Therapy For Endometrial Cancer Research Articles

Molecular subtype stratified response to adjuvant therapy in endometrial cancer (086)

Objectives: Molecular classification of endometrial cancer (EC) has been shown to have a strong prognostic value. Recent data support the predictive implications of molecular subtype assignment. Using combined EC cohorts that have undergone molecular classification, our objective was to assess the response to adjuvant therapy based on ESMO 2016 risk group criteria within the four molecular subtypes (MMRd, POLEmut, NSMP, and p53abn). Methods: Historical institutional (29%) and population-based cohorts of EC from 2016 (53%) and prior to 2016 (18%) that had undergone molecular classification were identified. We assessed outcomes (overall, disease-specific, or progression-free survival [OS, DSS, PFS]) based on the adjuvant treatment given, including none, vault brachytherapy (VB) only, external beam radiation (EBRT) ± VB, or chemotherapy (± any RT including EBRT or VB) across ESMO risk groups (low, intermediate, high-intermediate, high and advanced/metastatic) within the four molecular subtypes. Conclusions: Although retrospective data regarding where the treatment was given was not confined to clinical trial parameters and need to be interpreted with caution, these results are consistent with the PORTEC3 trial subgroup analysis showing chemotherapy does not appear to add benefit within MMRd EC but may improve outcomes for patients with p53abn EC. These findings support molecular subtype-directed trials, such as radiation alone ± investigational agent for MMRd, chemotherapy ± investigational agent for p53abn, and de-escalation of adjuvant therapy for POLEmut EC. Objectives: Molecular classification of endometrial cancer (EC) has been shown to have a strong prognostic value. Recent data support the predictive implications of molecular subtype assignment. Using combined EC cohorts that have undergone molecular classification, our objective was to assess the response to adjuvant therapy based on ESMO 2016 risk group criteria within the four molecular subtypes (MMRd, POLEmut, NSMP, and p53abn). Methods: Historical institutional (29%) and population-based cohorts of EC from 2016 (53%) and prior to 2016 (18%) that had undergone molecular classification were identified. We assessed outcomes (overall, disease-specific, or progression-free survival [OS, DSS, PFS]) based on the adjuvant treatment given, including none, vault brachytherapy (VB) only, external beam radiation (EBRT) ± VB, or chemotherapy (± any RT including EBRT or VB) across ESMO risk groups (low, intermediate, high-intermediate, high and advanced/metastatic) within the four molecular subtypes. Conclusions: Although retrospective data regarding where the treatment was given was not confined to clinical trial parameters and need to be interpreted with caution, these results are consistent with the PORTEC3 trial subgroup analysis showing chemotherapy does not appear to add benefit within MMRd EC but may improve outcomes for patients with p53abn EC. These findings support molecular subtype-directed trials, such as radiation alone ± investigational agent for MMRd, chemotherapy ± investigational agent for p53abn, and de-escalation of adjuvant therapy for POLEmut EC.

Molecular analysis of endometrioid and non-endometrioid uterine cancer and response to treatment (246)

<b>Objectives:</b> Carboplatin and Paclitaxel are the recommended first-line regimens for uterine cancer patients requiring systemic treatment. In light of promising new alternative systemic therapies, we aimed to identify biomarkers that may predict response to carboplatin. <b>Methods:</b> Uterine cancer tumor samples were analyzed using next-generation sequencing (NGS: NextSeq, 592 Genes) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). Real-world overall survival (OS) was obtained from insurance claims data, and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts from the first treatment of carboplatin to the last day of contact. The median survival of carboplatin-associated survival (CAS) was determined after the first carboplatin treatment. Two cohorts were created and compared: <i>1)</i> OS after carboplatin-based treatment that was less than the median CAS of the whole cohort (Non-Responders, "NR"); and <i>2)</i> OS after carboplatin-based treatment that was longer than the median CAS (Responders, "R"). NGS and IHC results of the tumor samples of these cohorts were compared. Statistical significance was calculated using Mann-Whitney U and Chi-square test and adjusted for multiple comparisons (adjusted p-value = q-value). <b>Results:</b> Total 2436 uterine cancer patients who received carboplatin treatment with molecular data were included in this analysis: 578 (23.7%) were of endometrioid histology, and 1051 (43.1%) serous, carcinosarcoma, or clear cell histology. Irrespective of histology, 20 genes were significantly altered (q<0.05) between R and NR, including genes related to the pathways involved in Base/Nucleotide Excision Repair, Cell Cycle Control, Chromatin Remodeling, RTK RAS, HR, PI3K, VEGF, and WNT signaling (Table 1). Of note, <i>KMT2C,</i> a histone methyltransferase, was more frequently mutated in Rs compared to NRs (8.44% vs 3.73% mutated, p=0.01). But <i>HOOK3</i> and <i>NSD3</i> were more frequently amplified in NRs compared to Rs (1.19% vs 0.12%, q=0.047; 2.14% vs 0.73%, q=0.11). <i>NSD3,</i> a gene involved in the regulation of tumorigenesis, was amplified in 1.07% of patients and was associated with a median difference in survival of 661 fewer days (HR: 2.75, 95% CI: 1.70-4.45, p<0.00001). Among endometrioid and serous uterine histology, ER positivity was seen significantly more frequently in Rs compared to NRs (83% vs 66.2%, q=0.03; 60.1% vs 45.8%, q=0.03). However, <i>CCNE1</i> amplification was less frequent in Rs compared to NRs (4.80% vs 16.4%, q=0.01). There were no molecular differences seen between Rs and NRs in carcinosarcoma and clear cell histologies treated with carboplatin. <b>Conclusions:</b> There are significant differences in the molecular profiles of endometrial cancers that have longer median CAS compared to those with shorter median CAS. Further investigation into biomarkers that may predict response to carboplatin-based therapy in endometrial cancer is needed.

