Uterine Serous Carcinoma Patients Research Articles

Abstract A007: Single nuclei analysis of uterine serous carcinoma reveals racial differences in immune signaling

Abstract Endometrial cancer (EC) is a growing public health concern, as incidence rates continue to rise every year. Even more troubling is the unequal survival rates between racial groups with EC, as Black EC patients are dying at twice the rate of white EC patients. Uterine serous carcinoma (USC) is an aggressive subtype of EC that affects Black patients more frequently than white patients. While USC accounts for only 10-15% of all reported EC cases, it has a disease specific mortality rate of over 40%. It is currently unclear what is causing the racial differences in subtype frequency and survival rate of USC. To gain insight on the transcriptomic differences of tumor cells and cells within the tumor microenvironment (TME), we performed single-nuclei RNA sequencing of 13 USC tumors, with 9 tumors from Black patients and 4 from white patients. We found significant gene expression differences, including the upregulation of PAX8 in tumors of Black patients. PAX8 is a lineage factor important in Mullerian duct tissues and is frequently upregulated in EC. In PAX8 high tumor cells, signaling pathways such as TGBF, JAK- STAT, and NFKB activity was enriched, while PAX8 low cells were enriched for p53, WNT, and estrogen signaling. To understand if PAX8 directly affects epithelial immune signaling, we performed RNA-seq on PAX8 knock down (KD) ARK2 cells. Analysis of DEGs showed that PAX8 KD cells express high IL-1A and IL-1B, while chemokines such as CXCL1 and Midkine were downregulated. When conditioned media (CM) from PAX8 KD cells were added to THP-1 macrophages, decreased levels of anti-inflammatory markers such as ARG1 and TGFB1 were observed, compared to PAX8 expressing cells. Additionally, pro-inflammatory molecules such as TNFa and IL-6 were expressed at higher levels. These observations were validated by a cytokine antibody array; macrophages treated with PAX8 KD CM secreted higher levels of pro- inflammatory cytokines such as IL-1A, IL-1B, IL-6, and CXCL5. Anti-inflammatory molecules such as TGFB1 and TGFB2, and growth factors such as FGF6 and FGF7, were secreted at lower levels than control. These studies indicate that PAX8 is a novel regulator of the epithelial- immune axis, which is upregulated in USC compared to normal tissue and modulates the TME in favor of immune suppression and tumor growth. Because PAX8 expression is higher in tumors of Black patients compared to white, this may indicate that Black patients have a higher degree of immunosuppression. Our studies are the first to report tumor differences between Black and white USC patients at the single nuclei level. Additionally, we report findings from the first study to use single nuclei sequencing to study a tumor from Black USC patients. Our results indicate that taking race into account when determining treatment for USC may improve outcomes for Black patients. Citation Format: Grace Foley, J. Julie Kim. Single nuclei analysis of uterine serous carcinoma reveals racial differences in immune signaling [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A007.

Abstract IA012: The role of the serine/threonine phosphatase PP2A in endometrial cancer development and progression: lessons learned from mutations and small molecules

Abstract Uterine cancer is the most common gynecologic malignancy in the United States with approximately 60,000 new diagnoses each year. While many cases of uterine endometrial carcinoma (EMCA) have favorable outcomes with recurrence-free long-term survival, outcomes for the high-grade, treatment-refractory histological subtypes, including uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS), remain an important clinical problem. Uterine serous carcinomas and uterine carcinosarcomas tumors are the most aggressive subtypes of uterine cancer, displaying a high propensity to invade the peritoneal cavity and to metastasize to distant sites. Accordingly, 50-70% of high-grade tumors exhibit extrauterine spread at time of initial surgery and have limited treatment options. The inherent aggressiveness of these tumors suggests that they are intrinsically equipped to disseminate and propagate tumors at secondary sites. The molecular drivers of this phenotype, however, have yet to be completely characterized. A lack of established and validated molecular drivers of the high-grade subtypes, especially those that are responsible for the high rate of metastasis, has limited the use of targeted treatment strategies. However, we and other groups have shown that PPP2R1A, the scaffolding subunit of the tumor suppressor protein phosphatase 2A, is mutated in up to 40% of USC patients, and these recurrent mutations are found at both the primary and metastatic sites. These mutations are heterozygous, and two specific mutations: P179R and S256F, occur exclusively within these high-grade subtypes of uterine cancer (i.e., are not found in any other cancer type). PP2A, is a family of serine/threonine phosphatases, where the active heterotrimeric form of the enzyme is comprised of a catalytic (C) subunit, a scaffolding (A) subunit, and a substrate directing regulatory (B) subunit. In aggregate, PP2A is considered a tumor suppressor protein, but certain heterotrimers have tumor promoting roles. Here we present data related to the molecular and biological basis through which these recurrent pathogenic mutations drive endometrial cancer development and progression using disease relevant cellular and in vivo model systems. Additionally, building from previously published work from our group, we have developed a novel series of small molecule molecular glues (PMGs) that specifically correct the mutant heterotrimer driving tumor regressions in both cellular and patient derived xenograft models of high-grade endometrial cancer. Collectively, this data suggests that recurrent pathogenic mutations in the PPP2R1A gene drive endometrial cancer pathogenesis and these mutations can be therapeutically targeted using a series of pharmaceutically tractable small molecules. Citation Format: Goutham Narla. The role of the serine/threonine phosphatase PP2A in endometrial cancer development and progression: lessons learned from mutations and small molecules [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA012.

