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Gynecologic Oncology May 2022Patients with advanced endometrial cancer have a poor prognosis, and treatment options are limited. The investigator-initiated, multicenter, phase II DOMEC trial...
BACKGROUND
Patients with advanced endometrial cancer have a poor prognosis, and treatment options are limited. The investigator-initiated, multicenter, phase II DOMEC trial (NCT03951415) is the first trial to report data on efficacy and safety of combined treatment with PD-L1 and PARP inhibition for advanced endometrial cancer.
PATIENTS AND METHODS
Patients with metastatic or recurrent endometrial cancer were enrolled. Patients received durvalumab 1500 mg intravenously q4w and olaparib 300 mg 2dd until disease progression, unacceptable toxicity, or patient withdrawal. Patients with at least 4 weeks of treatment were evaluable for analysis. The primary endpoint was progression-free survival at 6 months. Evidence for efficacy was defined as progression-free survival at 6 months in ≥50% of patients. Secondary endpoints included safety, objective response and overall survival.
RESULTS
From July 2019, through November 2020, 55 patients were enrolled. At data cut-off (September 2021), 4 of the 50 evaluable patients were still on treatment. Seventeen patients (34%) were progression-free at 6 months. Objective response rate was 16% (95% CI, 8.3 to 28.5) with 1 complete and 7 partial responses. With a median follow-up of 17.6 months, median progression-free survival was 3.4 months (95% CI, 2.8 to 6.2) and median overall survival was 8.0 months (95% CI, 7.5 to 14.3). Grade 3 treatment-related adverse events occurred in 8 patients (16%), predominantly anemia. There were no grade 4 or 5 treatment-related adverse events.
CONCLUSION
The combination of durvalumab and olaparib was well tolerated, but did not meet the prespecified 50% 6-month progression-free survival in this heterogeneous patient population with advanced endometrial cancer.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Phthalazines; Piperazines
PubMed: 35287967
DOI: 10.1016/j.ygyno.2022.02.025 -
International Journal of Molecular... Feb 2021Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only... (Review)
Review
Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and non-coding RNA, have been studied for the last two decades. Epigenetic dysregulation is often reported in the development and progression of various cancers. Recently, epigenetic changes in endometrial cancer have also been discussed. In this review, we give the main points of the role of DNA methylation and histone modification in endometrial cancer, the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials.
Topics: Acetylation; Chromatin Immunoprecipitation Sequencing; DNA Methylation; Disease Progression; Endometrial Neoplasms; Epigenesis, Genetic; Female; Gene Expression Regulation; Histones; Humans; Methylation; Neoplasm Recurrence, Local; RNA, Untranslated
PubMed: 33669072
DOI: 10.3390/ijms22052305 -
Radiology and Oncology Feb 2021Endometrial cancer (EC) represents a high health burden in Slovenia and worldwide. The incidence is increasing due to lifestyle and behavioural risk factors such as...
BACKGROUND
Endometrial cancer (EC) represents a high health burden in Slovenia and worldwide. The incidence is increasing due to lifestyle and behavioural risk factors such as obesity, smoking, oestrogen exposure and aging of the population. In many cases, endometrial cancer is diagnosed at an early stage due to obvious signs and symptoms. The standard treatment is surgery with or without adjuvant therapy, depending on the stage of the disease and the risk of recurrence. However, treatment modalities have changed in the last decades, considerably in the extent of lymphadenectomy.
CONCLUSIONS
The gold standard of treatment for is surgery, which may be the only treatment modality in the early stages of low-grade tumours. In recent years, a minimally invasive approach with sentinel node biopsy (SNB) has been proposed. A conservative approach with hormonal treatment is used if fertility preservation is desired. If EC is in advance stage, high-risk histology, or high grade, radiotherapy, chemotherapy, or a combination of both is recommended.
