Metastatic Endometrial Cancer Research Articles

Investigation of the anticancer, antimigration and antiangiogenesis effects of an oxadiazole derivative in two- and three-dimensional cultured Ishikawa and Huvec cells; in vitro and in silico studies

Introduction: There are various methods used in cases of metastatic endometrial cancer. However, the prognosis is generally poor. Therefore, new anticancer agents are expected to exhibit the potential to prevent metastasis, as well as their effects on the viability of cancer cells. In in vitro conditions, the Ishikawa cell line represents endometrial adenocarcinoma and the Huvec cell line represents human umbilical vein endothelial cells. Oxadiazole derivatives may be promising new agents for endometrial cancer treatments by exhibiting anticancer and antiangiogenic properties. Objective: The aim of this study was to examine the anticancer, antimigration and antiangiogenic effects of 5-[(4-Phenylpiperazine-1-yl)methyl]-1,3,4-oxadiazol-2-thiol (FP-Oxa) on co-cultured Ishikawa and Huvec cells. Materials and Methods: In silico molecular docking, ADME and toxicity analyzes were performed for FP-Oxa. The effect on the viability of two- and three-dimensional mono- and co-culture models created with HUVEC and Ishikawa cells was evaluated by MTT analysis and IC50 values were calculated. The effect on the migration of two-dimensional cultured cells was determined by wound healing assay. Changes in VEGF expression in three-dimensional co-culture models were evaluated by immunofluorescence staining. Results: As a result of in silico analyses, it was determined that FP-Oxa was within the oral bioavailability limits, exhibited class 4 toxicity, and had inhibition potential by binding to VEGR2. While FP-Oxa clearly inhibited migration in two-dimensionally cultured Ishikawa cells, it did not show the same level of success in Huvec and co-cultured cells. It was effective in reducing VEGF expression in three-dimensional co-cultures. Conclusion: FP-Oxa may have various therapeutic effects on endometrial adenocarcinoma cells. It will be important to conduct biological activity studies in three-dimensional models that mimic the tumor structure created with different types of cancer cells.

Abstract 5149: Extracellular matrix remodeling in metastatic mismatch repair deficient endometrial cancer:Implications for immune checkpoint inhibitor response prediction

