Chemotherapy For Endometrial Cancer Research Articles

Cost-effectiveness of atezolizumab plus chemotherapy for advanced/recurrent endometrial cancer.

This study assessed the cost-effectiveness of atezolizumab in combination with chemotherapy for patients with advanced or recurrent endometrial cancer (EC) from the U.S. payer's perspective. A cost-effectiveness study was conducted using a Markov model based on ENGOT-en7/MaNGO/AtTEnd clinical trials. The population consisted of patients with EC, stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups. The model simulated patients receiving either atezolizumab plus chemotherapy or chemotherapy alone. Cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated using a Willingness-to-Pay (WTP) threshold of $150,000/QALY. Sensitivity analyses were performed. Adding atezolizumab to chemotherapy in dMMR EC resulted in an incremental gain of 3.31 QALYs but at an additional cost of $855,042, leading to an ICER of $258,391.07/QALY compared to chemotherapy alone. In pMMR EC, there was a gain of 0.50 QALYs with an additional cost of $140,502, resulting in an ICER of $279,239.72/QALY. The overall ICER for EC was $216,459.34/QALY. Scenario analysis indicated that administering atezolizumab for a maximum of 2 years improved cost-effectiveness in dMMR EC, with an ICER of $70,695.96/QALY falling within the predetermined WTP threshold. For patients with advanced or recurrent EC, the combination of atezolizumab and chemotherapy may not prove cost-effective. However, administering atezolizumab for a limited period of maximum 2 years could improve cost-effectiveness in dMMR EC.

Knockdown of PROM2 Enhances Paclitaxel Sensitivity in Endometrial Cancer Cells by Regulating the AKT/FOXO1 Pathway.

Endometrial cancer is a very common and highly lethal reproductive malignant tumour in women. Paclitaxel (PTX) is a usual drug utilized in chemotherapy for endometrial cancer. It has been uncovered that PROM2 participates in the progression of various cancers through playing a promoter. However, the regulatory function of PROM2 in PTX treatment for endometrial cancer remains unclear. The cell viability (IC50) was examined through CCK8 assay. The mRNA and protein expressions of genes were measured through RT-qPCR and western blot. The proliferation was evaluated through colony formation and EdU assays. The cell apoptosis was assessed through flow cytometry. In this work, through bioinformatic analysis on online websites, it is found that the up-regulated expression of PROM2 existed in endometrial cancer. In addition, the survival probability of UCEC patients with high PROM2 expression was worse. This study adopted PTX treatment for obtaining the PTX-resistant cells (HEC-1A/PTX and KLE/PTX). Furthermore, suppression of PROM2 enhanced PTX sensitivity through decreasing IC50 and proliferation in endometrial cancer. Additionally, knockdown of PROM2 facilitated cell apoptosis in HEC-1A/PTX and KLE/PTX cells. Next, we found that silencing of PROM2 retards the AKT/FOXO1 pathway. At last, rescue assays reversed the strengthened PTX sensitivity mediated by PROM2 inhibition after SC79 treatment (AKT activator). Knockdown of PROM2 enhanced PTX sensitivity in endometrial cancer through modulating the AKT/FOXO1 pathway. This study hinted that PROM2 may be a useful therapeutic target for PTX treatment in endometrial cancer.

The role of adjuvant chemotherapy in endometrial cancer following pre-operative neoadjuvant chemoradiation therapy (1137)

The role of adjuvant chemotherapy in endometrial cancer following pre-operative neoadjuvant chemoradiation therapy (1137)

Retrospective Analysis of the Correlation of MSI-h/dMMR Status and Response to Therapy for Endometrial Cancer: RAME Study, a Multicenter Experience.

