Serous Endometrial Cancer Research Articles

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

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

Fam-Trastuzumab Deruxtecan in HER2/Neu-Expressing Serous Endometrial Cancer.

Trastuzumab deruxtecan treatment of 3 patients with HER2/neu-expressing serous endometrial cancer resulted in objective response

Intra-racial disaggregation reveals associations between nativity and overall survival in women with endometrial cancer

ObjectivePrior studies have demonstrated survival differences between Black women with endometrial cancer (EC) born in the US and Caribbean. Our objective was to determine if country of birth influences EC overall survival (OS) in disaggregated subpopulations of Black women. MethodsUsing the Florida Cancer Data System, women with EC diagnosed from 1981 to 2017 were identified. Demographic and clinical information were abstracted. Women who self-identified as Black and born in the US (USB), Jamaica (JBB), or Haiti (HBB) were included. Statistical analyses were performed using chi-square, Cox proportional hazards models, and Kaplan-Meier methods with significance set at p < 0.05. Results3817 women met the inclusion criteria. Compared to USB, JBB and HBB had more high-grade histologies, more advanced stage disease, had a greater proportion of uninsured or Medicaid insured, and had a higher proportion of women who received chemotherapy (all p < 0.05). In multivariate analyses, age (HR 1.03 [1.02–1.05]), regional stage (HR 1.52 [1.22–1.89]), distant stage (HR 3.73 [2.84–4.89]), lymphovascular space invasion (HR 1.96 [1.61–2.39]), receipt of surgery (HR 0.47 [0.29–0.75]), and receipt of chemotherapy (HR 0.77 [0.62–0.95]) were independently associated with OS. Compared to USB, Haitian nativity was an independent negative predictor of OS when evaluating all histologies together (HR 1.54 [1.18–2.00]) and for endometrioid EC specifically (HR 1.77 [1.10–2.83]). Among women with serous EC, HBB had markedly worse median OS (18.5 months [13.4–46.5]) relative to USB (29.9 months [26.3–35.9]) and JBB (41.0 months, [34.1–82.6], p = 0.013). ConclusionCountry of birth is associated with endometrial cancer survival in Black women, with HBB demonstrating worse outcomes.

Critical Overview of Serous Endometrial Intraepithelial Cancer Treatment: Systematic Review of Adjuvant Options.

SEIC is a non-invasive lesion of the endometrial epithelium considered to be the precursor to uterine serous carcinoma (USC) and is just as aggressive as USC. Currently, there are no reliable data about the behavior and prognosis of SEIC; therefore, the therapeutic management approach is not clear. Method: A systematic search of the Pubmed, Scopus and Embase databases was conducted, following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Of the 296 studies that matched the search criteria, only 9 met the inclusion criteria, covering a total of 81 patients. The main disease-presenting pattern was AUB (abnormal uterine bleeding). In 31 cases, SEIC was associated with extrauterine disease. All patients underwent hysterectomy and salpingo-oophorectomy, while only 15 of the 81 patients received adjuvant treatments. In the patients receiving adjuvant therapy, the RR was 42.67%, the DFS was 35.71% and the OS was 57.13%. In patients subjected to follow-up alone, the RR was only 28.78%, the DFS was 59.1% and the OS was 66.6%. Conclusions: The presence of an extrauterine disease significantly worsens outcomes, regardless of adjuvant treatment. In cases of disease confined to the uterine mucosa alone, the prognosis is good and follow-up allows a good control of the disease; however, adjuvant therapy could further increase survival rates and reduce relapse rates.

A randomized phase II study comparing single-agent olaparib, single-agent cediranib, and the combinations of cediranib/olaparib, olaparib/durvalumab (MEDI4736), cediranib/durvalumab (MEDI4736), and olaparib/AZD5363 (capivasertib) in women with recurrent, persistent, or metastatic endometrial cancer.

