Uterine carcinosarcoma: Unraveling the role of epithelial-to-mesenchymal transition in progression and therapeutic potential.

Uterine carcinosarcoma (UCS) is a rare and highly aggressive gynecological malignancy characterized by poor prognosis. Due to its rarity, UCS remains relatively unexplored, and specific treatment guidelines are scarce. Despite standard treatments, including surgery, adjuvant chemotherapy, and radiotherapy, UCS has a high recurrence rate and poor overall prognosis. The aggressive nature of UCS is attributed to the metaplastic transformation of carcinomatous elements into sarcoma. This "biphasic" neoplasm features a mixture of epithelial and mesenchymal/tumor components, which partially share molecular signatures and exhibit a typical epithelial-to-mesenchymal transition (EMT) gene expression profile. Recent scientific advancements have highlighted the pivotal role of EMT in UCS progression and mortality. This review covers the epidemiology of UCS, theories regarding its origin, and the current state of clinical trials with more emphasis on the role of EMT drivers in UCS progression and scope of targeting these molecules. By shedding light on the molecular mechanisms supporting UCS, particularly emphasizing the importance of EMT, we aim to provide a more comprehensive understanding of the disease to support the development of more effective therapeutic strategies.

Clinicopathological and molecular features of tubo-ovarian carcinosarcomas: a series of 51 cases.

Objective: Tubo-ovarian carcinosarcomas are rare, extremely aggressive malignant tumors that contain both carcinomatous and sarcomatous components. Due to the disease's rarity, developing an effective treatment strategy for ovarian carcinosarcomas has been challenging. A study was conducted to investigate the clinicopathologic and molecular features of this rare disease. Methods: We enrolled all patients diagnosed with tubo-ovarian carcinosarcomas from January 2007 to December 2022. The clinical and pathological data were gathered from medical records. Kaplan-Meier curves were plotted to calculate OS and PFS. The Log-rank test and Cox regression model were utilized to explore the relationship between clinicopathological parameters and survival. Patients with cancer tissues available had sequencing with a 242-gene panel done to investigate the mutational landscape and signature of the disease. Results: In total, 65% of the patients were diagnosed with advanced-stage cancer. The median PFS and OS of this cohort were 27 and 40 months, respectively, and there was no significant difference in survival between the homologous and heterologous components of sarcoma. Unexpectedly, staging did not have effects on prognosis. All patients had surgical attempts, and suboptimal debulking status was correlated with poorer PFS and OS. MSI was identified in 0% with low Tumor mutation burden (TMB) indicating a poor response to immunotherapy. Low HER2 expression is controversial, according to previous reports, and gives us limited choices with this rare and aggressive disease. We surprisingly found the homologous recombination deficiency (HRD)-positive status was identified in 64% of OCS, which is significantly higher than UCS and other types of epithelial ovarian cancer. The fact that all patients in our cohort who received olaparib as maintenance therapy had survived over 30 months and two had no evidence of recurrence at the latest follow-up might further validate the role of poly (ADP-ribose) polymerase inhibitors (PARPi) in the management of OCS. Conclusion: OCS patients seemed to respond to carboplatin/paclitaxel with optimal PFS and OS. Cytoreduction with no residuals proved to be the sole independent prognostic factor. WES should be done to assess the prognosis and assist with the targeted therapy, especially the HRD test, which might help select potential patients who benefit from PARPi.

The efficacy and safety of lenvatinib plus pembrolizumab therapy in patients with uterine carcinosarcoma.

Lenvatinib plus pembrolizumab (LP) therapy is currently used in patients with advanced or recurrent endometrial cancer. However, patients with uterine carcinosarcoma (UCS) were not included in the KEYNOTE-775, and the efficacy of LP therapy for patients with UCS in clinical practice remains unclear. We administered LP therapy to five patients with UCS. We aimed to report our clinical experience with LP therapy in these patients and investigate the genomic characteristics of those who responded to LP therapy. We retrospectively reviewed patients with UCS (n = 5) who underwent LP therapy at our hospital from January 2019 to December 2023. Efficacy was assessed using the response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1. Safety was evaluated in terms of adverse events. The median age was 65 (55-78) years, and the mismatch repair status was proficient in all of the patients. One patient had stage II disease, and four had stage III. The median number of LP therapy courses was 8 (1-35). The overall response rate was 40%. None of the patients experienced adverse events that were grade 3 or higher. The median follow-up duration was 9 (1-26) months, median progression-free survival was 9.1 (0.16 to NA) months, and median overall survival was 10.2 (1.41 to NA) months. LP therapy may be effective for patients with UCS. As this report was based on a limited number of patients, more cases are required to investigate the efficacy of LP therapy in patients with UCS.

