Uterine Serous Carcinoma Research Articles

Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort

Uterine serous carcinoma (USC) is a rare, aggressive malignancy accounting for 40% of all endometrial cancer deaths. Human Epidermal Growth Factor Receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in USC. Given recent randomized trial results, HER2-directed therapy is now recommended in advanced-stage or recurrent, HER2-positive disease. The objective of this study is to establish the significance of tumoral HER2 expression in early-stage disease.

Tumor Recurrence Rate and Survival Outcomes of Uterine Serous Carcinoma after Surgical Treatment

Background: Uterine serous carcinoma is a rare histologic subtype of endometrial cancer. Oncologic outcomes for this disease are sparsely reported, and adjuvant therapy after surgery is considerably heterogeneous. Objective: To determine the 2-year recurrence rate, recurrence-free survival, overall survival, and associated factors among patients with uterine serous carcinoma after surgical treatment at Siriraj Hospital. Materials and Methods: One hundred thirty uterine serous carcinoma patients diagnosed between December 2007 and June 2015 were enrolled. Patients who did not undergo surgery as a primary treatment or not achieve clinically complete response were excluded. Pathological slides were reviewed. Data were retrieved from the medical records including gynecologic data, surgical and pathological results, post-operative treatment, response status, recurrence status, and follow-up data. The recurrence rate at two years was calculated. Recurrence-free survival and overall survival were analyzed, and various characteristics were used to determine associated treatment outcomes. Results: One hundred nine patients were analyzed, 50 in stage I, 15 in stage II, 38 in stage III, and six in stage IV. Median follow-up time was 23 months. At two years, the recurrence rate was 35.8%. Post-operative treatment was performed in 91.7%, and chemotherapy was the most common modality used. Eleven patients (16.9%) in early-stage and twenty-five patients (56.8%) in the advanced stage had disease recurrence. Thirty patients (83.3%) had disease recurrence intra-abdominal or multiple metastases. No patient in stage I that received adjuvant chemotherapy had relapsed disease. Two-year recurrence-free survival and 2-year overall survival were 71.2% and 83.4%, respectively. FIGO staging was the only factor associated with recurrence-free survival. Conclusion: Uterine serous carcinoma represents a rare disease with a high recurrence rate and poor prognosis. FIGO staging is related to recurrence-free survival. Adjuvant chemotherapy showed survival benefits in early-stage uterine serous carcinoma. Keywords: Uterine serous carcinoma, Adjuvant therapy, Recurrence, Survival

Comparing mutation frequencies for homologous recombination genes in uterine serous and high-grade serous ovarian carcinomas: A case for homologous recombination deficiency testing in uterine serous carcinoma

Objective: Our goal was to compare the frequencies of somatic homologous recombination (HR) gene mutations identified in next-generation sequencing (NGS) genomic profiling of uterine serous carcinomas (USCs) and high-grade serous ovarian carcinomas (HGSOCs).

A novel model to predict cancer-specific survival in patients with early-stage uterine papillary serous carcinoma (UPSC)

Objective: Stage I–II uterine papillary serous carcinoma (UPSC) has aggressively biological behavior and leads to poor prognosis. However, clinicopathologic risk factors to predict cancer-specific survival of patients with stage I–II UPSC were still unclear. This study was undertaken to develop a prediction model of survival in patients with early-stage UPSC.

Perioperative factors affecting women with uterine serous carcinoma

Objective: Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer with a higher likelihood of lymphatic and intraperitoneal spread than endometrioid adenocarcinoma. About two-thirds of women with USC will have extra-uterine disease at initial presentation. Our goal was to determine the perioperative prognostic indicators that affect overall survival (OS) and progression-free survival (PFS) in women with USC.

Novel, immediately druggable targets in the ARK1 model of uterine serous papillary carcinoma (USPC): Proof-of-principle and clinical implications of blocking oncologically relevant posttranslational hydroxylations with a pioneer drug

Objective: The oxygenases that hydroxylate key proteins in cancer biology employ non-heme iron atoms for catalysis. Drugs targeting these atoms inhibit posttranslational hydroxylation (PTH) in preclinical tests and clinical trials. At clinical concentrations (≤150 μM), the drug deferiprone (DEF) blocks these non-heme iron atoms and thus every known PTH. The purpose of our study was to establish target expression response to DEF-blocked PTH activity in the ARK1 model of uterine serous papillary carcinoma (USPC).

Genome-directed identification of novel, immediately druggable targets in uterine serous papillary carcinoma (USPC)

Objective: Proteins whose function requires posttranslational hydroxylation (PTH) are pivotal for cancer biology. The purpose of our study was to establish expression of PTH-dependent proteins and their oxygenases in the genetically verified ARK1 culture model of uterine serous papillary carcinoma (USPC). This cancer is clinically notorious for limited treatment options and extraordinary lethality.

