Uterine Papillary Serous Carcinoma Patients Research Articles

TXNDC17 protein overexpression in uterine papillary serous carcinoma is associated with clinicopathological characteristics and prognosis

Objective: To analyze clinicopathological characteristics of patients with uterine papillary serous carcinoma (UPSC) in China, and investigate roles of TXNDC17 protein in UPSC clinicopathological characteristics and prognosis. Methods: Fifty-five patients with UPSC treated in Women's Hospital School of Medicine Zhejiang University from 2003 to 2016 were analysed retrospectively. Immunohistochemistry (IHC) were performed to TXNDC17 and BECN1 (Beclin 1 protein, a key regulator of autophagy) protein expression respectively. Kaplan-Meier was used to calculate the cumulative survival rate, Log-rank test was performed to compare the difference in cumulative survival rate among patients with different clinicopathological characteristics, and Cox regression model was used to analyze the related between TXNDC17 expression and prognosis of UPSC patients. Results: The median age of the 55 UPSC patients was 63(49, 79) years, 43.6%(24/55) with late stages (stage Ⅲ/Ⅳ), and 32.7 % (18/55) exhibiting more than half of myometrium invasion were enrolled. Notably, 28 (50.9%) patients had TXNDC17 protein overexpression, and associated with BECN1 overexpression(P=0.023). Besides, co-expression of TXNDC17 and BECN1 occurred at an advanced stage and deep myometrial invasion (P=0.013,0.009). The cumulative survival rate of TXNDC17 overexpression(37.4% vs 91.5%),FIGO Ⅲ/Ⅳ stage(44.1% vs 70.1%), deep myometrium invasion(36.1% vs 75.4%) and BECN1 overexpression(0 vs 83.0%)patients was low (P<0.05). The multivariate proportional hazards model revealed that myometrial invasion and TXNDC17 overexpression were associated with prognosis of UPSC patients. Conclusions: This study shows that TXNDC17 overexpression is associate with poor survival in UPSC patients. Co-expression of TXNDC17 and BECN1 shows characteristics of advanced stages and deep myometrial invasion. TXNDC17 may be a potential predictor or target in UPSC therapeutics..

Adjuvant vaginal interventional radiotherapy in early-stage non-endometrioid carcinoma of corpus uteri: a systematic review.

PurposeThis systematic review focused on rare histological types of corpus uteri malignancy, including uterine carcinosarcoma (UCS), uterine clear cell carcinoma (UCCC), and uterine papillary serous carcinoma (UPSC), and it is proposed to assist with clinical decision-making. Adjuvant treatment decisions must be made based on available evidences. We mainly investigated the role of vaginal interventional radiotherapy (VIRt) in UCS, UCCC, and UPSC managements.Material and methodsA systematic research using PubMed and Cochrane library was conducted to identify full articles evaluating the efficacy of VIRt in early-stage UPSC, UCCC, and UCS. A search in ClinicalTrials.gov was performed in order to detect ongoing or recently completed trials as well as in PROSPERO for ongoing or recently completed systematic reviews. Survival outcomes and toxicity rates were obtained.ResultsAll studies were retrospective. For UCS, the number of evaluated patients was 432. The 2- to 5-year average local control (LC) was 91% (range, 74.2-96%), disease-free survival (DFS) 88% (range, 82-94%), overall survival (OS) 79% (range, 53.8-84.3%), the average 5-year cancer-specific survival (CSS) was 70% (range, 70-94%), and G3-G4 toxicity was 0%. For UCCC, the number of investigated patients was 335 (UCCC – 124, mixed – 211), with an average 5-year LC of 100%, DFS of 83% (range, 82-90%), OS of 93% (range, 83-100%), and G3-G4 toxicity of 0%. For UPSC, the number of examined patients was 1,092 (UPSC – 866, mixed – 226). The average 5-year LC was 97% (range, 87.1-100%), DFS 84% (range, 74.7-95.6%), OS 93% (range, 71.9-100%), CSS 89% (range, 78.9-94%), and G3-G4 toxicity was 0%.ConclusionsThese data suggest that in adequately selected early-stage UPSC and UCCC patients, VIRt alone may be suitable in women who underwent surgical staging and received adjuvant chemotherapy. In early-stage UCS, a multidisciplinary therapeutic approach has to be planned, considering high-rate of pelvic and distant relapses.

