RESUMEN
BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts. METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage. RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts. CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.
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Neoplasias Endometriales , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Humanos , Animales , Ratones , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Neoplasias Endometriales/genética , Línea Celular Tumoral , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Secuenciación del Exoma , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Clasificación del Tumor , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasa 1 de Adhesión Focal/metabolismo , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Oxazepinas , Sulfonamidas , Pirazinas , Benzamidas , ImidazolesRESUMEN
BACKGROUND: Around 4% of women receive an endometrial cancer diagnosis before turning 40, mainly those without prior childbirth experience and a strong desire to preserve their ability to conceive. Consequently, for young patients diagnosed with atypical endometrial hyperplasia (AEH) or early endometrial carcinoma (EC), a fertility-preserving approach employing high-dose oral progesterone has been adopted. However, previous research has shown a notable relapse rate. Furthermore, the extended use of substantial oral progesterone doses may hinder ovarian function and raise the risk of weight gain, liver issues, blood clotting, and breast cancer. We previously assessed the clinical effectiveness and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH-a) based re-treatment for women with EC and AEH who did not respond to oral progestin therapy but achieved favorable treatment results and reproductive outcomes. METHODS: This study will be an open-label, two-armed, randomized, investigator-initiated multicenter trial evaluating the combination of GnRH-a with the levonorgestrel-releasing intrauterine system or the combination of GnRH-a with an aromatase inhibitor (comprising a subcutaneous GnRH-a injection every 4 weeks and daily oral letrozole 2.5 mg). A total of 226 participants will be randomly allocated to one of the two treatment groups in a 1:1 ratio. The primary objective is to determine the effectiveness of GnRH-a-based re-treatment in achieving a complete response (CR) at 24 weeks for patients with AEH or EC. Secondary objectives include assessing the pregnancy rate 12 weeks after treatment, as well as post-treatment pregnancy outcomes and the rate of recurrence. ETHICS AND DISSEMINATION: The protocol received approval from the Institutional Review Board of Peking Union Medical College Hospital and from boards at five other institutions. The trial will adhere to the principles outlined in the World Medical Association's Declaration of Helsinki and follow Good Clinical Practice standards. The trial results will be disseminated through publication in a peer-reviewed journal. CONCLUSIONS: Prospective evidence supporting conservative treatment for EC and AEH is limited. There is a need for new approaches that can achieve higher CR rates with fewer side effects. This trial will assess the effectiveness of GnRH-a-based fertility-sparing treatment in obese women and recurrent patients, offering a promising alternative for patients with EC and AEH. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry ChiCTR2200067099. Registered on December 27, 2022.
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Hiperplasia Endometrial , Neoplasias Endometriales , Preservación de la Fertilidad , Hormona Liberadora de Gonadotropina , Levonorgestrel , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Hiperplasia Endometrial/tratamiento farmacológico , Hiperplasia Endometrial/complicaciones , Neoplasias Endometriales/tratamiento farmacológico , Preservación de la Fertilidad/métodos , Embarazo , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Levonorgestrel/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Inhibidores de la Aromatasa/efectos adversos , Inhibidores de la Aromatasa/administración & dosificación , Dispositivos Intrauterinos Medicados , Resultado del Tratamiento , Adulto , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/administración & dosificación , Letrozol/administración & dosificación , Letrozol/uso terapéutico , China , Índice de EmbarazoRESUMEN
Obesity is a known driver of endometrial cancer. In this issue of the JCI, Gómez-Banoy and colleagues investigated a cohort of patients with advanced endometrial cancer treated with immune checkpoint inhibitors targeting the interaction between programmed cell death receptor-1 (PD-1) and its ligand (PD-L1). Notably, a BMI in the overweight or obese range was paradoxically associated with improved progression-free and overall survival. A second paradox emerged from CT analyses of visceral adipose tissue, viewed as an unhealthy fat depot in most other contexts, the quantity of which was also associated with improved treatment outcomes. Though visceral adiposity may have value as a biomarker to inform personalized treatment strategies, of even greater impact would be if a therapeutic strategy emerges from the future identification of adipose-derived mediators of this putative anticancer immune-priming effect.
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Neoplasias Endometriales , Grasa Intraabdominal , Humanos , Femenino , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/terapia , Neoplasias Endometriales/patología , Neoplasias Endometriales/tratamiento farmacológico , Grasa Intraabdominal/inmunología , Inmunoterapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Obesidad/inmunología , Obesidad/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.