Is hospitalization within 6 months of completion of radiation therapy for endometrial cancer associated with decreased survival? (584)

<b>Objectives:</b> Radiation therapy (RT) is a core component in the management of women with locally advanced endometrial cancer (EC). For patients with early-stage (I and II), intermediate-risk disease, adjuvant RT is considered the standard of care. We hypothesized that hospitalization within six months of the completion of RT was associated with decreased overall survival (OS) and progression-free survival (PFS). We tried to identify factors predictive of a patients' likelihood of hospitalization within a short term of RT completion. <b>Methods:</b> An IRB-approved, retrospective cohort study included all patients who were diagnosed with EC and treated with radiation at our institution from January 2019 through December 2020. Data collected included functional status, disease stage, treatment course, hospitalizations, and demographics. Performance status was monitored via the Kamofsky Performance Scale. Common terminology criteria for adverse event (CTCAE) constipation and fatigue grades were gathered to provide insight into a patient's tolerance of RT. Statistical analysis was performed via Fisher's exact test. The Kaplan-Meier product estimator was utilized to derive survival curves, which were then compared via log-rank test. A critical value of p <0.05 was set for statistical significance. <b>Results:</b> Of 287 eligible patients, 27 (9.4%) were hospitalized within six months of RT. Of those patients, 13 of 27 (48%) were hospitalized within 30 days of completion of RT, and an additional five patients were hospitalized within 45 days of completion of radiation. The median length of hospitalization was six days, with hospital stays ranging from one to 20 days. Of patients who were hospitalized, 15 received EBRT alone, ten received vaginal brachytherapy alone, and two received a combination of EBRT + brachytherapy. The most common indications for hospitalization included disease progression, vaginal bleeding, altered mental status, failure to thrive, infection, and cardiovascular events. Most patients (21/27) did not undergo procedural intervention during their hospitalization, although two patients were admitted to the intensive care unit, and ultimately five of 27 patients expired during the hospitalization. Of the patients who expired, 40% of deaths were disease-related, while 60% were from other causes. Of the six patients who underwent procedural intervention during their admission, interventions included palliative RT, uterine artery embolization, biopsy, pleural catheter placement, and scheduled procedures unrelated to their disease process, inclusive of cholecystectomy and colonoscopy. Hospitalization within six months was associated with both decreased OS (p < 0.0001) and decreased PFS (p <0.0001). There was no significant variation in performance status, as indicated by Kamofsky's performance score, between patients who were and were not hospitalized within six months of completion of RT. BMI, age, constipation, and fatigue were not statistically significant predictors of a patients' likelihood of short interval hospitalization. <b>Conclusions:</b> Women with EC who received RT as part of their treatment and were hospitalized within six months had a statistically significant decreased OS and PFS. Age, BMI, race, and performance status were not found to be predictive of a patient's risk of short interval hospitalization.