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

ObjectiveStage I‐II uterine papillary serous carcinoma (UPSC) has aggressive 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.MethodsUsing Surveillance, Epidemiology, and End Results (SEER) database, 964 patients were identified with International Federation of Gynecology and Obstetrics (FIGO) stage I‐II UPSC who underwent at least hysterectomy between 2004 and 2015. By considering competing risk events for survival outcomes, we used proportional subdistribution hazards regression to compare cancer‐specific death (CSD) for all patients. Based on the results of univariate and multivariate analysis, the variables were selected to construct a predictive model; and the prediction results of the model were visualized using a nomogram to predict the cancer‐specific survival and the response to adjuvant chemotherapy and radiotherapy of stage I‐II UPSC patients.ResultsThe median age of the cohort was 67 years. One hundred and sixty five patients (17.1%) died of UPSC (CSD), while 8.6% of the patients died from other causes (non‐CSD). On multivariate analysis, age ≥ 67 (HR = 1.45, P = .021), tumor size ≥ 2 cm (HR = 1.81, P = .014) and >10 regional nodes removed (HR = 0.52, P = .002) were significantly associated with cumulative incidence of CSD. In the age ≥67 cohort, FIGO stage IB‐II was a risk factor for CSD (HR = 1.83, P = .036), and >10 lymph nodes removed was a protective factor (HR = 0.50, P = .01). Both adjuvant chemotherapy combined with radiotherapy and adjuvant chemotherapy alone decreased CSD of patients with stage I‐II UPSC older than 67 years (HR = 0.47, P = .022; HR = 0.52, P = .024, respectively). The prediction model had great risk stratification ability as the high‐risk group had higher cumulative incidence of CSD than the low‐risk group (P < .001). In the high‐risk group, patients with post‐operative adjuvant chemoradiotherapy had improved CSD compared with patients who did not receive radiotherapy nor chemotherapy (P = .037). However, there was no such benefit in the low‐risk group.ConclusionOur prediction model of CSD based on proportional subdistribution hazards regression showed a good performance in predicting the cancer‐specific survival of early‐stage UPSC patients and contributed to guide clinical treatment decision, helping oncologists and patients with early‐stage UPSC to decide whether to choose adjuvant therapy or not.

Can morphometric analysis of the fallopian tube fimbria predict the presence of uterine papillary serous carcinoma (UPSC)?

Uterine serous papillary carcinoma (UPSC) is an aggressive tumor, often diagnosed as a metastatic disease and characterized by a high recurrence rate and poor prognosis. UPSC represents a distinct subtype of endometrial cancer which is different in clinical and pathological behaviors from endometrioid endometrial carcinoma (EEC) and resembles more to serous ovarian carcinoma. Since tumors of serous papillary of the ovary are hypothesized to stem from cells of the fallopian tube's fimbria, we hypothesized that UPSC may also origin in the fallopian tubes. In our previous study, using a novel method of computerized morphometry of the fimbrial epithelium we have found significant differences between fimbriae of healthy women and serous ovarian cancer patients. In this study we showed the presence of morphologic differences between twenty-four fimbriae from healthy women, and twenty six fimbriae from uterus cancer (13 from UPSC patients and 13 from EEC patients). All fimbriae reported by the pathologist as "normal" were subjected to a computerized histomorphometric analysis. Two-step method of computerized histomorphometry, i.e. Fast Fourier transformation (FFT) followed by a co-occurrence matrix analysis and an additional analysis of the nuclear symmetry of the tubal fimbrial epithelium were applied. Using these novel methods, we were able to show differences in the morphometric characteristics of the fimbriae in UPSC patients compared to EEC and healthy patients. It is yet to be determined the clinical significance of this observation.

Clinicopathological and survival analysis of uterine papillary serous carcinoma: a single institutional review of 106 cases.

ObjectivesThe objectives of this study were to analyze clinicopathological features and to investigate the prognostic determinants in patients with uterine papillary serous carcinoma (UPSC).Materials and methodsA cohort of 106 UPSC patients diagnosed and treated at Peking Union Medical College Hospital between 2000 and 2016 were retrospectively reviewed. The Kaplan–Meier method and Cox regression analysis were used for survival analysis. Differences between categorical data were calculated by using the chi-squared test.ResultsThe median follow-up was 29.0 months (range =2–170 months), with an overall recurrence rate of 35.8%. The coincidence rate between preoperative endometrial sampling and postoperative definitive pathology of hysteroscopy group was significantly higher than that of the dilation and curettage group (88.5% vs 65.0%, P=0.019). Adjuvant therapy-treated patients with stage I UPSC experienced significantly fewer recurrences than those receiving observation (P=0.003). Patients with advanced-stage UPSC who received combination therapy demonstrated a lower risk of local recurrence compared with those who received chemotherapy alone with a borderline significance (P=0.051). Elevated serum cancer antigen 125 level was associated with advanced-stage disease and recurrence (P<0.001). In multivariate analysis, tumor stage and optimal cytoreduction were independent predictors of survival. In substage analysis, complete surgical staging was associated with better overall survival (OS; yes vs no, HR: 0.05 [95% CI: 0.01–0.51], P=0.037) in patients with stage I UPSC. As for advanced stage, paclitaxel–platinum chemotherapy regimen and optimal cytoreduction were independent favorable prognostic factors for progression-free survival (paclitaxel–carboplatin [TC] vs other; HR =0.38, P=0.010; yes vs no, HR =0.45, P=0.032) and OS (TC vs other, HR =0.38, P=0.022; yes vs no, HR =0.54, P=0.013).ConclusionIn patients with stage I UPSC, complete staging was associated with better OS, and therefore, it should be performed in all patients. Tumor stage and optimal cytoreduction are the most significant prognostic factors. Recurrence can be improved in stage I patients treated with adjuvant therapy and in patients with advanced-stage disease treated with combined therapy. TC regimen may be the preferred regimen for chemotherapy.

