Paclitaxel, Carboplatin, and Bevacizumab in Advanced and Recurrent Endometrial Carcinoma.

OBJECTIVE: The aim of this study was to evaluate the efficacy of adding bevacizumab to paclitaxel and carboplatin and as maintenance in a larger cohort of patients with advanced or recurrent endometrial carcinoma. METHODS: We retrospectively identified endometrial cancer patients treated with paclitaxel (175 mg/m per 3 hours), carboplatin (area under the curve, 5) and bevacizumab (15 mg/kg) and maintenance bevacizumab treated in a post-protocol treatment cohort and evaluated them with our previously published phase 2 trial of this regimen. RESULTS: Twenty-seven additional patients were identified; 19 received the regimen as first-line therapy, and 8 received the regimen as second-line therapy after prior paclitaxel and carboplatin. The 19 patients who received first-line therapy were analyzed alone and with the 15 patients enrolled on protocol. The 2 cohorts were similar with respect to risk factors. Overall survival curves were not statistically different between the protocol and the postprotocol patients (log-rank test; P > 0.1). Collectively, a total of 266 courses (median, 6 courses; range, 1-20 courses) of carboplatin, paclitaxel, and bevacizumab combination therapy and 305 courses (median, 16 courses; range, 0-45courses) of bevacizumab maintenance therapy were administered as first-line therapy. Collectively, the median progression-free survival was 20 months, and median overall survival was 56 months. Among 29 patients with measurable disease, the response rate was 82.8% (95% confidence interval, 69.0%-96.5%; 15 complete responses and 9 partial responses). Among the 8 patients who received paclitaxel and carboplatin and bevacizumab as second-line therapy after paclitaxel and carboplatin, the response rate was 87.5% (6 complete responses, 1 partial response). Their median progression-free survival and median overall survival were not reached after a median follow-up of 23.5 months. CONCLUSIONS: Although there are inherent limitations to small retrospective studies, this second analysis confirms the high response rate, progression-free survival, and overall survival in the bevacizumab, paclitaxel, and carboplatin regimen as first-line therapy in advanced and recurrent endometrial carcinoma.

Impact of adjuvant chemotherapy and pelvic radiation on pattern of recurrence and outcome in stage I non-invasive uterine papillary serous carcinoma. A multi-institution study.

OBJECTIVES: To determine the impact of adjuvant chemotherapy or pelvic radiation on risk of recurrence and outcome in stage IA non-invasive uterine papillary serous carcinoma (UPSC). METHODS: This is a multi-institutional retrospective study for 115 patients with stage IA non-invasive UPSC (confined to endometrium) treated between 2000 and 2012. Kaplan-Meier and multivariable Cox proportional hazards regression modeling were used. RESULTS: Staging lymphadenectomy and omentectomy were performed in 84% and 57% respectively. Recurrence was seen in 26% (30/115). Sites of recurrences were vaginal in 7.8% (9/115), pelvic in 3.5% (4/115) and extra-pelvic in 14.7% (17/115). Adjuvant chemotherapy did not impact risk of recurrence (25.5% vs. 26.9%, p=0.85) even in subset of patients who underwent lymphadenectomy (20% vs. 23.5%, p=0.80). These findings were consistent for pattern of recurrence. Among those who underwent lymphadenectomy, adjuvant chemotherapy did not impact progression-free survival (p=0.34) and overall survival (p=0.12). However among patients who did not have lymphadenectomy, adjuvant chemotherapy or pelvic radiation was associated with longer progression-free survival (p=0.04) and overall survival (p=0.025). In multivariable analysis, only staging lymphadenectomy was associated with improved progression-free survival (HR 0.34, 95% CI 0.12-0.95, p=0.04) and overall survival (HR 0.35, 95% CI 0.12-1.0, p=0.05). Neither adjuvant chemotherapy nor pelvic radiation were predictors of progression-free or overall survivals. CONCLUSION: In stage IA non-invasive UPSC, staging lymphadenectomy was significantly associated with recurrence and outcome and therefore, should be performed in all patients. Adjuvant chemotherapy or pelvic radiation had no impact on outcome in surgically staged patients but was associated with improved outcome in unstaged patients.

Tumor size is an independent predictor of lymph node metastasis and survival in early stage endometrioid endometrial cancer.