TPS5629 Background: Identifying new approaches for the treatment of advanced endometrial cancer (EC) is a priority. A platform study design allows for a faster investigation of novel drug combinations. NRG-GY012 is an ongoing platform study investigating drug combinations with the PARP inhibitor olaparib (O) and the anti-angiogenic agent cediranib (C). Results from the first set of arms established improved PFS for combination cediranib/olaparib over C alone, but did not meet its prespecified statistical significance. In this second set of arms, based on preclinical data, we are investigating the combination of O with an AKT inhibitor (capivasertib), O with durvalumab and C with durvalumab compared to the reference arm of C alone. Methods: This is a multicenter randomized four arm study for patients with recurrent, metastatic or persistent EC. Patients are randomized 1:1:1:1 to cediranib PO 30 mg Daily; olaparib 300 mg PO BID and capivasertib 400mg 4 day on/3 off schedule; olaparib 300 mg PO BID and durvalumab 1500mg q28 days; or the combination of cediranib 20 mg PO Daily 5 days on/2 days and durvalumab 1500mg q28. All treatment cycles are 28 days. Primary endpoint is progression free survival (PFS). The study is powered to detect a doubling in median PFS from 3.6 (based on cediranib alone) to 7.2 months with 90% power, using a one-sided test with α = 0.05 per comparison. Forty patients will be enrolled per arm, with an interim futility analysis planned at 50% information time. Eligibility includes endometroid, serous, and mixed histology EC; at least 1 prior line of chemotherapy (no more than 2 lines for metastatic disease), prior endocrine or immunotherapy alone is allowed; prior treatment with lenvatinib and pembrolizumab is excluded. Archival tumor tissue and blood samples are being collected for translational studies. The study is open across the NRG network; 76 of a planned 168 patients are enrolled to date. Safety analysis at the time of 36 patients enrolled did not demonstrate any new safety signals and the study was approved to continue enrollment. Clinical trial information: NCT03660826 .

The clinico pathological features and survival in serous endometrial cancers

Background & IntroductionSerous cancers are a biologically aggressive variety of endometrial cancer (EC) with a high rate of recurrence and mortality among all the subtypes. Herein we describe our experience with serous endometrial cancer. ObjectiveThis study was conducted to identify the clinicopathological characteristics, treatment modalities and survival outcomes in women diagnosed with serous endometrial malignancies. MethodsThis was a retrospective descriptive analysis of data on patients diagnosed with serous endometrial tumours between January 2010 to September 2019 in our institute collected from electronic medical records. Descriptive statistics such as proportions, means and standard deviations and Cox regression hazards model on risk factors were performed. Survival was plotted by Kaplan-Meier curves. ResultsDuring the study period, 32 (5.7%) patients out of 564 diagnosed cases of endometrial cancer had serous histology. The mean age at diagnosis was 62.5 years (SD 7.6) while mean BMI was 26.4 kg/m2 (SD 4.6). Staging laparotomy was done in 27(84%) of the patients. Advanced stages (III and IV) were detected in 16 patients (50%) at primary surgery.Adjuvant chemo therapy and radiation was received by 21(65.6%) patients therapy. Out of 32 patients, 13 (40%) developed recurrence while another 13 expired. Stage at diagnosis and type of adjuvant therapy were important factors in determining the outcome. Median recurrence free and overall survival was 22(95% CI 1.4–42) and 36 months (95% CI 10.1–61.8) respectively. ConclusionSerous endometrial cancers are an intrusive subtype of EC. Comprehensive surgical staging with optimal cytoreduction should be aimed at. Adequate upfront molecular categorization of these tumors is mandated. Adjuvant therapy with chemotherapy and radiation is given in postoperative setting. Targeted therapies and immunotherapy could be considered in recurrences.