There is poor evidence regarding sensitivity to chemotherapy in endometrial cancer (EC) based on microsatellite instability (MSI)/mismatch repair (MMR) status. The RAME study is a retrospective analysis aiming to assess response to chemotherapy in MSI-high (h)/deficient (d) MMR and MSI-low (l)/proficient (p) MMR EC patients. Primary endpoints were recurrence-free survival (RFS) for patients with localized disease and progression-free survival (PFS) and overall survival (OS) in patients with advanced/recurrent disease. A total of 312 patients treated between 2010 and 2022 in four high-volume Multicenter Italian Trial in Ovarian cancer and gynecological malignancies (MITO) centers were selected. In total, 239 patients had endometrioid EC (76.6%), 151 had FIGO stage I at diagnosis (48.9%) and 71 were MSI-h/dMMR (22.8%). Median age was 65 (range 31-91) years. Among patients with localized disease, median RFS was 100.0 months (95% CI 59.4-140.7) for MSI-l/pMMR and 120.9 months (60.0-181.8) for MSI-h/dMMR (p = 0.39). Seventy-seven patients received first-line chemotherapy for advanced/recurrent disease. Patients with MSI-h/dMMR ECs had a significantly worse OS (p = 0.039). In patients receiving platinum-based chemotherapy, no statistically significant differences in PFS (p = 0.21) or OS (p = 0.057) were detected, although PFS and OS were numerically longer in the MSI-l/pMMR population. Patients with metastatic MSI-h/dMMR EC receiving first-line chemotherapy had a significantly worse OS.

Challenges in Treatment and the Importance of Radiotherapy in a Synchronous Endometrial and Breast Cancer

Abstract We report the case of a 69-year-old-female with synchronous endometrial and breast cancer. The imaging and pathology results confirmed the diagnosis. The patient underwent surgery and chemotherapy for endometrial cancer, and surgery followed by external beam radiotherapy for breast cancer. The patient’s clinical condition and imaging showed a favorable evolution after 2 months of follow-up.

The Prognostic Significance of the Depth of Cervical Stromal Invasion in Women with FIGO Stage II Uterine Endometrioid Carcinoma

<h3>Purpose/Objective(s)</h3> To explore the prognostic significance of the depth of cervical stromal invasion (CSI) on survival endpoints in women with FIGO stage II uterine endometrioid adenocarcinoma. <h3>Materials/Methods</h3> A total of 117 patients were included in this retrospective review. Between 1990 and 2021, all patients with FIGO stage II endometrial cancer (EC) underwent hysterectomy and oophorectomy at our institution, with or without lymph node dissection. Patients with synchronous ovarian or breast cancer, as well as those who had undergone adjuvant systemic chemotherapy for EC, were excluded from the study. Pathologic slides were retrieved for these patients and were reviewed by a gynecologic pathologist to determine stromal thickness and the depth of CSI. The depth of CSI was then measured as a percentage of invasion (% CSI) and used in the analysis as a continuous or dichotomous variable (< 50% vs > = 50%). Patients' demographics, pathologic, and treatment characteristics were analyzed using univariate and multivariate analysis to calculate recurrence-free (RFS) and disease-specific (DSS) rates. <h3>Results</h3> The median age for the study cohort was 65 years (range, 34–96), and the median follow-up was 131 months (range, 9–334). A total of 90 patients (77%) had lymph node dissection, with a median of 8 examined lymph nodes (range 0-18). Adjuvant radiation therapy (RT) with pelvic or vaginal cuff HDR brachytherapy, or a combination of the two, was completed in 92 patients (79 percent). The median % CSI was 27% (range, 1-100) with 68% of patients having ≥ 50% CSI. While there was a trend for a worse 5-year RFS and DSS for women with ≥ 50% CSI (69% vs. 83%, p = 0.093) and (78% vs. 91%, p = 0.034), respectively, the depth of CSI was not statistically significant as an independent predictor of 5-year RFS, DSS, or OS. The depth of CSI was not associated with a difference in the recurrence pattern (vaginal cuff, pelvic, paraaortic, or distant). In multivariate analysis, FIGO grade was the only predictor of 5-year OS. FIGO grade and the presence of lympho-vascular space invasion (LVSI) were independent predictors of 5-year RFS and DSS. <h3>Conclusion</h3> Deep cervical stromal invasion does not appear to be an independent predictive factor for survival endpoints in women with stage II uterine endometroid cancer, according to our findings. The presence of LVSI and tumor grade were both independent predictors of recurrence-free and disease-specific survival. Pooled data analysis may be needed to validate our study findings.

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.

Comparison between Pelvic IMRT and 3D-CRT in Combination with Chemotherapy via Nrf2 Expression on the High-Risk Endometrial Cancer.