Adjuvant Pelvic Radiation Therapy±Vaginal Brachytherapy in Patients With High-risk Stage I or Stage II Uterine Papillary Serous, Clear Cell, and High-grade Endometrioid Carcinoma.

Radiation therapy (RT) for stages I-II uterine papillary serous carcinoma (UPSC), clear cell (CC), and high-grade endometrioid (HGE) carcinoma present a treatment challenge. Regimens include external beam radiotherapy (EBRT) with or without brachytherapy. We examine the use of these radiation modalities in these endometrial cancers (EC) with respect to cause-specific survival (CSS). The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with AJCC stages I-II UPSC, CC, or HGE cancer treated with hysterectomy and RT between 1998 and 2008. Patients who did not receive adjuvant RT or received brachytherapy alone were excluded. CSS was evaluated by the Kaplan-Meier survival analysis and the log-rank test was used to compare CSS. Multivariate analysis was performed using the Cox proportional hazards regression model. Adjusted hazard ratios (HR) were calculated for risk of EC death. There were 1653 patients included in this analysis. The overall 100-month CSS for the entire cohort was 81.0%. The 100-month CSS was 85.3% for EBRT alone and 86.5% for EBRT+brachytherapy (P=0.72). Stage IC/IIA/IIB patients had a greater risk of EC death compared with stage IA/IB patients (adjusted HR=2.39; P<0.0001). Patients with UPSC and CC had a slightly higher risk of EC death compared with HGE (adjusted HR=1.01 [P=0.97] and 1.42 [P=0.02], respectively). On subset analysis, there was no difference in CSS with the addition of brachytherapy for UPSC (P=0.37), CC (P=0.27), or HGE cancer patients (P=0.42). Patients treated with brachytherapy in addition to EBRT did not demonstrate a reduced adjusted risk of EC death compared with EBRT alone (P=0.38). The addition of brachytherapy to adjuvant EBRT in stages I-II UPSC, CC, and HGE cancer did not demonstrate superior CSS. Thus, patients may not benefit from the addition of brachytherapy to EBRT.

Pedigree analysis of uterine papillary serous carcinoma patients

Pedigree analysis of uterine papillary serous carcinoma patients

Abstract 3559: Ubiquitin C-terminal hydrolase L1 (UCHL1) modulates uterine papillary serous cancer progression through interaction with cyclin B1