Abstract Mismatch repair deficient (MMRd) status is a predictive biomarker for Immune checkpoint inhibitors (ICI) in endometrial cancer (EC), however, half of these patients (pts) do not respond. Most studies exploring biomarkers of response to ICI have focused on tumor or immune cell factors. We aimed to describe the extracellular matrix components of the tumor microenvironment (TME) in ICI-Responder (R) versus Non-Responder (NR) MMRd EC pts to identify new predictive biomarkers of response. Clinical data and outcomes of metastatic MMRd EC pts, treated with ICI (2016-2021), were retrospectively collected. Pts were classified as Rs (CR, PR, or SD ≥12 months) or NRs (PD or SD <12 months). Pre-ICI FFPE tumor samples were subjected to Biognosys UltraDeep TrueDiscovery™ Mass Spectrometry (MS) for identification of differentially regulated protein expression between R and NR. Criteria for protein candidate selection were p-value < 0.01 and average absolute log2 fold change (AVG Log ratio) > 0.58. Collagen was visualized on whole slides using Masson’s trichrome and quantified by Qupath. Collagen density was expressed as % positive surface in the intratumoral area. Second-harmonic generation (SHG) microscopy plus polarimetry (p-SHG) was used to estimate collagen content and describe the spatial orientation of fibrillar collagen in the intratumoral area. intraepithelial (ie) and stromal (s) CD3+ and CD8+ cells were quantified by Qupath. Non-parametric t-tests and Spearman’s rank coefficient (r) for linear correlation were used. Twenty-five tumor samples were included in the analysis: 17 from Rs and 8 from NRs. MS identified collagen type V alpha-2 (AVR Log ratio 2.9, p 0.008) and type XXII alpha-1 chains (AVR Log ratio 1.14, p 0.006) as significantly upregulated in NRs. Using spatial imaging, collagen density in the intratumoral area was significantly higher in NRs (median: 14.2% vs 4.6%, p 0.01). Intratumoral collagen density was positively correlated with collagen type V expression (r 0,54, p 0.016), and negatively correlated with ie and s CD3+ cell (r -0.39, p 0.054; r -0.4, p 0.048, respectively) and ie and s CD8+ cell (r -0.39, p 0.053; and r -0.29, p 0.166) infiltration. SHG confirmed that fibrillar collagen content in the tumor area was significantly greater in NRs (p 0.02). p-SHG revealed that NR tumors tended to show a highly disorganized collagen matrix. In contrast, a linear collagen pattern was associated with response to ICI: 89% of tumors displaying this pattern were Rs. Both MS and two different spatial approaches consistently demonstrated that increased collagen expression or density may serve as a potential predictive biomarker of resistance to ICI in MMRd metastatic EC, contributing to create an immunosuppressive TME. The spatial orientation pattern of collagen fibers may also be crucial in shaping immune TME and influencing the response to ICI. Citation Format: Juan Francisco Grau, Carole Aimé, Martin Mehnert, Elisa Yaniz-Galende, Catherine Genestie, Audrey Le Formal, Elodie Edmond, Antoine Amaury Lachaud, Patricia Pautier, Judith Michels, Sébastien Gouy, Amandine Maulard, Emeline Colomba-Blameble, Felix Blanc-Durand, Marie-Claire Schanne-Klein, Alexandra Leary. Extracellular matrix remodeling in metastatic mismatch repair deficient endometrial cancer:Implications for immune checkpoint inhibitor response prediction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5149.

Abstract 5089: Therapeutically targeting endometrial cancer by ICAM1 antibody-drug conjugates

Abstract Background: Endometrial cancer is the most frequently occurring gynecologic cancer in developed countries and the third leading cause of cancer deaths among women. It remains one of the few malignant tumors with rapidly increasing mortality and morbidity. Patients with recurrent or metastatic endometrial cancer continue to experience poor outcomes. Antibody-drug conjugates (ADCs) represent a class of targeted therapeutic modalities that offer biomarker-based therapeutic options for patients with endometrial cancer. In this study, we proposed to identify a novel molecular target for the preclinical development of an ADC for endometrial cancer-targeted therapy. Methods: Firstly, to determine the level of target expression within endometrial cancer tissue components as well as differences, we performed immunohistochemical staining of human endometrial cancer and paracancerous tissue. Secondly, the expression of the target on the cell membrane surface was quantitated and qualitatively verified using flow cytometry and single-photon confocal microscopy. In the third step, an endocytosis assay was used to verify the endocytosis of the target antibody by EC cells. Confocal imaging can directly observe the endocytosis of the target antibody, and flow cytometry can be analyzed and quantified. Co-localization experiments with antibody fluorescence can verify the specific site where the target antibody is endocytosed into cancer cells. We then designed and characterized two targeted ADCs. Next, the in vitro inhibitory activities of these ADCs against endometrial cancer cell lines and normal cells were evaluated using the CCK8 assay. Finally, we established a cell line-derived xenograft (CDX) model of endometrial cancer to validate the in vivo efficacy and bio-safety of the ADCs. Results: We have determined a correlation between ICAM1 overexpression and EC, and IHC staining of patient tissues showed significantly higher levels of ICAM1 expression in endometrial cancer tissues than in paracancerous tissues. The high cell surface expression of ICAM1 was verified in a panel of various human endometrial cancer cell lines. Moreover, two ICAM1 ADCs were established using clinically-approved ADC linker and payload combinations. It was visually confirmed that ICAM1 ADCs selectively recognize endometrial tumors and efficiently enter endometrial cells via antigen-mediated endocytosis. We compared the anti-tumor activity of ICAM1 ADCs with standard-of-care chemodrugs, and ICAM1 ADCs outperformed chemodrugs in the CDX model of endometrial cancer without toxicity. Conclusion: We identified that ICAM1 is a promising ADC target for endometrial cancer and confirmed the potent anti-tumor activity and biosafety of ICAM1 ADCs in vitro and in vivo, warranting further pre-clinical and clinical investigations. Citation Format: Hanfei Xie, Lu Sun, ShiLi Yao, Peng Guo, YingLi Zhang. Therapeutically targeting endometrial cancer by ICAM1 antibody-drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5089.

