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Overview of systemic treatment options in recurrent endometrial cancer. ER: estrogen receptor; PR: progesterone receptor; MMR-D: mismatch repair deficient; MSI: microsatellite instability; MSS: microsatellite stable; pMMR: proficient mismatch repair; PFS: progression-free survival; OS: overall survival. * Preferably histology on recurrent tumor ** also approved for pMMR/MSS *** Dependent on level of expression.
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The treatment of recurrent endometrial cancer is a challenge. Because of earlier treatments and the site of locoregional recurrence, in the vaginal vault or pelvis, morbidity can be high. A total of about 4 to 20% of the patients with endometrial cancer develop a locoregional recurrence, mostly among patients with locally advanced disease. The trea...
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Citations
... High-risk EC often requires adjuvant radiation and systemic therapy [4,5]. Treatment options for advanced and recurrent ECs are limited, with radiotherapy and chemotherapy showing limited efficacy [6]. In this regard, EC molecular classification introduced by The Cancer Genome Atlas has enhanced diagnostic accuracy and refined risk stratification, identifying patients who can benefit from targeted therapies, ushering in a paradigm shift in patient treatment options [7,8]. ...
HER2-targeted therapies have transformed the management of advanced or recurrent serous endometrial cancer (EC), leading to an increased clinical demand for HER2 testing. Despite its adoption in select academic centers, the global extent of such tumor testing is unclear. In this study, we report on the initial two-year experience of HER2 testing at a major academic center with a reference gynecologic oncology service and biomarker reference laboratory. All patients who underwent HER2 testing based on physician discretion, reflex HER2 testing, and reference laboratory requests were included. From February 2021 to October 2023, HER2 testing was performed on 192 tumor tissue samples from 180 EC patients. Serous carcinoma constituted 52% of samples, reflecting diagnostic challenges and limited therapeutic options for advanced EC. HER2 positivity was found in 28% of all cases and 30% of p53-aberrant cases. An immunohistochemistry (IHC) score of 3+ was found in 15% of samples, while IHC 2+ was found in 45% (13% IHC 2+/ISH+ and 32% IHC 2+/ISH-). The newly identified 'HER2-low' category comprised 46% of the samples. Heterogeneity was noted in 42% of HER2-positive cases, with complex patterns in 3%. NGS and HER2 IHC-FISH showed a 24% discordance, attributed to intratumoral heterogeneity, tumor cellularity, a small number of amplified cells, and the HER2/CEP17 ratio near the cut-off. This study offers real-world insights into HER2 testing in EC, highlighting the challenges and underscoring the need for standardized guidelines in specimen handling, proficiency testing, and scoring criteria to enhance patient management and therapeutic decision-making.
... Up to 20% of patients will develop local recurrence or metastatic disease [3][4][5][6][7]. Curative treatment options for metastatic EC are limited to women who only have locoregional metastases or isolated metastases [1,8,9]. For women with more advanced disease, only palliative options remain and are limited to the following: chemotherapy and hormonal therapy (HT) or novel therapies, including immunotherapy and other targeted treatment options [9][10][11]. ...
Background:
Response to hormonal therapy in advanced and recurrent endometrial cancer (EC) can be predicted by oestrogen and progesterone receptor immunohistochemical (ER/PR-IHC) expression, with response rates of 60% in PR-IHC > 50% cases. ER/PR-IHC can vary by tumour location and is frequently lost with tumour progression. Therefore, we explored the relationship between ER/PR-IHC expression and tumour location in EC.
Methods:
Pre-treatment tumour biopsies from 6 different sites of 80 cases treated with hormonal therapy were analysed for ER/PR-IHC expression and classified into categories 0-10%, 10-50%, and >50%. The ER pathway activity score (ERPAS) was determined based on mRNA levels of ER-related target genes, reflecting the actual activity of the ER receptor.
Results:
There was a trend towards lower PR-IHC (33% had PR > 50%) and ERPAS (27% had ERPAS > 15) in lymphogenic metastases compared to other locations (p = 0.074). Hematogenous and intra-abdominal metastases appeared to have high ER/PR-IHC and ERPAS (85% and 89% ER-IHC > 50%; 64% and 78% PR-IHC > 50%; 60% and 71% ERPAS > 15, not significant). Tumour grade and previous radiotherapy did not affect ER/PR-IHC or ERPAS.
Conclusions:
A trend towards lower PR-IHC and ERPAS was observed in lymphogenic sites. Verification in larger cohorts is needed to confirm these findings, which may have implications for the use of hormonal therapy in the future.