All that enhances is not cancer: Cerebral amyloid angiopathy mimicking leptomeningeal enhancement in the two patients with advanced cancer (P14-13.002)

<h3>Objective:</h3> N/A <h3>Background:</h3> Cerebral amyloid angiopathy (CAA) leads to deposition of amyloid-beta-peptide in leptomeninges and cerebral blood vessels. A <i>β</i>-related angiitis (ABRA) is a severe form of CAA characterized by transmural inflammation and/or, granulomatous inflammation. We report two patients with advanced malignancy presenting with leptomeningeal enhancement (LME) concerning for leptomeningeal metastases, with biopsy demonstrating ABRA. <h3>Design/Methods:</h3> 76-year-old man presented with left facial droop, dysarthria and imbalance. MRI head showed acute infarcts in multiple vascular distributions and diffuse LME. CTA showed bilateral cervical lymphadenopathy, without evidence of vasculitis. CSF analysis demonstrated lymphocytic pleocytosis and negative flow cytometry and cytology. Cervical lymph node biopsy revealed a new diagnosis of metastatic papillary thyroid cancer. Repeat MRI brain one month later showed persistent and worsening cortical LME. Prior to surgery for the thyroid cancer, a brain biopsy was performed for staging. Pathology demonstrated fibrinoid necrosis of vessels walls and foci of thrombosis, consistent with CAA. The patient was treated with corticosteroids followed by cyclophosphamide for ABRA. 78-year-old woman with cognitive impairment and stage IV serous endometrial cancer presented after incidental findings of subarachnoid hemorrhage (SAH) with LME on MRI brain. CSF analysis was normal with negative cytology. Head CTA was negative for aneurysm or vascular malformation. A repeat MRI showed new small SAH in the right superior frontal gyrus and multiple new punctate cerebellar infarcts. Brain biopsy revealed amyloid positivity with congo red staining in cerebellar leptomeningeal vessels, consistent with CAA. She received a 5-day course of IVIG (steroids contraindicated) with plan to start immunosuppressive therapy outpatient. <h3>Results:</h3> N/A <h3>Conclusions:</h3> Our patients presented with LME in the setting of newly diagnosed malignancy, which raised concern for leptomeningeal metastases. The presence of SAH and infarcts are uncommon in leptomeningeal metastatic disease. In these cases, pathologic confirmation of CAA on brain biopsy changed the cancer-related prognosis and treatment plan. <b>Disclosure:</b> Dr. Waheed has nothing to disclose. Dr. Seyam has nothing to disclose. Dr. Thomas has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roon. The institution of Dr. Thomas has received research support from Novocure. The institution of Dr. Thomas has received research support from Spectrum Pharmaceuticals. The institution of Dr. Thomas has received research support from Ono Pharmaceuticals.

Abstract 5495: Combination therapy with poly (ADP-ribose) polymerase inhibitor in endometrial cancer

Abstract Objective: Endometrial cancer (EC) is the most common gynecologic malignancy and serous histology is the second most common subtype. It is associated with poorer outcomes as recurrent disease tends to be resistant to chemotherapy. Given the dearth of proven targeted therapies in this setting and the tendency for serous ECs to have homologous recombination deficiency (HRD), this study aimed to test the synergy between poly (ADP-ribose) polymerase inhibitors (PARPis) and SN38, an active metabolite of DNA topoisomerase I, irinotecan. PARPis are currently FDA approved in ovarian cancer and have their greatest efficacy in tumors with HRD while topoisomerase inhibitors are a standard chemotherapy option for recurrent cancer. Methods: A genomic instability score (GIS) was derived from low-pass whole genome sequencing-based bioinformatics analysis according to three previously reported HRD metrics: telomeric allelic imbalance, large state transitions, and loss of heterozygosity. GIS was calculated for 34 patient derived xenograft (PDX) tumors, of which eight had serous histology. PARPi, rucaparib, and SN38 were used to treat EC PDX tumors in ex vivo 3D cell culture experiments using RealTime Glo for viability after 4-5 days of drug exposure. Synergy was assessed by calculating the combination index (CI) using Chou-Talalay method. Results: GIS ≥ 42 was noted in 62.5% (5/8) of serous EC PDX tumors and only 19.2% (5/26) of non-serous EC PDX tumors. Synergy (CI &amp;lt; 1.0) between rucaparib and SN38 was demonstrated in 85.7% (6/7) of serous EC PDX ex vivo 3D cell culture experiments, but only 62.5% (10/16) of non-serous EC PDX tumors. Conclusions: Most serous EC PDX tumors had a high GIS, consistent with HRD, when compared to a minority of non-serous histologies. Furthermore, combination therapy of rucaparib and SN38 had a synergistic effect in almost all serous EC PDX models, while still being effective in a majority of non-serous models. Additional PDX tumors need to be assessed to establish the predictive value of a GIS on synergy between rucaparib and SN38. Further in vivo studies are also needed to confirm these ex vivo findings of synergy. Ultimately, the hope is to generate preclinical data which justifies the use of PARPis in serous ECs as monotherapy or in combination with other anticancer therapies. Citation Format: Conway Xu, Xiaonan Hou, Erik Jessen, Chen Wang, S. John Weroha. Combination therapy with poly (ADP-ribose) polymerase inhibitor in endometrial cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5495.