Comparison of rates of vaginal brachytherapy vs. external beam radiation post-hysterectomy for endometrial cancer patients in rural vs. urban settings (459)

<b>Objectives:</b> The GOG-99 trial published in 2004 demonstrated that patients with high-intermediate risk endometrial cancer benefit from adjuvant external beam radiation therapy (EBRT) post-hysterectomy to decrease the risk of recurrence. The PORTEC-2 trial was then published in 2010, which was an open-label, non-inferiority randomized control trial that compared vaginal brachytherapy (VBT) to EBRT for patients with high-intermediate risk endometrial cancer. This trial demonstrated non-inferiority of VBT compared to EBRT with no significant difference in vaginal or locoregional recurrence, overall survival, and disease-free survival. However, it did show a significant decrease in grade 1-2 gastrointestinal toxicities in the VBT group. VBT is now the standard of care given its decreased toxicity but is also notably less time-consuming for patients. Our objective was to identify if there was a difference in the administration of VBT versus EBRT for endometrial cancer patients post-hysterectomy in rural versus urban locations. <b>Methods:</b> This is a retrospective cohort study based on the SEER 18 dataset of the US National Cancer Institute. Women with localized endometrial cancer post-hysterectomy were included in this study. The SEER dataset defines a localized tumor as a tumor confined to the organ of origin without extending beyond the primary organ. Data were collected from 2011 to 2018, given that PORTEC-2 was published in 2010. Urban versus rural population was defined by the rural-urban continuum codes. Women were excluded if they received both VBT and EBRT or if a rural-urban continuum code was not provided. Statistical analysis was completed with relative risk and confidence interval calculation. <b>Results:</b> In total, 10,840 women were included. There were 9813 women identified in metropolitan counties; 22% (<i>n</i>=2136) received EBRT post-hysterectomy for localized endometrial cancer, whereas 78% underwent VBT. There were 1027 women identified in nonmetropolitan counties, 22% (<i>n</i>=230) received EBRT and 78% (<i>n</i>=797) received VBT. When comparing metropolitan versus nonmetropolitan counties, there was no statistical difference between rates of EBRT versus VBT, with a relative risk of 1.16 (95% CI: 0.91-1.16, p=0.64). There were 125 women identified in completely rural counties, 21% (<i>n</i>=26) received EBRT and 79% (<i>n</i>=99) received VBT. There was no statistical difference in rates of radiation therapy between completely rural and metropolitan counties, with a relative risk of 0.95 (95% CI: 0.67-1.34, p=0.77). <b>Conclusions:</b> Living in a nonmetropolitan county or even a completely rural county was not associated with a difference in receiving EBRT versus VBT in patients with localized endometrial cancer status post-hysterectomy compared to rates in metropolitan counties. It could be inferred that even though rural counties may have fewer medical resources, patients are still receiving the standard of care in regard to radiation therapy for endometrial cancer.

Clinical Outcomes of Patients with Recurrent Microsatellite-Stable Endometrial Cancer in Early-Phase Immunotherapy Clinical Trials.

Simple SummaryThere is a crucial need to improve treatment regimens in patients with recurrent endometrial cancer. Although immunotherapy treatments have shown impressive benefit in microsatellite instability-high endometrial cancer, they have been less predictable in the majority of endometrial cancers, which are microsatellite stable. Our aim was to characterize clinical outcomes in patients with recurrent microsatellite stable endometrial cancer treated in early-phase immunotherapy clinical trials in order unravel treatment regimens that would improve response and survival. Our findings suggest that utilizing immunotherapy in combination with other non-immunotherapy agents resulted in greater duration of disease control and improved survival outcomes compared to immunotherapy only (monotherapy) or in combination with other immunotherapy agents. Future studies are needed to validate these findings.Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO plus non-IO therapy, one had a partial response but 50% had clinical benefit. Patients who received combination IO plus non-IO therapy had improved PFS compared to those who received monotherapy (HR 0.56, 95% CI 0.33–0.97; p = 0.037) or combination IO-only therapy (HR 0.36, 95% CI 0.15–0.90; p = 0.028) and had improved OS when compared to monotherapy after adjusting for prior lines of therapy (HR 0.50, 95% CI 0.27–0.95; p = 0.036). The potential beneficial clinical outcomes of combination IO plus non-IO therapy in MSS endometrial cancer should be validated in a larger study.

An Exceptional Response to Dostarlimab in Mismatch Repair Deficient, Microsatellite Instability-High and Platinum Refractory Endometrial Cancer

Until recently, effective therapies for advanced endometrial cancer progressing to a platinum-based combination were lacking. In this setting, immunotherapy with anti PD-1/PDL-1 monoclonal antibodies is rising as a new paradigm in particular for patients with microsatellites instability/mismatch repair deficiency. In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency.

Novel Endometrial Cancer Models Using Sensitive Metastasis Tracing for CXCR4-Targeted Therapy in Advanced Disease.