... На прогноз, тактику лечения пациенток, а также риск рецидива заболевания после первичного лечения влияют стадия и гистологические характеристики опухоли. При III и IV стадии 5-летняя выживаемость составляет 50 и 15 % соответственно [2,3]. Тактика лечения пациенток после прогрессирования РЭ зависит от некоторых факторов, однако в качестве 1-й линии системной терапии «золотым стандартом» себя зарекомендовала комбинация паклитаксела и карбоплатина [4]. ...
Background. The inclusion of lenvatinib in the immunotherapy regimen for patients with MSS/pMMR endometrial cancer (EC) is due to its ability to modulate the tumor microenvironment, which allows the use of pembrolizumab in low-immunogenic tumors. However, only 30 % of patients with advanced or metastatic EC have a clinical response when treated with pembrolizumab and lenvatinib. In this regard, there is an obvious need to identify biomarkers that allow accurate selection of candidates for this type of therapy. Aim. To determine the predictive value of subpopulations of lymphocytes and macrophages, their expression of PD-1, expression of estrogen receptors, as well as vessel density in immunotargeted therapy for advanced or metastatic EC. Materials and methods. An open-label non-randomized observational association study was performed, involving a total of 22 patients with advanced or metastatic MSS/pMMR EC treated with pembrolizumab and lenvatinib. Duration of clinical effectiveness was used as a parameter to stratify patients. Using TSA-associated multiplex immunofluorescence, the proportions of CD8+ T lymphocytes, CD20+ B lymphocytes, FoxP3+ T regulatory lymphocytes and CD163+macrophages in tumor samples before the start of immunotargeted therapy were analyzed. Results. Three microenvironmental parameters were found to be associated with duration of clinical efficacy: the proportion of CD20+ B cells, the proportion of FoxP3+ T regulatory lymphocytes, and the ratio of CD8+/CD20+ lymphocytes in the tumor microenvironment. However, the CD8+/CD20+ lymphocyte ratio had the greatest predictive value; a value below 3.219 was associated with long clinical efficacy in patients with advanced or metastatic EC. Conclusion. The ratio of cytotoxic and B-lymphocytes in the microenvironment is a reliable predictor marker of the duration of the period of clinical effectiveness of immunotargeting therapy in advanced or metastatic EC.
... The decision to provide adjuvant treatment is based on the risk of the disease. Low-risk metastatic tumors can be treated with surgery alone, while in patients with high-risk metastatic tumors, additional adjuvant therapy is preferred [6]. ...
Background
Over the past decades, the rising incidence rates of endometrial cancer have made it a significant public health concern for women worldwide. Treatment strategies for endometrial cancer vary based on several factors such as stage, histology, the patient’s overall health, and preferences. However, limited amount of research on treatment patterns and potential correlations with sociodemographic characteristics among Hispanics is available. This study analyzes the treatment patterns for patients diagnosed with endometrial cancer in Puerto Rico.
Methods
A secondary database analysis was performed on endometrial cancer cases reported to the Puerto Rico Central Cancer Registry-Health Insurance Linkage Database from 2009 to 2015 (n = 2,488). The study population’s sociodemographic and clinical characteristics were described, along with an overview of the therapy options provided to patients receiving care on the island. Logistic regression models were used to evaluate the association of sociodemographic/clinical characteristics with treatment patterns stratified by risk of recurrence.
Results
In our cohort, most patients were insured through Medicaid and had a median age of 60 years. Almost 90% of patients received surgery as the first course of treatment. Surgery alone was the most common treatment for low-risk patients (80.2%). High-risk patients were more likely to receive surgery with radiotherapy and chemotherapy (24.4%). Patients with Medicare insurance were five times (HR: 4.84; 95% CI: 2.45–9.58; p < 0.001) more likely to receive surgery when compared with patients insured with Medicaid. In contrast, those with private insurance were twice as likely to receive surgery (HR: 2.38; 95% CI: 1.40–4.04; p = 0.001) when compared to those with Medicaid.
Conclusion
These findings provide insight into the treatment patterns for endometrial cancer in Puerto Rico and highlight the importance of considering factors such as disease risk when making treatment decisions. Addressing these gaps in treatment patterns can contribute to effective management of endometrial cancer.