Abstract Background: Uterine papillary serous carcinoma (UPSC) comprises less than 10% of all endometrial cancers but accounts for a disproportionately high number of deaths. Few prospective studies focus solely on this aggressive subtype, making it difficult to determine optimal treatment strategies. The purpose of this study was therefore to identify novel therapeutic targets that could aid in the management of UPSC. Methods: Clinical and RNA sequencing data from The Cancer Genome Atlas (TCGA) was used to identify genes that were differentially expressed between endometrioid endometrial carcinoma (EEC) and UPSC, which also showed a significant association with overall patient survival duration in UPSC patients. Ubiquitin C-terminal hydrolase L1 (UCHL1) upregulation and correlation with survival was validated by immunohistochemical staining of an independent cohort of paraffin samples. UCHL1 was silenced by siRNA transfection and lentiviral shRNA transduction in UPSC cell lines ARK1, ARK2 and HEC50 to evaluate the role of UCHL1 on cell proliferation, migration and cell cycle progression. RPPA data from TCGA was used to identify proteins whose expression correlated with UCHL1 expression. Interaction between UCHL1 and cyclin B1 was determined by co-immunoprecipitation. The effect of UCHL1 silencing on cyclin B1 levels was evaluated by Western blot analysis, and the effect on cell cycle progression was determined by flow cytometry. Results: UCHL1 mRNA and protein expression levels were significantly higher in in UPSC compared to EEC. Kaplan-Meier analysis and cox regression of the TCGA data set and an independent cohort of patient samples revealed that UCHL1 expression correlated significantly with poorer overall survival in UPSC, especially in late-stage patients. siRNA-mediated silencing did not affect cell migration, but reduced the proliferation rates of ARK1, ARK2 and HEC50 in vitro. UCHL1 RNA expression was positively correlated with cyclin B1 protein levels in the TCGA data set. Accordingly, UCHL1 silencing reduced cyclin B1 protein but not mRNA expression levels in ARK1, ARK2 and HEC50. Cell cycle analysis of ARK1, ARK2 and HEC50 after UCHL1 silencing showed a reduction in the percentage of cells in the S and G2/M phases, with or without cell synchronization. Conclusion: These findings indicate that UCHL1 contributes to the aggressiveness of UPSC by stabilizing cyclin B1 and increasing cell proliferation, suggesting that it may be a therapeutic target for UPSC. Citation Format: Suet Ying Kwan, Samuel C. Mok, Kwong-Kwok Wong, Rosemarie E. Schmandt, Karen H. Lu. Ubiquitin C-terminal hydrolase L1 (UCHL1) modulates uterine papillary serous cancer progression through interaction with cyclin B1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3559. doi:10.1158/1538-7445.AM2015-3559

Impact of management on the prognosis of pure uterine papillary serous cancer — A Taiwanese Gynecologic Oncology Group (TGOG) study

ObjectiveTo investigate the clinical and pathological characteristics and the management of uterine papillary serous carcinoma (UPSC) in relation to patients' outcomes. MethodsClinicopathological data and the management of patients treated between 1991 and 2010 at 11 member hospitals of the Taiwanese Gynecologic Oncology Group (TGOG) were retrospectively reviewed. The Kaplan–Meier method was used to generate survival curves, and factors predictive of outcome were compared using the log-rank test and Cox regression analysis. ResultsA total of 119 pure UPSC patients were recruited. Stages I, II, III, and IV were identified in 34.5%, 2.5%, 36.1%, and 26.9% of the patients, respectively. The recurrence rate was 20.5% in FIGO stage I/II disease and 55.2% in FIGO stage III/IV disease. The 5-year overall survival rates for the patients with stage I, II, III, and IV disease were 92.0%, 66.7%, 34.2%, and 17.3%, respectively. Multivariate analysis showed that tumor stage (stage III/IV hazard ratio [HR] 8.65, 95% confidence interval [CI] 3.00–24.9) and optimal cytoreduction (HR 0.40, 95% CI 0.22–0.73) independently influenced the overall survival rate of UPSC patients. In addition, optimal cytoreduction (HR 0.36, 95% CI 0.17–0.78) and the combination of chemotherapy and radiation (HR 0.11, 95% CI 0.04–0.37) improved the overall survival of the advanced stage (FIGO stage III/IV) UPSC patients. ConclusionsUPSC represents an aggressive subtype of endometrial cancer commonly accompanied by extra-uterine disease. Comprehensive surgical staging with cytoreductive surgery is mandatory and beneficial for UPSC patients. Systemic chemotherapy combined with radiation should be considered as an adjuvant therapy for advanced stage UPSC patients.

Cervical Cytology in Serous and Endometrioid Endometrial Cancer

The aim of this study was to determine the frequency of abnormal cervical cytology in preoperative cervical cytology of patients diagnosed with uterine papillary serous carcinoma (UPSC) and endometrioid endometrial carcinoma (EEC). In addition, associations between abnormal cervical cytology and clinicopathologic factors were evaluated. In this multicentre study, EEC patients diagnosed at two hospitals from 1999 to 2009 and UPSC patients diagnosed at five hospitals from 1992 to 2009, were included. Revision of the histologic slides was performed systematically and independently by 3 gynecopathologists. Cervical cytology within six months before histopathologic diagnosis of endometrial carcinoma was available for 267 EEC and 80 UPSC patients. Cervical cytology with atypical, malignant, or normal endometrial cells in postmenopausal women was considered as abnormal cytology, specific for endometrial pathology. Abnormal cervical cytology was found in 87.5% of UPSC patients, compared with 37.8% in EEC patients. In UPSC, abnormal cytology was associated with extrauterine spread of disease (P=0.043). In EEC, abnormal cytology was associated with cervical involvement (P=0.034). In both EEC and UPSC patients, abnormal cervical cytology was not associated with survival. In conclusion, abnormal cervical cytology was more frequently found in UPSC patients. It was associated with extrauterine disease in UPSC patients, and with cervical involvement in EEC patients. More prospective research should be performed to assess the true clinical value of preoperative cervical cytology in endometrial cancer patients.