This study aimed to explore the clinical efficacy of pelvic intensity-modulated radiation therapy (IMRT) and 3-dimensional conformal radiotherapy (3D-CRT) in combination with chemotherapy on high-risk endometrial cancer. The effect of these methods is evaluated via Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression, the levels of chitinase protein 40 (YKL-40), human epididymis protein 4 (HE4), and prolactin (PRL) in serum. For this purpose, between August 2014 and July 2017, 114 endometrial cancer patients admitted to this hospital for treatment were randomized into the observation group (n=60) and control group (n=54). Following the surgery, patients in these two groups received the chemotherapy of taxol and carboplatin (TC). Based on the chemotherapy, patients in the observation underwent the IMRT, while those in the control group adopted the 3D-CRT. The Nrf2 expression was performed based on the Real-time PCR technique. The incidence rate of adverse reactions was a 3-year recurrence rate and mortality rate. Results showed that after treatment, levels of YKL-40, HE4, and PRL in the serum of patients in two groups decreased compared to those before treatment (all P < 0.05). In comparison, the difference between the two groups showed no statistical significance (P > 0.05). The evaluation of Nrf2 transcription factor expression showed significant differences started in comparisons of the Nrf2 Expression between two groups (P > 0.05), and this enhancement was significant in the control group after treatment. Comparison of the incidence rates of the bone marrow suppression during treatment showed no significant difference (P > 0.05). However, the incidence rates of radiation enteritis and radio-cystitis in the observation group were much lower than those in the control group (P < 0.05). During the follow-up, there were five patients in the control group and 7 in the observation group losing to the follow-up, and among the remaining subjects, no significant difference was identified in the comparison of the recurrence rate or mortality rate between the two groups (all P > 0.05). In general, Pelvic IMRT in combination with chemotherapy is a promising and safe candidate for high-risk endometrial cancer with mild radiation injury; besides, YKL-40, HE4, and PRL are the effective indicator for the prediction of efficacy in chemotherapy for endometrial cancer.

Survival for endometrial cancer as a second primary malignancy.

BackgroundEndometrial cancer (EC) often occurs subsequently to a primary cancer arising from a different site. However, little is known regarding the survival experience of EC as a second primary (ECSP) malignancy, specifically in relation to the original primary site and prior treatment.MethodsUsing Florida's cancer registry, all EC cases (first, second, or higher‐order) diagnosed from 2005–2016 were analyzed. Kaplan–Meier methods and Cox Regression were used in a cause‐specific survival analysis.ResultsA total of 2879 clinically independent ECSPs and 42,714 first primary ECs were analyzed. The most common first primary sites for ECSPs were breast cancer (BC) (n = 1422) and colorectal cancer (CRC) (n = 359). Five‐year cause‐specific survival was 84.0% (95% CI: 83.6–84.3) for first primary ECs and 81.8% (95% CI: 80.0–83.4) for ECSPs. After adjusting for age, race/ethnicity, histology, and stage at diagnosis, ECSPs had a lower risk of EC mortality than first primary ECs (hazard ratios [HR] 0.88, 95% CI: 0.79–0.97). ECSPs with a first primary CRC had a higher risk of EC‐specific death (HR 1.47, 95% CI: 1.04–2.06) compared to ECSPs that followed BC in multivariable analysis. Finally, women who had chemotherapy for ECSP and preceding BC did not have a higher risk of death (HR 0.80, 95% CI: 0.49–1.31) compared to those who only received chemotherapy for first primary EC.ConclusionsECSPs present a complex clinical profile. ECSP survival is superior to that of first primary EC. However, ECSPs following CRC may constitute a population of interest for their worse prognosis. Chemotherapy for a previous BC does not seem to impact the effectiveness of chemotherapy for ECs.

Вторая линия терапии распространенного рака эндометрия. Обзор литературы и клинический случай