... However, a delayed dia gnosis leads to progression of the tumor worsening the overall survival of the patient. Although relapse occurs in roughly 15% of cases, there is a lack of effective risk classification and limited progress in treating recurrent or metastatic disease [3]. This underscores the need to enhance the early-stage identification and stratification of patients with this form of cancer. ...
Background:
Endometrial carcinoma (EC) is the most common cancer of the female reproductive tract in developed countries. The prognosis and 5-year survival rates are closely tied to the stage diagnosis. Current routine diagnostic methods of EC are either lacking specificity or are uncomfortable, invasive and painful for the patient. As of now, the gold diagnostic standard is endometrial biopsy. Early and non-invasive diagnosis of EC requires the identification of new biomarkers of disease and a screening test applicable to routine laboratory diagnostics. The application of untargeted metabolomics combined with artificial intelligence and biostatistics tools has the potential to qualitatively and quantitatively represent the metabolome, but its introduction into routine diagnostics is currently unrealistic due to the financial, time and interpretation challenges. Fluorescence spectral analysis of body fluids utilizes autofluorescence of certain metabolites to define the composition of the metabolome under physiological conditions.
Purpose:
This review highlights the potential of fluorescence spectroscopy in the early detection of EC. Data obtained by three-dimensional fluorescence spectroscopy define the quantitative and qualitative composition of the complex fluorescent metabolome and are useful for identifying biochemical metabolic changes associated with endometrial carcinogenesis. Autofluorescence of biological fluids has the prospect of providing new molecular markers of EC. By integrating machine learning and artificial intelligence algorithms in the data analysis of the fluorescent metabolome, this technique has great potential to be implemented in routine laboratory diagnostics.
... Primary treatment of uterine cancer consists of hysterectomy with ovariectomy, with or without lymph nodes dissection, and in case of positive risk factors adjuvant therapy (chemotherapy and/or irradiation) should be taken into consideration. Despite optimal surgical and adjuvant treatment, 7-15% women who initially had early stage endometrial canrcinoma (stages I and II as defined by The International Federation of Gynecology and Obstetrics -FIGO) develop recurrent disease, and women with more advanced disease at diagnosis have much higher chances of recurrence [6]. Endometrial cancer relapse can be difficult to treat, particularly in patients who already received radiotherapy, or have oligometastatic disease. ...
... Endometrial cancer relapse can be difficult to treat, particularly in patients who already received radiotherapy, or have oligometastatic disease. In the past couple of years, 5-year survival rate of women with relapsed endometrial carcinoma registered 3-fold increase, from 25% to 75%, due to better selection for treatment [6]. ...
... Therefore, for better patient selection, research of predictive biomarkers and prospective outcome analysis in larger study population is of key importance [6]. In patients with uterine sarcomas, high recurrence rate is present in all disease stages, despite surgery and adjuvant therapy, with the recurrence rate of 53-71%, from which 22% pelvic, 58% distant and 20% mixed [7]. ...
Introduction/Objective. The goal of our research was to evaluate diagnostic and prognostic role of positron emission tomography/computed tomography (PET-CT) in patients previously treated for uterine cancer and compare it to conventional imaging methods (CIM). Methods. We analyzed 37 patients examined on PET-CT for follow-up or suspicion of uterine cancer recurrence, and who were previously treated with surgery and/or chemoradiotherapy. All patients underwent computed tomography or magnetic resonance imaging prior to PET-CT, and were followed-up for at least one year. Results. PET-CT showed sensitivity, specificity and diagnostic accuracy in uterine cancer relapse detection of 96.3%, 70% and 89.2%, while those values for CIM were 92.6%, 40% and 78.4 %, respectively. Correlation of PET-CT and CIM findings was 78% (29/37). In 13 out of 25 true positive patients on CIM, PET-CT found greater number of active sites missed by conventional imaging. Positive findings on PET-CT were associated with shorter progression free survival (p = 0.023, logrank test). Conclusion. PET-CT constitutes an important diagnostic method in management of recurrent cancer of uterine corpus, demonstrating high sensitivity and accuracy. In comparison to CIM, PET-CT can discover larger number of active tumor sites, and also shows better specificity. PET-CT positive patients have worse prognosis with shorter progression free survival.
... Advanced endometrial cancers tend to exhibit a more malignant phenotype, leading to a staggering 5-year recurrence rate of 59% [6]. Patients with recurrent tumors face bleak prognoses, with a severe dip in long-term survival rates, the leading cause of death from endometrial cancer [7]. ...