Topics: Conservative Treatment; Contraceptives, Oral, Hormonal; Endometrial Neoplasms; Female; Fertility Preservation; Genetic Predisposition to Disease; Humans; Lymph Node Excision; Neoplasm Grading; Radiotherapy, Adjuvant; Risk Factors; Sentinel Lymph Node Biopsy; Slovenia
PubMed: 33583160
DOI: 10.2478/raon-2021-0009 -
Bioscience Reports Dec 2021Minichromosome maintenance (MCM) family members are a group of genes involved in regulating DNA replication and cell division and have been identified as oncogenes in...
Minichromosome maintenance (MCM) family members are a group of genes involved in regulating DNA replication and cell division and have been identified as oncogenes in various cancer types. Several experimental studies have suggested that MCMs are dysregulated in endometrial carcinoma (EC). However, the expression pattern, clinical value and functions of different MCMs have yet to be analyzed systematically and comprehensively. We analyzed expression, survival rate, DNA alteration, PPT network, GGI network, functional enrichment cancer hallmarks and drug sensitivity of MCMs in patients with EC based on diverse datasets, including Oncomine, GEPIA, Kaplan-Meier Plotter, HPA, Sangerbox and GSCALite databases. The results indicated that most MCM members were increased in EC and showed a prognostic value in survival analysis, which were considerately well in terms of PFS and OS prognostic prediction. Importantly, functional enrichment, PPI network and GGI network suggested that MCMs interact with proteins related to DNA replication and cell division, which may be the mechanism of MCM promote EC progression. Further data mining illustrated that MCMs have broad DNA hypomethylation levels and high levels of copy number aberrations in tumor tissue samples, which may be the mechanism causing the high expression level of MCMs. Moreover, MCM2 can activate or suppress diverse cancer-related pathways and is implicated in EC drug sensitivity. Taking together, our findings illustrate the expression pattern, clinical value and function of MCMs in EC and imply that MCMs are potential targets for precision therapy and new biomarkers for the prognosis of patients with EC.
Topics: Antineoplastic Agents; Biomarkers, Tumor; DNA Methylation; Databases, Genetic; Drug Resistance, Neoplasm; Endometrial Neoplasms; Epigenome; Epigenomics; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genomics; Humans; Minichromosome Maintenance Proteins; Prognosis; Protein Interaction Maps; Signal Transduction; Systems Biology; Transcriptome
PubMed: 34859821
DOI: 10.1042/BSR20211719 -
Modern Pathology : An Official Journal... Jan 2013The current World Health Organization classification divides endometrial sarcomas into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma....
The current World Health Organization classification divides endometrial sarcomas into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma. Recent studies suggest undifferentiated endometrial sarcoma is a heterogeneous group and a subgroup with uniform nuclei is more akin to low-grade endometrial stromal sarcoma in terms of morphologic, immunohistochemical and genetic features. We classified endometrial sarcomas treated at our institution from 1998 to 2011 into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma, the latter being further categorized into a group with either uniform or pleomorphic nuclei. Morphological features, immunoprofile and fluorescence in situ hybridization rearrangements of JAZF1 and PHF1 genes were correlated with tumor category and outcome. A total of 40 cases were evaluated comprising 23 low-grade endometrial stromal sarcomas, 10 undifferentiated endometrial sarcomas with nuclear uniformity and 7 undifferentiated endometrial sarcomas with nuclear pleomorphism. Low-grade endometrial stromal sarcomas were more often estrogen and progesterone receptor positive (83%) compared with undifferentiated endometrial sarcoma with nuclear uniformity (10%) or with nuclear pleomorphism (0%) (P<0.001). Positivity for p53 was restricted to undifferentiated endometrial sarcomas with more frequent expression in the group with nuclear pleomorphism (57%) than with nuclear uniformity (10%) (P=0.06). Ki-67 proliferation index in >10% of tumor cells more frequent in undifferentiated endometrial sarcoma than low-grade endometrial stromal sarcoma (P=<0.001). JAZF1 rearrangement was detected in 32% of low-grade endometrial stromal sarcomas and in none of the undifferentiated sarcomas. Rearrangement of PHF1 was found in two patients, one with JAZF1-PHF1 fusion. There were no significant differences in clinical behavior between undifferentiated endometrial sarcoma with nuclear uniformity versus nuclear pleomorphism. In conclusion, we found undifferentiated endometrial sarcoma subtypes and low-grade endometrial stromal sarcoma have distinct immunohistochemical and cytogentic profiles. Our data do not show any difference in clinical behavior between subgroups in undifferentiated sarcomas.