Association of allostatic load with overall survival in epithelial ovarian cancer.

OBJECTIVE: Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS: This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS: There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION: Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.

Molecular portraits of clear cell ovarian and endometrial carcinoma with comparison to clear cell renal cell carcinoma.

OBJECTIVE: Advanced clear cell gynecologic malignancies remain among the most challenging diseases to manage. We evaluated ovarian and endometrial clear cell carcinoma (OCCC and ECCC) specimens using comprehensive sequencing technology to identify mutational targets and compared their molecular profiles to histologically similar clear cell renal cell carcinoma (ccRCC). METHODS: Using next-generation sequencing (NGS), fragment analysis (FA), and in situ hybridization (ISH), 164 OCCC, 75 ECCC and 234 ccRCC specimens from 2015 to 2018 were evaluated and compared. RESULTS: The highest mutation rates in ECCC and OCCC were noted in: ARID1A (75.0%, 87.5%), TP53 (34.8%, 11.1%), PIK3CA (25.0%, 46.8%), PPP2R1A (8.7%, 16.7%), MSI-high (8.8%, 6.4%) and PTEN (8.3%, 7.1%). Among these mutations, there was no significant difference between OCCC and ECCC mutation prevalence except in TP53, with higher mutation rates in ECCC versus OCCC (34.8 vs. 11.1%, respectively, p < 0.05). ccRCC demonstrated different mutation profiles with higher mutation rates in VHL (80.3%), PBRM1 (43.9%), SETD2 (31.1%), and KDM5C (29.2%). By contrast, VHL, PBRM1, and SETD2 mutations were not found in ECCC and OCCC (0.0%). Compared to ccRCC and ECCC, OCCC was found to have a significantly higher tumor mutation burden (TMB) (19.1%). CONCLUSION: Gynecologic and renal CCC demonstrate separate and disparate somatic profiles. However, OCCC and ECCC are diseases with similar profiles. TMB and MSI analyses indicate that a subset of OCCC may benefit from immunotherapy. Prospective clinical trials are needed and are underway to examine targeted therapies in these gynecologic disease subtypes.

DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma.

PURPOSE: Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations. METHODS: We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression. RESULTS: DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel. CONCLUSIONS: Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

Immunotherapy in endometrial cancer.

The Cancer Genome Atlas (TCGA) endometrial cancer data expanded our knowledge about the role of different immunotherapeutic approaches based on molecular subtypes. Immune checkpoint inhibitors demonstrated distinct antitumor activities as monotherapy or in combination. In microsatellite unstable (microsatellite instability-high) endometrial cancer, immunotherapy with immune checkpoint inhibitors showed promising single agent activity in recurrent settings. Different strategies are needed to enhance the response or reverse resistance to immune checkpoint inhibitors, or both, in microsatellite instability-high endometrial cancer. On the other hand, single immune checkpoint inhibitors showed underwhelming efficacy in microsatellite stable endometrial cancer but this was significantly improved using a combination approach. Furthermore, studies are also needed to improve response along with ensuring safety and tolerability in microsatellite stable endometrial cancer. This review summarizes the current indications of immunotherapy for the treatment of advanced and recurrent endometrial cancer. We also outline potential future strategies for an immunotherapy based combination approach in endometrial cancer to combat resistance or enhance response to immune checkpoint inhibitors, or both.

Evolving treatment paradigms in metastatic or recurrent low-grade endometrial cancer: When is hormonal-based therapy the preferred option?

Endometrial cancer is the most common gynecologic malignancy in developed countries, with increasing incidence and mortality rates worldwide. While most cases are successfully treated with surgery, first-line treatment options for metastatic or recurrent endometrial cancer involve significant toxicities. Imprecise classification of heterogeneous subgroups further complicates treatment decisions and interpretation of clinical trial results. Recent advances in molecular classification are guiding treatment decisions for metastatic or recurrent endometrial cancers. Integrating molecular characteristics with traditional clinicopathology can both reduce overtreatment or undertreatment and help guide the appropriate choice of therapies and effective design of future studies. Here we discuss the treatment of metastatic or recurrent low-grade endometrioid adenocarcinoma of the uterine corpus, which is distinct from high-grade tumors histologically, molecularly, and in treatment response.