OBJECTIVE(S): To analyze the impact of tumor size (TS) on risk of lymph node metastasis (PLN) and prognosis in endometrioid endometrial cancer grossly confined to the uterus (EEC). METHOD(S): Patients with EEC grossly confined to the uterus were identified from Surveillance, Epidemiology, and End Results dataset from 1988 to 2007. Only surgically treated patients were included. TS was analyzed as a continuous and categorical variable (TS ≤ 2 cm, >2-5 cm and >5 cm). Multivariable logistic regression and Cox proportional hazards models were used. RESULT(S): 19,692 patients met the inclusion criteria. In patients with TS ≤ 2 cm, only 2.7 % (88/3,244) had PLN; this increased to 5.8 % (372/6,355) with TS > 2-5 cm and 11.1 % (195/1,745) with TS > 5 cm. The odds of PLN increased by 14 % for each 1 cm increase in TS after controlling for age, race, depth of myometrial invasion and grade (HR 1.14, 95 % CI 1.10-1.19, p < 0.001). Further, TS was an independent predictor of disease-specific survival (DSS) even after adjusting for age, race, grade, depth of myometrial invasion, lymph node status and adjuvant radiation therapy (HR 1.13 for each 1 cm increment in TS, 95 % 1.08-1.18, p < 0.001). In multivariable analysis, larger TS (>5 cm) was significantly associated with worse DSS (HR 2.09, 95 % 1.31-3.35, p = 0.002); however, there was no significant difference between TS > 2-5 cm versus ≤2 cm (HR 1.25, 95 % 0.85-1.83, p = 0.25). The impact of TS remained significant on DSS in subset of patients who underwent lymphadenectomy with negative lymph nodes. CONCLUSION(S): TS was an independent predictor of lymph node metastasis and disease-specific survival in patients with EEC grossly confined to the uterus. Tumor >5 cm was a predictor of disease-specific survival but no difference in outcome was noted between tumor >2-5 cm and tumor ≤2 cm.

The impact of obesity on the 30-day morbidity and mortality after surgery for endometrial cancer.

STUDY OBJECTIVES: To examine the effect of body mass index (BMI) on postoperative 30-day morbidity and mortality after surgery to treat endometrial cancer. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: National Surgical Quality Improvement Program. PATIENTS: Patients with endometrial cancer who underwent surgery from 2005 to 2011. INTERVENTIONS: Women were grouped according to weight, as follows: normal weight (BMI 18 to <30), obese (BMI 30 to <40), and morbidly obese (BMI ≥ 40). Univariate and multivariable logistic regression models were analyzed. MEASUREMENTS AND MAIN RESULTS: Of 3947 patients, 38% were of normal weight, 38% were obese, and 24% were morbidly obese. Of these, 48% underwent laparoscopy and 52% underwent laparotomy. Overall 30-day morbidity and mortality were 13% and 0.7%, respectively. Obesity and morbid obesity were associated with a higher American Society of Anesthesiologists class, diabetes, and hypertension. Preoperatively, elevated serum creatinine concentration, hypoalbuminemia, and leukocytosis were more common in morbidly obese women than those of normal weight. Laparoscopic surgery was performed less frequently in morbidly obese women than in those of normal weight (42.5% vs 50%; p = .001). Morbidly obese patients were more likely to develop postoperative complications (morbidly obese 16% vs normal weight 13% vs obese 11%; p = .001), in particular surgical (morbidly obese 14% vs normal weight 11% vs obese 9%; p < .001) and infectious complications (morbidly obese 10% vs normal weight 5% vs obese 5%; p = .01). After laparotomy, morbidly obese women demonstrated a higher rate of any complication (normal weight 21%, obese 18%, morbidly obese 25%; p = .002), surgical complications (normal weight 18%, obese 14%, morbidly obese 22%; p = .002) and infectious complications (normal weight 6%, obese 10%, morbidly obese 16%; p < .001). After laparoscopy there was no difference in complication rates according to BMI group. The 30-day mortality was not significantly different according to BMI. After adjusting for confounders, obesity and morbid obesity did not independently predict 30-day morbidity or mortality. CONCLUSIONS: Morbidly obese patients with endometrial cancer have more preoperative morbidities and postoperative complications, in particular surgical and infectious complications, and are less likely to undergo minimally invasive surgery. However, obesity was not an independent predictor of perioperative outcomes after controlling for other confounders.

Racial disparity in 30-day morbidity and mortality after surgery for ovarian cancer.

