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Antibody–drug conjugates (ADCs) are a new class of targeted anti-cancer therapies that combine a monoclonal tumor-surface-receptor-targeting antibody with a highly cytotoxic molecule payload bonded through specifically designed cleavable or non-cleavable chemical linkers. One such tumor surface receptor is human epidermal growth factor 2 (HER2), which is of interest for the treatment of many gynecologic tumors. ADCs enable the targeted delivery of a variety of cytotoxic therapies to tumor cells while minimizing delivery to healthy tissues. This review summarizes the existing literature about HER2-targeting ADC therapies approved for use in gynecologic malignancies, relevant preclinical studies, strategies to address ADC resistance, and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Antibody drug conjugates (ADCs) are a new class of targeted anti-cancer therapies that combine a monoclonal tumor surface receptor-targeting antibody with a highly cytotoxic molecule payload. They enable delivery of cytotoxic therapy more directly to tumor cells and minimize delivery to healthy tissues. This review summarizes the existing literature about ADC therapies approved for use in gynecologic malignancies, relevant preclinical studies, as well as ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper we addressed the challenges encountered by women diagnosed with endometrial cancers during their reproductive years. Depending on the genetic profile of the endometrial cancer, these young patients may benefit from fertility-sparing strategies, including hormonal, surgical and assisted reproductive technologies. Endometrial cancer is the most common gynecologic malignancy in developed countries and approximately 7% of the women with endometrial cancer are below the age of 45. Management of endometrial cancer in young women who desire to maintain fertility presents a unique set of challenges since the standard surgical treatment based on hysterectomy and salpingo-oophorectomy is often not compatible with the patient's goals. A fertility-preserving approach can be considered in selected patients with early stage and low-grade endometrial cancer. An increasing amount of data suggest that oncologic outcomes are not compromised if a conservative approach is utilized with close monitoring until childbearing is completed. If a fertility-preserving approach is not possible, assisted reproductive technologies can assist patients in achieving their fertility goals. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is the most common gynecologic malignancy. Outcomes for patients with advanced and/or recurrent disease have been modest with the use of chemotherapy. The approval of immune checkpoint inhibitors targeting PD-1 has recently revolutionized human cancer treatment. Recent trials with immune checkpoint inhibitors used alone or in combination with other agents, have demonstrated remarkable efficacy in the treatment of the all-comers EC patient population. In this article, we review major clinical trials on PD-1/PD-L1 inhibitors in advanced and recurrent EC and discuss the response rates of these agents in the context of their genomic background. Immune checkpoint inhibitors have significantly changed our approach to the treatment of advanced/recurrent EC. Single agent anti-PD-1 regimens are highly effective in MMRd/MSI-H patients, but their clinical efficacy remains modest in MMR proficient/TMB low EC patients. Combination regimens that can decrease the tumor microenvironments immunosuppression and increase tumor immunogenicity represent a viable treatment option to broaden the activity of immune checkpoint inhibitors in advanced/recurrent EC patients. An increased understanding of the biomarkers of response and the molecular mechanisms of resistance to immune checkpoint inhibitors remains key for the next advancement of the field. [ABSTRACT FROM AUTHOR]

BACKGROUND: Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE‐mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment. METHODS: A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one‐stage meta‐analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC). RESULTS: Three hundred fifty‐nine women with POLE‐mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47‐7.58; log‐rank P <.01). Except for stage (P <.01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease‐specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5‐14.2 years). Adjuvant treatment was not associated with outcome. CONCLUSIONS: Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de‐escalating treatment for these patients. LAY SUMMARY: Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE).Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics.Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE‐mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity.Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment. Despite often having unfavorable pathological features, women with pathogenic DNA polymerase epsilon (POLE)–mutated endometrial cancers have excellent cancer‐specific clinical outcomes, and this highlights the importance of molecular subtyping for endometrial cancer classification. Adjuvant therapy is not associated with improved outcomes for women with pathogenic POLE‐mutated endometrial cancers, and this supports de‐escalation of therapy for these patients in clinical trials. [ABSTRACT FROM AUTHOR]