Currently, endometrial cancer (EC) remains a socially significant and urgent problem in oncology. In the structure of malignant neoplasms of the uterus, endometrial carcinoma remains the most common type of cancer. According to GLOBOCAN, in 2018, there were 382 069 new cases of uterine cancer worldwide and 89 929 deaths associated with this pathology. Unlike the first line of chemotherapy for advanced EC, the second shows worse results. The overall response rate to second-line chemotherapy is much lower than first-line chemotherapy. Drugs such as oxaliplatin, topotecan, liposomal doxorubicin, etoposide, cyclophosphamide, pemetrexed, gemcitabine, and ifosfamide have shown worse results in studies compared to paclitaxel alone as second-line therapy for advanced endometrial cancer. The clinical efficacy of pembrolizumab monotherapy was a breakthrough in the treatment of EC, as evidenced by a Phase II study published in 2017. The results of molecular genetic studies allow the development and personalization of anticancer drug therapy. The FDA recently approved the use of the tyrosine kinase inhibitor lenvatinib (VEGFR1-3, FGFR 1-4, KIT, RET, PDGFRa) and pembrolizumab as a second-line EC without MSI-H or dMMR. The above clinical observation demonstrates the experience of treating a patient with advanced endometrial cancer in the second line. The combination of lenvatinib with pembrolizumab resulted in a partial response from the first months of therapy. Combination therapy showed a satisfactory tolerability profile in a patient with comorbid pathology; adverse events did not require discontinuation or dose reduction of pembrolizumab and lenvatinib.

Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue "Diagnosis and Management of Endometrial Cancer".

Simple SummaryPatients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment with unsatisfactory clinical outcomes. The combination of carboplatin + paclitaxel is the standard first-line chemotherapy, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with mTOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high/mismatch repair (MMR)-deficient EC.Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43–62%, a median progression-free survival (PFS) of 5.3–15 months and a median overall survival (OS) of 13.2–37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy.

A randomized, phase ii study comparing single-agent olaparib, single agent cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent or metastatic endometrial cancer

Objectives: The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Data from pre-clinical models suggest poly ADP-ribose polymerase (PARP) inhibitors alone or in combination with other targeted agents may be an effective therapeutic strategy in EC. Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study compared two experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J. Methods: A 1:1:1 randomized phase II study comparing cediranib (C) versus olaparib (O) or the combination of olaparib and cediranib (OC) for women with recurrent EC. Eligible patients had received at least 1 prior platinum containing chemotherapy but ≤2 prior lines of chemotherapy for recurrent EC. Cediranib was administered 30 mg PO daily, olaparib 300 mg PO BID and in the combination cediranib 20 mg PO daily / olaparib 300 mg PO BID. One cycle in all arms was 28 days. Primary endpoint was progression free survival (PFS) by RECIST1.1. Patients were stratified by histology (serous vs. endometrioid). Results: 120 patients were enrolled. 109 patients were treated: 34 patients C: 39 O and 36 OC. 10 patients withdrew consent prior to treatment. Median age was 66 years (range 41-86); 47 (39.2%) serous, 62 endometrioid (51.7%) and 8 (6.7%) mixed histology. The Kaplan Meir estimated median PFS was 3.8 months for C; 2.0 months O and 5.5 months for OC. The one-sided p value stratified log rank test comparing O vs. C was 0.935: HR 1.45 (95% CI 0.91-2.3) and C vs. OC 0.064; HR 0.7 (95% CI: 0.43-1.14). No new safety signals were reported. Conclusions: The combination of cediranib and olaparib demonstrated modest efficacy in patients with recurrent, metastatic or persistent EC, but was not significantly different compared to cediranib alone. The combination was safe with no unexpected toxicity. Single agent olaparib demonstrated insufficient efficacy to warrant further investigation as monotherapy in this patient population. The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Data from pre-clinical models suggest poly ADP-ribose polymerase (PARP) inhibitors alone or in combination with other targeted agents may be an effective therapeutic strategy in EC. Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study compared two experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J. A 1:1:1 randomized phase II study comparing cediranib (C) versus olaparib (O) or the combination of olaparib and cediranib (OC) for women with recurrent EC. Eligible patients had received at least 1 prior platinum containing chemotherapy but ≤2 prior lines of chemotherapy for recurrent EC. Cediranib was administered 30 mg PO daily, olaparib 300 mg PO BID and in the combination cediranib 20 mg PO daily / olaparib 300 mg PO BID. One cycle in all arms was 28 days. Primary endpoint was progression free survival (PFS) by RECIST1.1. Patients were stratified by histology (serous vs. endometrioid). 120 patients were enrolled. 109 patients were treated: 34 patients C: 39 O and 36 OC. 10 patients withdrew consent prior to treatment. Median age was 66 years (range 41-86); 47 (39.2%) serous, 62 endometrioid (51.7%) and 8 (6.7%) mixed histology. The Kaplan Meir estimated median PFS was 3.8 months for C; 2.0 months O and 5.5 months for OC. The one-sided p value stratified log rank test comparing O vs. C was 0.935: HR 1.45 (95% CI 0.91-2.3) and C vs. OC 0.064; HR 0.7 (95% CI: 0.43-1.14). No new safety signals were reported. The combination of cediranib and olaparib demonstrated modest efficacy in patients with recurrent, metastatic or persistent EC, but was not significantly different compared to cediranib alone. The combination was safe with no unexpected toxicity. Single agent olaparib demonstrated insufficient efficacy to warrant further investigation as monotherapy in this patient population.