ARG1 Is a Potential Prognostic Marker in Metastatic Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy. While the majority of patients present with early-stage and low-grade EC and have an excellent prognosis, a subset has metastatic disease at presentation or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EC is a critical barrier. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers. In the present study, ARG1 expression was evaluated as a potential prognostic marker for metastatic EC in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. While Pten mutation in the uterus is not sufficient for distant metastasis, mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Our immunostaining and RT-qPCR analysis revealed that the expression of ARG1 in early stage of EC as well as endometrial hyperplasia from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. The results suggest that a high level of ARG1 is associated with poor prognosis in association with EC of mouse.

Discovery of Endometrial Cancer After Removal of An Intrauterine Device Encrusted in the Myometrium

In our article, we report the case of a patient with metastatic endometrial cancer whose risk factor was an intrauterine device worn for over ten years.

Efficacy and safety of lenvatinib and pembrolizumab in the treatment of endometrial cancer: data from routine clinical practice in Russia

Aim. To assess the efficacy and safety of lenvatinib and pembrolizumab for the treatment of mismatch repair-proficient endometrial cancer (EC) in routine clinical practice in Russia.Materials and methods. This multicenter, retrospective, cohort study included patients with recurrent and metastatic EC from 37 cancer centers in Russia treated between May 2020 and April 2023. Patients with histologically verified EC without microsatellite instability who received ≥1 course of pembrolizumab/lenvatinib therapy were included in the study. The primary endpoint was progression-free survival; the clinical characteristics of the patients were additionally analyzed, the objective response rate and the toxicity profile of therapy were assessed.Results. The study included 100 patients. Median age was 65 (30–83) years. The most common histologic tumor subtype was endometrioid adenocarcinoma (68 %); serous adenocarcinoma was diagnosed in 22 % of cases, other types of tumor – 10 % of cases. All patients had pMMR/microsatellite-stable tumors. The median progression-free survival was 7.75 months (95 % confidence interval 0.7–33.8), and a partial response to therapy was observed in 24 % of patients. Almost half of the patients (44 %) required dose reduction due to adverse events. The most common adverse events included fatigue (n = 26; 26 %), hypertension (n = 20; 20 %), and hypothyroidism (n = 14; 14 %).Conclusion. This study confirms the clinical efficacy of lenvatinib and pembrolizumab in patients with recurrent and metastatic EC without mismatch repair system deficiency (pMMR-tumors) in routine clinical practice.

Identification of dMMR in metastatic colorectal and non-colorectal cancers in a private Mexican institution.