The promise of combining CDK4/6 inhibition with hormonal therapy in the first-line treatment setting for metastatic or recurrent endometrial adenocarcinoma.

Metastatic or recurrent endometrioid adenocarcinoma of the uterine corpus is often incurable with limited treatment options. First-line treatment often includes cytotoxic chemotherapy, which incurs significant toxicities for many patients. Endometrial cancer, specifically endometrioid cancer, is a hormone-sensitive disease and, while single-agent hormonal therapies have demonstrated clinical benefit, resistance to these agents often leads to the use of chemotherapy. There is a lack of approved endocrine treatment options in the metastatic setting for most recurrent endometrial cancers, representing an unmet clinical need. Emerging evidence suggests that hormonal therapy in combination with other targeted treatments, such as cyclin dependent kinase (CDK)4/6 inhibitors, is well tolerated and effective in select patient populations. We discuss the clinical evidence suggesting that the combination of CDK4/6 inhibitors and hormonal therapy has the potential to represent an important addition to the first-line treatment options for patients with low-grade advanced or recurrent endometrial cancer.

Changing treatments paradigms and role of immunotherapy in recurrent endometrial cancer.

PURPOSE OF REVIEW: Over the past decade, the treatment of patients diagnosed with endometrial cancer (EC) shifted away from the use of chemotherapy to more novel targeted therapy and immunotherapy approaches. RECENT FINDINGS: The Cancer Genome Atlas data demonstrated different subgroups within ECs, more specifically, it facilitated the identification of predictive biomarkers. In particular, immunotherapies (immuno-oncology (IO)) are active either as monotherapy or in combination with other agents, depending on the biomarker profile of the tumor. SUMMARY: In May 2017, pembrolizumab was approved for patients with microsatellite instability high (MSI-H) EC. More recently, this approval was extended for patients harvesting tumors with a high tumor mutational burden status. Furthermore, in July 2021, the combination of pembrolizumab and lenvatinib was approved for patients who do not exhibit MSI-H disease. Given the wealth of targets in EC and different targetable mutations, the challenge will be to choose the proper treatment and the proper sequencing to derive the best outcome in the first-line setting and improve outcomes in subsequent settings. This review summarizes the current indications of immunotherapy for the treatment of advanced and recurrent EC. We outline the role of testing for uterine cancer and its implication in therapy management. Finally, we address new concepts for immunotherapy combinations with other therapies.

PARP inhibitors decrease response to subsequent platinum-based chemotherapy in patients with BRCA mutated ovarian cancer.

To determine the effect of poly-adenosine ribose phosphatase inhibitors (PARPi) on the response to subsequent platinum-based chemotherapy (PBC) in patients with recurrent, platinum-sensitive BRCA-mutated epithelial ovarian, peritoneal, or fallopian cancer (BRCAm EOC). This is a retrospective, single-institution cohort study of patients with BRCAm EOC who received retreatment with PBC. The PFS of patients with BRCAm EOC to 2nd or 3rd PBC with and without a prior PARPi was determined. Additionally, we compared the PFS to subsequent PBC following a prior PARPi for BRCAm and non-BRCAm. One hundred and fifteen patients with BRCAm EOC received a 2nd PBC and 55 received a 3rd PBC. The median PFS was 2.3 and 2.4 times longer, respectively for patients who did not receive a PARPi, (2nd P = 0.005, 3rd P < 0.001). Among 20 PARPi exposed patients with BRCAm EOC the PFS to a 2nd or 3rd PBC was worse at 8.0 months vs. 19.1 months HR 4.01 [2.25,7.16], P < 0.001. Following PARPi exposure the PFS for patients with BRCAm EOC was similar for patients with platinum-free intervals of 6-12, 12-24 and >24 months. Following PARPi exposure the PFS was similar for patients with BRCAm EOC and non BRCAm EOC. Among patients with BRCAm EOC PARPi exposure significantly reduced PFS following 2nd and 3rd PBC. PARPi exposure nullifies established prognostic factors (i.e. platinum-free interval and BRCA mutational status) in platinum-sensitive recurrent ovarian cancer.

Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Low-grade serous ovarian cancer: State of the science.

In January 2019, a group of basic, translational, and clinical investigators and patient advocates assembled in Miami, Florida, to discuss the current state of the science of low-grade serous carcinoma of the ovary or peritoneum-a rare ovarian cancer subtype that may arise de novo or following a diagnosis of serous borderline tumor. The purpose of the conference was to review current knowledge, discuss ongoing research by established researchers, and frame critical questions or issues for future directions. Following presentations and discussions, the primary objective was to initiate future collaborations, uniform database platforms, laboratory studies, and clinical trials to better understand this disease and to advance clinical care outside the boundaries of single academic institutions. This review summarizes the state of the science in five principal categories: epidemiology and patient outcomes, pathology, translational research, patient care and clinical trials, and patients' perspective.

NCCN Guidelines Insights: Ovarian Cancer, Version 1.2019.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

Trends in Survival of Patients With Uterine Serous Carcinoma From 1988 to 2011: A Population-Based Study.

OBJECTIVE: Our study used the Surveillance, Epidemiology, and End Result database to determine if the changes in treatment paradigm observed over the last 2 decades have improved outcomes in patients with uterine serous carcinoma (USC). METHODS: Women with USC were identified using the Surveillance, Epidemiology, and End Result database from 1988 to 2011 (n = 8230) and grouped into 3 cohorts (1988-1997, 1998-2004, and 2005-2011). Disease-specific survival and overall survival were estimated. Kaplan-Meier survival curves and Cox regression models were used. RESULTS: Disease-specific survival (59 vs 94 months vs not reached; P < 0.001) and overall survival (31 vs 37 vs 45 months; P < 0.001) improved over time. In univariable analyses, only those with stage I-III and those who reside in the Western or Central regions were noted to have improvement over time. In multivariable analyses when adjusting for age, race, marital status, stage, geographic location, cancer-related surgery, extent of lymphadenectomy, and adjuvant radiation, patients who received the diagnosis during 2005 to 2011 were 22% less likely to die of uterine cancer (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.70-0.87; P < 0.001) and 17% less likely to die of any cause (HR, 0.83; 95% CI, 0.76-0.90; P < 0.0001) compared with patients who received a diagnosis during 1988-1997. Similarly, patients who received a diagnosis during 1998-2004 were 15% less likely to die of uterine cancer (HR, 0.85; 95% CI, 0.77-0.94; P = 0.0015) and 10% less likely to die of any cause (HR, 0.90; 95% CI, 0.83-0.97; P = 0.0048) compared with patients who received a diagnosis during 1988-1997. CONCLUSIONS: Changes in treatment trends for USC over the last 2 decades have resulted in an improvement in outcome especially those with stage I-III disease.

Racial disparity in survival of patients with uterine serous carcinoma: Changes in clinical characteristics, patterns of care and outcomes over time from 1988 to 2011.

OBJECTIVES: To determine if the disparities in the outcome between white (W) and African American (AA) patients with uterine serous carcinoma (USC) have changed over time. METHODS: Women with USC were identified using the SEER database from 1988 to 2011 (N=7667). Years of the study were divided into three periods (1988-1997, 1998-2004 and 2005-2011). Overall (OS) and disease-specific survivals (DSS) was estimated. RESULTS: Over the three time periods, African American patients continued to be younger and less likely to have cancer directed surgery and extensive lymphadenectomy when compared to white patients. In multivariable analysis adjusting for age, race, marital status, stage, cancer-directed surgery, extent of lymphadenectomy, adjuvant radiation, and geographic location, AA was significantly associated with worse DSS and OS in the three time periods compared to white race. African American patients were 29% (95% CI 1.03-1.62, p=0.027) in 1988-1997, 40% in 1998-2004 (95% CI 1.21-1.63, p<0.0001) and 34% in 2005-2011 (95% CI 1.13-1.59, p=0.0008) more likely to die from uterine cancer compared to their white counterparts. A slight improvement in the difference in OS over time was noted comparing African American and white patients. African American patients were 46% (95% CI 1.23-1.73, p<0.0001) in 1988-1997, 39% in 1998-2004 (95% CI 1.23-1.56, p<0.0001) and 26% in 2005-2011 (95% CI 1.10-1.45, p<0.0001) more likely to die from any cause compared to their white counterparts. CONCLUSIONS: Significant improvement in outcome was noted in both racial groups over time. However, African American patients continued to have worse outcome than white patients over time.