Advanced endometrial cancer (EC) lacks therapy, thus, there is a need for novel treatment targets. CXCR4 overexpression is associated with a poor prognosis in several cancers, whereas its inhibition prevents metastases. We assessed CXCR4 expression in EC in women by using IHC. Orthotopic models were generated with transendometrial implantation of CXCR4-transduced EC cells. After in vitro evaluation of the CXCR4-targeted T22-GFP-H6 nanocarrier, subcutaneous EC models were used to study its uptake in tumor and normal organs. Of the women, 91% overexpressed CXCR4, making them candidates for CXCR4-targeted therapies. Thus, we developed CXCR4+ EC mouse models to improve metastagenesis compared to current models and to use them to develop novel CXCR4-targeted therapies for unresponsive EC. It showed enhanced dissemination, especially in the lungs and liver, and displayed 100% metastasis penetrance at all clinically relevant sites with anti-hVimentin IHC, improving detection sensitivity. Regarding the CXCR4-targeted nanocarrier, 60% accumulated in the SC tumor; therefore, selectively targeting CXCR4+ cancer cells, without toxicity in non-tumor organs. Our CXCR4+ EC models will allow testing of novel CXCR4-targeted drugs and development of nanomedicines derived from T22-GFP-H6 to deliver drugs to CXCR4+ cells in advanced EC. This novel approach provides a therapeutic option for women with metastatic, high risk or recurrent EC that have a dismal prognosis and lack effective therapies.

Abstract 1962: The relevance of estrogen driven tumor growth within the molecular subgroups of endometrial cancer

Abstract Introduction: Immunohistochemical expression (IHC) of estrogen receptor (ER) and progesterone receptor (PR) are biomarkers for prognosis and response to hormonal therapy in endometrial cancer (EC). However, the presence of ER/PR is not inherently reflective of estrogen driven tumor growth. Previously, ER pathway activity score (ERPAS), a test to asses ER pathway, was shown to reflect estrogen driven tumor growth and to have additional prognostic and predictive value over ER and PR-IHC. Within the four molecular subgroups of EC, ER and PR-IHC are present in all subgroups. Yet, the relation of ERPAS with molecular subgroups is unclear. In this study we aim to identify estrogen driven tumor growth by application of ERPAS in the molecular subgroups. Methods: ER and PR-IHC expression, ERPAS testing and molecular analysis was available in 72 endometrial cancer cases. ER and PR-IHC expression was analyzed from formalin-fixed paraffin-embedded (FFPE) tumor sections using standard procedures. A cut-off value of 10% was defined as positive. ERPAS was performed using RT-qPCR analysis of the most relevant ER-related genes (www.philips.com/oncosignal). A Bayesian computational model was used to infer ERPAS that were normalized on a scale from 0 to 100. The cut-off value for an active ER pathway was 29.7, as previously defined. Molecular analysis was performed using Next Generation Sequencing with single-molecule Molecular Inversion Probes (smMIPs). Accordingly patients were grouped in the POLE-mutant, MSI high, TP53-mutant or no specific molecular profile, NSMP group. Results: The TP53-mutant-group had a worse outcome compared to other groups. ER pathway was active in 75% of POLE-mutant, 83.3% of MSI-high, 87.5% of NSMP and 38.9% of TP53-mutant cases. Similarly, PR-IHC expression was present in 100% of POLE-mutant, 72.2% of MSI-high, 81.3% of NSMP and 27.8% of TP53-mutant cases. The mean ERPAS was significantly higher in MSI-high and NSMP groups compared to the TP53-mutant group. Within the NSMP subgroup, an active ER pathway was significantly associated with improved disease-free survival and disease-specific survival in Kaplan-Meier analysis. Analysis in other subgroups was not possible due to limited number of cases. Conclusions: The majority of POLE-mutant, MSI-high and NSMP tumors showed an active ER pathway, indicating relevance of estrogen driven tumor growth in these groups. In the NSMP subgroup, ERPAS can be used to stratify patients for prognosis. Whether ER pathway is prognostic in the MSI-high and TP53-mutant subgroups needs to be evaluated in larger cohorts. If hormonal therapy is applied, we suggest to tailor it to patient with an active ER pathway. Citation Format: Willem Jan van Weelden, Stephanie Vrede, Louis van der Putten, Hans Bulten, Marc Snijders, Sanne Sweegers, Andrea Romano, Astrid Eijkelenboom, Anja van de Stolpe, Johanna Pijnenborg. The relevance of estrogen driven tumor growth within the molecular subgroups of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1962.