177 Background: DNA mismatch repair is a process in which normal cells maintain their original genomic information avoiding errors in mismatched nucleotides or base modifications from recombination processes. The failure of this process could drive carcinogenesis due to increased mutation rate as well as high microsatellite instability. It is estimated that the global average prevalence of dMMR/MSI-H across tumor types and stages is approximately 16%, with higher rates reported for early stages. However, the prevalence for colorectal (CRC) and non-colorectal cancers for this biomarker in Mexico has not been reported. Objective:To explore the prevalence of dMMR in metastatic CRC (mCRC) and non-CRC (gastric, esophageal, and endometrial cancer) from a private Mexican institution. Methods: In this retrospective study, the dMMR status of 215 samples were analyzed from a primary database of stored biopsies from patients diagnosed with metastatic CRC, gastric, esophageal, or endometrial cancers between January 2017 and December 2020. 65 records had information about MMR status. Samples were analyzed using a commercial kit to detect dMMR (BioSb). Prevalence of dMMR was stratified by age and gender and expressed as frequencies. Statistical analysis was conducted in SPSS. Results: dMMR was found in 18.5% (N=27) endometrial cancer cases, 12.7% (N=150) of CRC cases, and 8.3% (N=24) of gastric cancer cases. However, it was not detected in any cases of esophageal cancer (N=14). In CRC, we found a higher percentage of incidence in men than in women, 15.6% (n = 14/90) vs. 8.3% (n = 5/60) respectively. By age groups, the highest total percentage (20%) was observed among those 41-50 years old. The age group with the lowest dMMR rate was 31- 40 yo, with 7.7%. All cases of CRC patients over 91 yo (n=3), were pMMR. Conclusions: Even though this data is not representative for the entire Mexican population, it provides preliminary prevalence dMMR estimates for some key cancers. Additional research is needed to give the limited sample sizes available for non-CRC.

Metastases and Recurrence Risk Factors in Endometrial Cancer-The Role of Selected Molecular Changes, Hormonal Factors, Diagnostic Methods and Surgery Procedures.

The presence of metastatic endometrial cancer (EC) is a key problem in treatment failure associated with reduced overall survival rates. The most common metastatic location is the pelvic lymph nodes, and the least common is the brain. The presence of metastasis depends on many factors, including the molecular profile of cancer (according to the TCGA-Genome Atlas), the activity of certain hormones (estrogen, prolactin), and pro-inflammatory adipocytokines. Additionally, an altered expression of microRNAs affecting the regulation of numerous genes is also related to the spread of cancer. This paper also discusses the value of imaging methods in detecting metastases; the primary role is attributed to the standard transvaginal USG with the tumor-free distance (uTFD) option. The influence of diagnostic and therapeutic methods on EC spread is also described. Hysteroscopy, according to the analysis discussed above, may increase the risk of metastases through a fluid medium, mainly performed in advanced stages of EC. According to another analysis, laparoscopic hysterectomy performed with particular attention to avoiding risky procedures (trocar flushing, tissue traumatization, preserving a margin of normal tissue) was not found to increase the risk of EC dissemination.

Paraneoplastic cerebellar degeneration in a patient with metastatic endometrial cancer developed after two cycles of palliative chemotherapy: a clinical case

A clinical case of an atypical course of paraneoplastic cerebellar degeneration that occurred during chemotherapy in a patient with an established diagnosis of metastatic endometrial cancer is presented.

Clinical relevance of circulating ESR1 mutations during endocrine therapy for advanced hormone-dependent endometrial carcinoma

ObjectiveEndocrine therapy is frequently administered in patients with hormone dependent (HR+) metastatic endometrial cancer. ESR1 mutations have emerged as a key mechanism of aromatase inhibitor (AI) resistance in HR + metastatic breast cancer and can be monitored using circulating tumor DNA (ctDNA). The aim of this study was to explore the incidence and clinical relevance of circulating ESR1 mutations in patients treated by AI or megestrol acetate (M) for advanced endometrial carcinoma.MethodologyThis single-center retrospective study was performed at the Henri Becquerel Center (Rouen) and looked for circulating ESR1 gene mutations by droplet digital PCR (E380Q, L536R, Y537S, Y537N, Y537C, D538G, S463P) in patients with advanced HR + endometrial carcinoma treated between 2008 and 2020 for at least 30 days by AI or M. Analyses were performed before exposure and at progression/during endocrine therapy.ResultsTwenty-two patients were included: 13 were treated with AI, 12 of whom progressed; 9 patients were treated with M, 8 of whom progressed. 68.1% of the patients had low-grade endometrial carcinoma and 54.5% had received chemotherapy in the metastatic setting. The median duration of treatment was 152 days (min 47 – max 629) with AI and 155 days (min 91-max 1297) with M. Under AI, there was no ESR1 mutation at baseline, and one Y537C mutation at progression with a variant allele frequency (VAF) of 0.14%. Under M, one patient had a Y537C (VAF 0.2%) at baseline that disappeared during treatment. Another patient had a Y537S mutation emergence at progression after 91 days of treatment (VAF 1.83%). There was no significant difference between the circulating DNA concentration before and after hormone therapy (p = 0.16).ConclusionESR1 mutations do not seem to be involved in the mechanisms of resistance to AI or M in HR+ endometrial cancer. The clinical relevance of their detection is not demonstrated.