Mapping three-dimensional intratumor proteomic heterogeneity in uterine serous carcinoma by multiregion microsampling.

Although uterine serous carcinoma (USC) represents a small proportion of all uterine cancer cases, patients with this aggressive subtype typically have high rates of chemotherapy resistance and disease recurrence that collectively result in a disproportionately high death rate. The goal of this study was to provide a deeper view of the tumor microenvironment of this poorly characterized uterine cancer variant through multi-region microsampling and quantitative proteomics. Tumor epithelium, tumor-involved stroma, and whole "bulk" tissue were harvested by laser microdissection (LMD) from spatially resolved levels from nine USC patient tumor specimens and underwent proteomic analysis by mass spectrometry and reverse phase protein arrays, as well as transcriptomic analysis by RNA-sequencing for one patient's tumor. LMD enriched cell subpopulations demonstrated varying degrees of relatedness, indicating substantial intratumor heterogeneity emphasizing the necessity for enrichment of cellular subpopulations prior to molecular analysis. Known prognostic biomarkers were quantified with stable levels in both LMD enriched tumor and stroma, which were shown to be highly variable in bulk tissue. These USC data were further used in a comparative analysis with a data generated from another serous gynecologic malignancy, high grade serous ovarian carcinoma, and have been added to our publicly available data analysis tool, the Heterogeneity Analysis Portal ( https://lmdomics.org/ ). Here we identified extensive three-dimensional heterogeneity within the USC tumor microenvironment, with disease-relevant biomarkers present in both the tumor and the stroma. These data underscore the critical need for upfront enrichment of cellular subpopulations from tissue specimens for spatial proteogenomic analysis.

Comparison of clinical characteristics and prognosis in endometrial carcinoma with different pathological types: a retrospective population-based study

BackgroundEndometrial carcinoma (EC) is the second most common gynecological malignancy, and the differences between different pathological types are not entirely clear. Here, we retrospectively collected eligible EC patients to explore their differences regarding clinical characteristics and prognosis.MethodsFive hundred seventy EC patients from the First Affiliated Hospital of Zhengzhou University were included. Prognostic factors were measured using the univariate/multivariate Cox models. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively.ResultsIn total, 396 patients with uterine endometrioid carcinoma (UEC), 106 patients with uterine serous carcinoma (USC), 34 patients with uterine mixed carcinoma (UMC), and 34 patients with uterine clear cell carcinoma (UCCC) were included. Comparison of baseline characteristics revealed patients diagnosed with UEC were younger, had more early clinical stage, and had lower incidence of menopause and lymph node metastasis. Compared to UEC, other pathological EC obtained more unfavorable OS (UCCC: HR = 12.944, 95%CI = 4.231–39.599, P < 0.001; USC: HR = 5.958, 95%CI = 2.404–14.765, P < 0.001; UMC: HR = 1.777, 95%CI = 0.209–15.114, P = 0.599) and PFS (UCCC: HR = 8.696, 95%CI = 1.972–38.354, P = 0.004; USC: HR = 4.131, 95%CI = 1.243–13.729, P = 0.021; UMC: HR = 5.356, 95%CI = 0.935–30.692, P = 0.060). Compared with UEC patients, the OS of UCCC patients in stage I–II and USC patients in stage III–IV were significantly worse, while UMC patients in stage I–II favored poorer PFS. The OS of UCCC patients receiving no postoperative adjuvant therapy or chemotherapy alone were significantly worse.ConclusionsThe baseline characteristics of UEC and other rare EC types varied greatly, and the prognostic significance of different pathological types on EC patients depended on clinical tumor stages and therapeutic options.

Ascites-Derived Organoids to Depict Platinum Resistance in Gynaecological Serous Carcinomas.