Abstract 3065: Establishment and characterization of a platform of endometrial cancer organoids

Abstract Background: Endometrial cancer is the most commonly diagnosed gynecologic cancer in the US; the incidence is rising, and survival rates for this cancer are decreasing. There is a paucity of effective treatment for recurrent endometrial cancer, especially high grade endometrial cancers (HGEC) which include serous, carcinosarcoma, endometrioid, and clear cell histologies. Models that mimic the clinical and molecular characteristics of HGEC are lacking. To support the development of next generation therapeutics for endometrial cancer, we report on the establishment of 3D endometrial patient-derived organoids (PDOs) from HGEC. Methods: 26 Tumors from 21 different patients with HGEC (Serous, Carcinosarcoma, Clear Cell and High-grade Endometrioid subtypes) who underwent surgical resection (n= 13), biopsy (n = 7), paracentesis (n = 3) or thoracentesis (n = 3) were passaged as 3D organoid cultures in Matrigel in an optimized media. Robust models (defined by average days to passage &amp;lt;14 days) were viably banked. 3 frozen models were also thawed and re-cultured to assess the viability post freezing. PDOs were collected for H&amp;E staining and their histology was compared to the original diagnosis. DNA replication rate and the effect of replication stress on organoid growth were assessed by the DNA Fiber Assay and immunofluorescence (IF). Finally, an established clear cell endometrial cancer organoid model was engrafted in mice to generate a Patient-Derived Xenograft (PDX) model. Results: Endometrial PDOs were successfully developed from 19 of 26 original samples for an overall success rate of 73.1%. Successful PDOs were developed from multiple histologies, including 8 carcinosarcoma, 6 uterine serous, 2 endometrioid, 2 clear cell and 1 mixed uterine serous and endometrioid. Though biopsy samples had initially fewer viable cells, our overall success rate was similar at 85.7% compared to 84.6% for surgical resections and higher than 66.7% for paracenteses. Samples obtained via thoracentesis did not form PDOs. Endometrial PDOs were histologically validated to match the primary patient tumor. Freeze thawing had no effect on morphology and growth characteristics. DNA fiber assays could be successfully conducted in PDOs, with a reduction in replication rate observed in PDO models treated with ATR or WEE1 inhibitors, with concurrent increase in y-H2AX and decrease in pRPA2 observed by IF. We also successfully generated a validated PDX model from organoids. Studies to determine molecular fidelity between the original patient tumor and established organoids are ongoing. Conclusions: We describe the successful establishment of 19 endometrial PDO models which retain original tumor morphology and demonstrate sensitivity to drug-induced DNA damage. 3D endometrial organoids can therefore be used for further target discovery and validation as well as biomarker studies to advance targeted therapies for high-grade endometrial cancer. Citation Format: Aisha L. Saldanha, Ha V. Vo, Kevin Vasquez, Kenneth Ngo, Shrabasti Roychoudhury, Carina Feeney, Courtney H. Qi, Swati Narayan, Jennifer D. Curtis, Prafulla C. Gokhale, Dipanjan Chowdhury, Cloud P. Paweletz, Marisa R. Nucci, Ursula A. Matulonis, Elena Ivanova, Joyce F. Liu. Establishment and characterization of a platform of endometrial cancer organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3065.

Errate: Efficacy and Toxicity of Adjuvant Therapies for High-Risk Endometrial Cancer in Stage I-III: A Systematic Review and Network Meta-Analysis.

Source of support: This study was supported by grants from the Key Research and Development projects of Sichuan Province (No.2020YFS0129) and the Natural Science Foundation of China (No.61875249). Reference: Mengyin Ao, Ting Ding, Dan Tang, Mingrong Xi: Efficacy and Toxicity of Adjuvant Therapies for High-Risk Endometrial Cancer in Stage I-III: A Systematic Review and Network Meta-Analysis. Med Sci Monit, 2020; 26: e925595. DOI: 10.12659/MSM.925595.

Clinicopathologic and molecular features associated with response to anti-HER2 therapy in endometrial cancer.