Preclinical in vitro and in vivo activity of the RAF/MEK clamp avutometinib in combination with FAK inhibition in uterine carcinosarcomas.

OBJECTIVES: Uterine carcinosarcomas (UCS) are rare, biologically aggressive tumors. Since UCS may harbor mutations in RAS/MAPK pathway genes we evaluated the preclinical in vitro and in vivo efficacy of the RAF/MEK clamp avutometinib in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718 against multiple primary UCS cell lines and xenografts. METHODS: Whole-exome-sequencing (WES) was used to evaluate the genetic landscape of 5 primary UCS cell lines. The in vitro activity of avutometinib ± FAK inhibitor was evaluated using cell viability and cell cycle assays against primary UCS cell lines. Mechanistic studies were performed using western blot assays while in vivo experiments were completed in UCS tumor bearing mice treated with avutometinib ± FAK inhibitor by oral gavage. RESULTS: WES results demonstrated multiple UCS cell lines harbor genetic alterations including KRAS, PTK2, BRAF, MAP2K, and MAP2K1, potentially sensitizing to FAK and RAF/MEK inhibition. Four out of five of the UCS cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition when used alone or in combination. By western blot assays, exposure of UCS cell lines to the combination of defactinib/avutometinib demonstrated decreased phosphorylated (p)-FAK as well as decreased p-ERK. In vivo, the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition and longer survival compared to single agent treatment and controls starting at day 10 (p < 0.002) in UCS xenografts. CONCLUSION: The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.

Evaluation of Uterine Carcinosarcoma and Uterine Endometrial Carcinoma Using Magnetic Resonance Imaging Findings and Texture Features.

Aim  This study aimed to evaluate the diagnostic feasibility of magnetic resonance imaging (MRI) findings and texture features (TFs) for differentiating uterine endometrial carcinoma from uterine carcinosarcoma. Methods This retrospective study included 102 patients who were histopathologically diagnosed after surgery with uterine endometrial carcinoma (n=68) or uterine carcinosarcoma (n=34) between January 2008 and December 2021. We assessed conventional MRI findings and measurements (cMRFMs) and TFs on T2-weighted images (T2WI) and apparent diffusion coefficient (ADC) map, as well as their combinations, in differentiating between uterine endometrial carcinoma and uterine carcinosarcoma. The least absolute shrinkage and selection operator (LASSO) was used to select three features with the highest absolute value of the LASSO regression coefficient for each model and construct a discriminative model. Binary logistic regression analysis was used to analyze the disease models and conduct receiver operating characteristic analyses on the cMRFMs, T2WI-TFs, ADC-TFs, and their combined model to compare the two diseases. Results A total of four models were constructed from each of the three selected features. The area under the curve (AUC) of the discriminative model using these features was 0.772, 0.878, 0.748, and 0.915 for the cMRFMs, T2WI-TFs, ADC-TFs, and a combined model of cMRFMs and TFs, respectively. The combined model showed a higher AUC than the other models, with a high diagnostic performance (AUC=0.915). Conclusion A combined model using cMRFMs and TFs might be helpful for the differential diagnosis of uterine endometrial carcinoma and uterine carcinosarcoma.

Gemcitabine combination therapies induce apoptosis in uterine carcinosarcoma patient-derived organoids.