Gynaecological serous carcinomas (GSCs) constitute a distinctive entity among female tumours characterised by a very poor prognosis. In addition to late-stage diagnosis and a high rate of recurrent disease associated with massive peritoneal carcinomatosis, the systematic acquisition of resistance to first-line chemotherapy based on platinum determines the unfavourable outcome of GSC patients. To explore the molecular mechanisms associated with platinum resistance, we generated patient-derived organoids (PDOs) from liquid biopsies of GSC patients. PDOs are emerging as a relevant preclinical model system to assist in clinical decision making, mainly from tumoural tissue and particularly for personalised therapeutic options. To approach platinum resistance in a GSC context, proficient PDOs were generated from the ascitic fluid of ovarian, primary peritoneal and uterine serous carcinoma patients in platinum-sensitive and platinum-resistant clinical settings from the uterine aspirate of a uterine serous carcinoma patient, and we also induced platinum resistance in vitro in a representative platinum-sensitive PDO. Histological and immunofluorescent characterisation of these ascites-derived organoids showed resemblance to the corresponding original tumours, and assessment of platinum sensitivity in these preclinical models replicated the clinical setting of the corresponding GSC patients. Differential gene expression profiling of a panel of 770 genes representing major canonical cancer pathways, comparing platinum-sensitive and platinum-resistant PDOs, revealed cellular response to DNA damage stimulus as the principal biological process associated with the acquisition of resistance to the first-line therapy for GSC. Additionally, candidate genes involved in regulation of cell adhesion, cell cycles, and transcription emerged from this proof-of-concept study. In conclusion, we describe the generation of PDOs from liquid biopsies in the context of gynaecological serous carcinomas to explore the molecular determinants of platinum resistance.

Effect of the combination of trastuzumab, paclitaxel and carboplatin in the treatment of uterine serous carcinoma: A systematic review and meta-analysis

Purpose: To systematically review the efficacy of paclitaxel-carboplatin versus trastuzumab in combination with paclitaxel/carboplatin for the treatment of uterine serous carcinoma (USC) with high Her2/neu expression, in order to obtain an evidence-based reference for clinical treatment.Methods: Publications were obtained from China Knowledge Network (CNKI), VIP database (VIP), Wanfang database, PubMed, Embase, Cochrane Library, and Web of Science. The retrieval period was from the establishment of database to May 2022, and the efficacy of paclitaxel-carboplatin combination with trastuzumab (study group) versus paclitaxel-carboplatin (control group) for the treatment of Her2/neu high-expressing USC was collected. Two reviewers independently screened, extracted data, and evaluated the quality of evidence of included studies. RevMan 5.3 statistical software was used for meta-analysis. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events.Results: Meta-analysis showed that the study group had significantly longer OS than control group (p = 0.004), and PFS of study group was significantly longer than that of control group (p &lt; 0.0001). In terms of ORR, there was no difference between the two groups (p = 0.42). However, in terms of total and high-risk adverse events, the number of patients with adverse events in study group was higher than in control group (p = 0.05), (p = 0.0001).Conclusion: Paclitaxel-carboplatin combination with trastuzumab significantly prolongs OS and PFS in USC patients with high Her2/neu expression, but it may increase the incidence of adverse events.

Construction and validation of nomograms for predicting the prognosis of elderly patients with uterine serous carcinoma: a SEER-based study.

To investigate the prognostic indicators, develop and verify nomograms for predicting overall survival (OS) and cancer-specific survival (CSS) in elderly patients with uterine serous carcinoma (USC). Data of eligible USC patients aged ≥ 65years from 2004 to 2015 in the Surveillance, Epidemiology and End Results (SEER) database were collected for retrospective analysis. X-tile software was used to assess the optimal cut-off values. Univariate and multivariate Cox regression analyses were performed to explore the prognostic factors. Nomograms were developed to predict the probability of 1-, 3- and 5-year OS and CSS. Concordance indexes (c-index), receiver operating characteristic analysis and calibration curves were used to evaluate the model. Decision curve analysis (DCA) was introduced to examine the clinical value of the models. Age, Federation International of Gynecology and Obstetrics stage, N stage, tumor size, number of lymph nodes resected, and adjuvant therapy were independent prognostic factors for OS and CSS. The C-indexes were 0.736 (OS), 0.754 (CSS) in the training set and 0.731 (OS), 0.759 (CSS) in the validation set. The area under the curve (AUCs) of OS and CSS for 1-, 3-, and 5-years all exceeded 0.75. The calibration plots for the probability of survival were in good agreement. As shown in DCA curves, the nomograms showed better discrimination power and higher net benefits than the 6th American Joint Committee on Cancer staging system. The nomograms constructed based on prognostic risk factors could individually predict the prognosis of elderly USC patients and provide a reference for clinical decision-making.

Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers.

Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.

Neoadjuvant chemotherapy in patients with stage IVB uterine serous carcinoma: a Turkish multicentric study

The aim of this study was to evaluate the prognostic factors for and determine the effect of neoadjuvant chemotherapy (NACT) on oncologic outcome in stage IVB pure serous endometrial carcinoma patients who received taxane and platinum. Forty-two patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IVB uterine serous carcinoma were enrolled from six gynecologic oncology centers and a study group was created. The study group had a 2-year disease-free survival (DFS) of 32% and 2-year disease-specific survival (DSS) of 73%. On univariate analysis; lymphadenectomy (not performed vs. performed), paraaortic lymph node metastasis (positive vs. negative) and number of metastatic lymph node count (≤5 vs. >5) were found to have statistical significance for DFS (p < 0.001, p = 0.026 and p = 0.044, respectively). Adnexal metastasis (positive vs. negative) and type of cytoreductive surgery (maximal vs. optimal and suboptimal) had statistical significance for DSS (p = 0.041 and p = 0.015, respectively). Receiving NACT did not affect DFS and DSS in stage IVB uterine serous carcinoma patients. As our sample size was small, precise conclusions could not be made for suggesting the use of NACT in advanced stage uterine serous carcinoma. For more accurate results, more randomized controlled studies are needed in this patient group. IMPACT STATEMENT What is already known on this subject? Endometrial carcinoma is the most common type of gynecologic tract malignancies and usually it is diagnosed at early stages. Although the favorable prognosis, uterine serous carcinoma (USC), one of the rarest subtypes, has a poorer prognosis when compared to other histological subtypes. USC has a propensity to spread beyond pelvis. Due to this aggressive behavior, surgical intervention could not be feasible in advanced stage disease. What do the results of this study add? Our study evaluated the prognostic factors that affect survival in advanced stage USC patients. Also we investigated that neoadjuvant chemotherapy (NACT) could improve oncologic outcomes. Performing lymphadenectomy, presence of paraaortic lymph node and adnexal metastasis, number of metastatic lymph nodes and type of cytoreductive surgery improved survival in advanced stage USC patients. However, NACT did not have a statistical significance as a predictor for disease-specific survival (DSS) and disease-free survival (DFS). What are the implications of these findings for clinical practice and/or further research? Maximal surgical effort should be performed in advanced stage USC according to our results. On the other hand, NACT had no impact on DSS and DFS rates. For this reason, we could not be able to suggest the routine use of NACT in advanced stage USC. But more randomized controlled trials are warranted for confirmation of our results.

Prevalence and Prognostic Relevance of Homologous Recombination Repair Gene Mutations in Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial cancer lacking efficacious treatments. USC bears molecular and pathological resemblance to high-grade serous ovarian cancer, for which mutations in homologous recombination repair (HRR) genes have been associated with better treatment outcomes with platinum-based chemotherapy and poly-ADP ribose polymerase 1/2 inhibitors (PARPi). We aimed to investigate the prevalence of tumor HRR (tHRR) gene mutations and its potential prognostic value in USC patients. Sixty consecutive USC patients with available tumor tissue samples and complete follow-up records were included. Tumor mutations in relevant HRR genes were identified using next-generation sequencing and correlated with the progress-free survival (PFS) and disease-specific survival (DSS) of the patients. Among the 60 patients' USC, 22 (36.7%) carried tumor HRR gene mutations (tHRRmt), with ATM, BRCA1, and BRCA2 being the most frequently mutated genes. Survival analysis showed similar PFS (HR, 0.500; 95% CI, 0.203-1.232; p = 0.132), but significantly longer DSS in the tHRRmt patients than in the HRR gene wild-type (tHRRwt) patients (HR, 0.176; 95% CI, 0.050-0.626; p = 0.007). In FIGO stage III and IV patients, the tHRRmt group also displayed longer DSS than the tHRRwt group (p = 0.008). Notably, USC patients with abnormal p53 in our cohort, both PFS and DSS were significantly longer in the tHRRmt group over the tHRRwt group (p = 0.040 and p = 0.008, respectively). The HRR gene mutations are highly prevalent in USC and may be related to better clinical outcomes as a prognostic marker. Further study is needed to confirm whether tHRRmt patients may benefit from treatments targeting homologous recombination such as platinum and PARPi.