5584 Background: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States. Human epidermal growth factor 2 (HER2) overexpression or gene amplification occurs in 10-60% of EC. The addition of trastuzumab to carboplatin-paclitaxel chemotherapy improves survival in women with HER2-positive serous EC. However, criteria for assessment of HER2 status in EC are not standardized, and furthermore, intratumor heterogeneity may impact therapeutic efficacy. We aimed to identify factors associated with treatment response and survival outcomes in a retrospective cohort of ECs treated with anti-HER2 therapy. Methods: Patients with advanced/recurrent EC treated with trastuzumab or trastuzumab emtansine alone or in combination with chemotherapy from 2013-2021 at our institution were identified. Clinical and treatment information were retrieved from medical records. Central pathology review, HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) were performed. HER2 IHC was scored using modified ASCO/CAP 2007 guidelines for breast cancer. HER2 expression heterogeneity was defined as a 2-degree difference in staining intensity in ≥5% of tumor cells or discordant IHC score on different specimens. HER2 amplification (tumor/normal fold change) was also estimated from targeted next-generation sequencing (NGS). Best response was assessed by RECIST v1.1 as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), with clinical benefit defined as CR/PR/SD. Results: Among 39 patients included, median age was 69. Histologic subtypes included serous (n = 18, 46%), carcinosarcoma (n = 7, 18%), high-grade EC with ambiguous features (n = 13, 33%) and low-grade endometrioid carcinoma (n = 1, 3%). HER2 IHC results were 0 or 1+ (n = 2, 5%), 2+ (n = 17, 46%), 3+ (n = 18, 49%), with HER2 heterogeneity in 15 cases. By FISH, the HER2/CEP17 ratio was ≥2.0 in 34 (92%) and &lt; 2.0 in 3 (8%); HER2 copy number (CN) was ≥6.0 in 25 (68%) and &lt; 6.0 in 12 (32%). HER2 copy number ≥6.0 was significantly correlated with HER2 amplification by NGS ( p&lt; 0.001). 18 (49%) patients had a co-existing somatic PIK3CA mutation. Amongst parameters assessed, only higher level of HER2 amplification by NGS was significantly associated with clinical benefit ( p= 0.036). None of these features were associated with progression-free survival. Notably, 2 patients with IHC 0/1+ had PD and 1 patient with IHC 3+, but non-amplified by FISH, achieved PR. Conclusions: In our cohort of EC patients treated with anti-HER2 therapy, higher level of HER2 amplification was associated with clinical benefit. Further studies with larger sample sizes are needed to determine whether any additional characteristics are associated with treatment response and survival.

An open label, nonrandomized, multisite phase II trial combining bevacizumab, atezolizumab, and rucaparib for the treatment of previously treated recurrent and progressive endometrial cancer.

5510 Background: Patients with metastatic recurrent endometrial cancer have limited effective therapies. Single agent pembrolizumab is utilized in mismatch repair deficient (MMRd) patients, while the combination of lenvatinib and pembrolizumab is now more commonly used in MMR intact patients who have progressed after chemotherapy combinations. This trial investigated a novel three drug regimen. Methods: Patients with recurrent endometrial cancer not amenable to curative intent surgery or radiation after one or two lines of therapy were eligible regardless of histology. This study is a multicenter, open-label, nonrandomized phase II trial. All subjects initially received the three-drug combination of rucaparib, bevacizumab, and atezolizumab. The primary goal of this trial was to estimate the overall response rate in these patients, and secondarily to estimate the progression-free and overall survival of patients treated with this triplet combination. Total enrollment was 30, with the first six subjects participated in a safety lead-in. Treatments until progression, toxicity, or clinician choice. Subjects could continue past progression if, in the estimate of the treating clinician and subject, clinical benefit was being provided. Subjects were eligible for analysis if they received at least one cycle and had one post-dose tumor assessment. The ORR assumption was 27% with a lower bound of 14%. Results: 30 subjects were enrolled between 07/2019 and 06/2021. Of these 26 were evaluable. Median follow up at cut off was 14.9 months. 23 subjects had clinical benefit, with 1 (4%) with CR, 9 (39%) with PR, and 13 (57%) with stable disease as best response. Overall median event-free (progression or death) was 5.3 (95% CI 2.7-7.9) months and overall survival 13.3 (95% CI NA) months at cut off. Median duration of therapy was 4.4 months (IQR 1.7-7.3), with 4 subjects remaining on study directed therapy at data cut off. Histology distribution was 50% serous, 20% endometrioid, and 13% carcinosarcoma. 19 pts were White, 8 African American, 2 identified as Asian, 1 unknown. In the MMR deficient patients, event-free probability was 11.9 months. Grade 3 or 4 treatment related adverse events occurred in 50% patients. Conclusions: To our knowledge, this trial represents the first use of a non-chemotherapy-based triplet therapy for recurrent endometrial cancer. The combination of rucaparib, bevacizumab, and atezolizumab may safely be used to treat recurrent/persistent endometrial cancer. This combination demonstrates clinically meaningful improvement in response, with acceptable toxicity. Enhanced response to therapy was seen in MMR deficient subjects. Clinical trial information: NCT03694262.

Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least first-line therapy: Interim results of a single-arm phase II trial.