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Anticuerpos Monoclonales Humanizados , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales , Inhibidores de Puntos de Control Inmunológico , Terapia Neoadyuvante , Humanos , Femenino , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/diagnóstico por imagen , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anciano , Adulto , Resultado del TratamientoRESUMEN
Endometrial cancer is the most common malignant tumor of the female reproductive system. It develops in the mucous membrane lining the inside of the uterine body-the endometrium, through the abnormal and continuous growth of cancer cells originating from the uterine mucosa. In recent years, there has been a significant increase in the number of cases in European countries. Photodynamic therapy (PDT) is an innovative and dynamically developing medical procedure, useful in the treatment of cancer and non-cancer tissue conditions. The PDT reaction involves the activation of a photosensitizing substance with visible light, which in turn leads to the formation of free oxygen radicals, which contribute to the destruction of the cell. PDT is minimally invasive, has few side effects, and preserves organ anatomy and function. Both diagnostics and photodynamic therapy as modern methods of treatment are becoming more and more popular in many research units around the world. They are most often practiced and tested in in vitro experimental conditions. In clinical practice, the use of PDT is rare. Comprehensive cooperation between scientists contributes to taking steps towards obtaining new, synthetic photosensitizers, directing their physicochemical properties, and showing the impact on a given organism. This review examines the evidence for the potential and usefulness of PDT in the treatment of endometrial cancer. This review highlights that PDT is gaining popularity and is becoming a promising field of medical research.
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Neoplasias Endometriales , Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Fotoquimioterapia/métodos , Femenino , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , AnimalesRESUMEN
Background: Aberrant lipid metabolism is intricately linked to the development of endometrial cancer, and statin lipid-lowering medications are regarded as promising adjunctive therapies for future management of this malignancy. This study employed Mendelian randomization (MR) to explore the causal association between lipid traits and endometrial cancer while assessing the potential impact of drug targets on lower lipids on endometrial cancer. Method: Two-sample Mendelian randomization was employed to probe the causal association between lipid traits and endometrial carcinoma. Drug-target Mendelian randomization was also utilized to identify potential drug-target genes for managing endometrial carcinoma. In instances where lipid-mediated effects through particular drug targets were notable, the impacts of these drug targets on endometrial carcinoma risk factors were investigated to bolster the findings. Result: No causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC was found in two-sample Mendelian randomization. In drug target Mendelian randomization, genetic modeling of apolipoprotein B (APOB) (OR [95%CI]=0.31, [0.16-0.60]; p=4.73e-04) and cholesteryl ester transfer protein (CETP) (OR [95%CI]=1.83, [1.38-2.43]; p=2.91e-05) genetic mimicry was associated with non-endometrioid carcinoma. Conclusion: The results of our MR study revealed no causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC. Among the six lipid-lowering drug targets, we observed a significant association between lower predicted APOB levels and higher CETP levels with an increased risk of endometrioid carcinoma. These findings provide novel insights into the importance of lipid regulation in individuals with endometrial carcinoma, warranting further clinical validation and mechanistic investigations.
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Proteínas de Transferencia de Ésteres de Colesterol , Neoplasias Endometriales , Análisis de la Aleatorización Mendeliana , Humanos , Femenino , Neoplasias Endometriales/genética , Neoplasias Endometriales/tratamiento farmacológico , Proteínas de Transferencia de Ésteres de Colesterol/genética , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Polimorfismo de Nucleótido Simple , Reguladores del Metabolismo de Lípidos/uso terapéutico , Apolipoproteína B-100RESUMEN