Breast cancer patients are at increased risk of developing uterine serous cancer: Implications for counseling - SEER analysis (402)

<b>Objectives:</b> Several studies have investigated whether patients with prior breast cancer (BC) are at increased risk for endometrial cancer/uterine serous cancer (USC). We aimed to study the relationship between previous BC and uterine serous carcinoma (USC) and analyze the effect of prior BC on the incidence and prognosis of USC patients. <b>Methods:</b> With permission of the Surveillance, Epidemiology and End Results (SEER) program of the United States National Cancer Institute, clinical-pathologic information of women diagnosed with BC and following USC were analyzed. The recorded data included age at diagnosis, stage of disease, cause of death, interval time between BC and USC diagnosis, and overall survival. Further analysis was performed according to estrogen receptor status. <b>Results:</b> The SEER database included 10021 patients with USC during the years 1975-2015. Among the patients, 698 (6.96%) had been previously diagnosed with breast cancer (BC). The incidence of USC in patients with BC history was 57 times higher than in women without BC history (p value < 0.001). The incidence of USC did not differ between ER positive and ER negative BC patients (p. value 0.94). The mean survival of USC patients with previous BC history was eight years (96 months, 95% CI: 85.7-106.2), while for USC patients with no BC history the mean survival was 10.6 years (127 months, 95% CI: 124.0-130.8), suggesting a superior survival rate for USC patients with no history of BC (p. value=0.002). Fig. 1 <b>Conclusions:</b> Our results highlight the relationship between BC and USC, suggesting an increased risk for USC among BC patients. This clinical association should be introduced to BC patients, and physicians should be alert to any EC presenting symptom in BC survivors.

Abstract CT029: Safety and clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC)

Abstract Introduction: ZN-c3 is a selective, orally bioavailable small molecule inhibitor of WEE1, a crucial component of the G2/M cell cycle checkpoint, which prevents cells from entering mitosis to allow repair of DNA damage. ZN-c3 has demonstrated significant in vitro antitumor activity in multiple cell lines and xenograft models. Methods: ZN-c3-001 (NCT04158336) is an open label, multicenter, Phase I dose escalation and expansion study evaluating the safety and clinical activity of ZN-c3 in subjects with advanced or metastatic solid tumors, refractory to standard therapy or for whom no standard therapy is available. Oral, daily ZN-c3 dosing was escalated from 25 mg to 450 mg once daily (QD), with a recommended phase 2 dose of 300 mg QD. Here we report preliminary safety and efficacy results for subjects with USC who received ZN-c3 at doses ≥300 mg QD. Results: As of October 28, 2021, a total of 78 subjects were enrolled across all tumor types. For USC, there were 12 subjects who received ZN-c3 at doses ≥300 mg QD and were evaluated for safety. Median duration of treatment was 12 weeks (range, 2 - 33 weeks). The safety profile for this subgroup is comparable to the overall patient population with 11 of 12 subjects reporting at least one treatment-related adverse event (TRAE). TRAEs grades 1-4 occurring in ≥3 subjects, by decreasing frequency, included nausea, vomiting, fatigue, diarrhea, decreased appetite, dehydration, and anemia. Grade ≥3 TRAEs occurring in ≥2 subjects included anemia and thrombocytopenia. These hematologic events were limited to 2 subjects each. Nine of the 12 subjects had measurable disease and at least 1 post-baseline tumor assessment; 3 subjects (33.3%) had confirmed partial response and 5 (55.6%) had stable disease as their best overall response. Disease control rate, defined as those with complete response, partial response, and stable disease, was 88.9%. One subject with partial response achieved complete response at subsequent tumor assessment. Conclusions: ZN-c3 appears to be safe and well-tolerated as a single agent at oral doses ≥300 mg QD and demonstrated clinical activity in subjects with recurrent or advanced USC. Safety results in these subjects were consistent with those of the full study population. The ongoing dose expansion study is enrolling USC patients. The preliminary efficacy signal will be confirmed in a dedicated phase 2 study (ZN-c3-004, NCT04814108) in this patient population. Citation Format: Funda Meric-Bernstam, Pavani Chalsani, Hirva Mamdani, Cheng Zheng, Marcus Viana, Ruth Lambersky, Philippe Pultar, Anthony W. Tolcher. Safety and clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT029.