Uterine carcinosarcoma (UCS) is a rare but aggressive endometrial cancer. Survival outcomes for women diagnosed with UCS remain poor with lower survival than those of endometrioid or high-grade serous uterine cancers. The histopathological hallmark of carcinosarcoma is the presence of both sarcomatous and carcinomatous elements. The survival rates for UCS have not improved for over 40 years; therefore, there is a profound need to identify new treatments. To investigate novel chemotherapy treatment combinations for UCS, we generated a UCS patient-derived organoid (PDO) cell line from a patient that received neoadjuvant treatment with paclitaxel and carboplatin. The PDO cell line (UCS1) was grown in three-dimensional domes. The PDO domes were treated with six individual chemotherapies or nine combinations of those six drugs. Cell death in response to chemotherapy was assessed. We found that the six monotherapies had minimal effectiveness at inducing cell death after 48 h of treatment. The combination of paclitaxel and carboplatin (which is the standard-of-care chemotherapy treatment for UCS) led to a small increase in apoptosis compared with the monotherapies. Importantly, when either carboplatin or paclitaxel was combined with gemcitabine, there was an appreciable increase in cell death. In conclusion, for the UCS1 patient-derived tumor cells, gemcitabine combinations were more effective than carboplatin/paclitaxel. Our data support the use of PDOs to predict responses to second-line chemotherapy.

Social determinants of health in uterine carcinosarcoma.

OBJECTIVE: UCS survival outcome disparities by race have been reported. We aimed to investigate social determinants of health (SDOH) and their relation to survival outcomes in women at two affiliated high-volume institutions serving a racially and economically diverse population. METHODS: Women diagnosed with stage I-IV UCS treated at St. Paul University Hospital, University of Texas Southwestern (UTSW) Zale Lipshy Pavilion-William P. Clements Jr. University Hospital, and Parkland Memorial Hospital between 1992 and 2022 were eligible. Patients were identified by the local tumor registries; a retrospective study was conducted. The Pearson chi-square test was utilized for categorical variables. OS and PFS were calculated using Kaplan-Meier estimates and compared with the log-rank test. Multivariate Cox models were used to identify independent prognostic factors. All statistical analyses were performed using SAS, version 9.4. RESULTS: Over half of the 218 patients with UCS were NHB. 35% of the patients had stage IV disease. Most HSP and NHB patients had a lower median household income* than Asian/Pacific Islander (API) or NHW (p < 0.001). Stage at diagnosis significantly affected OS (p < 0.001) but not PFS (p = 0.46) in univariate analyses. Accounting for age at diagnosis, insurance, income*, hospital, distance between hospital and home, months from diagnosis to first treatment, stage, and adjuvant therapy, race was significant for OS (p = 0.03) and PFS (p = 0.04). *Median household income by ZIP Code. CONCLUSIONS: Racial disparities were seen in median household income. Most SDOH independently analyzed in this study did not affect OS. The complex interaction between race and stage in UCS survival outcomes needs further investigation.

Clinical and multiparametric MRI features for differentiating uterine carcinosarcoma from endometrioid adenocarcinoma.

INTRODUCTION: The purpose of our study was to differentiate uterine carcinosarcoma (UCS) from endometrioid adenocarcinoma (EAC) by the multiparametric magnetic resonance imaging (MRI) features. METHODS: We retrospectively evaluated clinical and MRI findings in 17 patients with UCS and 34 patients with EAC proven by histologically. The following clinical and pathological features were evaluated: post- or pre-menopausal, clinical presentation, invasion depth, FIGO stage, lymphaticmetastasis. The following MRI features were evaluated: tumor dimension, cystic degeneration or necrosis, hemorrhage, signal intensity (SI) on T2-weighted images (T2WI), relative SI of lesion to myometrium on T2WI, T1WI, DWI, ADCmax, ADCmin, ADCmean (RSI-T2, RSI-T1, RSI-DWI, RSI-ADCmax, RSI-ADCmin, RSI-ADCmean), ADCmax, ADCmin, ADCmean, the maximum, minimum and mean relative enhancement (RE) of lesion to myometrium on the arterial and venous phases (REAmax, REAmin, REAmean, REVmax, REVmin, REVmean). Receiver operating characteristic (ROC) analysis and the area under the curve (AUC) were used to evaluate prediction ability. RESULTS: The mean age of UCS was higher than EAC. UCS occurred more often in the postmenopausal patients. UCS and EAC did not significantly differ in depth of myometrial invasion, FIGO stage and lymphatic metastasis. The anterior-posterior and transverse dimensions were significantly larger in UCS than EAC. Cystic degeneration or necrosis and hemorrhage were more likely occurred in UCS. The SI of tumor on T2WI was more heterogeneous in UCS. The RSI-T2, ADCmax, ADCmean, RSI-ADCmax and RSI-ADCmean of UCS were significantly higher than EAC. The REAmax, REAmin, REAmean, REVmax, REVmin and REVmean of UCS were all higher than EAC. The AUCs were 0.72, 0.71, 0.86, 0.96, 0.89, 0.84, 0.73, 0.97, 0.88, 0.94, 0.91, 0.69 and 0.80 for the anterior-posterior dimension, transverse dimension, RSI-T2, ADCmax, ADCmean, RSI-ADCmax, RSI-ADCmean, REAmax, REAmin, REAmean, REVmax, REVmin and REVmean, respectively. The AUC was 0.997 of the combined of ADCmax, REAmax and REVmax. Our study showed that ADCmax threshold value of 789.05 (10-3mm2/s) can differentiate UCS from EAC with 100% sensitivity, 76.5% specificity, and 0.76 AUC, REAmax threshold value of 0.45 can differentiate UCS from EAC with 88.2% sensitivity, 100% specificity, and 0.88 AUC. CONCLUSION: Multiparametric MRI features may be utilized as a biomarker to distinguish UCS from EAC.