Treatment patterns, overall survival, and healthcare utilization among Medicare beneficiaries with endometrial cancer in the United States.

e18698 Background: Endometrial cancer (EC) is the most common gynecologic cancer in the US, yet real-world disease burden is poorly understood. To address this, we conducted a retrospective study exploring patient (pt) characteristics, treatment patterns, overall survival (OS), and healthcare resource utilization (HCRU) among elderly US pts with EC. Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data, we identified beneficiaries aged ≥65 y with newly diagnosed EC between Jan 1, 2007–Dec 31, 2013. Pts were followed from the EC diagnosis date to the earliest of death, loss to follow-up, or Dec 31, 2014. Descriptive analyses were conducted for pt characteristics assessed in the 6-mo baseline period and for treatment patterns and HCRU assessed during follow-up. Median OS was estimated from the start of each line of systemic therapy using the Kaplan-Meier method. Lines of therapy started when pts received a new systemic therapy regimen and ended when pts switched to another regimen, after a 90-d treatment gap, or at end of follow-up. For pts with surgery, systemic therapy starting &gt;120 d after surgery or after discontinuation of adjuvant therapy was defined as first-line (1L) therapy. Adjuvant therapy was defined as any systemic therapy starting ≤120 d after surgery for EC and ending after a 90-d treatment gap following the last prescription. Results: There were 12,710 eligible pts with EC during 2007–2013 in the SEER-Medicare database; median age at diagnosis was 73 y. At initial diagnosis, 9395 (73.9%) pts had stage I/II EC, 2042 (16.1%) had stage III, and 1273 (10.0%) had stage IV. 778 pts did not receive surgery/radiation, 1230 pts received surgery/radiation plus adjuvant therapy, 9729 pts received surgery/radiation only, and 973 (7.7%) pts received 1L systemic therapy. Of these 973 pts, 370 (38.0%) received second-line (2L) and 157 (16.1%) received third-line (3L) treatment. Pts receiving 1L therapy had a mean of 5.6 outpatient physician office visits per month, 22.1% had ≥1 hospitalization, and 38.5% had ≥1 emergency room visit during follow-up. Carboplatin-based regimens were the most frequently used 1L therapies (56.8%), typically combined with paclitaxel (43.5%). Median OS was generally short, particularly for those diagnosed with stage III/IV EC (Table). Conclusions: Medicare beneficiaries receiving systemic chemotherapy for EC generally had high HCRU and poor survival, particularly among pts diagnosed at later stages. This highlights the underlying disease burden and unmet need for more effective treatments in these pts.[Table: see text]

Garcinol inhibits the proliferation of endometrial cancer cells by inducing cell cycle arrest.

Endometrial cancer (EC) is the most common gynecological cancer, and one of the most important causes of cancer-related deaths in women worldwide. The long-term survival rate is lower in advanced-stage and recurrent EC, therefore it is important to identify new anticancer drugs. Garcinol, a polyisoprenylated benzophenone, is a promising anticancer drug for various cancer types but its effects on EC remain unclear. To investigate the anticancer effects of garcinol on EC, cell proliferation and cell cycle were assessed by real-time cell proliferation, cell counting, and colony formation assays, flow cytometric analysis, and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, in EC Ishikawa (ISH) and HEC-1B cell lines. Western blotting was used to evaluate the expression of cell cycle-related protein cyclins, cyclin-dependent kinase and tumor suppression proteins. Garcinol inhibited ISH and HEC-1B cell proliferation in a dose-dependent manner, and induced ISH and HEC-1B cell cycle arrest at the G1 phase and G2/M phase, respectively, and decreased the S phase and DNA synthesis in these two cell lines. Following garcinol treatment the expression levels of p53 and p21 were increased, while the expression levels of CDK2, CDK4, cyclin D1 and cyclin B1 were gradually decreased in a dose-dependent manner in both ISH and HEC-1B cells. In addition, the expression levels of phosphorylated c-JUN N-terminal kinase (JNK) and p-c-JUN were significantly increased in both types of cells. Collectively, garcinol can induce EC cell cycle arrest and may be a promising candidate for EC chemotherapy.