5591 Background: For advanced or recurrent endometrial cancer (EC), therapeutic options remain scarce. Immune or antiangiogenic monotherapy has shown moderate efficacy in EC. Preclinical and clinical data showed that camrelizumab (an anti-PD-1 antibody) plus apatinib (a selective VEGFR2 inhibitor) markedly enhanced anti-tumor efficacy in multiple solid tumors. This study was designed to assess the efficacy and safety of the combination of camrelizumab and apatinib as second-line or above therapy for advanced or recurrent EC. Methods: This was an open-label, single-arm, phase II trial conducted in China. Patients with advanced or recurrent EC who progressed after at least first-line therapy received camrelizumab (200 mg, intravenously, q2w) plus apatinib (250 mg, orally, qd). Using a minimax Simon two-stage design, 21 patients were enrolled at stage I and if a complete or partial response was observed in at least four patients, the enrollment would be continued to 40 patients. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. Secondary endpoints included time to objective response (TTR), disease control rate (DCR), duration of Response (DoR), progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF) and safety. Here, the results of stage I are reported. Results: Between January 20, 2020 and July 8, 2021, 21 patients were enrolled. The median age was 57 years (range 29–72). Thirteen patients (61.9%) had ECOG PS of 0, and eight patients (38.1%) received at least two prior therapies. As of November 9, 2021, the median follow-up time was 13.5 months (IQR 11.3-16.3). Among 21 evaluable patients, the confirmed ORR was 47.6% (95% CI 25.7%-70.2%) with complete response in one patient (4.8%) and partial response in nine patients (42.9%); eight patients had stable disease for a DCR of 85.7% (95% CI 63.7%-97.0%). The median PFS was 11.8 months (95% CI 5.2-14.4). Treatment-related adverse events (TRAEs) of any grade and of grade ≥ 3 were reported in 21 (100%) patients and 10 (47.6%) patients, respectively. The most common grade ≥ 3 TRAEs included gamma-glutamyltransferase increased (six [28.6%]), direct bilirubin increased (four [19.0%]), alanine aminotransferase increased (three [14.3%]), aspartate aminotransferase increased (three [14.3%]) and hyperglycaemia (three [14.3%]). Four patients (19.0%) experienced reactive cutaneous capillary endothelial proliferation, all of which were grade 1-2. No treatment-related deaths were reported. Conclusions: Camrelizumab plus apatinib demonstrated promising antitumor activity and a manageable safety profile in patients with advanced or recurrent EC after failure of at least first-line therapy. Clinical trial information: ChiCTR2000031932.

Heteroleptic Gold(I)-bisNHC complex with excellent activity in vitro, ex vivo and in vivo against endometrial cancer

Endometrial cancer (EC), one of the most common gynaecologic malignancies, can seriously impair female health. Although great advances in EC therapy have been achieved, specific and effective drugs for the disease are still limited. Here, different types of gold(I)–NHC compounds originated from 4,5-bis (4-methoxyphenyl) imidazole were designed and synthesised to target EC. Interestingly, the heteroleptic gold(I)-bisNHC complex 10 was 10 times more toxic than cisplatin or auranofin towards Ishikawa cells. Ex vivo studies found that complex 10 was characterised with a stronger anticancer effect than auranofin in the EC organoid model. Additionally, in vivo studies showed that complex 10 possessed a stronger anticancer effect (IRT = 44.86%) than auranofin (IRT = 19.93%) in the xenograft model of EC. Mechanistically, complex 10 could suppress the expression of thioredoxin reductase (TrxR) and nuclear factor E2-related factor 2 (Nrf2) in vitro and in vivo, which are essentially involved in EC development. Collectively, our findings demonstrated that complex 10 is a gold-based complex with a strong anti-EC activity and has the potential to be regarded as a promising option for the treatment of EC.

Roles of Pyroptosis-Related Gene Signature in Prediction of Endometrial Cancer Outcomes

Endometrial cancer (EC) is one of the most common gynecological malignancies in women, accompanied by the increasing incidence and decreasing age of onset. Pyroptosis plays an important role in the occurrence and development of malignant tumors. However, the relationship between pyroptosis-related genes and tumor prognosis remains unclear. In this study, analyzing the expression levels and survival data of 33 pyroptosis-related genes in the Cancer Genome Atlas (TCGA) between normal samples and tumor samples, we obtained six pyroptosis-related prognostic differentially expressed genes (DEGs). Then, through the least absolute shrinkage and selection operator (LASSO) regression analysis, a gene signature composed of six genes (GPX4, GSDMD, GSDME, IL6, NOD2 and PYCARD) was constructed and divided patients into high- and low-risk groups. Subsequently, Kaplan-Meier (KM) plot, receiver operating characteristic (ROC) curve and principal component analysis (PCA) in two cohorts demonstrated that the gene signature was an efficient independent prognostic indicator. The enrichment analysis and immune infiltration analysis indicated that the high-risk group generally has lower immune infiltrating cells and less active immune function. In short, we constructed and validated a pyroptosis-related gene signature to predict the prognosis of EC, which is correlated to immune infiltration and proposed to help the precise diagnosis and therapy of EC.