Uterine serous carcinoma: role of surgery, risk factors and oncologic outcomes. Experience of a tertiary center

ObjectiveTo evaluate factors impacting survival outcomes in patients with uterine serous carcinoma (USC). MethodsData of consecutive patients diagnosed with USC undergoing surgery between 2000 and 2020 at Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy) were reviewed. Progression-free (PFS) and overall survival (OS) outcomes were evaluated using Kaplan-Meier and Cox proportional hazard models. ResultsRecords of 147 consecutive patients meeting the inclusion criteria were analyzed. Stage distribution was: 67 (45.6%) patients with early-stage with uterine confined disease and 80 (54.4%) with advanced stages disease. Minimally invasive surgery was performed in 43 patients (29.5%). The median follow-up period was 78.6 months (IQ range = 35.7–117.3 months). The overall recurrence rate was 41% (60 patients): 19/67 patients (28.4%) with early-stage disease and 41/80 patients (51.3%) with advanced stage. The 5-year PFS rate was 35.0% (95% confidence interval [CI]: 27.5–44.7%). In multivariate analysis, age, BMI, depth of myometrial invasion, cytology, and optimal cytoreduction with postoperative residual tumor absent significantly impacted on PFS. The 5-year OS rates were 46.5% (95% CI: 38.1–56.8). The result of multivariate analysis showed that there was significant difference in OS based only on optimal cytoreduction and accuracy of retroperitoneal surgery. ConclusionsIn apparent early-stage USC, peritoneal and retroperitoneal staging allows to identify patients with disease harboring outside the uterus. Optimal cytoreduction is the most significant prognostic factor. Further collaborative studies are warranted in order to improve outcomes of USC patients.

The prognostic factors of survival and recurrence in patients with serous ovarian and uterine cancers treated in a single institution for 17 years

Objective: In this study, we aimed to identify the prognostic factors of survival and recurrence in ovarian and uterine serous cancer patients. Materials and methods: This was a retrospective study conducted at Tepecik Research and Education Hospital, İzmir, Turkey, between January 2002 and January 2019. The medical files of 2,027 endometrial and 821 ovarian patients who underwent examination for endometrial cancer and epithelial ovarian cancer were examined retrospectively by the same author. The data of eligible 385 and 49 patients diagnosed with ovarian and uterine serous carcinoma, respectively, were identified for analysis from the hospital database. Descriptive, univariate, and multivariate Cox regression and binary logistic regression analyses of patients were performed. Results: The mean age of ovarian serous cancer patients (n = 385) was 53.9 ± 10.9 years. The mean age of uterine serous cancer patients (n = 49) was 67.2 ± 10.6 years. A total of 81 ovarian serous cancer patients (21.0%) had stage 1, while 24 (6.2%) had stage 2, and 31 (8.1%) had stage 4 disease. A total of 26 uterine serous carcinoma patients (53.1%) had stage 1 disease, 6 (12.2%) had stage 2, 10 (20.4%) had stage 3, and 7 (14.3%) had stage 4 disease. For ovarian serous patients, stage, grade, optimality, neoadjuvant chemotherapy, adjuvant chemotherapy cycle number, and recurrence had impact on both overall and disease-free survival (p &lt; 0.05). For uterine serous cancer patients, optimality was the only prognostic factor for both survival and recurrence (p = 0.01 and p = 0.01, respectively). Conclusion: In ovarian serous cancer patients, we found that disease stage, grade, optimality, neoadjuvant chemotherapy, and adjuvant chemotherapy cycle number had impact on overall and disease-free survival in both univariate and multivariate Cox regression analysis, whereas disease stage and optimality were the only significant prognostic factors for recurrence in ovarian serous cancer patients. However, in patients with uterine serous carcinomas, optimal surgery was the only independent prognostic factor both for survival and recurrence.

Abstract 3174: Spatial immune cell and transcriptome profiling of tumors from primary and metastatic sites in advanced uterine serous carcinoma patients