Abstract PO-150: Epidemiology of endometrial cancer as a second primary malignancy in Florida

Abstract Background: According to cancer registry data, nearly 20% of Endometrial Cancer (EC) cases in the US are second or higher-order primary cancers. Little is known in regard to the epidemiology of EC as a Second Primary (ECSP) cancer. Purpose: To compare ECSPs and EC as a first primary in relation to histological types and cause- specific survival; examine survival of ECSP according to original primary site, and treatment received for the first primary. Methods: All cases of EC diagnosed from 2005-2016 were obtained from the Florida Cancer Data System. Chi-square tests, Kaplan-Meier methods and Cox Regression were used in the analysis. Results: Of 9,002 initial ECSPs, 73% were not “clinically independent”, i.e. without treatment distinctions between first and second cancers. These included ECSPs of different histologies from a first EC, and ECSPs following ovarian and cervical cancers (&amp;lt;1 year). After excluding these, there were 2,401 ECSPs and 37,128 ECs as a first primary; 1,260 ECSPs followed breast cancer (BC), 299 followed colorectal cancer (CRC), and other sites(n=842). The 5-year, age-standardized cause-specific survival was 72.2% (95%CI: 71.8-72.7) for first ECs and 60.7% for ECSPs (95%CI: 58.5-63.0). However, after adjusting for age, race/ethnicity, histology, and stage there was no significant difference between ECSP and first EC (HR 0.92, 95%CI: 0.83-1.03). Post- colorectal ECSPs had lower 5-year survival (55.3%, 95%CI: 48.9-61.7) than post- breast cancer ECSPs (64.8%, 95%CI: 61.8-67.9), and significantly higher risk of EC- specific death (HR 1.78, 95%CI:1.23-2.58) in multivariable analysis. Lastly, women who had chemotherapy for both ECSP and a preceding BC did not have a higher EC- specific risk of death (HR 0.79, 95% CI: 0.46-1.36) compared to those who only received chemotherapy for EC as a first primary. Conclusions: ECSP survival is similar to that of EC as a first primary. However, ECs post-CRC may constitute a population of interest with much worse survival than those post-BC. There was no information to separately assess Lynch syndrome cases or those receiving tamoxifen as part of BC treatment. Lastly, chemotherapy for a previous BC does not seem to affect the effectiveness of chemotherapy for ECSPs. Further research is needed in the epidemiology of second cancers. Citation Format: Heidy N. Medina, Matthew P. Schlumbrecht, Paulo S. Pinheiro. Epidemiology of endometrial cancer as a second primary malignancy in Florida [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-150.

Abstract 6222: Inhibition of 6-Phosphofructo-2-kinase (PFKFB3) induces cell death and synergistically enhances chemosensitivity in endometrial cancer