BACKGROUND: The improved survival observed in recent years for women with ovarian cancer (OC) has not been realized among African American (AA) compared with white (W) women. The contribution of immediate postoperative morbidity and mortality to this survival disparity remains unclear. This study aims to examine disparities in postoperative 30-day morbidity and mortality between AA and W women with OC. MATERIALS AND METHODS: Patients with OC were identified from the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) 2005 to 2011. African American and subgroups were studied. Multivariable logistic regression models were performed. RESULTS: Of 1649 women, 1510 (92%) were W and 139 (8%) were AA. The rate of 30-day postoperative complications and mortality among the entire cohort were 30% and 2%, respectively. No differences in postoperative complications were noted between AA and W women (33% vs 30%, P = 0.47) including surgical (29% vs 26%, P = 0.40) and nonsurgical (10% vs 9%, P = 0.75) complications. The mean length of hospital stay was longer in AA women, but there was no difference in surgical re-exploration and operative time. No difference in 30-day mortality was found between AA and W women (3% vs 2%, P = 0.45). African Americans were younger and more likely to be obese, have diabetes, hypertension, preoperative weight loss, higher serum creatinine level greater than or equal to 2 mg/dL, hypoalbuminemia, and anemia. After adjusting for surgical complexity and associated comorbidities, AA race was not an independent predictor of 30-day postoperative complications (odds ratio, 0.99; 95% confidence interval [CI], 0.65-1.5; P = 0.96) or mortality (odds ratio, 0.89; 95% confidence interval, 0.25-2.43; P = 0.83). CONCLUSIONS: African American race was not an independent predictor of poor 30-day outcomes. Interestingly, AAs with OC are underrepresented in quality-seeking hospitals. Efforts to minimize this racial disparity should target optimization of comorbidities and improving access to high-volume centers for AA women.

Racial disparity in the 30-day morbidity and mortality after surgery for endometrial cancer.

OBJECTIVES: To examine postoperative 30-day morbidity and mortality in African American (AA) compared to white patients (W) with endometrial cancer (EC). METHODS: Patients with EC were identified from the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2011. AA and W subgroups were studied. Multivariable logistic regression models were performed. RESULTS: Of 3248 patients, 2899 (89%) W and 349 (11%) AA were identified. AA were more likely to have diabetes, hypertension, ascites, neurologic morbidities, weight loss, non-independent functional status, higher ASA class, higher serum creatinine ≥ 2 mg/dl, hypoalbuminemia and anemia. Laparoscopic surgery was performed less frequently in AA than W (41.4% vs. 50.3%, p<0.001). AA had a significantly higher risk of postoperative complications than W (21% vs. 12%, p<0.001) including surgical (17% vs. 10%, p<0.001) and non-surgical complications (7% vs. 4%, p=0.022). Mean length of hospital stay and operative time were longer in AA than W but there was no difference in surgical re-exploration. In multivariable model after adjustment for confounders including surgical complexity and associated morbidities, AA race was not an independent predictor of "any postoperative complications" for both laparotomy group (OR 1.1, 95% CI 0.73-1.61, p=0.65) and laparoscopic group (OR 1.43, 95% CI 0.80-2.45, p=0.21). No difference in 30-day mortality was found between AA and W (1% vs. 1%, p=0.11). CONCLUSIONS: AA patients with EC have more preoperative morbidities, postoperative complications and were less likely to undergo minimally invasive surgery. However, AA race was not an independent predictor of poor 30-day outcomes after controlling for other confounders.

Predictors of surgical site infection in women undergoing hysterectomy for benign gynecologic disease: a multicenter analysis using the national surgical quality improvement program data.