Obesity and breast cancer: Preventive and therapeutic possibilities for bariatric surgery.

Breast cancer is the most common and second deadliest malignancy in women. With rising obesity rates and building evidence for a strong association with obesity, the incidence of breast cancer can be expected to increase. Weight loss reduces breast cancer risk, the mechanisms of which are still poorly understood. As an effective therapy for obesity, bariatric surgery may be a powerful tool in breast cancer prevention and treatment. This review details the potential physiologic mechanisms that may underlie this association, as well as recently published studies that reinforce the link between bariatric surgery and a reduction in incident breast cancer. The use of bariatric surgery as an adjunct therapy in endometrial cancer also raises the potential for similar use in select breast cancer patients. Despite the expanding potential applications of bariatric surgery in this field, publications to date have been strictly observational, highlighting a need for future clinical trials.

Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer

BackgroundStandard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear.MethodsIn this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician’s choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly [with a cycle of 3 weeks on and 1 week off]). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair–proficient (pMMR) disease and in all patients. Safety was also assessed.ResultsA total of 827 patients (697 with pMMR disease and 130 with mismatch repair–deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy.ConclusionsLenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme [a subsidiary of Merck]; Study 309–KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.)

Research Progress of PARP Inhibitor Monotherapy and Combination Therapy for Endometrial Cancer.

Endometrial cancer is one of the three most common malignant tumors in the female reproductive system. Advanced and recurrent endometrial cancers have poor prognoses and lack effective treatments. Poly (ADP-ribose) polymerase (PARP) inhibitors have been applied to many different types of tumors, and they can selectively kill tumor cells that are defective in homologous recombination repair. Endometrial cancer is characterized by mutations in homologous recombination repair genes; accordingly, PARP inhibitors have achieved positive results in off-label treatments of endometrial cancer cases. Clinical trials of PARP inhibitors as monotherapies and within combination therapies for endometrial cancer are ongoing. For this review, we searched PubMed with "endometrial cancer" and "PARP inhibitor" as keywords, and we used "olaparib", "rucaparib", "niraparib" and "talazoparib" as search terms in clinicaltrials.gov for ongoing trials. The literature search ended in October 2020, and only English-language publications were selected. Multiple studies confirm that PARP inhibitors play an important role in killing tumor cells with defects in homologous recombination repair. Its combination with immune checkpoint inhibitors, PI3K/AKT/mTOR pathway inhibitors, cell cycle checkpoint inhibitors, and other drugs can improve the treatment of endometrial cancer.

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Increased risk of secondary bladder cancer after radiation therapy for endometrial cancer

To investigate the effect of radiation therapy (RT) after endometrial cancer (EC) diagnosis on the risk of occurring secondary bladder cancer (SBC) as well as on the survival outcome of those patients who suffered with SBC. Data was extracted from the Surveillance, Epidemiology, and End Results database between 1973 and 2015. Chi-squared test was utilized to compare clinicopathological characteristics among different groups. The Fine and Gray’s competing risk model was utilized to assess cumulative incidence and risk of occurring SBC in EC survivors. The Kaplan–Meier method and the Cox regression model were used for survival analysis. As a result, a total of 108,060 EC patients were included, among which 37,118 (34.3%) patients received RT while others did not. The incidence of SBC was 1.31%, 1.76% and 0.96% among patients who received prior brachytherapy, external-beam radiotherapy (EBRT) and others, respectively. Both of the EBRT (standardized incidence ratio (SIR) = 2.24, 95% CI [1.94–2.58]) and brachytherapy (SIR = 1.76, 95% CI [1.44–2.13]) group had a higher incidence of SBC than the general population in USA. The competing risk analysis demonstrated that receiving EBRT (HR = 1.97, 95% CI [1.64–2.36]) or brachytherapy (HR = 1.46, 95% CI [1.14–1.87]) were all independent risk factors for developing SBC. A survival detriment was only observed in SBC patients who received prior EBRT after EC diagnosis, but not for brachytherapy, when compared with those who did not undergo RT. Additionally, there were no significant survival differences between primary bladder cancer and SBC with or without prior RT history. Patients who underwent RT after EC had an increased risk of developing bladder cancer as secondary primary cancer. The prognosis of these SBC patients varied depending on types of RT that received after EC diagnosis.