P271 - Case report: Uncommon presentation of metastatic endometrial cancer with synchronous adrenal and renal involvement

P271 - Case report: Uncommon presentation of metastatic endometrial cancer with synchronous adrenal and renal involvement

Pyroptosis: the dawn of a new era in endometrial cancer treatment.

Endometrial cancer (EC) is a malignancy of the inner epithelial lining of the uterus. While early-stage EC is often curable through surgery, the management of advanced, recurrent and metastatic EC poses significant challenges and is associated with a poor prognosis. Pyroptosis, an emerging form of programmed cell death, is characterized by the cleavage of gasdermin proteins, inducing the formation of extensive gasdermin pores in the cell membrane and the leakage of interleukin-1β (IL-1β) and interleukin-18 (IL-18), consequently causing cell swelling, lysis and death. It has been found to be implicated in the occurrence and progression of almost all tumors. Recent studies have demonstrated that regulating tumor cells pyroptosis can exploit synergies function with traditional tumor treatments. This paper provides an overview of the research progress made in molecular mechanisms of pyroptosis. It then discusses the role of pyroptosis and its components in initiation and progression of endometrial cancer, emphasizing recent insights into the underlying mechanisms and highlighting unresolved questions. Furthermore, it explores the potential value of pyroptosis in the treatment of endometrial cancer, considering its current application in tumor radiotherapy, chemotherapy, targeted therapy and immunotherapy.

Management of metastatic endometrial cancer: physicians' choices beyond the first line after approval of checkpoint inhibitors.

Endometrial cancer (EC) represents 3.4% of all newly diagnosed cancer cases and is responsible for 2.1% of all cancer-related deaths. Approximately 10%-15% of women with EC are diagnosed with advanced-stage disease, resulting in a reported 5-year survival rate of only 17% for those with distant metastases. A better understanding of its molecular features has ushered in a new era of immunotherapy for the treatment of EC, allowing for alternative therapeutic approaches, even in cases of advanced disease. We administered a multi-choice online survey for Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) members. The questionnaire was available for 2 months, starting in October 2022. Our objective was to evaluate the current attitude of incorporating molecular characterization of EC into routine clinical practice, appraise the implementation of newly available therapies, and compare the outcomes with the previous survey conducted in April-May 2021 to ascertain the actual changes that have transpired during this recent time period. The availability of molecular classification in Italian centers has changed in 1 year. Seventy-five percent of centers performed the molecular classification compared with 55.6% of the previous survey. Although this percentage has increased, only 18% performed all the tests. Significant changes have occurred in the administration of new treatments in EC patients in MITO centers. In 2022, 82.1% of the centers administrated dostarlimab in recurrent or advanced MMR-deficient (dMMR) EC experiencing disease progression after platinum-based chemotherapy regimens, compared to only 24.4% in 2021. In 2022, 85.7% of the centers already administrated the pembrolizumab plus lenvatinib combination as a second-line therapy for MMR-proficient (pMMR) patients with advanced or recurrent EC who had progressed from first-line platinum-based therapy. Both the therapeutic and diagnostic scenarios have changed over the last couple of years in MITO centers, with an increased prescription of immune checkpoint inhibitors and use of the molecular classification.