Abstract Objectives: Endometrial cancer (EC) is the most common gynecological cancer in the developed countries with rising incidence rates. However, the knowledge about targeted therapies that can improve response rates to chemotherapy in EC is limited. Of the cancer afflicting women, women with metabolic disorders such as diabetes and obesity have an increased risk of developing EC. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a glycolytic enzyme, is found to be highly expressed in many solid tumors. This study aimed to investigate the role and molecular mechanism of PFKFB3 in endometrial cancer. Methods: HEC-1B and ARK-2 endometrial cancer cell lines were used as models to evaluate the potential antitumor effects of pharmacological (treatment with PFK158, a selective PFKFB3 inhibitor) and genetic (PFKFB3 knockdown using CRISPR/Cas9 technology) inhibition of PFKFB3 on EC. In vitro, we evaluated the effects of PFKFB3 inhibition, and its synergistic effects when combined with carboplatin (CBPt) or cisplatin on cell viability, glucose metabolism, autophagy, apoptosis, and changes of cell signaling using MTT and colony formation assays, Chou-Talalay methodology, immunofluorescence assay, flow cytometry and western blotting. In vivo, two EC subcutaneous xenograft models derived from HEC-1B and ARK-2 cell lines were used to investigate the effect of single-agent PFK158 and in combination with CBPt on tumor growth, followed by western blotting, TUNEL and immunohistochemistry staining of excised tumor tissue. Results: Targeting PFKFB3 via PFK158 considerably reduced glucose uptake, ATP production, lactate release in EC cell lines. In vitro, inhibition of PFKFB3 induced cell death and synergistically enhanced CBPt/cisplatin sensitivity in EC cell lines by suppressing cell viability, inducing autophagy and apoptosis in a time- and dose-dependent manner. In vivo xenograft studies revealed that treatment with PFK158, either alone or in combination with CBPt, led to a marked reduction in tumor growth. In addition, PFK158 caused significant upregulation of cleaved PARP, cleaved caspase 3, and reduction of mTOR, Akt, ERK phosphorylation levels, both in vitro and in vivo. Conclusions: Our results indicate that PFKFB3 plays a prominent role in the growth and chemoresistance in EC cells. Therefore, a selective PFKFB3 inhibitor or in combination with chemotherapy, may be used as a novel therapeutic strategy for patients with chemoresistant EC. Citation Format: Yinan Xiao, Ling Jin, Sayantani Sarkar Bhattacharya, Julie Staub, Chaolin Deng, Xiaoling Fang, Viji Shridhar. Inhibition of 6-Phosphofructo-2-kinase (PFKFB3) induces cell death and synergistically enhances chemosensitivity in endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6222.

A Big Ten Cancer Research Consortium phase II trial of pembrolizumab with carboplatin and paclitaxel for advanced or recurrent endometrial cancer.

6022 Background: There are limited chemotherapeutic options for patients (pts) with advanced or recurrent endometrial cancer (EC). Reported objective response rates (ORR) for first-line doxorubicin/cisplatin/ paclitaxel combination therapy was 57%; with a median progression-free survival (PFS) of 8.3 months. The goal of this phase II study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in pts with measurable advanced or recurrent EC. Methods: This was a single-arm, open-label, multi-center phase II study for pts with RECIST measurable advanced or recurrent EC coordinated by the Big Ten Cancer Research Consortium. Patients may have had received 1 prior platinum-based regimen, with a platinum free interval &gt; 6 months, &lt; one non-platinum chemotherapy, or prior hormonal therapy. Pts received carboplatin AUC 6, paclitaxel 175mg/m2 (CT) and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles; with dose reduced for prior radiation. The primary endpoint was ORR per immune-related RECIST. Planned sample size of 46 subjects provided 77% power to detect 15% ORR improvement compared to historical controls, with one-tailed test and 10% type I error rate. Results: 46 pts were enrolled. Median age was 67 (range: 43-86). 32 pts had recurrent and 14 had primary metastatic EC. Histological types were: 26 endometrioid, 11 serous, 3 clear cell, 6 other. 19 patients had received prior carboplatin/paclitaxel, 23 pelvic EBRT, 14 brachytherapy, 1 adriamycin and 1 hormonal therapy. Grade 3-4 adverse events (AEs) included: laboratory abnormalities (20), hematological (8), metabolism (6), nervous system (4), gastrointestinal (2), and others (6). There were 15 grade 3-4 SAEs occurring in 7 pts: vomiting (1), anaphylaxis (3), fever (2), dehydration (1), syncope (2), vascular (2), fatigue (1), neurological (2), thrombocytopenia (1), and no grade 5 SAEs. 36 patients were evaluable for response at the time of abstract submission. ORR was 77.8% (28/36) and median PFS was 10.55 months. Conclusions: The addition of pembrolizumab to standard of care CT chemotherapy for advanced or recurrent EC induced a clinically significant improvement in ORR compared to historical outcomes and toxicity did not exceed anticipated toxicity with standard treatment, supporting further testing in a phase III trial. Clinical trial information: NCT02549209.

TRAF4 knockdown triggers synergistic lethality with simultaneous PARP1 inhibition in endometrial cancer.