Accurate normalization is a primary component of a reliable gene expression analysis based on qRT-PCR technique. While the use of one or more reference genes as internal controls is commonly accepted as the most appropriate normalization strategy, many qPCR-based published studies still contain data poorly normalized and reference genes arbitrarily chosen irrespective of the particular tissue and the specific experimental design. To date, no validated reference genes have been identified for endometrial cancer tissues. In this study, 10 normalization genes (GAPDH, B2M, ACTB, POLR2A, UBC, PPIA, HPRT1, GUSB, TBP, H3F3A) belonging to different functional and abundance classes in various tissues and used in different studies, were analyzed to determine their applicability. In total, 100 endometrioid endometrial cancer samples, which were carefully balanced according to their tumor grade, and 29 normal endometrial tissues were examined using SYBR Green Real-Time RT-PCR. The expression stability of candidate reference genes was determined and compared by means of geNorm and NormFinder softwares. Both algorithms were in agreement in identifying GAPDH, H3F3A, PPIA, and HPRT1 as the most stably expressed genes, only differing in their ranking order. Analysis performed on the expression levels of all candidate genes confirm HPRT1 and PPIA as the most stably expressed in the study groups regardless of sample type, to be used alone or better in combination. As the stable expression of HPRT1 and PPIA between normal and tumor endometrial samples fulfill the basic requirement of a reference gene to be used for normalization purposes, HPRT1 expression showed significant differences between samples from low-grade and high-grade tumors. In conclusion, our results recommend the use of PPIA as a single reference gene to be considered for improved reliability of normalization in gene expression studies involving endometrial tumor samples at different tumor degrees. [ABSTRACT FROM AUTHOR]

The increased understanding of the genetic landscape of clear cell endometrial cancer should guide the development of precision medicine strategies to improve survival. See also pages 3261‐8. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the impact of body mass index (BMI) on the short- and long-term outcomes of patients with endometrial cancer who underwent robotic-assisted staging and to analyze disease recurrence and recurrence-free survival (RFS).The charts of all consecutive patients with endometrial cancer who underwent robotic surgery from March 2007 to October 2012 were analyzed. Patients with follow-up less than 12 months after surgery were censored from the RFS analysis.Mean (SD) age for the 364 patients was 63.6 (10) years, and mean (SD) BMI was 34.8 (10.1) kg/m2. Conversions were in 3 (0.8%) of 364 cases. The mean (SD) operative time was 162.3 (54.6) minutes. Mean (SD) postoperative hospitalization was 1.6 (1.9) days. Histology included 80.5% endometrioid and 19.5% clear cell, serous, and carcinosarcomas. Mean (SD) pelvic and paraaortic lymph node counts were 15.9 (8.2) and 3.6 (4.3), respectively. Metastatic disease was diagnosed in 58 (16%) of 364 patients. The median follow-up was 29.3 months. The recurrence rates were 4.1% for the patients with endometrioid carcinoma and 14.1% for nonendometrioid histologies. Recurrences in patients with BMI less than 30 kg/m2 accounted for 68.2% of all recurrences (15/22 patients). The rest of recurrences (7/22 patients, 31.8%) were in obese patients. Moreover, when analyzed for each histologic subtype, recurrence rates were consistently higher for patients with BMI less than 30 kg/m2 when compared with patients with BMI greater than 30 kg/m2. The 3-year overall survival was 98.2%, and the 3-year RFS was 92%.Obesity and morbid obesity did not affect adversely the operative outcomes for patients with endometrial cancer who were operated on using the robotic system. The recurrence rates were lower for patients with BMI greater than 30 kg/m2 compared with patients with BMI less than 30 kg/m2 for both endometrioid and nonendometrioid cancers. [ABSTRACT FROM AUTHOR]

