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Endometrial cancer (EC) patients make up the second largest group of female cancer survivors. Patient-reported outcomes (PROs) including quality of life (QOL) and sexual function and satisfaction (SF and S) are critical facets of survivorship. This prospective, longitudinal study assesses associations between baseline characteristics and PROs after treatment. Herein, we report the baseline clinical characteristics and PROs prior to treatment initiation. Outcomes post-treatment over time will be reported separately. Patients with planned surgery for EC were prospectively enrolled in 2019–2021 and administered the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC Module (EN24), Patient-Reported Outcomes Measurement Information System (PROMIS), and the Mayo Clinic lower extremity lymphedema (LEL) questionnaire. This study enrolled 198 patients with a mean (SD) age of 63.6 (9.8) years and body mass index of 35.5 (8.3) kg/m2. No significant differences in the PROs for the QOL were seen when compared to the reference means (SD) except for the lower interest in sexual activity (31.9 (9.8) vs. 47.5 (SE0.70)) and lower fatigue (21.3 (19.8) vs. 31.7 (25.9)). Increased obesity was associated with an increased likelihood of LEL (p < 0.01) and multiple QOL scales, including poorer global health status (p < 0.01) and physical functioning (p < 0.01). Prior to treatment initiation for EC, the patients had a similar QOL compared to that of the general population. The patients with increasing obesity, a known risk factor for EC, had worse overall global health status and physical functioning. A better understanding of these QOL measures is imperative for earlier identification and intervention of patients at risk of chronic impairments from EC treatment. [ABSTRACT FROM AUTHOR]

Introduction: There are no reliable blood biomarkers for monitoring endometrial cancer patients in the current clinical practice. Circulating tumor DNA (ctDNA) is emerging as a promising non-invasive method to measure tumor burden, define prognosis and monitor disease status in many solid cancers. In this pilot study, we investigated if unique tumor-specific DNA junctions can be used to detect ctDNA levels in patients with endometrial cancer. Methods: Chromosomal rearrangements in primary tumors of eleven patients with high-grade or advanced stage endometrial cancer were determined by whole-genome Mate-Pair sequencing. Identified unique tumor-specific junctions were evaluated in pre- and six-week post-surgery patient plasma using individualized quantitative polymerase chain reaction (qPCR) assays. The relationship between clinicopathological features and detection of ctDNA was investigated. Results: CtDNA was detected in 60% (6/10) of cases pre-surgery and in 27% (3/11) post-surgery. The detection of ctDNA pre-surgery was consistent with clinical indicators of aggressive disease such as advanced stage (80% - 4/5), lymphatic spread of disease (100% - 3/3), serous histology (80% - 4/5), deep myometrial invasion (100% - 3/3), lympho-vascular space invasion (75% - 3/4). All patients in which ctDNA was detected post-surgically had type II endometrial cancer. Discussion: This pilot study demonstrates the feasibility of using personalized tumor-specific junction panels for detecting ctDNA in the plasma of endometrial cancer patients. Larger studies and longer follow-up are needed to validate the potential association between pre-surgical ctDNA detection and the presence of cancers with aggressive pathologic tumor characteristics or advanced stage observed in this study. [ABSTRACT FROM AUTHOR]