STUDY OBJECTIVE: To estimate the rate and predictors of surgical site infection (SSI) after hysterectomy performed for benign indications and to identify any association between SSI and other postoperative complications. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: National Surgical Quality Improvement Program data. PATIENTS: Women who underwent abdominal or laparoscopic hysterectomy performed for benign indications from 2005 to 2011. INTERVENTIONS: Univariable and multivariable logistic regression analyses were used to identify predictors of SSI and its association with other postoperative complications. Odds ratios were adjusted for patient demographic data, comorbidities, preoperative laboratory values, and operative factors. MEASUREMENTS AND MAIN RESULTS: Of 28 366 patients, 758 (3%) were diagnosed with SSI. SSI occurred more often after abdominal than laparoscopic hysterectomy (4% vs 2%; p < .001). Among patients who underwent abdominal hysterectomy, predictors of SSI included diabetes, smoking, respiratory comorbidities, overweight or obesity, American Society of Anesthesiologists class ≥ 3, perioperative blood transfusion, and operative time >180 minutes. Among those who underwent laparoscopic hysterectomy, predictors of SSI included perioperative blood transfusion, operative time >180 minutes, serum creatinine concentration ≥ 2 mg/dL, and platelet count ≥ 350 000 cells/mL(3). For patients with deep or organ/space SSI, significant predictors included perioperative blood transfusion and American Society of Anesthesiologists class ≥ 3 for abdominal hysterectomy, and non-white race, renal comorbidities, preoperative or perioperative blood transfusion, and operative time >180 minutes for laparoscopic hysterectomy. SSI was associated with longer hospital stay and higher rates of repeat operation, sepsis, renal failure, and wound dehiscence. SSI was not associated with increased 30-day mortality. CONCLUSIONS: SSI occurred more often after abdominal hysterectomy than laparoscopic hysterectomy performed to treat benign gynecologic disease. SSI was associated with increased postoperative complications but not mortality. Several risk factors for SSI after each abdominal and laparoscopic hysterectomy were identified in this study.

Surgical site infection in women undergoing surgery for gynecologic cancer.

OBJECTIVES: The objectives of this study were to describe the rate and predictors of surgical site infection (SSI) after gynecologic cancer surgery and identify any association between SSI and postoperative outcome. MATERIALS AND METHODS: Patients with endometrial, cervical, or ovarian cancers from 2005 to 2011 were identified from the American College of Surgeons National Surgical Quality Improvement Program. The extent of surgical intervention was categorized into modified surgical complexity scoring (MSCS) system. Univariate and multivariate logistic regression analyses were used. Odds ratios were adjusted for patient demographics, comorbidities, preoperative laboratory values, and operative factors. RESULTS: Of 6854 patients, 369 (5.4%) were diagnosed with SSI. Surgical site infection after laparotomy was 3.5 times higher compared with minimally invasive surgery (7% vs 2%; P < 0.001). Among laparotomy group, independent predictors of SSI included endometrial cancer diagnosis, obesity, ascites, preoperative anemia, American Society of Anesthesiologists class greater than or equal to 3, MSCS greater than or equal to 3, and perioperative blood transfusion. Among laparoscopic cases, independent predictors of SSI included only preoperative leukocytosis and overweight. For patients with deep or organ space SSI, significant predictors included hypoalbuminemia, preoperative weight loss, respiratory comorbidities, MSCS greater than 4, and perioperative blood transfusion for laparotomy and only preoperative leukocytosis for minimally invasive surgery. Surgical site infection was associated with longer mean hospital stay and higher rate of reoperation, sepsis, and wound dehiscence. Surgical site infection was not associated with increased risk of acute renal failure or 30-day mortality. These findings were consistent in subset of patients with deep or organ space SSI. CONCLUSIONS: Seven percent of patients undergoing laparotomy for gynecologic malignancy developed SSI. Surgical site infection is associated with longer hospital stay and more than 5-fold increased risk of reoperation. In this study, we identified several risk factors for developing SSI among gynecologic cancer patients. These findings may contribute toward identification of patients at risk for SSI and the development of strategies to reduce SSI rate and potentially reduce the cost of care in gynecologic cancer surgery.

Type II endometrial cancer in Hispanic women: tumor characteristics, treatment and survival compared to non-Hispanic white women.