CCNE1 is a predictive and immunotherapeutic indicator in various cancers including UCEC: a pan-cancer analysis

BackgroundCCNE1 plays an important oncogenic role in several tumors, especially high-stage serous ovarian cancer and endometrial cancer. Nevertheless, the fundamental function of CCNE1 has not been explored in multiple cancers. Therefore, bioinformatics analyses of pan-cancer datasets were carried out to explore how CCNE1 regulates tumorigenesis.MethodsA variety of online tools and cancer databases, including GEPIA2, SangerBox, LinkedOmics and cBioPortal, were applied to investigate the expression of CCNE1 across cancers. The pan-cancer datasets were used to search for links between CCNE1 expression and prognosis, DNA methylation, m6A level, genetic alterations, CCNE1-related genes, and tumor immunity. We verified that CCNE1 has biological functions in UCEC cell lines using CCK-8, EdU, and Transwell assays.ResultsIn patients with different tumor types, a high mRNA expression level of CCNE1 was related to a poor prognosis. Genes related to CCNE1 were connected to the cell cycle, metabolism, and DNA damage repair, according to GO and KEGG enrichment analyses. Genetic alterations of CCNE1, including duplications and deep mutations, have been observed in various cancers. Immune analysis revealed that CCNE1 had a strong correlation with TMB, MSI, neoantigen, and ICP in a variety of tumor types, and this correlation may have an impact on the sensitivity of various cancers to immunotherapy. CCK-8, EdU and Transwell assays suggested that CCNE1 knockdown can suppress UCEC cell proliferation, migration and invasion.ConclusionOur study demonstrated that CCNE1 is upregulated in multiple cancers in the TCGA database and may be a promising predictive biomarker for the immunotherapy response in some types of cancers. Moreover, CCNE1 knockdown can suppress the proliferation, migration and invasion of UCEC cells.

Treatment options for molecular subtypes of endometrial cancer in 2023.

This article reviews treatment strategies in endometrial cancer by molecular subtype. The Cancer Genome Atlas (TCGA) classifies four molecular subtypes of endometrial cancer - mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H), copy number high (CNH)/p53abn, copy number low (CNL)/no specific molecular profile (NSMP), and POLEmut - which are validated and highly prognostic. Treatment consideration by subtype is now recommended. FDA-approved immune checkpoint inhibitors (ICIs) include pembrolizumab and dostarlimab for previously treated dMMR/MSI-H EC, and pembrolizumab/lenvatinib for mismatch repair-proficient/microsatellite-stable endometrial cancer, including CNH/p53abn and CNL/NSMP. ICIs are being studied as first-line therapy in advanced/recurrent endometrial cancer by MMR status, as well as in combination with other targeted agents. Trastuzumab is NCCN compendium listed for HER2-positive serous endometrial cancer, which are primarily p53-abnormal. Antibody-drug conjugates targeting low and high HER2 levels show promise in breast cancer, and are beginning to be studied in endometrial cancer. In addition to hormonal therapy, maintenance therapy with selinexor (XPO1-inhibitor) showed potential benefit in p53 -wildtype endometrial cancer and is being investigated prospectively. Multiple prospective trials are evaluating de-escalation of care for POLEmut endometrial cancer given favorable survival regardless of adjuvant therapy. Molecular subtyping has important prognostic and therapeutic implications and should be guiding patient management and clinical trial design in endometrial cancer.