Background: Most endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. Although clinical guidelines exist for diagnostic workup of abnormal uterine bleeding, consensus is lacking regarding optimal management for women with abnormal bleeding to diagnose endometrial cancer.Objective: We report the baseline data from a prospective clinical cohort study of women referred for endometrial evaluation at the Mayo Clinic, designed to evaluate risk stratification in women at increased risk for endometrial cancer. Here, we introduce a risk-based approach to evaluate diagnostic tests and clinical management algorithms in a population of women with abnormal bleeding undergoing endometrial evaluation at the Mayo Clinic.Study Design: A total of 1163 women aged ≥45 years were enrolled from February 2013 to May 2019. We evaluated baseline absolute risks and 95% confidence intervals of endometrial cancer and endometrial intraepithelial neoplasia according to clinical algorithms for diagnostic workup of women with postmenopausal bleeding (assessment of initial vs recurrent bleeding episode and endometrial thickness measured through transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (<60 vs 60+ years) as an alternative example. For this approach, biopsy would be conducted for all women aged 60+ years and those aged <60 years with an endometrial thickness of >4 mm. We assessed the clinical efficiency of each strategy by estimating the percentage of women who would be referred for endometrial biopsy, the percentage of cases detected and missed, and the ratio of biopsies per case detected.Results: Among the 593 women with postmenopausal bleeding, 18 (3.0%) had endometrial intraepithelial neoplasia, and 47 (7.9%) had endometrial cancer, and among the 570 premenopausal women with abnormal bleeding, 8 (1.4%) had endometrial intraepithelial neoplasia, and 7 (1.2%) had endometrial cancer. Maximum risk was noted in women aged 60+ years (17.7%; 13.0%-22.3%), followed by those with recurrent bleeding (14.7%; 11.0%-18.3%). Among women with an initial bleeding episode for whom transvaginal ultrasound was recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer and endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4 mm (5.8%; 1.3%-10.3%) and ≤4 mm (3.6%; 0.9%-8.6%). In contrast, among those aged <60 years with an endometrial thickness of >4 mm, the risk of endometrial cancer and endometrial intraepithelial neoplasia was 8.4% (4.3%-12.5%), and in those with an endometrial thickness of ≤4 mm, the risk was 0% (0.0%-3.0%; P=.01). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged <60 years with an endometrial thickness of >4 mm, with the lowest percentage referred to biopsy while still detecting all cases.Conclusion: Existing clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with the underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared with the assessment of recurrent bleeding. Future research will include a formal assessment of clinical and epidemiologic risk prediction models in our study population as well as validation of our findings in other populations. [ABSTRACT FROM AUTHOR]

Alterations in DNA methylation are early events in endometrial cancer (EC) development and may have utility in EC detection via tampon-collected vaginal fluid. For discovery, DNA from frozen EC, benign endometrium (BE), and benign cervicovaginal (BCV) tissues underwent reduced representation bisulfite sequencing (RRBS) to identify differentially methylated regions (DMRs). Candidate DMRs were selected based on receiver operating characteristic (ROC) discrimination, methylation level fold-change between cancers and controls, and absence of background CpG methylation. Methylated DNA marker (MDM) validation was performed using qMSP on DNA from independent EC and BE FFPE tissue sets. Women ≥45 years of age with abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB) or any age with biopsy-proven EC self-collected vaginal fluid using a tampon prior to clinically indicated endometrial sampling or hysterectomy. Vaginal fluid DNA was assayed by qMSP for EC-associated MDMs. Random forest modeling analysis was performed to generate predictive probability of underlying disease; results were 500-fold in-silico cross-validated. Thirty-three candidate MDMs met performance criteria in tissue. For the tampon pilot, 100 EC cases were frequency matched by menopausal status and tampon collection date to 92 BE controls. A 28-MDM panel highly discriminated between EC and BE (96% (95%CI 89–99%) specificity; 76% (66–84%) sensitivity (AUC 0.88). In PBS/EDTA tampon buffer, the panel yielded 96% (95% CI 87–99%) specificity and 82% (70–91%) sensitivity (AUC 0.91). Next generation methylome sequencing, stringent filtering criteria, and independent validation yielded excellent candidate MDMs for EC. EC-associated MDMs performed with promisingly high sensitivity and specificity in tampon-collected vaginal fluid; PBS-based tampon buffer with added EDTA improved sensitivity. Larger tampon-based EC MDM testing studies are warranted. • Whole methylome sequencing identified novel endometrial cancer (EC) methylated DNA markers (MDMs). • A 28-MDM EC panel discriminated between EC and benign endometrium in vaginal fluid collected by tampons. • An abbreviated 3-MDM EC panel performed with similar sensitivity and specificity as the 28-MDM panel. [ABSTRACT FROM AUTHOR]