BACKGROUND: The combination of anti-programmed death 1 (PD-1) inhibitors and tyrosine kinase inhibitors is an effective treatment strategy in endometrial cancer. We aimed to explore the efficacy and safety of camrelizumab plus apatinib as an alternative therapeutic option in patients with previously treated endometrial cancer. METHODS: This single-arm Simon's two-stage phase II trial was conducted at the Fudan University Shanghai Cancer Center. Patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy were screened for potential participation. Eligible patients were treated with intravenous camrelizumab (200 mg d1 q2w) and oral apatinib (250 mg qd) every 4 weeks. The primary end point was the objective response rate (ORR) per RECIST v1.1 in the intention-to-treat principle. RESULTS: Between January 20, 2020, and October 14, 2022, 36 patients (29 with microsatellite stability/mismatch repair proficient [MSS/pMMR] tumors; two with microsatellite instability-high/mismatch repair deficient [MSI-H/dMMR] tumors) were enrolled and treated. The confirmed ORR was 44.4% (95% CI: 27.9, 61.9) and the disease control rate was 91.7% (95% CI: 77.5, 98.2). The median duration of response was 9.3 (95% CI: 4.3, not reached) months, the median progression-free survival was 6.2 (95% CI: 5.3, 11.1) months, and the median overall survival was 21.0 (95% CI: 13.4, not reached) months during a median follow-up of 14.2 (interquartile range: 10.3, 27.6) months. Treatment-related adverse events of grade 3 or 4 occurred in 20 (55.6%) patients, with the most common being increased γ-glutamyl transferase (27.8%), alanine aminotransferase (16.7%) and aspartate aminotransferase (13.9%), and hypertension (11.1%). No treatment-related death occurred. CONCLUSIONS: Camrelizumab plus apatinib showed promising antitumor activity with manageable toxicity in patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy. The findings of this study support further investigation of camrelizumab plus apatinib as an alternative therapeutic option, especially for patients with MSS/pMMR tumors. TRIAL REGISTRATION: This trial was retrospectively registered with ChiCTR.org.cn, number ChiCTR2000031932.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Endometriales , Piridinas , Humanos , Femenino , Persona de Mediana Edad , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Neoplasias Endometriales/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificaciónRESUMEN
BACKGROUND: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population. METHODS: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184. FINDINGS: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group). INTERPRETATION: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup. FUNDING: F Hoffmann-La Roche.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatino , Neoplasias Endometriales , Recurrencia Local de Neoplasia , Paclitaxel , Humanos , Femenino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Neoplasias Endometriales/mortalidad , Método Doble Ciego , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Anciano , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Carboplatino/administración & dosificación , Supervivencia sin Progresión , AdultoAsunto(s)
Antineoplásicos Fitogénicos , Neoplasias Endometriales , Paclitaxel , Penfigoide Ampolloso , Humanos , Femenino , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/uso terapéutico , Anciano , Persona de Mediana EdadRESUMEN
OBJECTIVE: While human epidermal growth factor receptor 2 (HER2) is upregulated in endometrial carcinoma-especially in the p53 aberrant type- conventional anti-HER2 therapy is not typically used for this cancer type. Recently, HER2-targeted antibody-drug conjugates have shown antitumor effects against HER2 low-expressing cancers. Therefore, we analyzed the clinicopathological characteristics of HER2-positive endometrial carcinomas including those with low expression, as well as the prognostic significance of p53 and HER2 co-expression. METHODS: Immunohistochemistry for HER2 and p53 was performed in 530 patients with endometrial carcinoma; 124 cases (23%) were HER2-positive. RESULTS: Of the HER2-positive cases, >50% were 1+. A high prevalence of HER2 expression was observed in serous (64%), clear-cell (73%), and mixed (64%) carcinomas. Notably, 19% of endometrioid carcinomas were HER2-positive. HER2 positivity was significantly associated with age ≥60 years, high-grade histological subtype, deep myometrium invasion, stage III/IV, recurrence, and death. Univariate analysis showed that HER2-positive cases had reduced progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.012). However, after adjusting for stage, HER2 positivity was not associated with survival. In the early stage, co-expression of HER2-positive and p53 aberrant types was associated with shorter PFS (p < 0.001) and OS (p < 0.001) compared with at least one negative result. Multivariate analysis of PFS showed HER2 and p53 co-expression (hazard ratio, 1.891; 95% confidence interval, 1.183-5.971, p = 0.008) as an independent prognostic factor. CONCLUSIONS: This study presents detailed clinicopathological characteristics and the prognostic impact of HER2-positivity in endometrial carcinomas. HER2-targeted antibody-drug conjugate therapy may be broadly applicable to endometrial carcinoma.