Recurrence rates in patients with uterine papillary serous cancer with and without breast cancer.

e16529 Background: Women with uterine papillary serous carcinoma (UPSC) are at increased risk for breast cancer and the converse is true. A genetic association between breast cancer and UPSC was recently described and counseling women faced with more than one cancer diagnosis can be difficult. Our objective was to evaluate recurrence rates of women with UPSC to those with UPSC and a personal history of breast cancer (UPSCBR). Methods: Data was collected for UPSCBR patients at two academic institutions between 7/1990 and 7/2012. Patient demographics, pathology, disease stage, and treatments were recorded. A UPSC literature review was performed focusing on recurrences per number of at-risk patients by stage. We used the fixed effect Mantel-Haenszel method to estimate the common pooled effect (recurrence rate) for the UPSC studies and compared these to UPSCBR patients. Results: Forty-three UPSCBR patients were identified. Median age at diagnosis was 72 (49-93). Twenty-six patients were Caucasian, 14 African-American and 3 other. Twenty-four (56%) had early stage at diagnosis (IA-IC) and 19 (44%) had late stage (III-IV). All but one underwent surgical staging/debulking; 36 (90%) were optimally debulked. Twelve (50%) early stage and 17 (89.5%) late stage patients underwent adjuvant therapy with radiation and/or chemotherapy. Nine studies were identified with available recurrence data for early stage UPSC; 8 for late stage. The recurrence rate for stage IA UPSCBR patients was 2/11 (18%) [95% CI: 2 to 52%] compared to 11% [95% CI: 9.8 to 13%] in the UPSC literature. In IB/IC UPSCBR patients we had 3/13 (23%) [95% CI: 5 to 54%] recur versus 21% [95% CI: 19 to 23%]. In later stages III/IV, 7/19 (37%) [95% CI:16 to 62%] UPSCBR patients had recurrences compared to 58% [95% CI: 56 to 60%] of UPSC patients. Conclusions: There is an association between breast cancer and UPSC with regard to incidence. We failed to find evidence of an appreciable difference in recurrence rates between our UPSCBR patients and UPSC patient groups from other reported studies. While diagnosis with two primary malignancies can be challenging for patients, this does not appear to impact their risk of recurrence.

A comparison of uterine papillary serous, clear cell carcinomas, and grade 3 endometrioid corpus cancers using 2009 FIGO staging system

ObjectiveThis study was designed to compare survival outcomes of patients with uterine papillary serous carcinoma (UPSC) or clear cell carcinoma (CC) to those of patients with grade 3 endometrioid carcinoma (G3EC) according to 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) staging systems.MethodsWe retrospectively reviewed all patients with endometrial cancer treated at a single institution between 1995 and 2009. Among the 647 patients with endometrial cancer, 51 with G3EC and 46 with UPSC and CC histology were confirmed.Results1988 FIGO stage, 2009 FIGO stage, and extrauterine metastasis were significantly different between the UPSC and CC group and G3EC group (p=0.002, p=0.041, and p=0.020, respectively). Restaging from the 1988 FIGO to the 2009 FIGO criteria increased the number of stage I cases by 10 (11.0%). Overall, 8 in the UPSC and CC and 2 in the G3EC group were down-staged to stage I. In the UPSC and CC group, the 3-year overall survival for 1988 FIGO stage I was 92.9%. When UPSC and CC patients were restaged using the 2009 staging system, the 3-year overall survival of 2009 FIGO stage I dropped to 81.6%. UPSC and CC was associated with poor OS outcome compared with G3EC, after adjustment for 2009 FIGO stage and other clinicopathologic factors.ConclusionWe observed that UPSC and CC patients had different prognosis according to the old and new FIGO staging system. Our results suggest that UPSC and CC compared with the G3EC may retain the 1988 FIGO to be a slightly better discriminator than 2009 FIGO.