Preclinical data suggest that mammalian target of rapamycin inhibitors may potentiate the efficacy of topotecan. We evaluated the optimal schedule of oral topotecan in combination with everolimus in patients with endometrial cancer.Women with a history of advanced or recurrent endometrial cancer were enrolled. Escalating dose of oral topotecan (1.5 mg/m2, 1.9 mg/m2, and 2.3 mg/m2) daily on days 1 to 5 and everolimus (5 mg every other day, 5 mg daily, and 10 mg daily) were administered in a 21-day cycle. A “run-in” treatment of topotecan daily for 5 days followed by everolimus for 7 days (4-7 doses depending on dose level) was administered for the purpose of pharmacokinetic assessments.Ten patients were enrolled on the study, and 9 were evaluable for safety analysis. A total of 28 cycles were administered (range, 1-10 cycles per patient). The patients had a median age of 73 years (range, 42-79 years). Previous lines of chemotherapy were 1 (n = 2), 2 (n = 5), 3 (n = 2), and 4 (n = 1). Seven patients had previous vaginal brachytherapy, and 2 had pelvic external beam radiation therapy. The median number of cycles (including cycle 1) is 2 (range, 1-10). Dose-limiting toxicity occurred in 3 patients (1 patient treated with 1.9-mg/m2 topotecan and 5-mg everolimus given every other day as well as 2 patients treated with 1.9-mg/m2 topotecan and 5-mg of everolimus daily) and included neutropenia and thrombocytopenia. Seven patients were evaluable for response. Stable disease was the best response in 3 patients who completed the 3, 4, and 10 cycles each.The dose-limiting toxicity for the combination of oral topotecan and everolimus was myelosuppression. The maximum tolerated dose was topotecan 1.9 mg/m2 on days 1 to 5 in combination with oral everolimus 5 mg every other day. Administration of higher dose of each agent in combination was limited because of overlapping myelosuppression. [ABSTRACT FROM AUTHOR]

Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer. Although it only represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer. Comprehensive surgical staging followed by carboplatin and paclitaxel chemotherapy represents the mainstay of USC therapy. Vaginal cuff brachytherapy is also of potential benefit in USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. These results emphasize the relevance of these novel therapeutic targets for biologic therapy of chemotherapy-resistant recurrent USC. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer is the most common gynecologic malignancy in developed countries. Trop-2 is a glycoprotein involved in cellular signal transduction and is differentially over-expressed relative to normal tissue in a variety of human adenocarcinomas, including endometrioid endometrial carcinomas (EEC). Trop-2 over-expression has been proposed as a marker for biologically aggressive tumor phenotypes. Methods: Trop-2 protein expression was quantified using tissue microarrays consisting of formalin-fixed paraffin embedded specimens from 118 patients who underwent surgical staging from 2001–9 by laparotomy for EEC. Clinicopathologic characteristics including age, stage, grade, lymphovascular space invasion, and medical comorbidities were correlated with immunostaining score. Univariate and multivariate analyses were performed for overall survival, disease-free survival, and progression-free survival in relation to clinical parameters and Trop-2 protein expression. Results: Clinical outcome data were available for 103 patients. Strong Trop-2 immunostaining was significantly associated with higher tumor grade (p=0.02) and cervical involvement (p<0.01). Univariate analyses showed a significant association with reduced disease-free survival (DFS) (p=0.01), and a trend towards significance for overall and progression-free survival (p=0.06 and p=0.05, respectively). Multivariate analyses revealed Trop-2 over-expression and advanced FIGO stage to be independent prognostic factors for poor DFS (p=0.04 and p <0.001, respectively). Conclusions: Trop-2 protein over-expression is significantly associated with higher tumor grade and serves as an independent prognostic factor for DFS in endometrioid endometrial cancer. [ABSTRACT FROM AUTHOR]