Prognostic Value of Lymph Node Ratio in Patients with Uterine Carcinosarcoma.

Uterine carcinosarcoma is a rare high-grade endometrial cancer. Controversy has surrounded a number of aspects in the diagnosis and management of this unique clinicopathological entity, including the efficacy of adjuvant therapy, which has been questioned. An unusual surgico-pathological parameter with prognostic significance in a number of tumour sites is the lymph node ratio (LNR). The availability of data in this respect has been scarce in the literature. The primary aim of this collaborative study was to evaluate the prognostic value of LNR in patients with uterine carcinosarcoma. LNR is a recognized lymph node metric used to stratify prognosis in a variety of malignancies. In this European multinational retrospective study, 93 women with uterine carcinosarcoma were included in the final analysis. We used t-tests and ANOVA for comparison between quantitative variables between the groups, and chi-square tests for qualitative variables. A multivariate analysis using Cox regression analysis was performed to determine potential prognostic factors, including the LNR. Patients were grouped with respect to LNR in terms of 0%, 20% > 0% and >20%. The analysis revealed LNR to be a significant predictor of progression-free survival (HR 1.69, CI (1.12-2.55), p = 0.012) and overall survival (HR 1.71, CI (1.07-2.7), p = 0.024). However, LNR did not remain a significant prognostic factor on multivariate analysis. Due to limitations of the retrospective study, a prospective large multinational study, which takes into effect the most recent changes to clinical practice, is warranted to elucidate the value of the pathophysiological metrics of the lymphatic system associated with prognosis.

Mesothelin expression in gynecologic carcinosarcoma: clinicopathological significance and correlation with HER2 expression.

OBJECTIVE: This study aimed to evaluate mesothelin (MSLN) expression and determine its clinical significance and correlation with human epidermal growth factor receptor 2 (HER2) expression in gynecological carcinosarcoma. METHODS: We retrospectively evaluated patients with uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) who underwent surgery between 1997 and 2019. Immunohistochemical staining of formalin-fixed, paraffin-embedded specimens for MSLN (clone SP74) and HER2 (clone 4A5) was also performed. MSLN was scored using the H-score and 4-tired scoring system (0-3+). MSLN positivity was defined as any positive cell at any intensity, while high MSLN expression was defined as an intensity of ≥2+ in ≥30% of tumor cells. HER2 expression was scored according to modified 2018 American Society of Clinical Oncology/College of American Pathologists criteria. RESULTS: A total of 128 patients were recruited, including 119 with UCS and 9 with OCS. All cases in UCS exhibited MSLN positivity, and 33.9% showed high-MSLN expression. Clinicopathological characteristics were not significantly associated with high or low-MSLN expression. However, the high-MSLN group showed more prolonged overall survival (OS) than the low-MSLN group (not assessed vs. 36.8 months; hazard ratio=0.48, 95% confidence interval=0.26-0.89, p=0.016). HER2-high patients had higher MSLN expression than HER2-negative patients. In high-MSLN and low-MSLN expression groups, HER2 status did not affect OS. OCS showed 100% MSLN positivity, with 66.6% high-MSLN. CONCLUSION: MSLN expression is widely observed in gynecological carcinosarcomas. Moreover, high-MSLN expression is a favorable prognostic factor for UCS. MSLN could be a promising therapeutic target for UCS, even in the era of anti-HER2 therapy.