Pure Compared With Mixed Serous Endometrial Carcinoma

To analyze whether mixed compared with pure uterine papillary serous carcinoma histology affects clinical outcome, and to assess uterine papillary serous carcinoma for its association with the precursor lesion endometrial intraepithelial carcinoma. A multi-institution observational study of stage I-IV uterine papillary serous carcinoma patients was performed. Histopathologic slides were reviewed by four expert pathologists, with determination of the percentage serous histology within each tumor. The pre-existent endometrium was evaluated for the presence of endometrial intraepithelial carcinoma. We included 108 uterine papillary serous carcinoma patients. Fifty-eight patients had mixed and 50 patients had pure uterine papillary serous carcinoma histology. On multivariable analysis, advanced International Federation of Gynecology and Obstetrics (FIGO) stage (hazard ratio [HR] 3.15, 95% confidence interval [CI] 1.57-6.32), mixed uterine papillary serous carcinoma histology (HR 0.35, 95% CI 0.19-0.66), and lymphovascular space invasion (HR 2.10, 95% CI 1.07-4.16) were significantly associated with recurrence. International Federation of Gynecology and Obstetrics stage (HR 4.67, 95% CI 2.25-9.70) and mixed uterine papillary serous carcinoma histology (HR 0.39, 95% CI 0.20-0.76) were significantly and independently associated with survival. Endometrial intraepithelial carcinoma was identified in 83.9% of all cases, with no significant difference between mixed and pure uterine papillary serous carcinoma patients. Atrophic or weakly proliferative endometrium was found in 90.7% of pure uterine papillary serous carcinoma cases, whereas hyperplastic endometrium with atypia was more commonly found in 34.7% of mixed carcinoma patients with uterine papillary serous carcinoma (P=.004). Pure uterine papillary serous carcinoma histology and FIGO stage are the most important risk factors for recurrence and survival in patients with uterine papillary serous carcinoma. Adjusted for covariates, patients with pure uterine papillary serous carcinoma had a 2.9-times greater risk for recurrence and a 2.6-times higher risk of death compared with patients with mixed uterine papillary serous carcinoma. Furthermore, endometrial intraepithelial carcinoma was equally found among pure and mixed uterine papillary serous carcinoma cases, whereas the nonneoplastic endometrium was atrophic or weakly proliferative in pure uterine papillary serous carcinoma cases compared with more hyperplastic endometrium with atypia in mixed uterine papillary serous carcinoma cases.

Impact of tubal ligation on the natural history of uterine papillary serous carcinoma

Objectives: Potential mechanisms of intraperitoneal (IP) metastases with uterine papillary serous carcinoma (UPSC) include trafficking of tumor cells via the fallopian tubes and/or a field effect involving the fallopian tube or peritoneal epithelium. We test the hypothesis that tubal ligation (TL) favorably impacts the prevalence of IP metastases and, consequently, survival in UPSC patients.\

Preoperative CA-125 predicts extra-uterine disease and survival in uterine papillary serous carcinoma patients

We determined the clinical utility of preoperative serum CA-125 as predictor of extra-uterine disease and as prognosticator for survival in patients with uterine papillary serous carcinoma (UPSC). Patients diagnosed with UPSC, identified between 1992 and 2009, and with preoperative CA-125 measurement were included. A receiver operator characteristic (ROC) curve was used to quantify marker performance. Overall and progression free survival were analyzed using the Kaplan-Meier method. Regression analyses were used to investigate the association of preoperative CA-125 levels and other clinicopathological variables with the presence of extra-uterine disease and the effects on survival. Sixty-six patients met the study criteria. Using ROC, the CA-125 concentration of 45 U/mL as cutoff level provided the best sensitivity (75%) and specificity (74%) for extra-uterine disease, with a positive predictive value of 86%. Survival was significantly longer in patients with preoperative CA-125 ≤ 45 U/mL (p<0.001). Only preoperative CA-125 >45 U/mL remained significantly associated with extra-uterine disease (OR=6.30, 95% CI 1.93-20.62). Furthermore, advanced FIGO stage (HR=4.53, 95% CI 1.50-13.62) and preoperative CA-125 >45 U/mL (HR=3.12, 95% CI 1.13-8.73) were associated with decreased survival. Preoperative elevated serum CA-125 is an independent predictor for the presence of extra-uterine disease and an independent risk factor for survival in UPSC patients.

Performance of Serum CA125 as a Prognostic Biomarker in Patients With Uterine Papillary Serous Carcinoma

