Treatment Of Uterine Serous Carcinoma Research Articles

High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines

ObjectiveUterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. MethodsCell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. ResultsHigh-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. ConclusionsAscorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

Effect of the combination of trastuzumab, paclitaxel and carboplatin in the treatment of uterine serous carcinoma: A systematic review and meta-analysis

Purpose: To systematically review the efficacy of paclitaxel-carboplatin versus trastuzumab in combination with paclitaxel/carboplatin for the treatment of uterine serous carcinoma (USC) with high Her2/neu expression, in order to obtain an evidence-based reference for clinical treatment.Methods: Publications were obtained from China Knowledge Network (CNKI), VIP database (VIP), Wanfang database, PubMed, Embase, Cochrane Library, and Web of Science. The retrieval period was from the establishment of database to May 2022, and the efficacy of paclitaxel-carboplatin combination with trastuzumab (study group) versus paclitaxel-carboplatin (control group) for the treatment of Her2/neu high-expressing USC was collected. Two reviewers independently screened, extracted data, and evaluated the quality of evidence of included studies. RevMan 5.3 statistical software was used for meta-analysis. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events.Results: Meta-analysis showed that the study group had significantly longer OS than control group (p = 0.004), and PFS of study group was significantly longer than that of control group (p < 0.0001). In terms of ORR, there was no difference between the two groups (p = 0.42). However, in terms of total and high-risk adverse events, the number of patients with adverse events in study group was higher than in control group (p = 0.05), (p = 0.0001).Conclusion: Paclitaxel-carboplatin combination with trastuzumab significantly prolongs OS and PFS in USC patients with high Her2/neu expression, but it may increase the incidence of adverse events.

Targeted Therapies in the Treatment of Uterine Serous Carcinoma.

Despite the dismal prognosis of uterine serous carcinoma (USC), recent advances in molecular classification and targeted treatments have demonstrated improvements in survival outcomes for patients both in the upfront and recurrent treatment settings. After appropriate surgical staging and surgical cytoreduction as indicated, correct pathologic and molecular classification of USC is important to provide the most appropriate systemic adjuvant treatment. HER2-targeted agents are one of the most important advances in the treatment of USC in decades. Thus, for HER2-positive tumors, the addition of trastuzumab to conventional chemotherapy is indicated in those with advanced stage and/or recurrent disease. Treatment with pembrolizumab and lenvatinib suggests a 50% response rate in women with recurrent disease which serves as a promising targeted treatment strategy. Overall, emerging targeted therapeutic options with antibody-drug conjugates (i.e. targeting HER2, folic acid receptor alpha, or Trop-2), combinations of immunotherapies and tyrosine kinase inhibitors, PARP inhibitors, WEE1 inhibitors, and AKT inhibitors shed further promise in advancements of effective disease-modifying treatments for this unmet medical need for patients with USC. Several trials evaluating these targeted agents are ongoing, and those results are eagerly awaited. As such, enrollment of patients in clinical trials is highly recommended as it will provide patients with a higher level of personalized cancer care.

The role of omentectomy in the surgical treatment of uterine serous carcinoma.

ObjectiveThe aims of this study were to assess the role of omentectomy in the staging of uterine serous carcinoma (USC) and to evaluate its impact on patient outcomes.Study designPatients diagnosed with USC at the First Affiliated Hospital of Sun Yat-sen University of China were retrospectively reviewed. The clinicopathological characteristics and survival data of 187 patients were analyzed. Risk factors for omental metastasis were evaluated. Kaplan–Meier survival curves were used to compare survival status and the presence of omental metastasis.ResultsWe found that 35 of 187 patients (18.7%) had omental metastases. Omental metastasis was significantly associated with adnexal involvement (40.0% vs 19.1%, P = 0.008, OR 2.828, 95% CI 1.286–6.218). Multivariate analysis showed that in addition to lymph node metastases and suboptimal surgery, omental metastasis in USC remained an independent predictor of decreased PFS and OS (PFS, HR 1.48, 95% CI 1.14–4.63, P = 0.024; OS, HR 1.39, 95% CI 1.04–3.60, P = 0.043).ConclusionsThe incidence of omental metastasis is not low in patients with USC. Visual assessment and omental biopsy may be insufficient for recognizing occult metastases. Omentectomy should be part of the staging surgery in USC patients because it provides additional information about survival. Prospective studies are needed to confirm these results.