In Vivo Intra-Uterine Delivery of TAT-Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53-Deficient Endometrial Cancers.

Phosphatase and TENsin homolog (Pten) and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, it is demonstrated that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel intravaginal delivery method using HIV1 trans-activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT-Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high-grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten/p53 deficient epithelial cells are mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. The results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo.

Clinicopathological and molecular analyses of uterine carcinosarcomas using next-generation sequencing: A single-center experience.

Background: Uterine carcinosarcomas (UCS) constitute 3-4% of all uterine malignancies and 16% of deaths caused due to uterine neoplasms. Aim: In this study, we aimed to perform DNA-based mutation analysis in 12 genes (KRAS, NRAS, EGFR, C-KIT, BRAF, PDGFRA, ALK, ERBB2, ERBB3, ESR1, RAF1, PIK3CA) to determine the molecular subtypes of UCS using next-generation sequencing (NGS) in patients with aggressive UCS and poor prognosis. We aimed to compare the results of our analysis with clinicopathological data to contribute to the development of targeted therapy approaches related to the molecular changes of UCS. Materials and Methods: In this study, we included 12 cases diagnosed with uterine carcinosarcomas and examined the changes in oncogenes that play a role in UCS pathogenesis. For the analysis of mutation, the clinicopathological data were compared with the variations in the DNA-based gene panel consisting of 12 genes and 1237 variants in the UCS using the NGS method. Results: EGFR mutation was found in 91.7% of the cases, mutation in 41.7%, PDGFRA mutation in 25%, KRAS and PIK3CA mutation in 16.7%, and C-KIT mutation in 8.3% of the cases. Although no statistical significance was found between the detected mutation and clinicopathological data, it was concluded that PDGFRA mutation might be associated with advanced-stage disease development. Conclusion: This study's findings regarding different molecular types of UCS and information on oncogenesis of UCS can provide inferences for targeted therapies in the future by identifying targetable mutations representing early oncogenic events and thereby contribute toward further studies on this subject.

Folate receptor alpha is widely expressed and a potential therapeutic target in uterine and ovarian carcinosarcoma.

OBJECTIVE: Folate receptor alpha (FRα), which is expressed in various cancers, is a potential therapeutic target. However, its expression and clinical significance in uterine (UCS) and ovarian carcinosarcoma (OCS) remain to be elucidated. METHODS: This retrospective study included patients with gynecologic carcinosarcoma who underwent primary surgery between 1997 and 2019 at our institution. Immunohistochemical staining of surgical FFPE specimens was performed for FRα and HER2. FRα was evaluated using the H-score and the 4-tired scoring system (0 to 3+). Subsequently, FRα expression (≥5% of tumor cells with ≥1+ intensity) and FRα-high (score 2+ and 3+) were evaluated. HER2 was scored according to the modified ASCO/CAP criteria. The association between FRα-high and clinicopathological features, HER2 expression, and survival was assessed in UCS. RESULTS: A total of 120 patients with UCS and nine patients with OCS were included. In UCS, FRα expression was observed in all patients, whereas FRα-high status was present in 20% of patients. Among HER2-negative UCS, 34% exhibited FRα-high. No significant association was observed between clinicopathological characteristics and FRα status. During the follow-up period (median 34.5 mo), FRα-high was not strongly associated with progression, free survival, and overall survival. All the OCS tumor specimens showed FRα-high expression. CONCLUSIONS: FRα expression was observed in all the UCS and OCS specimens, including HER2-negative UCS patients. This widespread FRα expression suggests that FRα-targeted therapies may hold promise for the treatment for gynecologic carcinosarcoma. However, in uterine carcinosarcoma, no significant relationship was observed between FRα expression and clinicopathological features or prognosis.

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.