The oncologic outcomes of endometrial cancer metastasizing to the adrenal gland and kidney: from case to analysis.

To evaluate the oncologic outcomes of endometrial cancer metastasis to the adrenal gland and kidney, based on a case study and review of the literature. A systematic review of the medical literature was performed to identify articles about metastatic endometrial cancer to the adrenal gland and kidney from 1975 until 2021. A 55-year-old female patient was admitted to our center. On pelvic examination, a mass protruding out of the cervix was observed, which was shown to be endometrioid carcinoma on biopsy. Disease stage was IVB, based on radiological and pathological results and the International Federation of Gynecology and Obstetrics 2018 staging. Neo-adjuvant chemotherapy was given. After therapy, the patient underwent type 2 hysterectomy, bilateral salpingo-oophorectomy, total omentectomy and lymph node dissection. Left nephrectomy, left adrenalectomy and left hemicolectomy were also performed because the conglomerate tumor invaded the left kidney, left adrenal gland, and left colon mesentery. Pathological findings were consistent with metastasis of endometrioid carcinoma in the left adrenal gland, left kidney parenchyma and hilum. Metastasis of endometrial cancer to the adrenal gland and kidney is extremely rare and metastasis to the kidney has been reported in only two previous cases. When there is an intraperitoneal spread of endometrial cancer, as well as ovarian cancer, cytoreductive surgery without leaving a residual tumor should be undertaken andshould include adrenalectomy and nephrectomy, if necessary.

Molecular Classification of Endometrial Cancer and the 2023 FIGO Staging: Exploring the Challenges and Opportunities for Pathologists.

This commentary explores the complexities of the FIGO 2023 staging system and the inclusion of The Cancer Genome Atlas's (TCGA) molecular classification in the management of endometrial cancer. It highlights the importance of histology as a prognostic tool, while scrutinizing the merits and demerits of its application to aggressive endometrial cancers. The commentary review sheds light on the recent introductions of lymphovascular space invasion (LVSI) and lymph node metastasis size in cancer staging. It outlines the difficulties in differentiating between synchronous and metastatic endometrial and ovarian cancers, underlining their implications on treatment strategies. Furthermore, the commentary discusses the integration of molecular classifications within the FIGO 2023 framework, emphasizing the pivotal yet challenging implementation of the pathogenic POLE mutation test. The commentary concludes by reaffirming the vital role of pathologists in executing the FIGO 2023 staging system.

Should we abandon hormonal therapy in endometrial cancer? Outcomes of recurrent and metastatic endometrial cancer treated with systemic progestins.

The objective of this study is to determine primary survival endpoints in women with recurrent and metastatic endometrial carcinoma (RMEC) treated with progestins. A retrospective chart review was conducted at The Ottawa Hospital using electronic medical records. Inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥one line of progestin treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Of 2342 cases reviewed, 74 met inclusion criteria. Sixty-six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of tumors by grade was: 1: 25 (33.3%), 2: 30 (40.0%), and 3: 20 (26.7%). The PFS and OS for the entire study sample was 14.3 months (95% CI 6.2-17.9) and 23.3 months (14.8-36.8), respectively. The PFS for patients with Grade 1-2 RMEC was 15.7 months (8.0, 19.5), compared to 5.0 months (3.0, 23.0) with Grade 3 disease. The OS for patients with Grade 1-2 versus Grade 3, was 25.9 months (15.3, 40.3) versus 12.5 months (5.7, 35.9), respectively. Thirty-four (45.9%) and 40 (54.1%) patients were treated with 0 and ≥1 line of chemotherapy. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed. This real-world data on RMEC suggests there is a role for progestins in select subgroups of women. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed.