Endometrial cancer (EC) is one of the most common cancers among females worldwide. Advanced stage patients of EC have poor prognosis. Inevitable side effects and treatment tolerance of chemotherapy for EC remain to be addressed. Our results in this study showed that EC cells with higher tumor necrosis factor receptor-associated factor 4 (TRAF4) expression have lower sensitivity to poly ADP-ribose polymerase 1 (PARP1) inhibitors. Upon TRAF4 knockdown, the colony numbers of EC cells were markedly down-regulated, and the markers of DNA double-strand breakage were significantly up-regulated after the treatment of olaparib, a PARP1 inhibitor. TRAF4 knockdown reduced the phosphorylation of protein kinase B (Akt), promoted DNA double-strand breakage, and decreased levels of DNA repair related proteins, including phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). In addition, TRAF4's effect on the sensitivity of EC cells to olaparib was further found to be mainly mediated by Akt phosphorylation. Moreover, in vivo results showed that TRAF4 knockdown enhanced the sensitivity of EC to PARP1 inhibitors using a mouse xenograft model. Collectively, our data suggest that combined application of TRAF4 knockdown and PARP1 inhibition can be used as a promising strategy for synthetic lethality in EC treatment.

Sulfated glycolipid PG545 induces endoplasmic reticulum stress and augments autophagic flux by enhancing anticancer chemotherapy efficacy in endometrial cancer

The sulfated glycolipid PG545 shows promising antitumor activity in various cancers. This study was conducted to explore the effects and the mechanism of PG545 action in endometrial cancer (EC). PG545 exhibited strong synergy as assessed by the Chou-Talalay-Method in vitro when combined with cisplatin, or paclitaxel in both type I (Hec1B) and type II (ARK2) EC cell lines. While PG545 showed antitumor activity as monotherapy, a combination of PG545 with paclitaxel and cisplatin was highly effective in reducing the tumor burden and significantly prolonged survival of both Hec1B and ARK2 xenograft bearing mice. Mechanistically, PG545 elicits ER stress as an early response with resultant induction of autophagy. Our data demonstrated an increase in pERK, Bip/Grp78, IRE1α, Calnexin and CHOP/GADD153 within 6–24 hrs of PG545 treatment in EC cells. In parallel, PG545 also blocked FGF2 and HB-EGF mediated signaling in EC cells. Moreover, melatonin-mediated ER stress inhibition reduced PG545-mediated autophagy and PG545 in combination with cisplatin further heightened this stress response. Collectively these data indicate that PG545 exhibits strong synergistic effects with chemotherapeutics in vitro and showed promising antitumor activity in vivo. Our preclinical data indicates that in future studies PG545 can be a useful adjunct to chemotherapy in endometrial cancer.

Adjuvant chemotherapy in endometrial cancer.

The role of adjuvant chemotherapy (CT) is controversial in endometrial carcinoma (EC). Surgery alone is usually curative for women who are at a low risk of disease recurrence. The treatment of EC following surgical staging is based on the risk of relapse, which is defined by the cancer stage at diagnosis, histology of the tumor and other prognostic factors such as grade differentiation, the presence of substantial lymphovascular invasion (LVSI), or depth of myometrial invasion (MI). External beam radiotherapy (EBRT) and/or vaginal brachytherapy (VBT) improved local control and are used as adjuvant treatment for early-stage disease. The role of adjuvant CT is controversial in early-stage EC, and there is no uniform approach to the treatment of women with stage III EC or early-staged non-endometrioid EC. Available evidence did not support the indication of adjuvant CT in stage I-II endometroid EC. In those cases at higher risk of relapse, defined as grade 3 tumors with substantial (no focal) LVSI, specifically with deep MI or cervical involvement, could be considered. Adjuvant CT should be administered to stage III EC patients. When RT is indicated (extensive lymph node involvement or deep MI), sequential treatment with RT or "sandwich" regimen may be considered rather than concurrent CRT. The patients with stage IA MI or IB USC may be offered adjuvant CT alone or in combination with VBT, whereas in stage II uterine serous carcinoma patients adding EBRT may be reasonable. Management approach for patients with stage IA without MI USC who underwent a comprehensive surgery remains controversial, and surveillance alone or CT plus VBT is an appropriate option. Early-stage clear-cell carcinoma patients might not benefit for adjuvant CT, but stage III patients might benefit from the combination of CT and EBRT. Stage I-III uterine carcinosarcoma patients might be offered adjuvant CT followed by RT or as a "sandwich" régimen.