Discordances in expression of human epidermal growth factor receptor 2 between primary and metastatic uterine carcinosarcoma: A proposal for HER2-targeted therapy specimen selection.

Uterine carcinosarcoma (UCS) frequently expresses human epidermal growth factor receptor 2 (HER2) and metastasizes. However, little is known about changes in the HER2 expression status in metastatic lesions and its impact on clinical outcomes. In 41 patients with synchronous or metachronous metastases and matched primary UCSs, we assessed the HER-2 expression using immunohistochemistry and scored it per the 2016 American Society of Clinical Oncology/College of American Pathologists guidelines, modified for UCS. We compared HER2 scores between paired primary and metastatic lesions and reviewed the association between clinicopathological characteristics and impact on overall survival. HER2 scores of 3+, 2+, 1+, and 0 were observed in 12.2 %, 34.2 %, 26.8 %, and 26.8 % of primary tumors, respectively, and 9.8 %, 19.5 %, 43.9 %, and 26.8 % of metastatic tumors, respectively. HER2 intratumoral heterogeneity occurred in 46.3 % and 19.5 % of the primary and metastatic lesions, respectively. The agreement rate of the HER2 score was 34.2 % in the four-tiered scale, while it was 70.7 % in the two-tiered scale (score 0 vs. score ≥ 1+) with fair agreement (к = 0.26). Patients with HER2 discordance showed significantly shorter overall survival (hazard ratios = 2.38, 95 % confidence interval 1.01-5.5, p = 0.049). HER2 discordance was not associated with specific clinicopathological characteristics. Discordance in HER2 status between primary and metastatic tumors in UCS was frequently observed regardless of clinicopathological characteristics and was a poor prognostic factor. Even if one tumor (primary or metastatic) is HER2 negative, HER2 testing of other tumors may be beneficial in terms of patient treatment options.

Influence of Clinical and Surgical Factors on Uterine Carcinosarcoma Survival.

BACKGROUND: The aim of this study was to assess the impact of prognostic factors on the survival of patients diagnosed with uterine carcinosarcoma. METHODS: A sub-analysis of the SARCUT study, a multicentric retrospective European study, was carried out. We selected 283 cases of diagnosed uterine carcinosarcoma for the present study. Prognosis factors influencing survival were analyzed. RESULTS: Significant prognostic factors for overall survival were: incomplete cytoreduction (HR = 4.02; 95%CI = 2.68-6.18), FIGO stages III and IV (HR = 3.21; 95%CI = 1.83-5.61), tumor persistence after any treatment (HR = 2.90; 95%CI = 1.97-4.27), presence of extrauterine disease (HR = 2.62; 95%CI = 1.75-3.92), a positive resection margin (HR = 1.56; 95%CI = 1.05-2.34), age (HR = 1.02; 95%CI = 1.00-1.05), and tumor size (HR = 1.01; 95%CI = 1.00-1.01). Significant prognostic factors for disease-free survival were: incomplete cytoreduction (HR = 3.00; 95%CI = 1.67-5.37), tumor persistence after any treatment (HR = 2.64; 95%CI = 1.81-3.86), FIGO stages III and IV (HR = 2.33; 95%CI = 1.59-3.41), presence of extrauterine disease (HR = 2.13; 95%CI = 1.44-3.17), administration of adjuvant chemotherapy (HR = 1.84; 95%CI = 1.27-2.67), a positive resection margin (HR = 1.65; 95%CI = 1.11-2.44), presence of LVSI (HR = 1.61; 95%CI = 1.02-2.55), and tumor size (HR = 1.00; 95%CI = 1.00-1.01). CONCLUSIONS: Incomplete cytoreduction, presence of tumor residual after treatment, advanced FIGO stage, extrauterine disease, and tumor size are significant prognostic factors decreasing disease-free survival and overall survival of patients with uterine carcinosarcoma.

Uterine carcinosarcoma with intestinal involvement: A case report and literature review.