The evaluation of women with perimenopausal abnormal uterine bleeding (AUB) and postmenopausal bleeding (PMB) to detect endometrial cancer (EC) and its precursors is not standardized and can vary widely. Consequently, costs associated with the workup and management undoubtedly vary. This study aimed to quantify costs of AUB/PMB evaluation to understand the healthcare burden associated with securing a pathologic diagnosis. Women ≥45 years of age presenting to a single institution gynecology clinic with AUB/PMB for diagnostic workup were prospectively enrolled February 2013–October 2017 for a lower genital tract biospecimen research study. Clinical workup of AUB/PMB was determined by individual provider discretion. Costs of care were collected from administrative billing systems from enrollment to 90 days post enrollment. Costs were standardized and inflation-adjusted to 2017 US Dollars (USD). In total, there were 1017 women enrolled with 5.6% diagnosed with atypical hyperplasia or endometrial cancer (EC). Within the full cohort, 90-day median cost for AUB/PMB workup and management was $2279 (IQR $512–4828). Among patients with a diagnostic biopsy, median 90-day costs ranged from $2203 (IQR $499–3604) for benign or disordered proliferative endometrium (DPE) diagnosis to $21,039 (IQR $19,084-24,536) for a diagnosis of EC. The costs for diagnostic evaluation of perimenopausal AUB and PMB vary greatly according to ultimate tissue-based diagnosis. Even reassuring benign findings that do not require further intervention—the most common in this study's cohort—yield substantial costs. The development of sensitive, specific, and more cost-effective diagnostic strategies is warranted. • Cost for diagnostic evaluation and management of abnormal uterine bleeding is substantial. • Costs vary greatly according to ultimate tissue-based diagnosis. • Even reassuring benign findings that do not require further intervention yield substantial costs. • The development of sensitive, specific, and more cost-effective diagnostic strategies is warranted. [ABSTRACT FROM AUTHOR]

Emerging technologies may enable detection of endometrial cancer with methods that are less invasive than standard biopsy methods. This study compares patient pain scores among 3 office gynecologic tract sampling methods and explores their potential determinants. A prospective study including 3 sampling methods (tampon, Tao brush (TB), endometrial biopsy (EB)) was conducted between December 2015 and August 2017 and included women ≥45 years of age presenting with abnormal uterine bleeding, postmenopausal bleeding, or thickened endometrial stripe. Patients rated pain after each sampling procedure using a 100-point visual analog scale (VAS). Of 428 enrolled, 190 (44.39%) patients underwent all 3 sampling methods and reported a VAS score for each. Nearly half were postmenopausal (n = 93, 48.9%); the majority were parous (172, 90.5%) of which 87.8% had at least one vaginal delivery. Among the 190 patients, the median (IQR) pain score was significantly lower for sampling via tampon (0 [0,2]) compared to TB (28 [12, 52]) or EB (32 [15, 60]) (both p < 0.001, Wilcoxon signed rank test). Among women who underwent tampon sampling, age and pain scores showed a weak positive correlation (Spearman rank correlation, r = 0.14; p = 0.006); EB sampling was associated with a weak inverse correlation between parity and pain scores (r = −0.14; p = 0.016). Gynecologic tract sampling using a tampon had significantly lower pain than both EB and TB. Pain with tampon sampling was positively correlated with age and pain with EB sampling was inversely correlated with parity. Pain scores for TB and EB were not significantly related to age, menopausal status, or BMI. • Gynecologic sampling using a tampon was less painful than endometrial biopsy or cytology. • Increasing age was associated with higher pain scores with tampon sampling. • Future studies of tampon-collected vaginal fluid and molecular markers of cancer are needed. [ABSTRACT FROM AUTHOR]