Risk-Reducing Breast and Gynecological Surgery for BRCA Mutation Carriers: A Narrative Review.

This narrative review aims to clarify the role of breast and gynecological risk-reduction surgery in BRCA mutation carriers. We examine the indications, contraindications, complications, technical aspects, timing, economic impact, ethical issues, and prognostic benefits of the most common prophylactic surgical options from the perspectives of a breast surgeon and a gynecologist. A comprehensive literature review was conducted using the PubMed/Medline, Scopus, and EMBASE databases. The databases were explored from their inceptions to August 2022. Three independent reviewers screened the items and selected those most relevant to this review's scope. BRCA1/2 mutation carriers are significantly more likely to develop breast, ovarian, and serous endometrial cancer. Because of the Angelina effect, there has been a significant increase in bilateral risk-reducing mastectomy (BRRM) since 2013. BRRM and risk-reducing salpingo-oophorectomy (RRSO) significantly reduce the risk of developing breast and ovarian cancer. RRSO has significant side effects, including an impact on fertility and early menopause (i.e., vasomotor symptoms, cardiovascular disease, osteoporosis, cognitive impairment, and sexual dysfunction). Hormonal therapy can help with these symptoms. Because of the lower risk of developing breast cancer in the residual mammary gland tissue after BRRM, estrogen-only treatments have an advantage over an estrogen/progesterone combined treatment. Risk-reducing hysterectomy allows for estrogen-only treatments and lowers the risk of endometrial cancer. Although prophylactic surgery reduces the cancer risk, it has disadvantages associated with early menopause. A multidisciplinary team must carefully inform the woman who chooses this path of the broad spectrum of implications, from cancer risk reduction to hormonal therapies.

Targeted therapy in advanced/recurrent endometrial cancer: modern approaches

BackgroundIdentification of molecular subgroups and more precise characterization have led to a variety of new targeted therapies in advanced/recurrent endometrial cancer (EC) demonstrating not only response but better overall survival.Modern approachesUntil now chemotherapy with carboplatin/paclitaxel in the first-line setting and monochemotherapy in subsequent lines were options with limited efficacy. Knowledge of molecular subgroups is an opportunity for individualization through targeted therapies. The most established is currently immunotherapy used in second line; however, studies in the first line are already evaluating the impact of these compounds in combination with chemotherapy as well as monotherapy. Further promising approaches that are being evaluated in trials are, for example, antiHER2 (human epidermal growth factor receptor 2) therapy in HER2-positive serous EC, WEE inhibition, antihormonal medication with CDK4/6 inhibitors and antiangiogenetic agents.

STK4 protein expression pattern follows different trends in endometrioid and serous endometrial adenocarcinoma upon tumor progression

In a previous study, we showed that serine/threonine-protein kinase 4 (STK4) is involved in the control on proliferation and migration of endometrial cancer (EC) cells in vitro. In the present paper, we studied STK4 expression in EC tissues from a large cohort of patients to determine whether STK4 can serve as a marker for the aggressiveness and prognosis of EC. Tissue samples from patients with EC were examined for tumor type, grade, and stage. The STK4 protein expression in EC cells was assessed by immunohistochemistry and related to clinicopathological data of patients, such as progression and patient survival rate. The STK4 mRNA levels and its relation to the survival rate were analyzed also in publicly available databases. The STK4 gene expression was low at both, the mRNA and protein levels in EC, especially in serous tumors. Comparison of STK4 expression with the patient survival rate shows that the higher expression is associated with worse prognosis in serous EC, while no such dependence was found in endometrioid EC. Hence, the determination of the SKT4 expression pattern could be used as a putative prognostic marker for serous EC.