We evaluated the expression of human trophoblast cell surface marker (Trop-2) in endometrial endometrioid carcinoma (EEC) and the potential application of hRS7, a humanized monoclonal anti-Trop-2 antibody, as a therapeutic agent against poorly differentiated EEC.Trop-2 expression was evaluated by immunohistochemistry in 131 EEC with different degrees of differentiation and 32 normal endometrial controls (NEC). Trop-2 expression was also evaluated by quantitative real-time polymerase chain reaction and flow cytometry in 3 primary EEC cell lines derived from patients harboring poorly differentiated EEC. Finally, the sensitivity of grade 3 EEC cell lines to hRS7 antibody-dependent cellular cytotoxicity was tested in standard 5-hour 51Cr release assays.Trop-2 expression was detected in 126 (96.2%) of 131 EEC samples. Tumor tissues showed markedly increased Trop-2 positivity compared with NEC (P = 0.001). Trop-2 expression was significantly higher in all grades of EEC versus NEC. Grade 3 tumors displayed significantly stronger Trop-2 immunostaining compared with grade 1 EEC (P = 0.01). High Trop-2 expression by quantitative real-time polymerase chain reaction and flow cytometry was found in 1 grade 3 EEC primary cell line (EEC-ARK-1). Unlike Trop-2-negative EEC cell lines, EEC-ARK-1 was found highly sensitive to hRS7-mediated antibody-dependent cellular cytotoxicity in vitro (range of killing, 33.9%-50.6%; P = 0.004). Human serum did not significantly inhibit hRS7-mediated cytotoxicity against EEC-ARK-1 (P = 0.773).Trop-2 is highly expressed in EEC, and its expression is significantly higher in poorly differentiated EEC when compared with well-differentiated EEC. Primary grade 3 EECs overexpressing Trop-2 are highly sensitive to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for the treatment of high-grade EEC refractory to standard treatment modalities. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the serum amyloid A (SAA) expression and secretion in human endometrial carcinoma (EC). It states that to evaluate the SAA gene and protein expression levels in EC and normal endometrial, real-time polymerase chain reaction (PCR), immunohistochemistry (IHC), and flow cytometry were utilized. Results indicate that when compared with EC tissues, the SAA gene expression levels were higher in EC. It concludes that SAA is conveyed and released by G3 EC.

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer. Multimodality treatment with surgery, radiotherapy, and chemotherapy is commonly used, given its propensity for extrauterine spread, distant recurrences, and poor prognosis. However, the use of molecularly-based therapy is expanding. Here, we review key molecular features of USC, discuss current management, and assess the landscape of novel therapies and combinations. • USC is a distinct type of uterine cancer with poor prognosis, responsible for up to 40% of uterine cancer-related deaths. • Molecular features of USC include TP53 mutation, cell cycle changes, ERBB2 amplification, and changes in PI3K signaling. • Recent advances in USC therapy include addition of trastuzumab to chemotherapy in ERBB2-amplified cancers. • The combination of pembrolizumab and lenvatinib has also demonstrated substantial activity in USC. • Novel therapies targeting HER2 and PI3K signaling or the DNA damage response pathway are being developed in USC. [ABSTRACT FROM AUTHOR]

Lenvatinib and pembrolizumab (LEN+PEMBRO) demonstrated clinically meaningful and statistically significant improvements in efficacy versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer (aEC) in the phase 3 Study 309/KEYNOTE-775. Health-related quality-of-life (HRQoL) is reported. Patients were randomly assigned to receive LEN+PEMBRO (n = 411; LEN 20 mg/day; PEMBRO 200 mg Q3W) or TPC (n = 416; doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 [weekly, 3 weeks on/1 week off]). Impact of treatment on HRQoL assessed by the global health status/quality of life (GHS/QoL) score of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) was a secondary objective; other scales of the Quality-of-Life Questionnaire (QLQ-C30), EORTC QLQ-Endometrial, 24 questions (EORTC QLQ-EN24), and EuroQoL 5 dimensions, 5 levels (EQ-5D-5L) were exploratory objectives. HRQoL was assessed on day 1 of each cycle. Completion/compliance, change from baseline, time to first and definitive deterioration were assessed. No multiplicity adjustments were applied for HRQoL endpoints. The latest timepoint at which the predefined rates of completion (≥60%) and compliance (≥80%) were met was week 12. HRQoL at week 12 between treatment groups was generally similar. Time to first deterioration symptom scales favoured LEN+PEMBRO for QLQ-C30 dyspnoea, and QLQ-EN24 for poor body image, tingling/numbness, and hair loss; and TPC was favoured for QLQ-C30 pain, appetite loss, and diarrhoea, and QLQ-EN24 muscular pain. While the QLQ-C30 physical functional scale favoured TPC, other functional scales were generally similar between arms. Time to definitive deterioration favoured LEN+PEMBRO on most scales. HRQoL data from Study 309/KEYNOTE-775, with previously published efficacy and safety results, indicate that LEN+PEMBRO has an overall favourable benefit/risk profile versus TPC for the treatment of patients with aEC. NCT03517449. • HRQoL was assessed in patients with endometrial cancer in Study 309/KEYNOTE-775. • Week 12 declines from baseline in most scales were similar between treatment arms. • Some differences existed (e.g. diarrhoea favoured TPC, dyspnoea favoured LEN+PEMBRO). • Coupled with efficacy and safety data, the PRO data support use of LEN+PEMBRO in EC. [ABSTRACT FROM AUTHOR]