OBJECTIVES: To compare survival of Hispanic white (HW) and non-Hispanic white (NHW) women with type II endometrial adenocarcinoma (EC). METHODS: Patients with serous, clear cell or grade 3 endometrioid EC were identified from the Surveillance, Epidemiology, and End Results (SEER) program 1988-2009 and were divided into HW and NHW. HW were subdivided into natives and immigrants. RESULTS: Of the 14,434 women, 13,012 (90.2%) were NHW and 1422 (9.8%) were HW. HW were younger than NHW (mean 63 vs. 68years, p<0.001). A higher proportion of HW presented with late stage disease than NHW (43.8% vs. 36.6%, p=0.04). Performing lymphadenectomy was not different but HW were more likely to have positive lymph nodes than NHW (27.6% vs. 23.1%, p=0.02). Further, HW were less likely to receive radiation than NHW (39.5% vs. 42.3%, p=0.04). No difference in clinicopathologic characteristics was found between immigrant and native HW. In multivariate models adjusting for age, stage, histology, surgical treatment, extent of lymphadenectomy, and radiation therapy, no difference in overall survival (OS) (HR 1.06, 95% CI 0.97-1.16, p=0.19) and cancer-specific survival (CSS) (HR 1.02, 95% CI 0.91-1.14, p=0.75) was found between HW and NHW. Interestingly, immigrant HW had better OS (HR 0.74, 95% CI 0.62-0.89, p<0.001) and CSS (HR 0.72, 95% CI 0.58-0.90, P=0.003) than native HW. CONCLUSIONS: Although they were more likely to present with advanced stage and positive nodal disease, no difference in outcome was noted between Hispanic and non-Hispanic whites with EC. Interestingly, immigrant HW had more favorable outcome compared to native HW.

Endometrial cancer in Asian and American Indian/Alaskan Native women: tumor characteristics, treatment and outcome compared to non-Hispanic white women.

OBJECTIVE: The objective of this study is to compare survival of Asian (AS), American Indian/Alaskan Native (AI/AN) and non-Hispanic white (NHW) women with endometrial adenocarcinoma (EC). METHODS: Patients with EC were identified from the Surveillance, Epidemiology, and End Results program from 1988 to 2009. Kaplan-Meier survival methods and Cox proportional hazards regression were performed. RESULTS: Of the 105,083 women, 97,763 (93%) were NHW, 6699 (6.4%) were AS and 621 (0.6%) were AI/AN. AS and AI/AN were younger than NHW with mean age of 57.7 and 56.5 vs. 64.3 years (p < 0.001 and 0.059). Advanced stage and high-risk histology were more prominent in AS than NHW (15.6% vs. 13.3%, p = 0.04, 10.6% vs. 9.6%, p= 0.041). Lymphadenectomy was performed more frequently in AS than NHW (56.7% vs. 48.2%, p < 0.001). Asian immigrants were younger than Asian natives (mean age 57 vs. 60.5 years, p < 0.001). In multivariate analysis, AS had better overall (OS) (HR 0.86, 95% CI 0.81-0.91, p < 0.001) and cancer-specific survival (CSS) (HR 0.92, 95% CI 0.84-1.00, p = 0.05) than NHW. Further, Asian immigrants had better OS (HR 0.83, 95% CI 0.73-0.94, p = 0.002) and CSS (HR 0.66, 95% CI 0.54-0.80, p < 0.001) than Asian natives. In contrast, AI/AN had worse OS (HR 1.35, 95% CI 1.15-1.59, p < 0.001) but no difference in CSS (HR 1.06, 95% CI 0.80-1.40, p = 0.69) than NHW. CONCLUSIONS: Asians were younger at presentation, more likely to have lymphadenectomy and had an improved outcome compared to NHW. Interestingly, Asian immigrants had more favorable outcome than Asians born in the US. Further studies are warranted to find possible explanations for such a difference.

Prevalence and prognostic impact of lymphadenectomy and lymph node metastasis in clinically early-stage ovarian clear cell carcinoma.

OBJECTIVES: The objective of this study was to estimate the prevalence and prognostic impact of lymphadenectomy and lymph node involvement in patients with ovarian clear cell carcinoma (OCCC) grossly confined to the ovary. METHODS: Patients with a diagnosis of OCCC grossly confined to the ovary were identified from Surveillance, Epidemiology, and End Results program from 1988 to 2007. Only surgically treated patients were included. Statistical analysis using Student t test, Kaplan-Meier survival methods, and Cox proportional hazards regression were performed. RESULTS: One thousand eight hundred ninety-seven patients with OCCC who have undergone surgical treatment and deemed at time of the surgery to have disease grossly confined to the ovary were included: 538 (28.3%) had no lymphadenectomy (LND -1), and 1359 (71.7%) had lymphadenectomy. Of the 1359 patients who had lymphadenectomy, 1298 (95.5%) were International Federation of Gynecology and Obstetrics (FIGO) surgical stage I (LND +1), and 61 (4.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND +3C). The 5-year disease-specific survival was 84.9% for LND -1, 88.0% for LND +1, and 65.0% for LND +3C (P < 0.001). Among those with histologically negative lymph nodes, the 5-year disease-specific survival was 85% for patients with 1 to 10 nodes removed, and 91% for those with more than 10 nodes removed (P = 0.054). On multivariate analysis after controlling for stage, age, and race, lymph node metastasis was an independent predictor of poor disease-specific survival (hazard ratio, 3.1; 95% confidence interval, 1.86-5.28; P < 0.001). On other hand, there was a trend toward an improved survival when more extensive lymphadenectomy is performed in patients with histologically negative nodes (1-10 vs >10 nodes), but it did not reach statistical significance (hazard ratio, 0.71; 95% confidence interval, 0.49-1.02; P = 0.064). CONCLUSIONS: Lymph node metastasis was uncommon in patients diagnosed with OCCC grossly confined to the ovary; however, patients with positive nodes were more likely to die compared to those with negative nodes. More extensive lymphadenectomy plays an important role in providing accurate staging and prognostic information.