Serum CA125 is a potential biomarker for metastatic disease and recurrence in patients with uterine papillary serous carcinoma (UPSC). All patients with UPSC who had preoperative CA125 measurement and surgical staging between 1998 and 2008 at the participating institutions were included in this analysis (N = 52). Data were extracted from patients' records. Fisher exact and χ² tests were used to assess the association of CA125 levels with clinical and pathological variables. The correlation between CA125 levels (high/low) and lymph node metastases (positive/negative) was evaluated using Spearman correlation coefficients. The association of CA125 elevation with recurrence-free survival was assessed using Cox proportional hazards regression modeling. Preoperative CA125 elevation (>30 U/mL) was observed in 9 (17%) patients and was associated with advanced International Federation of Gynecologists and Obstetricians (FIGO) stage III/IV disease (P = 0.002), lymph node involvement (P = 0.007), and presence of omental metastases (P = 0.001). Disease recurrence and survival data were available for 51 of the 52 patients. During a mean follow-up time of 36 months, 15 (29%) patients experienced disease recurrence and 10 (19%) patients died. There was a moderate positive correlation between CA125 levels and lymph node metastases (r² = 0.39). On multivariate survival analysis, an elevated CA125 level compared to nonelevated CA-125 was not associated with disease recurrence (hazard ratio, 1.61; 95% confidence interval, 0.55-4.77). Preoperative CA125 levels were significantly associated with metastatic disease in patients with UPSC. However, in this study of surgically staged UPSC patients, preoperative CA125 elevation was not an independent predictor of disease recurrence.

Abstract 3548: Role of synuclein-gamma (SNCG) in paclitaxel resistance and mitogen activated protein kinase activation in uterine papillary serous carcinoma(UPSC)

Abstract Objectives: SNCG is a novel prognostic biomarker in UPSC. We have shown that its overexpression correlates with aggressive cellular properties and resistance to paclitaxel in a UPSC cell line (SPEC2) as well as poor prognosis in a pilot set of UPSC patients. The goal of this study was to determine the mechanism of SNCG-associated taxane resistance by evaluating the effect of SNCG on the mitotic checkpoint and its propensity to modulate extracellular signal-regulated protein kinase 1/2 (ERK 1/2) signaling pathways. Methods: A stably transfected SPEC2 cell line was created using shSNCG versus shControl oligonucleotides. Similarly, Ishikawa cells were transiently transfected with an SNCG expression vector versus empty vector. Differences in cell proliferation were measured using a cell viability assay and BrdU incorporation assay after treatment with paclitaxel. Cell cycle analysis was used to study the effect of SNCG on the mitotic checkpoint. Differences in expression of the checkpoint kinase BubR1 due to SNCG were studied using real time PCR, Western blot, 26S ubiquitin-proteasome inhibition, and siRNA to BubR1. ERK and phospho-ERK levels were measured in SPEC2 cells with and without SNCG expression by Western blot. SPEC2 cells were treated with paclitaxel with and without the MEK inhibitor UO126 and apoptosis was measured using cleaved PARP analysis. Results: SNCG overexpression lead to acquired, reversible paclitaxel resistance in endometrial cancer cell lines. SNCG was noted to interfere with mitotic checkpoint function by causing degradation of the critical checkpoint protein BubR1 thereby allowing cells to escape paclitaxel-induced mitotic arrest. SPEC2 cells exhibited sustained activation of ERK which was attenuated by silencing SNCG. When SPEC2 cells were exposed to paclitaxel combined with the MEK inhibitor UO126, decreased cell viability and increased apoptosis was noted compared to either agent alone. SNCG knockdown further enhanced paclitaxel and UO126 sensitivity. Cell cycle analysis revealed that silencing SNCG in SPEC2 cells and adding UO126 acted synergistically in overcoming paclitaxel resistance. Conclusions: SNCG overexpression in UPSC leads to taxane resistance by interacting with the mitotic checkpoint kinase BubR1 causing its degradation. SNCG is also associated with sustained ERK activation. Targeting SNCG in conjunction with MEK inhibition may represent a novel therapeutic strategy to overcome taxane resistance in these cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3548.

An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC)

Objectives Stage I–II uterine papillary serous carcinoma (UPSC) patients have a significant risk for extrapelvic recurrence. However, clinicopathologic risk factors for recurrence are not well understood. This study was undertaken to define the prognostic factors for recurrence and survival in patients with early-stage UPSC. Methods A retrospective, multi-institution analysis of surgically staged I–II UPSC patients was performed. Patients were treated by various adjuvant modalities. Age, race, sub-stage, percentage UPSC histology, lymphvascular space invasion (LVSI), tumor size and adjuvant treatment modality were evaluated for their effect on recurrence and survival outcomes. Results We identified 206 patients. Forty patients (19.4%) had 5–49% UPSC, 55 (26.7%) had 50–99% and 111 patients (53.9%) had 100% UPSC in their respective uterine specimens. Twenty one percent of patients experienced a primary recurrence. On univariate analysis, age, increasing %UPSC, LVSI, and tumor size were not significantly associated with recurrence or progression-free survival (PFS). However, substage ( p = 0.005) and treatment with platinum/taxane-based chemotherapy ( p = 0.001) were associated with recurrence/PFS. On multivariate analysis, only chemotherapy ( p = 0.01) was a significant factor affecting PFS, whereas age ( p = 0.05), substage ( p = 0.05), and chemotherapy ( p = 0.02) were associated with overall survival. Conclusions Traditional risk factors for recurrence and survival in patients with early-stage endometrial cancer may not be relevant in patients with UPSC. Patients with any percentage UPSC in their uterine specimens are at a significant risk for recurrence and poor survival outcomes. Given that current clinicopathologic data does not accurately identify women most likely to benefit from adjuvant therapy, alternative prognostic markers based on novel techniques should be explored.