Uterine carcinosarcoma (UCS) is a high-grade endometrial cancer characterized by two components: Carcinomatous (epithelial) and sarcomatous (stromal tissue) elements. The present study describes a clinical case of this type of UCS and also provides a brief literature review of this type of tumor. A 72-year-old female visited the emergency department of the authors' hospital with pain in the hypogastric region, intestinal dysrhythmia since 3 months prior, fever and a palpable abdominal mass. Laboratory test results revealed sepsis and mild anemia and an imaging test revealed a large uterine tumor with wide areas of necrosis and adenopathies. As determined by the multidisciplinary committee, surgery was considered the main treatment option and this was performed with no incidences. Carcinosarcoma is a rare tumor, which most frequently occurs in older women. The diagnosis is based on symptoms and imaging tests, such as ecography and scans. The gold standard of treatment is surgery, although it is possible that other types of therapies, such as chemotherapy and radiotherapy may also be effective, depending on the tumor stage. On the whole, the prognosis of patients with this type of tumor is poor, with a low survival rate, even in earlier stages due to its malignant component and the possibility for metastasis. Surgery is the optimal treatment for this type of tumor, if this is possible, always individualizing patients.

Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with topoisomerase I inhibitor payload, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/neu expression.

OBJECTIVES: Carcinosarcomas are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression and limited therapeutic options. We compared the efficacy of trastuzumab deruxtecan (DS-8201a), a novel HER2/neu-targeting antibody-drug conjugate (ADC) to an ADC isotype control (MAAA-9199) against primary uterine and ovarian carcinosarcomas in vitro and in vivo. METHODS: Twelve primary carcinosarcoma (CS) cell lines were evaluated for HER2/neu surface expression by immunohistochemistry (IHC) and by flow cytometry, and gene amplification by fluorescence in situ hybridization (FISH) assays. The in vitro experiments included cytotoxicity and bystander killing effect assays on three cell lines of variable HER2/neu expression. In vivo activity was studied in a mouse CS xenograft model of 3+ HER2/neu uterine CS. RESULTS: In vitro studies showed that DS-8201a was highly effective against uterine and ovarian CS cell lines demonstrating 3+ HER2/neu expression compared to MAAA-9199 control; there was no significant improvement in the 0 HER2/neu CS cell line. However, DS-8201a induced efficient bystander killing of 0 HER2/neu tumor cells when admixed with 3+ HER2/neu cells. In vivo studies confirmed that DS-8201a was more effective than MAAA-9199 in 3+ HER2/neu-expressing CS xenografts. CONCLUSION: DS-8201a may represent a novel and highly effective ADC against HER2/neu-expressing CS.

Identification of drug targets and prognosis projection for uterine carcinosarcoma based on alternative splicing events.

BACKGROUND: Uterine carcinosarcoma (UCS) is an invasive variant of endometrial cancer. The complicated heterogeneity and low frequency of UCS suggest the relevant research is lack. There is an urgent need to further explore the pathogenic mechanism and identify new biomarkers of UCS from different angels to improve its diagnosis and prognosis. OBJECTIVE: This study is to explore the importance of alternative splicing (AS) events in UCS, construct AS-based prognosis model and excavate key splicing factors (SFs). METHOD: UCS related gene transcriptome data and AS events data were collected from The Cancer Genome Atlas (TCGA) and TCGA SpliceSeq database. The AS events related to survival were determined by Cox regression analysis, Least absolute shrinkage and selection operator (Lasso) regression analysis and optimal subset analysis. The corresponding risk score was calculated and its efficiency on prognosis was evaluated by Kaplan-Meier (K-M) survival estimate and validated by the receiver operating characteristic (ROC) curve. The prognosis model was constructed with risk score and clinic characters as independent variables to predict patients' survival. On the other hand, Kendall test was applied to inspect the correlation between the SFs and the prognosis-related AS events and a AS-SF network was constructed. Finally, the key SFs were screened through network nodes analysis and survival analysis. RESULT: Seven AS events the most related to survival were detected and the risk score was obtained. K-M survival estimate and ROC curve validation suggested the risk score was effective. Then Cox model was constructed based on the risk score and a nomogram model was obtained which provided the highest prediction accuracy of 95%. Through the AS-SF network analysis, 16 SFs were screened, among which four survival-related SFs were eventually obtained. CONCLUSION: The prognosis model could predict the survival rate of UCS patients by their clinical characters and AS-based risk score. And four newly discovered SFs could reveal the molecular mechanism of UCS and act as the potential drug targets and prognosis biomarkers.