Lymph Node Metastases and Local Cancer Spread in Serous Endometrial Cancer and Endometrial Adenocarcinoma – A Retrospective Study

Abstract Serous endometrial carcinoma is characterized by its highly aggressive nature and represents about 10% of all endometrial carcinomas. It causes about 80% of deaths among women suffering from endometrial cancer. The aim of our study was to determine the frequency, lymphatic and local spread of serous endometrial cancer compared with endometrial adenocarcinoma. Materials and methods: This was a retrospective study conducted in a period of 4 years (from 2015 to 2019). One hundred and twenty-three women aged between 39 and 84 years suffering from endometrial carcinoma in various stages according to FIGO from stage I to IV were included in the study. Diagnosis was established clinically and by imaging studies and was histologically proven in all women. We performed radical hysterectomy type B or C (2017 Update on the Querleu-Morrow Classification of Radical Hysterectomy) and pelvic lymph node dissection (PN) with or without paraaortic (PAR) lymph node dissection in all patients. Results: In 106 (86.2%) patients we found adenocarcinoma, in 9 (7.3%) of them – serous carcinoma, in 4 (3.3%) women – carcinosarcoma, in 4 (3.3%) women – clear cell carcinoma. The study compared the results only of 115 (100%) women with adenocarcinoma and serous carcinoma. In 17.8% of the patients with adenocarcinoma we found the presence of lymph node metastases, and in the group of patients with serous carcinoma we found lymph node metastases in 77.7% of them. There was a significant difference in the frequency of lymph node metastases according to the histological type EC (p &lt; 0.00001). In 22.6% of patients with adenocarcinoma there was a local cancer spread, while such a spread was found in 66.7% of patients with serous cancer. After statistical processing of the results, we found a significant difference in the frequency of local tissue spread depending on the histological type of EC. Conclusion: Patients with serous endometrial cancer have significant more frequent lymphatic metastases and local spread than those with endometrial adenocarcinoma.

6 Racial differences in the mutational landscape of serous endometrial cancer

6 Racial differences in the mutational landscape of serous endometrial cancer

CRABP2 – A novel biomarker for high-risk endometrial cancer

ObjectiveInvestigate the clinical and functional implications of elevated CRABP2 expression in endometrial cancer (EC) patients. MethodsPatients were stratified into high and low CRABP2 expression groups using a decision tree classifier. Univariate and multivariate statistical analyses determined the prognostic and clinicopathological consequences of increased CRABP2 expression. A CRABP2 gene signature was generated using differential expression analysis, and analyzed using network-based approaches. The findings were validated in The Clinical Proteomic Tumor Analysis Consortium (CPTAC), a newly generated cohort of 120 endometrial tissues, and The Cancer Dependency Map (DepMap). Results60 (11%) patients in TCGA had high CRABP2 expression, whilst 468 (89%) had low expression. High expression was associated with serous EC, reduced overall survival, advanced stage and grade. Downstream retinoic acid receptors (RARG and RARA) were correlated with CRABP2 expression and were associated with worse prognosis in serous EC. The CRABP2 gene signature was enriched for Polycomb target gene sets, and was regulated by ELP3 and BMP7. BMP7 expression was increased in the CRABP2-high group, was associated with worse prognosis, and CRISPR-Cas9 screens revealed correlations in its cell-fitness score with CRABP2 following gene knockout. The opposite was true for ELP3, suggesting opposing effects from both master regulators. ConclusionsCRABP2 expression is associated with poor prognosis and advanced EC. The expression of RARA and RARG correlates with CRABP2 and are associated with worse prognosis in advanced histological subtypes. Polycomb target gene sets and two master regulators, ELP3 and BMP7, were identified as functionally relevant mechanisms driving aberrant CRABP2 expression.