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Co-Repressor Proteins; DNA-Binding Proteins; Endometrial Neoplasms; Female; Gene Rearrangement; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Middle Aged; Neoplasm Proteins; Polycomb-Group Proteins; Sarcoma, Endometrial Stromal; Tissue Array Analysis; Transcription Factors
PubMed: 22918161
DOI: 10.1038/modpathol.2012.136 -
Women's Health (London, England) Jul 2009There is no standard approach to managing women with advanced or recurrent endometrial cancer; however, there is increasing evidence to support a role for cytoreductive... (Review)
Review
There is no standard approach to managing women with advanced or recurrent endometrial cancer; however, there is increasing evidence to support a role for cytoreductive surgery in these women to improve survival outcome. The existing literature is limited by the inherent biases of retrospective studies, as well as small numbers of patients in individual studies; however, the association between optimal or complete cytoreductive surgery in patients with advanced and recurrent endometrial cancer and improved overall survival has been consistent. Furthermore, there is also a strong association between the size of postoperative residual disease and survival; as such, maximal cytoreduction should be the goal in carefully selected patients with advanced or recurrent endometrial cancer who are candidates for surgical management. Additional prospective research is needed in order to further define the role of cytoreductive surgery in advanced and recurrent endometrial cancer, and to develop effective adjuvant therapy to be used postoperatively in order to improve the prognosis in these women.
Topics: Endometrial Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm, Residual; Surgical Procedures, Operative; Treatment Outcome
PubMed: 19586432
DOI: 10.2217/whe.09.26 -
Medicine Jan 2022To investigate the clinicopathological characteristics of patients with high-grade endometrial stromal sarcoma (HG-ESS).The clinicopathological characteristics,...
To investigate the clinicopathological characteristics of patients with high-grade endometrial stromal sarcoma (HG-ESS).The clinicopathological characteristics, treatments, and prognostic information of consecutive HG-ESS patients were collected from medical records and then evaluated.A total of 40 women were included in the analysis. The immunohistochemical profiles indicated that HG-ESS tumors tend to be locally or weakly positive for vimentin (100%) and CD10 (72.0%) but mostly negative for desmin (7.7%) and AE1/AE3 (9.1%). The progression-free survival intervals and the clinical benefit rates of patients receiving radiotherapy and/or chemotherapy were slightly longer and higher than those receiving simple observation (progression-free survival: 6 and 5 months vs 2 months; clinical benefit rate: 83.3% and 75.0% vs 28.6%). The 1-year disease-specific survival (DSS) rate was 62.7%. Tumor size, myometrial invasion, lymphovascular space invasion, cervical involvement, Federation International of Gynecology and Obstetrics (FIGO) stage, and residual disease all significantly affected the DSS rate (P < .001, =.002, <.001, =.004, <.001, and <.001, respectively). For patients with stage I disease, the 1-year DSS rate was as high as 91.7%, in contrast to 66.7%, 26.7%, and 0% for those with stage II, III, and IV disease, respectively.HG-ESS is associated with an adverse prognosis. FIGO stage could effectively predict the prognosis of patients with this lethal disease. Immunohistochemical markers, vimentin+/CD10+ (local or very weak), in combination with desmin-/AE1/AE3-, may be helpful for improving the diagnostic accuracy of this lethal condition. The therapeutic roles of adjuvant chemotherapy and radiotherapy warrant further investigation.