Objective: We sought to identify effective chemotherapy regimens against uterine serous papillary adenocarcinoma (USPC). Study Design: Six USPC, half of which overexpress HER-2/neu at 3+ level, were evaluated for growth rate and in vitro sensitivity to 14 single-agent chemotherapies and 5 combinations by ChemoFx (Precision Therapeutics Inc, Pittsburgh, PA). Results: Cell lines overexpressing HER-2/neu showed higher proliferation when compared to low HER-2/neu-expressing cell lines and a lower half maximum inhibitory concentration (IC50) when exposed to the majority of single-agent chemotherapies. High HER-2/neu expressors were more sensitive to platinum compounds, manifesting a 5.22-fold decrease in carboplatin-IC50 (P = .005) and a 5.37-fold decrease in cisplatin-IC50 (P = .02). When all cell lines were analyzed as a group, chemotherapy agents tested demonstrated lower IC50 when used in combination than as individual agents. Conclusion: USPC overexpressing HER-2/neu display greater in vitro sensitivity to platinum compounds when compared to low HER-2/neu expressors. Higher proliferative capability rather than increased drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in USPC. [Copyright &y& Elsevier]

Recurrent/metastatic endometrial adenocarcinoma that is not amenable to cure with local or regional therapy and/or chemotherapy represents a discouraging clinical entity for the clinician. We report the case of 58-year-old woman with recurrent endometrial carcinoma that was resistant to chemotherapy that was treated successfully with the aromatase inhibitor anastrozole. [Copyright &y& Elsevier]

Due to previously reported trastuzumab safety concerns and the scant data available in endometrial cancer patients, we sought to assess the safety, tolerability and toxicity profile of trastuzumab in patients with advanced/recurrent uterine serous carcinoma (USC) that overexpress HER2/neu in our multicenter randomized phase II trial. Patients were randomized 1:1 to receive carboplatin/paclitaxel (C/P) for 6 cycles ± trastuzumab (T) with the experimental arm continuing to receive single agent trastuzumab maintenance treatment until disease progression/toxicity. Progression-free-survival was the primary endpoint; overall-survival and toxicity were secondary endpoints. Adverse events (AEs) were compared between treatment arms. There were 28 patients in the C/P arm and 32 patients in the experimental (C/P + T) arm. Fifty-eight patients (97%) experienced 977 treatment-related AEs of which 875 (89.6%) were low-grade (grade 1–2) and 102 (10.4%) were high-grade (grade 3–5). The mean ± standard deviation of AEs per patient was 15.5 ± 16.3 in the C/P arm and 17.0 ± 16.0 in the C/P + T arm. Gastrointestinal AEs were the most common in both arms (n = 155, 15.7%) of which 94.2% were low-grade (n = 146). Importantly, no significant difference between treatment arms was detected in any system-organ class of AE including cardiac AE. Five (17%) of 29 patients who received prolonged trastuzumab maintenance therapy had no sign of cumulative toxicity after an average (range) of 5.1 (4.2–6.3) years. Trastuzumab appears to be safe and has a manageable toxicity profile both when used in combination with chemotherapy and when used for single agent maintenance in patients with HER2/neu positive USC. This safety profile is reassuring given the proven efficacy of trastuzumab in advanced/recurrent HER2/neu positive USC. • Our patients received an average of 21.2 and maximum of 94 cycles of Trastuzumab without significant toxicity. • The majority of adverse events were low-grade, most commonly fatigue, nausea, and constipation. • Patients who received trastuzumab maintenance had no sign of increased toxicity after an average of 5.1 years of treatment. • Elderly patients (≥70 years old) were more likely to experience a high-grade adverse event in both treatment arms. • Trastuzumab with chemotherapy appears to be safe and has a manageable toxicity profile in patients with HER2/Neu-positive USC. [ABSTRACT FROM AUTHOR]