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Biomarcadores de Tumor , Neoplasias Endometriales , Inmunoconjugados , Receptor ErbB-2 , Proteína p53 Supresora de Tumor , Humanos , Femenino , Neoplasias Endometriales/patología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análisis , Proteína p53 Supresora de Tumor/metabolismo , Persona de Mediana Edad , Anciano , Inmunoconjugados/uso terapéutico , Adulto , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Anciano de 80 o más Años , Inmunohistoquímica , Supervivencia sin Progresión , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
Background: Various trials have demonstrated the clinical benefits of lenvatinib plus pembrolizumab in patients with advanced or recurrent endometrial cancer, regardless of mismatch repair (MMR) status or histologic subtype. The majority of the previously published trials had small sample sizes. Here, we aimed to assess the reported efficacy and safety profile of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer. Methods: We utilized the Cochrane Library, PubMed, Web of Science and Embase databases to identify clinical trials evaluating the efficacy and safety of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer. The outcomes analyzed were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR) and the incidence of adverse events (AEs). Subgroup analysis was conducted on the basis of MMR status (deficient, dMMR or proficient, pMMR). Results: Four trials (582 patients) were included. The pooled ORR was 32.7% [95% confidence interval (CI): 28.9-36.5]. Subgroup analysis revealed an ORR of 48.1% (95% CI: 26.1-70.2) for dMMR group and 33.1% (95% CI: 25.7-40.6) for pMMR group. The pooled DCR was 74.9% (95% CI: 71.3-78.4%). Subgroup analysis revealed a DCR of 81.0% (95% CI: 64.5-97.6) for the dMMR group and 76.3% (95% CI: 66.3-86.3) for the pMMR group. Follow-up was reported in all included studies. The median range time of PFS and OS was 5.3 months-258 days and 17.2 months-not reached, respectively. Regarding safety, the overall pooled proportions of any-grade AE and AEs ≥ grade 3 were 95.8% (95% CI: 89.5-100.0) and 80.2% (95% CI: 59.9-100.0), respectively. Conclusion: Lenvatinib plus pembrolizumab showed a relevant clinical benefit and significant toxicity in patients with advanced and recurrent endometrial cancer. Further studies encompassing long-term outcomes are warranted. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=522160/, identifier CRD42024522160.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Recurrencia Local de Neoplasia , Compuestos de Fenilurea , Quinolinas , Femenino , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/mortalidad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Resultado del TratamientoRESUMEN
To examine the potential correlation between chemotherapy and the risk of individual of second primary endometrial cancer (SEC) in patients with rectal cancer (RC) and assess survival outcomes. The study employed the Surveillance, Epidemiology, and End Results database (SEER) as the primary data source, it encompasses a substantial cohort of patients diagnosed with RC between 1975 and 2018. This study involved a total of 30,847 individuals diagnosed with RC, of whom 168 individuals (5.45) experienced SEC. Among them, 107 patients (3.47) received chemotherapy treatment, while 61 patients (1.98) did not receive chemotherapy. The analysis of the overall occurrence of SEC revealed a significant association between SEC and chemotherapy treatment. Univariate and multivariate analyses confirmed a significant association between chemotherapy treatment and an increased risk of developing SEC in RC patients. Upon implementation of a dynamic analysis on the variables of relative risk and standardized incidence ratios, the results revealed that the likelihood of SEC escalated in tandem with advancing age. The examination of patients who developed SEC after receiving and not receiving chemotherapy revealed no substantial disparities in the 10-year overall survival (OS) and (cancer-specific survival) CSS rates. The results were the same after propensity score matching. Nevertheless, a notable discrepancy emerged when comparing the OS and CSS rates at 10 years between patients afflicted with SEC subsequent to chemotherapy and those afflicted with primary endometrial cancer, and the result was the same situation in the no-chemotherapy group. The use of chemotherapy in RC patients has been associated with an increased probability of developing specific SEC. Therefore, it is imperative to prioritize efforts aimed at reducing chemotherapy-related SEC occurrences and improving the prognosis of affected individuals.