Introduction: Recurrence signifies the primary mortality factor in patients suffering from endometrial cancer, with few efficacious treatments currently available for recurrent cases. This research investigates the anti-tumoral capacities of WEE1 inhibitors within the context of endometrial cancer, aiming to establish a novel therapeutic avenue for high recurrence-risk patients.
Materials and methods: We evaluated WEE1 expression in endometrial cancer patients utilizing immunohistochemistry on paraffin-embedded tissue sections. The cytotoxic potential of WEE1 inhibitors on endometrial cancer cells was assessed by CCK8 assay. Assays to gauge the influence of WEE1 inhibitors on cell proliferation and migration included clonal proliferation, wound healing, and transwell assays. We determined the impacts on apoptosis and cell cycle stages by flow cytometry. Employing qRT-PCR and western blotting, we investigated the mechanistic pathways underlying the anti-tumoral activity of WEE1 inhibitors. In vivo evaluations were executed to ascertain the inhibitory effect of WEE1 inhibitors on tumor growth in mice.
Results: WEE1 exhibited high-level expression in endometrial cancer tissues, particularly pronounced in recurrent compared with non-recurrent patients. WEE1 inhibitors effectively eliminated endometrial cancer cells while inhibiting their proliferation and migration. Flow cytometric analyses revealed a significant promotion of apoptosis and an increase in G2/M phase cell proportion upon WEE1 inhibitor treatment. qRT-PCR and western blotting elucidated that WEE1 inhibitors activated the innate immune signaling pathway in endometrial cancer cells. Furthermore, in vivo assessments demonstrated substantial tumor growth suppression due to WEE1 inhibitors.
Conclusions: WEE1 inhibitors initiated an innate immune response in endometrial cancer, exhibiting considerable anti-tumoral effects, which was promising for postoperative treatment of endometrial cancer, especially recurrent endometrial cancer patients.
... With risk factors including advanced age, obesity and prolonged unopposed estrogen exposure, the incidence of endometrial cancer is rising. [35][36][37] As most patients are diagnosed with early-stage disease, surgical removal of the uterus and adnexa is generally the treatment of choice. 35 Chemotherapy, locoregional radiotherapy, or a combination of both is usually used as an adjuvant treatment based on the risk of locoregional recurrence or metastasis. ...
... [35][36][37] As most patients are diagnosed with early-stage disease, surgical removal of the uterus and adnexa is generally the treatment of choice. 35 Chemotherapy, locoregional radiotherapy, or a combination of both is usually used as an adjuvant treatment based on the risk of locoregional recurrence or metastasis. However, even getting the optimal surgical and adjuvant treatment, 7~15% of early-stage (I-II) patients have recurring disease. ...
Background
Endometrial cancer (EC) is one of the most prevalent gynecologic cancers, which poses a serious threat to women’s health worldwide. Olaparib, the first FDA-approved PARP inhibitor for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers, triggers apoptosis of cancer cells through synthetic lethality by inhibiting PARP1/2 enzymatic activity and BRCA1/2-dependent homologous recombination (HR) repair deficiency. However, the synergistic lethal effects between Olaparib and inhibitors of other DNA damage response proteins, such as ATM, PTEN and RAD51, are still unknown.
Aim
Exploring the synergistic lethal effect between Olaparib and KU-55933 on EC.
Methods
The GEPIA database was used to test EC patient survival rate. CCK8 was used for cell viability assays. Western blot was used for examining gene levels. The wound healing assay was used to detect cell migration ability. Flow cytometry was used for detecting the apoptosis rate. All experimental conditions were repeated independently in triplicate and analyzed in three separate experiments.
Results
In this study, we discovered that the frequency of ATM alterations in endometrial cancer reaches nearly 20% and that there is a positive correlation between ATM alterations and prognosis. Furthermore, we discovered that endometrial cells with low expression levels of ATM are sensitive to Olaparib. Treatment with KU-55933, a specific inhibitor of ATM, significantly enhanced the sensitivity of endometrial cancer cells to Olaparib, as evidenced by colony formation, cell migration and apoptosis assay. Further analysis revealed that KU-55933 potentiates Olaparib-induced cell apoptosis by inhibiting ATM phosphorylation.
Conclusion
Our study demonstrates that inhibiting ATM could enhance the sensitivity of endometrial cancer to Olaparib, thereby providing a potential alternative treatment for the clinical treatment of endometrial cancer.