Recommandations pour la pratique clinique Nice/Saint-Paul-de-Vence 2022–2023 : Prise en charge du cancer de l'endomètre métastatique et/ou en rechute

Recommendations for clinical practice Nice/Saint-Paul-de-Vence 2022-2023 : Management of advanced/relapsing endometrial cancer Since the first recommendations in 2020 concerning metastatic and/or relapsed endometrial cancer, new treatment options have shown a benefit on patients' life expectancy, justifying their update. In first line, the choice will be made between chemotherapy with carboplatin/paclitaxel or hormone therapy with progestin, depending on tumor characteristics (histological type, grade, expression of hormone receptors, rate of progression). In case of a dMMR tumors, the use of immunotherapy within the framework of a therapeutic trial is an option. Beyond first-line chemotherapy, current standard treatment consists of the combination of pembrolizumab and lenvatinib, regardless of MMR status. Close clinical and biological monitoring is however necessary given the potential toxicity. Chemotherapy retains its place either as monotherapy (paclitaxel or doxorubicin) in the event of failure or contraindication to pembrolizumab-lenvatinib, or in combination with carboplatin in the event of a long free interval and pMMR tumor. The numerous ongoing clinical trials evaluating new therapeutic targets or strategies adapted to molecular or histological types should allow further improvements the prognosis of patients with metastatic endometrial cancer.

A phase II, randomized, double-blind study of the use of rucaparib vs placebo maintenance therapy in metastatic and recurrent endometrial cancer.

TPS5626 Background: There are currently no approved maintenance therapies for metastatic and recurrent endometrial cancer, which carries a dismal long-term prognosis. The PARP inhibitor drug class has demonstrated significant clinical benefit as a maintenance therapy for patients with germline/somatic BRCA mutations or homologous recombination deficiency (HRD) in ovarian cancers. However, BRCA mutations are not common in endometrial cancer. Loss of function of the tumor suppressor gene PTEN has been demonstrated in greater than 80% of endometrioid endometrial cancers 1. PTEN loss of function is well known to lead to activation of the PI3K-AKT-mTOR pathway but has also been shown to lead to defects in homologous recombination (HR) DNA repair of double strand breaks 2. Specifically, PTEN silencing leads to decreased RAD51 foci formation. Based on this mechanism, in vitro data on endometrial cancer cell lines has demonstrated sensitivity to PARP inhibitors. Notably, sensitivity of PARP inhibition in PTEN loss of function is independent of microsatellite instability (MSI) 3. Methods: This is a multi-center phase II, placebo controlled, double-blinded study of the use of rucaparib as maintenance therapy in patients with metastatic or recurrent endometrial cancer. A maximum of 138 patients will be randomized 1:1 to receive rucaparib at starting dose of 600mg BID dosing vs. placebo. Standard dose reductions of known toxicities will be followed based on FDA approved indications of rucaparib. Patients will remain on therapy until progression of disease or toxicity induced discontinuation. Eligible patients will have Stage III/IV or recurrent endometrial cancer and must have received one or two prior lines of chemotherapy. All histologic subtypes, including carcinosarcoma will be included. Treatment arms will be stratified on histology, number of lines of prior therapy, and complete vs partial response to prior line of therapy. The primary endpoint is progression free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), and toxicity. To date, 79 patients have been enrolled. 1. Mutter GL, Lin MC, Fitzgerald JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92(11):924-930. 2. Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128(1):157-170. 3. Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75. Clinical trial information: NCT03617679 .

TROPiCS-03: A phase 2 basket study of sacituzumab govitecan (SG) in patients (pts) with metastatic solid tumors—Early analysis in pts with advanced/metastatic endometrial cancer (EC).