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Neoplasias Endometriales , Neoplasias Primarias Secundarias , Neoplasias del Recto , Programa de VERF , Humanos , Femenino , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/cirugía , Persona de Mediana Edad , Anciano , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/cirugía , Neoplasias del Recto/mortalidad , Neoplasias Primarias Secundarias/epidemiología , Adulto , Anciano de 80 o más Años , Tasa de SupervivenciaRESUMEN
BACKGROUND: High-grade endometrial stromal sarcoma (HG-ESS) is a rare malignant tumor with poor prognosis. To overcome the limitations of current treatment for advanced patients, the intervention of targeted drug therapy is urgently needed. CASE PRESENTATION: A 74-year-old married woman who presented with abdominal distension and lower abdominal pain was admitted to Hebei General Hospital. After surgery, immunohistochemical staining revealed a malignant tumor which was consistent with HG-ESS. Tumor recurrence occurred 2 months after surgery. Then the patient underwent chemotherapy with two courses but responded poorly. Subsequently we observed ATM, BLM, and CDH1 co-mutations by Next Generation Sequencing (NGS). Then the patient received pamiparib, which resulted in a 10-month progression-free survival (PFS) and is now stable with the administration of sintilimab in combination with pamiparib and anlotinib. CONCLUSIONS: Due to the successful use of poly ADP-ribose polymerase inhibitor (PARPi) on HG-ESS, we suggest that the selection of effective targeted drugs combined with anti- programmed death-1 (PD-1) drug therapy based on genetic testing may become a new option for the treatment of homologous repair deficient (HR-deficient) HG-ESS.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada , Cadherinas , Neoplasias Endometriales , RecQ Helicasas , Sarcoma Estromático Endometrial , Humanos , Femenino , Anciano , Neoplasias Endometriales/genética , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/tratamiento farmacológico , Sarcoma Estromático Endometrial/diagnóstico , Proteínas de la Ataxia Telangiectasia Mutada/genética , RecQ Helicasas/genética , Cadherinas/genética , Antígenos CD/genética , MutaciónRESUMEN
OBJECTIVE: Levonorgestrel intrauterine system (LNG-IUS) has been widely used in patients with endometrial carcinoma (EC), endometrial hyperplasia without atypical (EH), and atypical endometrial hyperplasia (AEH). The purpose of our Network meta-analysis (NMA) is to evaluate the efficacy of the treatments based on the LNG-IUS in patients with EC and EH with or without atypical. METHODS: We examined PubMed, EMBASE, Web of Science and the Cochrane Library up to 22 April 2024 to determine studies reporting treatment outcomes in EC and EH patients receiving LNG-IUS therapy, LNG-IUS + metformin (MET), oral progestins (OP), etc. We used EndNote 9 to select studies, Jadad scale and NOS scale to assess quality, stata(16.0) and R (4.3.1) to analysis the data. RESULTS: Overall, 28 studies involving 3752 patients were included in our NMA. As for EH patients, LNG-IUS (RR 1.21; 95% CrI [1.11, 1.34]) and LNG-IUS + MET (RR 323.57; 95% CrI [1.61, 214,223,188.1])] significantly increased CR rate in comparison with OP. Based on SUCRA, LNG-IUS + OP was the best treatment to improve CR(SUCRA = 67.2%) in patients with EC, whereas LNG-IUS + MET was superior in increasing CR (SUCRA = 99.8%) than any other treatments for EH patients. Besides, the ranking based on SUCRA illustrated that LNG-IUS alone was the best choice to raise CR rates (SUCRA = 76.7%) for AEH patients. In head-to-head meta-analysis, OP has a higher progression rate (RR 4, 95% CI 1.89-8.46, p = 0.062; I2 = 71.3%), a higher nausea rate (RR 1.93, 95% CI 1.24-3.01, p = 0.187; I2 = 40.4%) than LNG-IUS in patients with EH. In contrast, LNG-IUS had a irregular vaginal bleeding rates (RR 0.76, 95% CI 0.64-0.90, p = 0.034; I2 = 77.7%) than OP in EH patients. In addition, as for AEH patients, OP has a higher persistence rate (RR 4.31, 95% CI 1.43-13.00, p = 0.93; I2 = 0.0%) than LNG-IUS. CONCLUSION: According to the NMA, LNG-IUS related studies are feasible for conservative therapy in patients with EC and EH with or without atypical. Therefore, concerning the curative effect, we recommend LNG-IUS-based treatments as the best conservative therapy for EC and EH patients. However, future studies require large sample sizes and more outcomes to further evaluate the differences of treatment selections based on LNG-IUS.
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Hiperplasia Endometrial , Neoplasias Endometriales , Dispositivos Intrauterinos Medicados , Levonorgestrel , Metaanálisis en Red , Progestinas , Humanos , Femenino , Levonorgestrel/administración & dosificación , Levonorgestrel/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Hiperplasia Endometrial/tratamiento farmacológico , Progestinas/uso terapéutico , Progestinas/administración & dosificación , Metformina/uso terapéutico , Metformina/administración & dosificación , Agentes Anticonceptivos Hormonales/administración & dosificación , Agentes Anticonceptivos Hormonales/uso terapéutico , Resultado del TratamientoRESUMEN
Until recently, patients diagnosed with locally advanced and metastatic endometrial cancer faced significant challenges in their treatment due to limited options and poor prognostic outcomes. The sequencing of tumors has been a major advancement in its management. It has led to The Cancer Genome Atlas classification currently used in clinical practice and the initiation of several clinical trials for innovative treatments targeting principally signaling pathways, immune checkpoints, DNA integrity, growth factors, hormonal signaling, and metabolism. Numerous clinical trials are investigating a combinatorial approach of these targeted therapies to counter tumoral resistance, cellular compensatory mechanisms, and tumor polyclonality. This review provides a comprehensive overview of historical, current, and promising therapies in advanced and metastatic endometrial cancer. It particularly highlights clinical research on targeted and hormonal therapies, but also immunotherapy, reflecting the evolving landscape of treatment modalities for this disease.