Correlation of CCNE1 copy number levels with molecular profiles and outcomes for high grade serous ovarian and endometrial cancer (121)

<b>Objectives:</b> This study aimed to characterize <i>CCNE1</i> copy number (CN) in relation to other molecular characteristics of tumors, along with patient outcomes, to help guide future clinical trial design and potential novel targeted therapeutics development for these aggressive molecular subtypes of high-grade serous ovarian (HGSOC) and endometrial cancers (EMCA). <b>Methods:</b> Tumor samples were analyzed using Next-Gen sequencing (NGS) of the DNA (NextSeq, 592 genes or NovaSeq, whole-exome sequencing) and RNA (NovaSeq, whole-transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). PD-L1 IHC used SP-142 (cut-off ≥1%). Microsatellite instability (MSI) was tested by fragment analysis, IHC, and NGS. Tumor mutation burden (TMB) was measured by totaling somatic mutations per tumor (high ≥10 mutations/MB). Relative abundance of immune-cell infiltrates was calculated by MCPCounter. <i>CCNE1</i> amplification (<i>CCNE1</i>^Amp) was defined as CN ≥6 and calculated by NGS/WES. Real-world overall survival (OS) was obtained from insurance claims data, and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using Chi-square and Wilcoxon rank-sum test, and p-values adjusted for multiple comparisons (q) to be <0.05. <b>Results:</b> <i>CCNE1</i> was amplified in 608/6306 (9.6%) of HGSOC, 214/2098 (10.2%) of serous EMCA, 191/749 (15.3%) of uterine carcinosarcomas (UCS), and 17/2053 (0.80%) of endometrioid EMCA. <i>TP53</i> mutations positively correlated with <i>CCNE1</i>^Amp. <i>CCNE1</i>^Amp HGSOC had fewer mutations in <i>BRCA1/2</i>, <i>ARID1A</i>, and <i>NF1</i> but increased CN amplification in other genes (Table 1). <i>PTEN</i> mutations were negatively correlated with <i>CCNE1</i>^Amp in UCS and endometrioid EMCA. There was no difference in immuno-oncology biomarkers (TMB, dMMR/MSI, PD-L1). However, increased <i>CCNE1</i> levels were associated with decreased fibroblasts in HGSOC and serous EMCA, decreased B cells in serous EMCA, and decreased CD3+ T cells in UCS. In HGSOC, <i>CCNE1</i>^Amp was associated with increased expression of cell-cycle checkpoint regulators, Fanconi anemia, homologous recombination, mismatch repair, and single-strand break repair pathway genes, but decreased expression of these genes in endometrioid EMCA. In tumors with >1 specimen serially submitted, there was a significant increase in <i>CCNE1</i> CN over time in 29% (49/169) of HGSOC and 23% of EMCA (36/158). There was no difference in <i>CCNE1</i> CN in tumors harboring <i>BRCA</i> reversion mutations (<i>n</i>=8) compared to wild-type (<i>n</i>=5110). <i>CCNE1</i>^Amp correlated with mRNA expression in HGSOC and EMCA. <i>CCNE1</i>^Amp was associated with worse OS after carboplatin-based treatment in HGSOC as well as in serous EMCA and UCS. <b>Conclusions:</b> <i>CCNE1</i>^Amp in HGSOC and EMCA is less common than previously identified. Both HGSOC and endometrioid EMCAs have distinct molecular characteristics of <i>CCNE1</i>^Amp tumors. <i>CCNE1</i> CN may increase with the emergence of treatment resistance. Finally, <i>CCNE1</i>^Amp tumors appear overall non-immunogenic.

Combining molecular subtype and traditional histo-pathologic tumor classifications to predict survival in patients with endometrioid or serous endometrial cancers (221)