Patterns of care, associations and outcomes of chemotherapy for uterine serous carcinoma: Analysis of the National Cancer Database

ObjectiveEvaluate rates of chemotherapy and radiotherapy delivery in the treatment of uterine serous carcinoma, and compare clinical outcomes of treated and untreated patients. MethodsThe National Cancer Database was queried to identify patients diagnosed with uterine serous carcinoma between 2003 and 2011. The impact of chemotherapy on survival was analyzed using the Kaplan–Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. ResultsA total of 13,752 patients met the study eligibility criteria. Stage I, II, III, and IV disease accounted for 4355 (31.7%), 1023 (7.4%), 3484 (25.3%), and 2451 (17.8%) of the study population, respectively. 2439 (17.7%) women had unknown stage. Chemotherapy was administered in 4290 (35.4%) patients, radiotherapy to 1673 (12.2%), adjuvant chemo-radiation to 2915 (21.2%), and 4874 (35.4%) of women did not receive adjuvant therapy during the study period. Utilization of chemotherapy became more frequent over time. Over the entire study period, after adjusting for age, period of diagnosis, race, facility location, facility type, insurance provider, socioeconomic status, comorbidity index, lymph node dissection, treatment modality, and stage, there was an association between treatment modality and survival, with the lowest hazard ratio in patients that received chemo-radiation. After adjusting for the same factors in women with stages I and II, chemo-radiation was associated with improved survival compared to patients that received no treatment. Radiotherapy or chemotherapy alone was not associated with improved survival. ConclusionUtilization of chemotherapy is increased in this population over the study period from 2003–2012 and more importantly that survival, particularly in advanced stage patients, is improving.

Trends in Treatment of Uterine Serous Cancer in the Medicare Population.

The objectives of this study were to evaluate the rates of chemotherapy and radiotherapy delivery in the treatment of uterine serous carcinoma in the Medicare population and to compare clinical outcomes in treated and untreated patients. The linked Surveillance, Epidemiology, and End Results and Medicare databases were queried to identify patients with a diagnosis of uterine serous carcinoma between 1992 and 2009. The impact of chemotherapy on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. A total of 2188 patients met study eligibility criteria. Stages I, II, III, and IV diseases accounted for 890 (41%), 174 (8%), 470 (21%), and 654 (30%) of the study population, respectively. Chemotherapy, radiotherapy, both, or none, were administered as adjuvant therapy in 635 (29%), 536 (24%), 308 (14%), and 709 (32%) of the study population, respectively. Use of chemotherapy became more frequent over time. Over the study period, and after adjusting for race, time of diagnosis, SEER registry, marital status, stage, age, surgery, lymph node dissection, socioeconomic status, and comorbidity index, there was an association between receipt of radiotherapy alone (hazard ratio [HR], 1.3; 95% CI, 1.04-1.67) and not receiving any treatment (HR, 1.5; 95% CI, 1.2-2.01) and worst survival. Survival was not improved over time. Although adjuvant chemotherapy and combination treatment with chemotherapy and radiation were associated with improved survival in our model, there was no significant improvement in survival over time.

Abstract 13: Trends in treatment of uterine serous cancer in the medicare population

Objectives: The objective of this investigation is to evaluate the rates of chemotherapy and radiotherapy use in the primary treatment of uterine serous carcinoma (USC) in the US Medicare population and analyze how therapies are being utilized in the general community. The study also compares clinical outcomes for treated and untreated patients.

Trends in treatment of uterine serous cancer in the medicare population

Objectives: Only a small number of cases of uterine serous carcinoma (USC) have been reported in randomized control trials. The objective of this investigation is to evaluate the rates of chemotherapy and radiotherapy in the primary treatment of USC in the US Medicare population and its effect on survival.