To evaluate endometrial cancer (EC) risk assessment and early detection strategies in high-risk populations, we designed a large, prospective cohort study of women undergoing endometrial evaluation to assess risk factors and collect novel biospecimens for future testing of emerging EC biomarkers. Here we report on the baseline findings of this study. Women aged ≥45 years were enrolled at the Mayo Clinic from February 2013–June 2018. Risk factors included age, body mass index (BMI), smoking, oral contraceptive and hormone therapy use, and parity. We collected vaginal tampons, endometrial biopsies, and Tao brush samples. We estimated mutually-adjusted odds ratios (OR) and 95% confidence intervals (CI) using multinomial logistic regression; outcomes included EC, atypical hyperplasia, hyperplasia without atypia, disordered proliferative endometrium, and polyps, versus normal endometrium. Subjects included 1205 women with a mean age of 55 years; 55% were postmenopausal, and 90% had abnormal uterine bleeding. The prevalence of EC was 4.1% (n = 49), predominantly diagnosed in postmenopausal women (85.7%). Tampons and Tao brushings were obtained from 99% and 68% of women, respectively. Age (OR 1.14, 95% CI 1.1–1.2) and BMI (OR 1.39, 95% CI 1.1–1.7) were positively associated with EC; atypical hyperplasia (OR 1.07, 95% CI 1.0–1.1; OR 2.00, 95% CI 1.5–2.6, respectively), and polyps (OR 1.06, 95% CI 1.0–1.1; OR 1.17, 95% CI 1.0–1.3, respectively); hormone therapy use and smoking were inversely associated with EC (OR 0.42, 95%, 0.2–0.9; OR 0.43, 95% CI, 0.2–0.9, respectively). Parity and past oral contraception use were not associated with EC. Well-established EC risk factors may have less discriminatory accuracy in high-risk populations. Future analyses will integrate risk factor assessment with biomarker testing for EC detection. • This large clinical prospective cohort study evaluates risk factors for endometrial cancer and its precursors. • Vaginal tampons, endometrial biopsies, and Tao brushes were collected for future testing of emerging biomarkers. • Of the 1205 participants, 90% had abnormal uterine bleeding and the prevalence of endometrial cancer was 4.1% (n = 49). • Endometrial cancer and benign uterine conditions (e.g., polyps) shared risk factors such as age and body mass index. • Parity and oral contraception use were not associated with endometrial cancer risk in this high-risk population. [ABSTRACT FROM AUTHOR]

Up-regulation of ERBB pathways represent targetable alterations in many high grade endometrial cancers (EC); ERBB3 amplifications in particular may contribute to ineffective pathway targeting due to persistent co-activation of other ERBB binding partners, leading to tumor growth and survival. The efficacy of downstream dual-inhibition of MEK+AKT or MEK+PI3K in an ERBB3 amplified EC primary tumor was studied using a microcancer 3D ex-vivo tumor cell viability assay. Tumor was prospectively collected from a patient with stage II, FIGO grade 3, serous EC and genomic characterization was performed using multiple sequencing methods: whole exome, RNA, and MatePair analysis. Somatic mutations, structural variance, with transcriptomic profiling was used to identify potential driver pathways for subsequent pharmacologic inhibition. Primary tumor cells were grown in a three-dimensional environment and the formed microcancers were subjected to drug treatment. Cell viability was determined by the CellTiter-Glow Luminescent Assay. Data transformation and dose-response curves were generated using GraphPad PRISM using four parameter logistic regression. CompuSyn software with the Chou-Talalay method was used to analyze drug interactions and synergy. The Fractional response-Combination index (Fa-CI) plot was generated with Microsoft Excel. Capivasertib, GDC-0084, and cobimetinib were used to inhibit AKT, PI3K/mTOR, and MEK, respectively. Inhibitory effect was defined as percent reduction in ATP at clinically-defined predicted plasma maximum concentration (Cmax) values. Genomic sequencing revealed overexpression of a mutated ERBB3 (c.889G>T; p.Asp297Tyr) transcript within a 6N focal amplification. Additional pertinent alterations included a MYC mid-level gain, and TP53 double hit (loss and exonic splicing silencer (ESS)). Inhibition of cell viability was moderate by single agents: capivasertib, cobimetanib, or GDC-0084, as shown by inhibitory effect values of 33.9%, 35.9% and 49.9%, respectively. Two combinations with cobimetinib demonstrated increasing inhibitory effect values of 76.2% for cobimetanib/capivasertib at the Cmax of capivasertib and 79.7% for cobimetanib/GDC-0084 at the Cmax of cobimetanib. Synergy was evidenced by a combination index <1 at all points with Fa>0.8 (Figure 1). [Display omitted] Combined inhibition of MEK and PI3K-AKT-mTOR pathways synergistically suppress viability in a patient-derived high-grade serous EC harboring a ERBB3 amplification. Further ex-vivo testing should be performed in endometrial tumors with other ERBB3 aberrations to allow generalization of results. [ABSTRACT FROM AUTHOR]