Treatment of early-stage uterine papillary serous carcinoma at Roswell Park Cancer Institute, 1992–2006

Objective Optimal management of early-stage uterine papillary serous carcinoma (UPSC) remains controversial. We reviewed our outcomes in this patient population. Methods The Roswell Park Cancer Institute (RPCI) tumor registry identified all patients with Stages I and IIA UPSC treated between January 1992 and June 2006. The Fisher's exact test was used to compare recurrence rates by adjuvant therapy received. Overall survival (OS) estimates were made using the Kaplan–Meier method. Results Fifty-eight patients with Stage I or IIA UPSC underwent surgery. Thirty-four patients (59%) were surgically staged. Among 21 patients with Stage IA disease, 15 received adjuvant therapy. With a median follow-up of 44.7 months, only one recurrence was observed in a patient who received adjuvant brachytherapy. The 5-year OS was 66%. Among 37 patients with Stages IB–IIA, 30 patients received adjuvant therapy. With a median follow-up of 29 months, there were 7 recurrences. The 5-year OS was 60%. Although there were no significant differences in recurrence by adjuvant therapy received, a significant OS benefit was found in those who received radiation. There was no significant difference in OS distributions of those patients who received Carboplatin/Paclitaxel chemotherapy. Conclusions Despite the limitations of our retrospective study, we have shown that even comprehensively staged early-stage UPSC patients are still at risk for recurrence despite adjuvant therapy received. Hence, all patients with this histologic diagnosis should be considered at high risk for recurrence and counseled appropriately regarding the risks and benefits of adjuvant therapy.

Can primary recurrences in surgical stage I-II uterine papillary serous carcinoma (UPSC) patients be salvaged?

e16503 Background: There is an absence of data in the literature on salvage rates for vaginal, pelvic, and extra-pelvic recurrences for early-stage UPSC patients (pts). The purpose of this study is to determine whether primary recurrences can be salvaged with chemotherapy or radiotherapy. Methods: A retrospective, multi-institution study of pts with stage I-II UPSC diagnosed from 1993–2006. All pts underwent comprehensive surgical staging. Postoperative treatment included either observation (OBS), radiotherapy (RT: brachytherapy, pelvic, abdominal or combo) or ≥ 3 cycles carboplatin/paclitaxel (CT) alone or with RT (CT+RT). Results: We identified 197 stage I-II pts; 44/197 (22.3%) experienced a primary recurrence during a median follow-up of 35 months. Patterns of recurrence analysis revealed that 17 (38.6%) were vaginal/pelvic (V/P) and 27 (61.4%) were extra-pelvic (EP). Multi-site relapses occurred in 13/44 (30%). Pts initially treated with adjuvant CT±RT (n = 108) had a significantly decreased risk of primary recurrence (9.9%) when compared to those patients treated with RT alone (n = 45; 37%) or OBS (n = 43; 35%; p &lt; 0.001). There were no distinguishing risk factors for development of V/P versus EP recurrence. Median time to recurrence after diagnosis was 16 months. The majority of pts (86%) were not salvaged by second line therapy, with a median time from recurrence to death of 8.9 months. However, more pts with isolated vaginal recurrences (5/12 or 42%) were salvaged when compared to those with pelvic or EP recurrences (1/32 or 3.1%; p = 0.004). The 5 pts who are NED after vaginal relapse were treated with CT±RT (n = 3) or RT (n = 2); 80% had not received prior treatment and 20% had received prior CT. To date, more pts with EP recurrence are dead of disease (23/27) than with V/P recurrences (7/17; p = 0.003). Conclusions: Stage I-II USPC pts are more likely to experience an extra-pelvic than vaginal/pelvic primary recurrence, are unlikely to be salvaged and will have a short interval from recurrence to death. The exception is in those with isolated vaginal recurrence, who may be salvaged in select cases. The current best strategy to avoid primary recurrences in this setting is an initial staging surgery followed by adjuvant carboplatin/paclitaxel. No significant financial relationships to disclose.