5610 Background: Pts with advanced/metastatic EC who progressed on or after platinum (PT)-based and anti–PD-(L)1 therapies have a poor prognosis with limited treatment options. SG is a Trop-2–directed antibody-drug conjugate. In the open-label, phase 1/2 IMMU-132-01 basket study, SG monotherapy resulted in a 22% objective response rate (ORR) with a manageable safety profile in 18 pts with metastatic EC who had relapsed after or were refractory to ≥1 prior standard therapeutic regimen (Bardia et al. Ann Oncol. 2021). Here, we report early data in pts with advanced/ metastatic disease from the EC cohort of the TROPiCS-03 Ph2 study. Methods: TROPiCS-03 (NCT03964727) is a multicohort, open-label, Ph 2 basket study in pts with metastatic solid tumors. Adult pts in the EC cohort progressed after prior PT-based chemotherapy and anti–PD-(L)1 directed therapy [requirement for PD-(L)1 progression added in amendment], had ECOG PS 0-1 and creatinine clearance ≥30 mL/min. Pts received 10 mg/kg of SG on D1 and D8 of a 21-D cycle. The primary endpoint was ORR by investigator’s assessment per RECIST 1.1. Secondary endpoints included duration of response (DOR), clinical benefit rate (CBR), and progression-free survival (PFS) per investigator’s assessment, overall survival, and safety. The safety population included pts who received ≥1 dose of SG; the efficacy population included pts receiving ≥1 dose of SG and had ≥13 weeks of follow-up. Results: As of data extraction on October 11, 2022, 28 pts received ≥1 dose of SG. Median study follow-up was 5.3 mo (range, 0.4-13.1); median age 69 y (range, 44-83), 57% ECOG PS 1,14% microsatellite instability high. Pts received a median of 3 prior therapies (range, 1-6); 100% received prior PT-based chemotherapy, 61% prior immunotherapy, 54% prior targeted agents, and 11% prior hormonal therapy. In 20 pts with ≥13 weeks of follow-up, ORR was 25% (95% CI, 8.7-49.1). Regarding best overall response, all responses were partial response (PR). In addition, stable disease (SD) was 40% and progressive disease was 15%; CBR (confirmed complete response + PR + SD ≥ 6 mo) was 35% (95% CI, 15.4-59.2). Median PFS was 5.6 mo (95% CI, 2.3 mo-not reached [NR]) and median DOR was NR (95% CI, 2.76 mo-NR; n = 5). Treatment was ongoing for 50% of pts. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 64% of pts; most common grade ≥3 TRAEs were neutropenia (25%), febrile neutropenia (14%), and diarrhea (14%). Discontinuation rate due to TRAEs was 7%. While on treatment, two deaths occurred due to causes unrelated to SG. Conclusions: Preliminary findings showed encouraging efficacy of SG with a manageable toxicity profile in a pretreated population with advanced/metastatic EC. Safety signals were consistent with the known SG safety profile. This early analysis will be updated with the full dataset. Clinical trial information: NCT03964727 .

Targeted Treatment of Advanced Endometrial Cancer: Focus on Pembrolizumab.

Endometrial cancer (EC) accounts for 2% of all new cancers. Advanced forms have a poor prognosis with barely 17% 5-year survival. The last few years improved our knowledge of EC with a new molecular classification derived from The Cancer Genome Atlas (TCGA). They are now divided between POLE mutant, Microsatellite Instability High (MSI-H) or deficient in Mismatch Repair System (dMMR), TP53 mutant and no specific molecular profile. Until now, treatments for advanced EC have included conventional platinum-based chemotherapy or hormonotherapy. The revolution in oncology represented by the advent of immune checkpoints inhibitors (ICI) has also led to a major advance in the management of recurrent and metastatic EC. Pembrolizumab, a well-known anti PD-1, has firstly been approved as monotherapy in the second-line setting for dMMR/MSI-H advanced EC. More recently, a combination of lenvatinib with pembrolizumab offered a new effective option in the second line setting irrespectively of the MMR status, giving a new opportunity for these patients who had no actual standard of care before. This combination is currently being evaluated as frontline therapy. Despite exciting results, the main problem in identifying solid biomarkers remains unresolved and further investigations are required. New original combinations of pembrolizumab with other drugs including chemotherapy, poly ADPribose polymerase inhibitors (PARP-i) or tyrosine kinase inhibitors are being tested and promise exciting new therapeutic evolutions in a close future.