... Firstly, using ultrastaging, significantly more micrometastases in pelvic lymph nodes can be diagnosed [29], reducing the rate of isolated para-aortic lymph node metastases by up to 1% [30]. Furthermore, the rate and pattern of recurrence observed by us was similar between the LND and SLNB groups and is comparable with the data reported by others [31]. For example, the observed recurrences in the regional and para-aortic and/or distant lymph nodes were similar in the LND and SLNB groups. ...
Background:
Recently, sentinel lymph node biopsy (SLNB) has been introduced in the surgical staging of endometrial cancer as an alternative to systematic lymph node dissection (LND). However, the survival impact of SLNB is not yet well characterised.
Methods:
We performed a retrospective study of 419 patients with endometrial cancer treated with SLNB alone or with pelvic and para-aortic LND. For SLNB mapping, indocyanine green was used.
Results:
Median follow-up was 66 months. After exclusions, 337 patients were eligible for analysis. Of them, 150 underwent SLNB and 187 LND. During the follow-up time, 27 (24.7%) of the 150 who underwent SLNB and 54 (28.9%) of the 187 who underwent LND were diagnosed with recurrent disease (p = 0.459). The estimated 5-year disease-free survival (DFS) rate was 76.7% and 72.2% for patients in the SLNB and LND group, respectively (p = 0.419). The 5-year overall survival (OS) rates were 80.7% and 77.0% in the SLNB and LND group, respectively (p = 0.895). Survival rates were similar in both groups independent of lymph node status. Multivariable analysis confirmed that the staging approach was not associated with oncological outcome. For patients without lymph node metastases, patient outcome was worsened by advanced tumour stage and non-endometrioid tumour histology. In the group of patients with confirmed lymph node metastases, advanced tumour stage and inadequate adjuvant treatment significantly reduced DFS and OS.
Conclusion:
Our data suggested that SLNB did not compromise the oncological outcome of patients with endometrial cancer compared to LND.
... Likewise, the mortality rate has been increasing, despite 75% of women presenting with early-stage disease (1,2). Recurrent disease, characterized by locoregional recurrence, distant metastasis, or both, occurs in approximately 7% to 15% of early-stage (I-II) patients (3). The prognosis for those with recurrent disease remains poor, with widely varying survival depending on the site of recurrence, tumor size, and treatment modality (4). ...
... Treatment for recurrent endometrial carcinoma can include surgery, radiotherapy, chemotherapy, immunotherapy, endocrine treatment, or combinations of these modalities (3,4). Endocrine therapy targets endometrial cancers positive for estrogen (ER) and progesterone receptors (PR) (3,6). ...
... Treatment for recurrent endometrial carcinoma can include surgery, radiotherapy, chemotherapy, immunotherapy, endocrine treatment, or combinations of these modalities (3,4). Endocrine therapy targets endometrial cancers positive for estrogen (ER) and progesterone receptors (PR) (3,6). These hormone receptors, expressed in 90% of endometrial endometrioid carcinomas (EEC), have been associated with higher response rates to endocrine therapy (6). ...
Background
Endometrial carcinoma is the most common gynecologic cancer, with increasing incidence and mortality. Combination endocrine therapy comprised of tamoxifen and progestational agents has demonstrated promising results in treating recurrent disease. This case report describes the prolonged clinical benefit of treatment with tamoxifen and megestrol acetate in a woman with recurrent, metastatic endometrial endometrioid carcinoma positive for estrogen (ER) and progesterone receptors (PR).
Case
A 71-year-old gravida 1 para 1 woman presented with postmenopausal bleeding and vaginal discharge. Pelvic ultrasound and magnetic resonance imaging confirmed a 4.7 cm endometrial mass. The patient underwent a total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cystoscopy; pathology revealed a FIGO stage IA grade 1 ER/PR-positive endometroid endometrial adenocarcinoma. She continued under active surveillance for approximately 42 months until she experienced bone metastases in her pelvis, for which she received radiation therapy. Five months later, pulmonary metastases were detected, and she received six cycles of carboplatin and paclitaxel. She then started megestrol acetate and tamoxifen and has remained clinically stable with minimal side effects and reasonable quality of life for approximately 57 months.
Conclusion
Our case suggests that combination endocrine therapy has the potential to provide substantial long-term clinical benefit in women with recurrent endometrial cancer and bone metastases, despite multiple prior treatments, allowing patients to experience stable disease and quality of life. In patients with recurrent endometrioid, ER/PR-positive disease, endocrine therapy alone or in combination with other targeted therapies are regimens that may be considered due to their low overall toxicity.