Randomized phase II trial of carboplatin-paclitaxel compared to carboplatin-paclitaxel-trastuzumab in advanced or recurrent uterine serous carcinomas that overexpress HER2/Neu (NCT01367002): Updated survival analysis

Objective: HER2/Neu is a growth-factor receptor expressed in 30% of uterine serous carcinomas (USC). Based on the preliminary results of a multicenter, randomized phase II trial, trastuzumab (a humanized monoclonal antibody targeting HER2/Neu) in combination with carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu+ USC. Herein, we report updated survival data.

A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma

Objective: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma characterized by frequent TP53 mutations (>90%), often concomitantly with oncogenic mutations or amplifications that can increase replication stress. We hypothesized that USCs would therefore be uniquely sensitive to further interference of cell cycle regulation by Wee1 inhibition. This 2-stage single-arm phase 2 study was conducted to assess the activity of the oral Wee1 inhibitor adavosertib as monotherapy in recurrent USCs.

Is platinum-free interval relevant in recurrent uterine serous carcinoma?

Objective: Uterine serous carcinoma (USC) behaves aggressively and carries a poor prognosis. The study objective was to delineate platinum-free interval and other variables that may pose a prognostic impact on patients with recurrent USC.

The role of the microbiome in predicting development of uterine cancer

Objective: The human microbiome is thought to influence the inflammatory response and cancer development. This pilot study aimed to characterize the role of the gastrointestinal, cervico-vaginal, and endometrial microbiome in uterine cancer development in postmenopausal women with benign conditions, grade 1 endometrioid adenocarcinoma (EC), and uterine serous carcinoma (USC).

Long-term survival results of minimally invasive surgery in patients with uterine serous carcinoma

Long-term survival results of minimally invasive surgery in patients with uterine serous carcinoma

Recurrence patterns and recurrence free survival following primary surgical staging among women with early-stage uterine serous carcinoma who receive adjuvant vaginal brachytherapy in addition to chemotherapy versus chemotherapy alone

Objective: The purpose of this study was to evaluate the effect of adding vaginal brachytherapy (VBT) to adjuvant chemotherapy on patterns of recurrence and recurrence-free survival (RFS) among women with stage I–II uterine serous carcinoma (USC).

The role of CCNE1 amplification in refractory ovarian and endometrial cancer

Objective: CCNE1 gene amplification has been associated with decreased disease-free survival rates in different types of cancers. Cyclin E1 (CCNE1) gene amplification has been reported in 15%–20% of high-grade serous ovarian tumors and 89.5% of uterine serous carcinomas. This study investigated the role of CCNE1 amplification in ovarian and endometrial cancer in determining prognosis and survival.

Adjuvant treatment for patients with FIGO stage I uterine serous carcinoma confined to the endometrium

Adjuvant treatment for patients with FIGO stage I uterine serous carcinoma confined to the endometrium

The Impact of Different Adjuvant Managements on Survival Endpoints in Women with Adequate Surgical Staging Early Stage Uterine Serous Carcinoma

Non-endometrioid carcinomas, which includes uterine serous carcinoma (USC), comprise only 15% of all endometrial carcinomas but cause about 40% of deaths in this patient population. The ideal adjuvant management of patients with early-stage USC is remains unknown. To report survival outcomes in women with early stage USC after adequate surgical staging with various adjuvant management options. After IRB study approval, our prospectively-maintained database for women with endometrial carcinoma was queried for women with 2009 International Federation of Gynecology and Obstetrics (FIGO) stages I-II USC based on WHO pathologic definition who underwent adequate surgical staging between 1/1991 and 4/2017 followed by adjuvant management [surveillance, radiation treatment (RT) or chemotherapy (CT) or combination (CRT)]. Chi-squared tests were performed to compare differences in outcome by type of adjuvant management. Recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were assessed by Kaplan-Meier and log-rank tests. Univariate and multivariate analyses were performed to identify statistically significant predictors of survival endpoints. We identified 155 women who met our inclusion criteria. The median follow-up time was 54.8 months. 75% of the study cohort were with stage IA, 14% stage IB and 11% with stage II. All women underwent pelvic lymph node dissection with a median number of dissected lymph nodes of 15. Omentectomy was performed in 62% of women. Adjuvant RT was utilized in 55% of women (54 with vaginal brachytherapy alone, 22 with pelvic RT and 10 with combination). Most commonly used chemotherapy was carboplatin and paclitaxel with a median number of cycles of 6 5-year RFS was 78% for those received CRT, 84% for RT alone, 65% who received CT alone and 48% for those who were observed (p=0.03). 5-year DSS was 79%, 92%, 66% and 53%, respectively (p=0.02). 5-year OS was 76%, 79%, 63% and 53%, respectively (p=0.21). On multivariate analysis of OS, old age, and not receiving any adjuvant therapies were independent predictors of worse OS. Independent predictors of better RFS and DSS included adjuvant RT alone or with chemotherapy, and lack of lymphovascular space invasion. In this cohort of women with adequate surgical staging, adjuvant radiation treatment with or without chemotherapy is associated with reduced tumor recurrence with improved survival endpoints.

