular, and genetic features, including microsatellite instability (MSI). As MSI is generally associated with a more favorable outcome in colorectal cancers, it is feasible that microsatellite instability may also influence endometrial cancer survival. We examined MSI and survival in 45 African American and 31 white women diagnosed with endometrial cancer at a large, urban cancer center. Fifty-five tumors were classified as type I and 21 tumors were classified as type II. Unconditional logistic regression models found that microsatellite stable tumors were more frequently observed in white women compared with African American women (odds ratio, 8.61; 95% confidence interval, 1.01-73.69). Type I tumors with MSI were not found to be significantly associated with smoking status, tumor stage, or age. Only one type II tumor was classified as MSI. Neither race nor MSI status was a predictor of death from all causes or only endometrial cancer-related deaths were considered in univariate and multivariate survival models. The potential significance of a larger proportion of MSI tumors found in African American women with type I endometrial cancer should be assessed in a larger prospective study.

External Pelvic and Vaginal Irradiation Versus Vaginal Irradiation Alone as Postoperative Therapy in Medium-Risk Endometrial Carcinoma—A Prospective Randomized Study

To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity. Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity. Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone. Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.

Abstract 5175: Predictors of metastatic spread and progression free survival in uterine papillary serous carcinoma: A pilot study

Abstract Background: Uterine Papillary Serous Carcinoma (UPSC) comprises 5-10% of all endometrial cancers but is responsible for nearly 40% of all endometrial cancer-related deaths. Progression-free survival (PFS) controlled for stage is also markedly shorter in UPSC compared to Type 1 endometrial cancers. Unlike endometrioid carcinoma, in which depth of myometrial invasion, grade, and lymphovascular space invasion (LVSI) are risk factors for extrauterine spread, UPSC often metastasizes in those with no myometrial invasion. Objective: The objective of this study is to identify markers that may predict metastatic disease in women with non-invasive UPSC or portend a shorter progression free survival. Materials: A retrospective chart review was performed on women diagnosed with Stage IA or Stage III/IV UPSC without myometrial invasion from 1995-2008. Examined factors include age, parity, race, weight, LVSI, CA125 levels, and tumor location within the endometrium. Tissue microarrays (TMAs) were constructed using paraffin blocked specimens and stained for ER, PR, p53, VEGF, Claudin 3, Claudin 4, Her-2/neu, Her-3, Synuclein gamma, and Maspin. Chi-square analysis, Student's t-test, and Fisher's Exact analysis were used where appropriate to detect statistically significant differences in these 2 groups with Kaplan-Meyer analysis used to determine PFS. Significance was represented at p&amp;lt;0.05. Results: Thirty-two patients were identified to have UPSC without myometrial invasion, 24 (75%) comprising Stage IA and 8 (25%) having Stage III/IV disease. Pathology blocks were available for 21 patients (14 Stage I and 7 Stage III/IV). CA125 was the only factor to achieve significance (p=0.04) in predicting metastatic spread; biomarkers, either alone or in combination, were not predictive of metastatic disease. In Stage I disease, positive ER status was associated with a significantly longer PFS (p&amp;lt;0.001) while in Stage III/IV disease, positive Her-3 status was associated with a shorter PFS (p=0.014). Conclusions: In addition to traditional risk factors not being predictive of metastatic disease, molecular markers that have been associated with metastatic disease and a worsening prognosis do not appear to be predictive in UPSC. However, the contribution of ER status and Her-3 needs to be further evaluated as this may offer new insight into therapeutic options for treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5175. doi:10.1158/1538-7445.AM2011-5175

The impact of race on survival in uterine serous carcinoma: A hospital-based study