Tubulin‐β‐III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones

Uterine serous carcinoma (USC) is a subtype of endometrial cancer associated with chemoresistance and poor outcome. Overexpression of tubulin-β-III and p-glycoprotein has been linked to paclitaxel resistance in many cancers but has been undercharacterized among USCs. Epothilones have demonstrated activity in certain paclitaxel-resistant malignancies. In this study, relationships are clarified, in USCs relative to ovarian serous carcinomas (OSCs), between tubulin-β-III and p-glycoprotein expression, clinical outcome, and in vitro chemoresponsiveness to epothilone B, ixabepilone, and paclitaxel. Tubulin-β-III and p-glycoprotein were quantified by real-time polymerase chain reaction in 48 fresh-frozen tissue samples and 13 cell lines. Copy number was correlated with immunohistochemistry and overall survival. Median inhibitory concentration (IC50 ) was determined using viability and metabolic assays. Impact of tubulin-β-III knockdown on IC50 was assessed with small interfering RNAs. USC overexpressed tubulin-β-III but not p-glycoprotein relative to OSC in both fresh-frozen tissues (552.9 ± 106.7 versus 202.0 ± 43.99, P = .01) and cell lines (1701.0 ± 376.4 versus 645.1 ± 157.9, P = .02). Tubulin-β-III immunohistochemistry reflected quantitative real-time polymerase chain reaction copy number and overexpression stratified patients by overall survival (copy number ≤ 400: 615 days; copy number > 400: 165 days, P = .049); p-glycoprotein did not predict clinical outcome. USCs remained exquisitely sensitive to patupilone in vitro despite tubulin-β-III overexpression (IC50,USC 0.245 ± 0.11 nM versus IC50,OSC 1.01 ± 0.13 nM, P = .006). Tubulin-β-III overexpression in USCs discriminates poor prognosis, serves as a marker for sensitivity to epothilones, and may contribute to paclitaxel resistance. Immunohistochemistry reliably identifies tumors with overexpression of tubulin-β-III, and a subset of individuals likely to respond to patupilone and ixabepilone. Epothilones warrant clinical investigation for treatment of USCs.

Updates in therapy for uterine serous carcinoma

Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer with distinct molecular pathogenesis. This review summarizes the rationale behind current clinical approaches, as well as advances made in 2012 toward the elucidation of underlying pathway aberrations and development of targeted therapies that exploit these unique characteristics. Within the last year, exome-wide analyses have highlighted key mutations to guide rational drug design. The PI3/AKT/mTOR pathway and regulators of cell cycle such as cyclin E/F-box proteins appear to be particularly important. Understanding the epithelial to mesenchymal transition may explain the aggressive pattern of spread frequently observed in this disease. There is heightened evidence for heritable syndromes in association with USC. Conflicting retrospective data continue to emerge regarding optimal therapy, especially for early-stage disease, although prospective studies are underway. Immunotherapies targeting Her2/Neu and vascular endothelial growth factor remain an area of active research. Upregulation of class III β-tubulin observed in paclitaxel-resistant disease may identify candidates for therapy with novel microtubule-stabilizing agents such as epothilones. There is an expanding role for contemporary novel approaches in the treatment of USC. The results of clinical investigations using new target antigens, epothilones, and small molecule inhibitors are eagerly awaited.

Molecular alterations of EGFR and PIK3CA in uterine serous carcinoma

Objectives Uterine serous carcinoma (USC) is an aggressive endometrial cancer associated with poor prognosis despite comprehensive surgical staging and adjuvant chemotherapy and radiation therapy. Biologic targets have yet to be fully explored in this disease and research on such targets could lead to clinical trials utilizing a new class of therapeutics. This study sought to evaluate primary USC tumors for molecular alterations in epidermal growth factor receptor ( EGFR) and the recently characterized oncogene PIK3CA, which encodes the catalytic p110-alpha subunit of phosphatidylinositol 3-kinase (PI3K) and thus activates the AKT–mTOR oncogenic pathway. Methods Paraffin-embedded archival tissue of 45 primary USC tumors was utilized in this study. Immunohistochemical analysis of EGFR was performed and cases given a score of 0 to 12 calculated as the product of staining intensity (0 to 3+) and the percentage of positively stained cells (0–4), with 1 = 1–25%, 2 = 26–50%, 3 = 51–75%, and 4 = 76–100%. For mutational analysis, neoplastic tissue was microdissected and DNA was extracted with phenol–chloroform. Exons 18 through 21 of EGFR and exons 9 and 20 of PIK3CA, the most commonly mutated exons of these genes, were amplified and directly sequenced. Results When EGFR was evaluated, moderate or strong EGFR membranous staining was observed in 25/45 (56%) USC cases. Thus, a mutational analysis was performed on 35 cases, including all cases with moderate and strong EGFR staining. No mutations were identified in EGFR. In contrast, PIK3CA mutations were confirmed in 5/34 (15%) of USC cases. Four cases were mutated in exon 20 and one case was mutated in exon 9. Conclusions Since optimal treatment of uterine serous carcinoma remains unknown, novel therapeutic approaches need to be actively pursued. In the current study of primary USC tumors, oncogenic mutations of the PIK3CA gene were seen in 15% of USC cases. This represents the first report of this gene mutation in USC. In addition, EGFR stained positively in the majority of cases, suggesting a possible target protein. These findings warrant further investigation and suggest a potential role for therapeutic agents targeting the PI3K–AKT–mTOR pathway, such as rapamycin, as well as possible targets of EGFR in the treatment of uterine serous carcinoma.