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Neoplasias Endometriales , Humanos , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Inmunoterapia/métodos , Terapia Molecular Dirigida/métodos , Metástasis de la NeoplasiaRESUMEN
In the past year, notable advances were achieved toward improving oncological outcomes in patients with advanced and recurrent endometrial cancer because of reporting of high-level results of several phase 3 clinical trial combining an immune checkpoint inhibitor with chemotherapy in the first-line setting. For the first time, patients with recurrent or advanced endometrial cancer have options for treatment that are superior to traditional chemotherapy alone. What remains to be determined is population specificity of these recommendations. All four major studies were in agreement that patients with endometrial cancer with deficient mismatch repair markedly benefited from addition of an immune checkpoint inhibitor for progression-free survival; some showed preliminary results demonstrating a potential overall survival. Molecular characterization details are needed to determine if and which patients with tumors that are mismatch proficient should receive this new combination approach. PLAIN LANGUAGE SUMMARY: Combining an immune checkpoint inhibitor with chemotherapy in the first-line setting treatment of patients with advanced endometrial cancer improved progression-free survival, especially in patients with mismatch repair deficiency. Improving patient selection with potential biomarkers of sensitivity and biomarkers of resistance is key in developing the next clinical trials and will assist in directing therapy to the correct patients and minimize toxicity.
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Neoplasias Endometriales , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Humanos , Femenino , Neoplasias Endometriales/terapia , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Neoplasias Endometriales/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Reparación de la Incompatibilidad de ADN , Supervivencia sin Progresión , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Endometrial cancer (EC) is the most common cancer of the female reproductive tract, and there is an urgent need to develop new candidate drugs with good efficacy and safety to improve the survival rate and life quality of EC patients. Herein, a series of new azaphenothiazine derivatives were designed and synthesized and their anti-EC activities were evaluated. Among them, compound 33 showed excellent antiproliferative activities against both progesterone-sensitive ISK cells and progesterone-resistant KLE cells. Moreover, 33 could significantly inhibit colony formation and migration of EC cells and induce cell apoptosis. Remarkably, 33 significantly suppressed KLE xenograft tumor growth without influencing body weights or key organs. In addition, 33 exhibited good pharmacokinetic properties and low extrapyramidal side effects. Mechanism research indicated that 33 reduced Ca2+ levels in mitochondria by targeting GRP75 and disrupting its interaction with IP3R. Overall, 33 showed promising potential as an anti-EC candidate agent.
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Antineoplásicos , Calcio , Proliferación Celular , Neoplasias Endometriales , Receptores de Inositol 1,4,5-Trifosfato , Mitocondrias , Fenotiazinas , Humanos , Femenino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Animales , Fenotiazinas/farmacología , Fenotiazinas/síntesis química , Fenotiazinas/química , Fenotiazinas/uso terapéutico , Calcio/metabolismo , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Neoplasias Endometriales/metabolismo , Proliferación Celular/efectos de los fármacos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Línea Celular Tumoral , Homeostasis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratones Desnudos , Proteínas HSP70 de Choque Térmico/metabolismo , Descubrimiento de Drogas , Relación Estructura-Actividad , Ratones Endogámicos BALB C , Proteínas de la MembranaRESUMEN
OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.
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Carcinoma Endometrioide , Neoplasias Endometriales , Tumor de Células de la Granulosa , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Receptores de Progesterona , Humanos , Femenino , Persona de Mediana Edad , Anciano , Receptores de Progesterona/metabolismo , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Tumor de Células de la Granulosa/tratamiento farmacológico , Tumor de Células de la Granulosa/metabolismo , Tumor de Células de la Granulosa/patología , Adulto , Gonanos/administración & dosificación , Gonanos/efectos adversos , Preparaciones de Acción Retardada/administración & dosificación , Anciano de 80 o más Años , Administración Oral , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/metabolismoRESUMEN
BACKGROUND: Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking. METHODS: We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis. RESULTS: Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3). CONCLUSIONS: These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.