Objective Around 7-10% of endometrial carcinomas are characterized by polymerase-e-(POLE) exonuclease-domain-mutations, an ultra-mutated-phenotype and a favorable prognosis. It is currently unknown whether POLE ultra-mutated-tumors are more immunogenic when compared to the other groups of endometrial cancers. Methods We used autologous-dendritic-cells (DC) pulsed with whole-tumor-extracts to assess the level of CD8 + and CD4 + T-cell-activation induced by POLE-ultramutated (+) and POLE wild-type (-) endometrial cancer cells in vitro. T-lymphocyte-proliferations were evaluated using CFSE and/or [3H]thymidine-incorporation-assays while the ability to specifically kill autologous-tumor-cells by cytotoxic-T-lymphocyte (CTL) was tested in standard 4-h-51Cr-cytotoxicity-assays. In order to correlate cytotoxic activity and proliferation by CD4 + and CD8 + T-lymphocytes, respectively, with a particular lymphoid subset, two-color-flow-cytometric analysis of intracellular-cytokine-expression (IFN-? vs IL-4) at the single cell level was also performed. Results DC-pulsed with tumor extracts were able to induce CTL-responses against autologous-tumor-cells in both POLE (+) and POLE (-) cancer patients (P = 0.305). These CD8 + T-cell-populations were cytotoxic against tumor-cells but they did not lyse PHA-stimulated-autologous-lymphocytes or autologous-EBV-transformed-lymphoblastoid-control-cell-lines. In contrast, only POLE (+) tumor-lysate-pulsed-DC were able to induce significant proliferation and high IFN-? expression (i.e., Th1-cytokine-bias) in autologous in vitro DC-stimulated CD4 + T-cells as well as naïve CD4 + and CD8 + T-cells from patients-peripheral-blood (P < 0.05). Conclusions POLE ultra-mutated-tumors are significantly more immunogenic when compared to POLE (-) tumors, in particular to the helper arm of the immune system. These data lend support to the hypothesis that the better prognosis of patients with POLE (+) tumors may at least in part be linked to their enhanced immunogenicity. [ABSTRACT FROM AUTHOR]

Objective To describe the clinical outcome and tolerability of weekly ixabepilone (16-20 mg/m² days 1, 8, 15 of a 28-day cycle) ± biweekly bevacizumab (10 mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. Methods A single-institution retrospective review was performed inclusive of all patients who received ≥ 2 cycles from 01/2010 to 06/2014. Progression-free (PFS) and overall (OS) survival were determined using the Kaplan-Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. Results A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range:1-10) prior lines of chemotherapy. Patients completed a mean of 4.7 ± 2.9 cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, objective response rate (ORR) was 41.7% (12.5% complete, 29.2% partial); median duration of response or stabilization was 7 months (range:2-30). Median PFS and OS were 5.2 and 9.6 months, respectively. PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0 months, p = 0.01, HR 0.2, 95% CI 0.05-0.77; 9.6 versus 4.2 months, p = 0.02, HR 0.58, 95% CI 0.04-0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. Conclusions Weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane-resistant endometrial and ovarian cancers. This combination warrants further prospective study in these populations. [ABSTRACT FROM AUTHOR]