Abstract Uterine serous carcinoma (USC) is a rare but the most aggressive subtype of endometrial cancer (EC) that represents less than 10% of all cases but contributes to more than 40% of EC related deaths. The low 5-year overall survival (OS) rate and high lethality of USC patients are mainly caused by aggressive extra-uterine metastasis frequently to lymph nodes and omentum. Deeply understanding the underneath mechanism that leads to USC progression is essential for the development of therapeutic strategies for USC patients. The communication between tumor and different subpopulations of immune cells has been widely proven to determine tumor cells fate and plays critical role during tumor proliferation and metastasis. Given the immunological study in USC still much lags behind other cancer types, the purpose of this study is to use tumors collecting from primary and metastatic sites in USC patients to demonstrate the role of immune cell landscape and associated molecular signaling networks in USC progression. Formalin fixed embedded (FFPE) tissue sections from both primary and metastasis sites (lymph node metastasis) of 12 USC patients were used. A panel of 6 reactive fluorophores, spectral DAPI together with functional markers granzyme B and Ki-67 were used to examine the spatial localization of a variety of tumor-infiltrating immune cells by multiplex immunofluorescence IHC assay using OpalTM immunology detection kit. Images were acquired by a Vetra 3.0 microscope and data analysis was performed by the VisioPharm software and bioinformatics tools. Transcriptome analyses were performed on RNA isolated from microdissected tumor cells the human Clariom D transcriptomics assay. Transcriptome Analysis Console was employed to identify altered differential genes and signaling pathways between primary tumor and metastatic sites. The primary and metastatic USC displayed quite distinct immune landscapes suggesting the essential role of immune system during metastasis. Primary sites contained markedly higher density of intratumoral activated tumor-infiltrating cytotoxic T cells (CD8+granzyme B+), and CD8+LCK+ T cell subpopulation than the metastatic sites in lymph nodes. In addition, we found that the density and spatial distribution of activated CD8+ T cells positively correlated with the overall survival of USC patients. Transcriptome analyses demonstrated that 781 of upregulated genes with fold &amp;gt; 2, p &amp;lt;= 0.05 were identified in tumor cells in primary sites compared to metastatic sites. Furthermore, multiple signaling pathways associated with immune cell activation and tumor cell metastasis were also found to be enriched in primary sites. Our study suggests that distinct immune cell landscapes and molecular signaling networks in the lymph nodes provide a permissive niche that support USC progression, which may lead to poor survival rates in patients with advanced USC. Citation Format: Li Zhang, Angela Rynne-Vidal, Karen H Lu, Samuel C Mok. Spatial immune cell and transcriptome profiling of tumors from primary and metastatic sites in advanced uterine serous carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3174.

[Diagnosis, treatment and prognosis of uterine serous carcinoma].

Objective: To investigate the diagnosis, treatment and prognosis of uterine serous carcinoma (USC), and further analyze the prognostic factors. Methods: USC patients who underwent surgery with complete follow-up at Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences between January 1, 2004 and December 31, 2014 were retrospectively reviewed. The Kaplan-Meier method and Cox regression analysis were used for survival analysis. Results: (1) Diagnosis and treatment: the study included 71 USC patients. Only 32 patients (45%, 32/71) were diagnosed preoperatively with USC, and 25 cases of them (35%, 25/71) underwent USC standard comprehensive staging surgery. Of the 25 patients, 10 cases (40%, 10/25) had up-staged after operation. (2) Prognosis: the 5-year disease free survival (DFS) rate and overall survival (OS) rate for all patients were 76.5% and 80.6%, respectively. (3) The results of prognostic factors analysis: univariate analysis on age, range of lymphadenectomy, peritoneal cytology, the depth of myometrial invasion, adnexal and (or) serosa involvement and omentum metastasis were significantly associated with 5-year DFS rate (all P<0.05); range of lymphadenectomy, range of surgical staging, peritoneal cytology, adnexal and (or) serosa involvement and postoperative adjuvant treatment were significantly associated with 5-year OS rate (all P<0.05). Multivariate analysis on range of surgical staging (HR=5.18, 95%CI: 1.04-25.70, P=0.044) and adnexal and (or) serosa involvement (HR=8.41, 95%CI: 2.28-31.05, P=0.001) were independent prognostic factors for 5-year DFS rate; range of lymphadenectomy [no lymphadenectomy vs pelvic lymphadenectomy (PLN)+para-aortic lymphadenectomy (PALN), HR=27.76, 95%CI: 1.76-437.78, P=0.018;PLN vs PLN+PALN, HR=5.98, 95%CI: 1.11-32.27, P=0.038] and peritoneal cytology (HR=5.47, 95%CI: 1.18-25.39, P=0.030) were independent prognostic factors for 5-year OS rate. Conclusions: The preoperative pathological diagnosis of USC is difficult, resulting in incomplete surgical staging and inaccurate staging. Range of surgical staging, adnexal and (or) serosa involvement, peritoneal cytology and range of lymphadenectomy are independent prognostic factors, which deserve much attention in clinical practice.

Tumor Recurrence Rate and Survival Outcomes of Uterine Serous Carcinoma after Surgical Treatment