Topics: Desmin; Endometrial Neoplasms; Female; Humans; Hysterectomy; Neoplasm Staging; Prognosis; Radiotherapy, Adjuvant; Retrospective Studies; Sarcoma, Endometrial Stromal; Vimentin
PubMed: 35029198
DOI: 10.1097/MD.0000000000028490 -
Lakartidningen Dec 2015Endometrial cancer is the most common gynecological cancer in developed countries and the observed rise in incidence is mainly caused by life style factors including... (Review)
Review
Endometrial cancer is the most common gynecological cancer in developed countries and the observed rise in incidence is mainly caused by life style factors including obesity and diabetes. The management of the disease has undergone major changes in the past 5-10 years. Morphological and genetic studies constitute the basis for the new classification of the disease, and data emerging from the Cancer Genome Atlas suggest that genomic patterns differ within the two types of endometrial cancer. The prognosis seems to be related to occult lymphatic spread but the role of lymphadenectomy is heavily debated. Development of novel biomarkers, sentinel lymph node technique and refined radiological methods may reduce the need of comprehensive staging in the future. The results from the Cancer Genome Atlas suggest that women with endometrial cancer may benefit from »targeted therapies« in the evolving era of personalised medicine.
Topics: Disease Management; Endometrial Neoplasms; Female; Humans; Neoplasm Staging; Prognosis; Risk Factors
PubMed: 26646959
DOI: No ID Found -
Folia Histochemica Et Cytobiologica Sep 2010Endometrial cancer is the most common gynecologic malignancy in more developed countries. Approximately 75% of cases are diagnosed at an early stage with a tumor... (Review)
Review
Endometrial cancer is the most common gynecologic malignancy in more developed countries. Approximately 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus. Although most patients are cured by surgery alone, about 15-20% with no signs of locally advanced or metastatic disease at primary treatment recurs, with limited responsiveness to systemic therapy. The most common basis for determining the risk of recurrent disease has been classification of endometrial cancers into two subtypes. Type I, associated with a good prognosis and endometrioid histology and type II, associated with a poor prognosis and non-endometrioid histology. This review will focus primarily on the molecular biomarkers that have supported the dualistic model of endometrial carcinoma and help determine which patients would benefit from either adjuvant therapy or more aggressive primary treatment.
Topics: Biomarkers, Tumor; Chemotherapy, Adjuvant; Combined Modality Therapy; Endometrial Neoplasms; Female; Humans; Neoplasm Staging; Prognosis; Radiotherapy, Adjuvant; Uterine Neoplasms
PubMed: 21071332
DOI: 10.2478/v10042-10-0061-8 -
BMC Cancer Apr 2018Previous studies have suggested that metformin may be useful for preventing and treating endometrial cancer (EC), while the results have been inconsistent. This... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Previous studies have suggested that metformin may be useful for preventing and treating endometrial cancer (EC), while the results have been inconsistent. This systematic review and meta-analysis aimed to investigate the association between metformin use and risk and prognosis of patients with EC.
METHODS
PubMed, Embase, and the Cochrane Library databases were searched for observational studies evaluating the effect of metformin on EC prevention or treatment. The odds ratio (OR) was used for analyzing risks, and the hazard ratio (HR) was used for analyzing survival outcomes. A random-effects model was used for data analysis.
RESULTS
Seven studies reported data on EC risk. The pooled results suggested that metformin was not significantly associated with a lower risk of EC [OR = 1.05, 95% confidence interval (CI) 0.82-1.35, P = 0.70]. For patients with diabetes, metformin showed no advantage in reducing the EC risk compared with other interventions (OR = 0.99, 95% CI 0.78-1.26, P = 0.95). Further, seven studies were included for survival analysis. The pooled data showed that metformin could significantly improve the overall survival of patients with EC (HR = 0.61, 95% CI 0.48-0.77, P < 0.05) and reduce the risk of EC recurrence (OR = 0.50, 95% CI 0.28-0.92, P < 0.05) Finally, we noted metformin was associated with significantly improving the overall survival of EC patients among diabetes (HR = 0.47; 95%CI 0.33-0.67, P < 0.05).
CONCLUSIONS
This meta-analysis did not prove that metformin was beneficial for preventing EC. However, metformin could prolong the overall survival of patients with EC and reduce their risk of cancer relapse.
Topics: Endometrial Neoplasms; Female; Humans; Hypoglycemic Agents; Metformin; Neoplasm Recurrence, Local; Odds Ratio; Prognosis; Proportional Hazards Models
PubMed: 29669520
DOI: 10.1186/s12885-018-4334-5