Objective Although less common than endometrioid carcinoma, uterine serous carcinoma (USC) accounts for a disproportionate number of endometrial cancer-related deaths. It is relatively more common in black compared to white women. The aim of our study is to analyze the impact of race on survival in USC. Methods We conducted a retrospective review in women with USC managed at two large urban medical centers. Clinical and histopathologic parameters were retrieved. Recurrence and survival data were obtained from medical records and the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in overall survival between African American and Caucasian women were compared using Kaplan–Meier curves and log rank test for univariate analysis. Cox regression models for multivariate analyses were built to evaluate the relative impact of the various prognostic factors. Results One hundred seventy-two women with USC were included in this study, including 65 Caucasian women and 107 African American women. Both groups were similar with respect to age, stage at diagnosis, angiolymphatic invasion ( p = 0.79), and the depth of myometrial invasion ( p = 0.36). There was no statistical difference in overall survival between African American and Caucasian patients in univariate analysis ( p = 0.14). In multivariate analysis, stage at diagnosis, angiolymphatic invasion, and depth of myometrial invasion, but not race, were significantly associated with overall survival. Conclusion In this study, African American women with USC had a similar survival to Caucasian women. This suggests that the racial differences seen in USC at a larger population level may be diminished in hospital-based studies, where women are managed in a uniform way.

Abstract A111: Race is a predictor for endometrioid endometrial cancer cause-specific survival, but not all-cause survival

Abstract Endometrial cancer is the most common gynecologic cancer, with an estimated 42,000 new cases in 2010. The reported difference in overall five year survival between white women and African American (AA) women represents significant survival disparity in cancer. Histologic types of endometrial cancer and stage at diagnosis differ substantially between AAs and whites, but AA women experience poorer survival even after adjusting for these factors. After IRB approval, we performed a case-only retrospective analysis of 362 patients with surgically treated endometrioid endometrial cancer. Data from 120 AA and 242 white women, diagnosed from 1990-2005 at a single institution were analyzed to examine risk factors associated with survival. Age at diagnosis, co-morbid conditions in the 5 years prior to diagnosis, BMI, and smoking history were obtained from medical record review. Tumor histologic type, 1988 FIGO stage, grade, vital status and number of months surviving were obtained from the Metropolitan Detroit Cancer Surveillance System, part of the SEER program. Differences in stage, co-morbid conditions (using a modified Charlson Comorbidity Index, CCI), and BMI were examined by race. Chisquare tests were used to assess differences in distribution of clinical and demographic variables. Log-rank tests and Cox proportional hazards models were used to assess the risk of all-cause and endometrial cancer-related deaths. AA women were more likely than white women to have high grade tumors (p=0.009), hypertension (p=0.0005) and higher mean BMI (p=0.009). No differences by race were identified among the total group for age (p=0.98), stage at diagnosis (p=0.78), categorical modified CCI (p=0.51) or smoking history (p=0.96). When data were stratified by grade, hypertension (p=0.0009) and high BMI (p=0.002) were more frequent among AAs compared to whites with low grade tumors, but not high grade tumors. Among women with high grade tumors, AAs had a greater number of co-morbid conditions (p=0.005) and were more likely to be current or former smokers compared to whites (p=0.003). In univariate survival analysis, age at diagnosis, CCI, stage, and grade were all significantly associated with any cause survival, whereas race was not. When examining deaths due to endometrial cancer, only stage (HR=3.37,95% CI: 2.52-4.51), grade (HR=4.32,95% CI: 2.89-6.47) and race (HR=2.12,95% CI: 1.13-3.97) were predictors of survival. Analysis of endometrial cancer-related deaths by grade suggest this difference in survival by race is seen for high grade (p=0.03) but not low grade (p=0.87) tumors. In this single institution study, race was not a predictor of overall survival, but was associated with endometrial cancer-related survival. Excess of co-morbid conditions was associated with AA race, and overall survival, but not endometrial cancer-related survival in this population. A larger, more comprehensive study, including information regarding socio-economic factors, molecular tumor markers, and treatment modality is necessary to elucidate the causes underlying the large disparity in endometrial cancer survival between AA and white women. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A111.