Background: Uterine serous carcinoma is a rare histologic subtype of endometrial cancer. Oncologic outcomes for this disease are sparsely reported, and adjuvant therapy after surgery is considerably heterogeneous. Objective: To determine the 2-year recurrence rate, recurrence-free survival, overall survival, and associated factors among patients with uterine serous carcinoma after surgical treatment at Siriraj Hospital. Materials and Methods: One hundred thirty uterine serous carcinoma patients diagnosed between December 2007 and June 2015 were enrolled. Patients who did not undergo surgery as a primary treatment or not achieve clinically complete response were excluded. Pathological slides were reviewed. Data were retrieved from the medical records including gynecologic data, surgical and pathological results, post-operative treatment, response status, recurrence status, and follow-up data. The recurrence rate at two years was calculated. Recurrence-free survival and overall survival were analyzed, and various characteristics were used to determine associated treatment outcomes. Results: One hundred nine patients were analyzed, 50 in stage I, 15 in stage II, 38 in stage III, and six in stage IV. Median follow-up time was 23 months. At two years, the recurrence rate was 35.8%. Post-operative treatment was performed in 91.7%, and chemotherapy was the most common modality used. Eleven patients (16.9%) in early-stage and twenty-five patients (56.8%) in the advanced stage had disease recurrence. Thirty patients (83.3%) had disease recurrence intra-abdominal or multiple metastases. No patient in stage I that received adjuvant chemotherapy had relapsed disease. Two-year recurrence-free survival and 2-year overall survival were 71.2% and 83.4%, respectively. FIGO staging was the only factor associated with recurrence-free survival. Conclusion: Uterine serous carcinoma represents a rare disease with a high recurrence rate and poor prognosis. FIGO staging is related to recurrence-free survival. Adjuvant chemotherapy showed survival benefits in early-stage uterine serous carcinoma. Keywords: Uterine serous carcinoma, Adjuvant therapy, Recurrence, Survival

Pathogenesis and Clinical Management of Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer–related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC.

A 73-gene proliferative transcriptomic signature predicts uterine serous carcinoma patient survival and response to primary therapy

ObjectivesTo develop a transcriptomic signature capable of predicting overall survival (OS) for uterine serous carcinoma (USC). MethodsRNAseq data for 58 USC patients were obtained from TCGA. Expression of 73 candidate genes was measured for 67 Augusta University (AU) samples using NanoString technology. ResultsAnalysis of the TCGA RNAseq data identified 73 genes that individually predict prognosis for USC patients and an elastic net model with all 73 genes (USC73) distinguishes a good OS group with low USC73 score from a poor OS group with high USC73 score (5-year OS = 83.3% and 13.3% respectively, HR = 40.1; p = 3 × 10−8). This finding was validated in the independent AU cohort (HR = 4.3; p = 0.0004). The poor prognosis group with high USC73 score consists of 37.9% and 32.8% of patients in the TCGA and AU cohort respectively. USC73 score and pathologic stage independently contribute to OS and together provide the best prognostic value. Early stage, low USC73 patients have the best prognosis (5-year OS = 85.1% in the combined dataset), while advanced stage, high USC73 patients have the worst prognosis (5-year OS = 6.4%, HR = 30.5, p = 1.2 × 10−12). Consistent with the observed poor survival, primary cell cultures from high USC73 patients had higher proliferation rate and cell cycle progression; and high USC73 patients had lower rates of complete response to standard therapy. ConclusionsThe USC73 transcriptomic signature and stage independently predict OS of USC patients and the best prediction is achieved using USC73 and stage. USC73 may also serve as a therapeutic biomarker to guide patient care.

Adjuvant chemotherapy in endometrial cancer.

The role of adjuvant chemotherapy (CT) is controversial in endometrial carcinoma (EC). Surgery alone is usually curative for women who are at a low risk of disease recurrence. The treatment of EC following surgical staging is based on the risk of relapse, which is defined by the cancer stage at diagnosis, histology of the tumor and other prognostic factors such as grade differentiation, the presence of substantial lymphovascular invasion (LVSI), or depth of myometrial invasion (MI). External beam radiotherapy (EBRT) and/or vaginal brachytherapy (VBT) improved local control and are used as adjuvant treatment for early-stage disease. The role of adjuvant CT is controversial in early-stage EC, and there is no uniform approach to the treatment of women with stage III EC or early-staged non-endometrioid EC. Available evidence did not support the indication of adjuvant CT in stage I-II endometroid EC. In those cases at higher risk of relapse, defined as grade 3 tumors with substantial (no focal) LVSI, specifically with deep MI or cervical involvement, could be considered. Adjuvant CT should be administered to stage III EC patients. When RT is indicated (extensive lymph node involvement or deep MI), sequential treatment with RT or "sandwich" regimen may be considered rather than concurrent CRT. The patients with stage IA MI or IB USC may be offered adjuvant CT alone or in combination with VBT, whereas in stage II uterine serous carcinoma patients adding EBRT may be reasonable. Management approach for patients with stage IA without MI USC who underwent a comprehensive surgery remains controversial, and surveillance alone or CT plus VBT is an appropriate option. Early-stage clear-cell carcinoma patients might not benefit for adjuvant CT, but stage III patients might benefit from the combination of CT and EBRT. Stage I-III uterine carcinosarcoma patients might be offered adjuvant CT followed by RT or as a "sandwich" régimen.