Objectives Uterine serous carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associated with USC in approximately 30-35% of cases. The objective of this study was to determine the sensitivity of a panel of primary USC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo. Methods HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro. Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo. Results HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean ± SEM IC50: 0.011 ?M ± 0.0008 vs. 0.312 ?M ± 0.0456 p < 0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p = 0.0019). Conclusions Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare the outcomes of 155 cases of endometrial cancer who had robot-assisted surgical staging to 150 open cases. Methods: Retrospective chart review of cases of endometrial cancer that underwent staging two different ways by two surgeons at an academic institution. Results: Mean age was 62.4years in the robotic arm and 65 (P =0.04) in the open arm. Mean body mass index was 34.5Kg/m2 in the robotic arm and 33Kg/m2 in the open arm (P =0.2). Pelvic and para-aortic lymph node dissection were performed in 94.8% and 67.7% of the robotic cases versus 95.3% and 74% of the open cases, respectively. Mean operative time was 127min in the robotic arm, and 141min in the open arm (P =0.0001). Mean lymph node count was 20.3 in the robotic arm, and 20 in the open arm (P =0.567). Mean estimated blood loss was 119ml in the robotic arm and 185 in the open arm (P =0.015). Mean hospital stay was 1.5days in the robotic arm, and 4days in the open arm (P =0.0001). The incidence of postoperative ileus (0.6% vs. 10.7%, P=0.0001), infections (5.2% vs. 24%, P =0.0001), anemia/transfusion (1.3% vs. 7.7%, P =0.005), and cardiopulmonary complications (3.2% vs.14.7%, P =0.003) was significantly lower in the robotic arm vs. the open arm. There was one death in the robotic arm attributed to pre-existing cardiac condition. Conclusion: Robotic-assisted staging reaps the benefits of minimally invasive surgery without compromising the adequacy of the procedure. Dedication to the technique shortens the operative time. [Copyright &y& Elsevier]

Abstract: Purpose.: To evaluate and compare autocrine expression and production of interleukin-6 (IL-6), a pleiotropic cytokine involved in the resistance to cytotoxic agents and inhibition of anti-tumor immune function in endometrial carcinoma in vitro as well as in vivo. Patients and methods.: IL-6 gene expression levels were evaluated in twenty-four primary endometrial tumors including 14 endometrioid carcinomas (EC) and 10 uterine serous papillary carcinoma (USPC) as well as in normal control endometrial cells (NEC) by real-time PCR. Secretion of IL-6 protein by 6 primary endometrial tumor cultures including USPC and EC was measured using a sensitive enzyme-linked immunosorbent assay (ELISA) in vitro. Finally, IL-6 concentration in 71 serum samples including 20 apparently healthy women, 19 women with benign abdominal diseases, 19 women with primary EC, and 13 USPC patients was studied. Results.: IL-6 gene expression levels were significantly higher in USPC when compared to EC (mean copy number by RT-PCR = 313 ± 55 vs. 53 ± 11, USPC vs. EC, respectively: P &#60; 0.01). IL-6 serum concentrations between normal healthy females (range 0.01–21.23 pg/ml; mean 3.1 pg/ml) and benign disease patients (range 0.01–95.77 pg/ml; mean 13.07 pg/ml) were not statistically different. In contrast, significantly higher levels of IL-6 were detected in both patients with EC (range 2.86–82.13 pg/ml; mean 20.43 pg/ml) and patients with UPSC (range 16.3–500.1 pg/ml; mean 125.7 pg/ml) when compared to the healthy females (P &#60; 0.01), with a mean serum IL-6 level in USPC patients 6.1-fold higher when compared to EC patients (P &#60; 0.03). Accordingly, higher levels of IL-6 secretion were noted in primary USPC cell lines (mean 3121 pg/ml, range between 1099 and 5017 pg/ml/105 cells/48 h) when compared to primary EC (mean 88, range between 19 and 112 pg/ml/105 cells/48 h) (P &#60; 0.01) in vitro. Conclusions.: IL-6 is highly expressed in USPC, and it is released in high concentration in the serum of USPC patients. IL-6 may be a novel biomarker for USPC. Drugs used to inhibit the expression of IL-6 or the IL-6 signal transduction pathway may potentially be highly beneficial in USPC. [Copyright &y& Elsevier]