Comparing mutation frequencies for homologous recombination genes in uterine serous and high-grade serous ovarian carcinomas: A case for homologous recombination deficiency testing in uterine serous carcinoma

ObjectiveTo compare the frequencies of somatic homologous recombination (HR) gene mutations identified in next-generation sequencing (NGS) genomic profiling of uterine serous carcinomas (USCs) and high-grade serous ovarian carcinomas (HGSOCs). MethodsData for this analysis was obtained from AACR Project GENIE, a multi-institutional dataset of clinical-grade NGS genomic profiling results for many cancer sites and histologic subtypes, through cBioPortal. Patient/specimen groups used for analysis were USC and HGSOC.14 HR genes were queried for each group with respect to mutation frequency. For each HR gene, the difference in mutation frequency between the two groups was evaluated using Fisher's exact test. The threshold for statistical significance was p-value < .05. ResultsIn the USC group, there were 457 samples from 451 patients. In the HGSOC group, there were 1537 samples from 1515 patients. The most frequently mutated HR gene for USC was BRCA2 (4.84%) and for HGSOC was BRCA1 (9.07%). Mutation frequency was significantly different between USC and HGSOC for BRCA 1 (p < .001) and BRCA2 (p = .0379). For the 12 non-BRCA HR genes, mutation frequency was not significantly different between USC and HGSOC. The rate of patients with at least one HR gene mutation in their profiled tumor was 16.85% for USC and 25.21% of HGSOC. Most USC patients with a somatic HR mutation had only one HR gene mutated. ConclusionsSomatic HR gene mutations were commonly identified in NGS genomic profiling of USC. Mutation frequencies for non-BRCA HR genes were not significantly different between USC and HGSOC. These data add to the growing rationale for HR deficiency tumor testing and targeting (e.g., with PARP inhibitors) in future clinical trial development for women with USC.

Thrombocytosis as a Biomarker in Type II, Non-Endometrioid Endometrial Cancer.

Thrombocytosis (platelets ≥ 400K) is a common hematologic finding in gynecologic malignancies and associated with worse outcomes. Limited data exist on the prognostic capability of thrombocytosis in women with high-grade endometrial cancer (EC). Our objective was to describe the associations between elevated platelets at diagnosis, clinicopathologic features, and survival outcomes among women with high-grade, non-endometrioid EC. A review of the institutional cancer registry was performed to identify these women treated between 2005 and 2017. Sociodemographic, clinical, and outcomes data were collected. Analyses were performed using chi-square tests, Cox proportional hazards models, and the Kaplan–Meier method. A total of 271 women were included in the analysis. A total of 19.3% of women had thrombocytosis at diagnosis. Thrombocytosis was associated with reduced median overall survival (OS) compared with those not displaying thrombocytosis (29.4 months vs. 60 months, p < 0.01). This finding was most pronounced in uterine serous carcinoma (16.4 months with thrombocytosis vs. 34.4 months without, p < 0.01). While non-White women had shorter median OS for the whole cohort in the setting of thrombocytosis (29.4 months vs. 39.6 months, p < 0.01), among those with uterine serous carcinoma (USC), this finding was reversed, with decreased median OS in White women (22.1 vs. 16.4 months, p = 0.01). Thrombocytosis is concluded to have negative associations with OS and patient race.

Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study

BackgroundHuman epidermal growth factor receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in advanced stage and recurrent uterine serous carcinoma (USC). The significance of tumoral HER2 expression in early-stage disease has not been established. MethodsThis multi-center cohort study included women with stage I USC treated from 2000 to 2019. Demographic, treatment, recurrence, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0–3+. Equivocal IHC results (2+) were further tested with fluorescence in-situ hybridization (FISH). HER2 positivity was defined as 3+ IHC or FISH positive. ResultsOne hundred sixty-nine patients with stage I USC were tested for HER2; 26% were HER2-positive. There were no significant differences in age, race, stage, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. Presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p = .003).After a median follow-up of 50 months, there were 43 (25.4%) recurrences. There were significantly more recurrences in the HER2-positive cohort (50.0% vs 16.8%, p < .001). HER2 positive tumors were associated with worse progression-free (PFS) and overall survival (OS) (p < .001 and p = .024). On multivariate analysis, HER2 positive tumors were associated with inferior PFS (aHR 3.50, 95%CI 1.84–6.67; p < .001) and OS (aHR 2.00, 95%CI 1.04–3.88; p = .039) compared to HER2-negative tumors. ConclusionsGiven its significant association with worse recurrence and survival outcomes, HER2 positivity appears to be a prognostic biomarker in women with stage I uterine serous carcinoma. These data provide support for clinical trials with anti-HER2-directed therapy in early-stage disease.

Adjuvant treatment for patients with FIGO stage I uterine serous carcinoma confined to the endometrium

ObjectivesThe role of adjuvant treatment for early-stage uterine serous carcinoma is not defined. The goal of this study was to investigate the impact of adjuvant treatment on survival of patients...