Intraoperative hypothermia during cytoreductive surgery for ovarian cancer and perioperative morbidity.

OBJECTIVE: To evaluate intraoperative hypothermia as a predictor for morbidity after open abdominal surgery for ovarian cancer. METHODS: This cohort study included 146 women with stage IIIC and IV ovarian cancer who underwent debulking surgery at our institution from January 1, 2001, through December 31, 2003. Hypothermia was defined as end operative temperature lower than 36°C. Early complications (occurring within 30 days of surgery) included: mortality, infectious morbidities, cardiovascular events, venous thromboembolic (VTE) events, anastomotic leak, readmission, and reoperation. Survival was also evaluated. Logistic regression models were used to adjust for known confounders. RESULTS: The mean age was 63.9 ± 11.7 years; 46 (32%) patients had a body mass index higher than 30; mean operative time was 239 ± 85 minutes. There were five deaths perioperatively, all in the hypothermic group. Hypothermia was associated with an increased risk of any early complications (34 [42.0%] compared with 11 [16.9%]) with an adjusted odds ratio (OR) of 3.40 (95% confidence interval [CI] 1.48-8.33). For individual complications, hypothermic patients were at higher risk for VTE events with an adjusted OR of 3.53 (95% CI 1.02-16.44); infectious morbidity with an adjusted OR of 2.99 (95% CI 0.97-11.35); and reoperation with an adjusted OR of 4.96 (95% CI 0.80-95.7). The overall survival was shorter in hypothermic group with a median of 34 compared with 45 months (P=.045); this remained significant for an optimally resected subgroup with a median overall survival of 40 compared with 48 months (P=.049). CONCLUSION: Surgical hypothermia is an independent predictor of early perioperative complications and overall survival after cytoreductive surgery for ovarian cancer. This is a critically important finding, because maintaining normothermia is an inexpensive modifiable factor, which could result in reduced morbidity.

Expression and functional significance of HtrA1 loss in endometrial cancer.

PURPOSE: The purpose of this study was to determine if loss of serine protease HtrA1 in endometrial cancer will promote the invasive potential of EC cell lines. EXPERIMENTAL DESIGN: Western blot analysis and immunohistochemistry methods were used to determine HtrA1 expression in EC cell lines and primary tumors, respectively. Migration, invasion assays and in vivo xenograft experiment were performed to compare the extent of metastasis between HtrA1 expressing and HtrA1 knocked down clones. RESULTS: Western blot analysis of HtrA1 in 13 EC cell lines revealed complete loss of HtrA1 expression in all seven papillary serous EC cell lines. Downregulation of HtrA1 in Hec1A and Hec1B cell lines resulted in a three- to fourfold increase in the invasive potential. Exogenous expression of HtrA1 in Ark1 and Ark2 cells resulted in three- to fourfold decrease in both invasive and migration potential of these cells. There was an increased rate of metastasis to the lungs associated with HtrA1 downregulation in Hec1B cells compared to control cells with endogenous HtrA1 expression. Enhanced expression of HtrA1 in Ark2 cells resulted in significantly less tumor nodules metastasizing to the lungs compared to parental or protease deficient (SA mutant) Ark2 cells. Immunohistochemical analysis showed 57% (105/184) of primary EC tumors had low HtrA1 expression. The association of low HtrA1 expression with high-grade endometrioid tumors was statistically significant (P = 0.016). CONCLUSIONS: Collectively, these data indicate loss of HtrA1 may contribute to the aggressiveness and metastatic ability of endometrial tumors.