Objectives: We sought to determine the interaction between pathologic and histologic features and impact on overall survival (OS) among patients with endometrial cancer classified by the four molecular subtypes, identified by The Cancer Genome Atlas (TCGA). Methods: Using TCGA’s Pan-Cancer Atlas accessed via the cBioPortal, we identified patients with endometrioid or serous endometrial cancer. Patients with available molecular data were included in our analysis. We recorded available outcomes data, and FIGO stage and pathologic factors were manually extracted from surgical pathology reports. OS was compared among groups using Kaplan-Meier curves. Results: A total of 507 patients with molecularly subtyped endometrioid or serous endometrial cancers were identified. FIGO stage was inferred using surgical pathology reports, and data regarding LVSI and histologic grade were available in 467 patients. Tumors were categorized as POLE hypermutated (43/467; 9.2%), microsatellite instable (MSI) hypermutated (139/467; 29.8%), copy number low (CN-low) (142/467; 30.4%), and CN-high (143/467; 30.6%). While molecular subtype was significantly correlated with OS among the entire study population (p <0.0001), this correlation was only significant among stage III tumors when divided by FIGO stages (n=100, p = 0.012). Increasing histologic grade was associated with worse OS among patients with CN-low tumors (5-year survival: G1 100%, G2 88%, G3 59.4%; p = 0.0051) but not among patients with other TCGA molecular subtypes or low-grade tumors. Of the 73 patients with CN-high tumors with LVSI, 32 (43.8%) were node-positive. Of the 35 patients with CN-low tumors with LVSI, four (11.4%) were node-positive. The presence of LVSI was associated with worse OS than those without LVSI among patients with CN-high (3-year survival rate: 56.9% vs 83.1%, p = 0.0048) and CN-low (3-year survival rate: 88.5% vs 94.4%, p = 0.0024) tumors. Conclusions: In this cohort of patients with endometrioid and serous endometrial cancer from the TCGA, the presence of LVSI was associated with worse OS among patients with CN-low and CN-high tumors. Patients with CN-low tumors with LVSI were less likely to be node positive than patients with CN-high tumors with LVSI. Increasing histologic grade was associated with worse OS only among patients with CN-low tumors. These data support a combined molecular histopathologic classification for prognosis in endometrial cancer. Objectives: We sought to determine the interaction between pathologic and histologic features and impact on overall survival (OS) among patients with endometrial cancer classified by the four molecular subtypes, identified by The Cancer Genome Atlas (TCGA). Methods: Using TCGA’s Pan-Cancer Atlas accessed via the cBioPortal, we identified patients with endometrioid or serous endometrial cancer. Patients with available molecular data were included in our analysis. We recorded available outcomes data, and FIGO stage and pathologic factors were manually extracted from surgical pathology reports. OS was compared among groups using Kaplan-Meier curves. Results: A total of 507 patients with molecularly subtyped endometrioid or serous endometrial cancers were identified. FIGO stage was inferred using surgical pathology reports, and data regarding LVSI and histologic grade were available in 467 patients. Tumors were categorized as POLE hypermutated (43/467; 9.2%), microsatellite instable (MSI) hypermutated (139/467; 29.8%), copy number low (CN-low) (142/467; 30.4%), and CN-high (143/467; 30.6%). While molecular subtype was significantly correlated with OS among the entire study population (p <0.0001), this correlation was only significant among stage III tumors when divided by FIGO stages (n=100, p = 0.012). Increasing histologic grade was associated with worse OS among patients with CN-low tumors (5-year survival: G1 100%, G2 88%, G3 59.4%; p = 0.0051) but not among patients with other TCGA molecular subtypes or low-grade tumors. Of the 73 patients with CN-high tumors with LVSI, 32 (43.8%) were node-positive. Of the 35 patients with CN-low tumors with LVSI, four (11.4%) were node-positive. The presence of LVSI was associated with worse OS than those without LVSI among patients with CN-high (3-year survival rate: 56.9% vs 83.1%, p = 0.0048) and CN-low (3-year survival rate: 88.5% vs 94.4%, p = 0.0024) tumors. Conclusions: In this cohort of patients with endometrioid and serous endometrial cancer from the TCGA, the presence of LVSI was associated with worse OS among patients with CN-low and CN-high tumors. Patients with CN-low tumors with LVSI were less likely to be node positive than patients with CN-high tumors with LVSI. Increasing histologic grade was associated with worse OS only among patients with CN-low tumors. These data support a combined molecular histopathologic classification for prognosis in endometrial cancer.

Myosteatosis is associated with toxicity and recurrence free survival in women with serous endometrial cancer (475)

Myosteatosis is associated with toxicity and recurrence free survival in women with serous endometrial cancer (475)

Overall survival with or without adjuvant radiotherapy among different molecular subtypes of endometrial cancer (211)

Overall survival with or without adjuvant radiotherapy among different molecular subtypes of endometrial cancer (211)