Prostate-Type Adenocarcinoma in Mature Cystic Ovarian Teratoma.

We report our experience with prostatic-type tissue in ovarian teratomas, and in particular we highlight a case of prostatic-type adenocarcinoma arising within a mature cystic ovarian teratoma in a 32-yr-old woman. On gross examination, the cyst consisted of typical features of a dermoid cyst. Closer examination revealed a single 1.5-cm solid nodule within the cyst. Microscopically, it was composed of a small cyst-like structure lined by urothelium and to one side glandular and stromal tissue consistent with prostate parenchyma. Within the prostatic-type tissue, there were malignant glands morphologically and immunohistochemically supportive of prostatic-type adenocarcinoma Gleason score 3+3=6. There were also areas consistent with high-grade prostatic intraepithelial neoplasia. Although there are several reports in the literature of benign prostatic-type tissue arising within ovarian as well as testicular teratomas, to our knowledge, prostatic-type adenocarcinoma arising in a mature ovarian teratoma is an extremely rare phenomenon, with only 1 previous report in the literature.

Activity of Bevacizumab in Patients With Low-Grade Serous Ovarian Carcinoma.

OBJECTIVES: The aim of this study was to evaluate the antitumor activity of bevacizumab in low-grade serous ovarian carcinoma (LGSOC). METHODS: We retrospectively identified patients with LGSOC treated with bevacizumab. RESULTS: Twelve patients with LGSOC who received bevacizumab were identified. Eleven patients received bevacizumab alone. Only 1 (8.3%) of 12 patients had evidence of a partial response. Ten (90.9%) of the 11 patients were progression free at 6 months. All but 1 patient who received only 2 courses before treatment interruption had a progression-free survival (PFS) of greater than 6 months. The median PFS was 48 months (range, 5-123+ months). Three of the patients reported in this series had extended disease stabilization that lasted for 123+, 48, and 15+ months after progression-free intervals on prior chemotherapy regimens of 2.5, 4, and 7 months, respectively. The median overall survival was not reached at a median follow-up of 32 months, with only 1 of the 12 patients dying of disease. CONCLUSIONS: In our series, in patients with LGSOC treated primarily with bevacizumab, primarily as a single agent, a low response rate but very long PFS is observed. In addition, patients have had secondary PFS durations that exceeded their prior PFS, which is a sign of anticancer activity.

The Impact of Obesity on the 30-day Morbidity and Mortality After Surgery for Ovarian Cancer.

OBJECTIVES: To examine the effect of body mass index (BMI) on postoperative 30-day morbidity and mortality after surgery for ovarian cancer (OC). METHODS: Patients with OC were identified from the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2011. Women were divided into 3 groups: nonobese (BMI <30 kg/m), obese (30 to <40 kg/m), and morbidly obese (≥40 kg/m). Multivariable logistic regression models were performed. RESULTS: Of 2061 women included in this study, 1336 (65%) were nonobese, 560 (27%) were obese, and 165 (8%) were morbidly obese. The overall 30-day mortality and morbidity rates for the entire cohort were 2% and 31%, respectively. In multivariate analyses adjusting for confounders, both obese (odds ratio [OR], 0.9; 95% confidence interval [CI], 0.4-2.0; P = 0.87) and morbid obesity (OR, 0.8; 95% CI, 0.1-3.0; P = 0.73) were not significant predictors of increased 30-day postoperative mortality. Likewise, rates of any complication in 30 days were comparable between nonobese, obese, and morbidly obese patients (31% vs. 28% vs. 33%, respectively; P = 0.35) with no significant difference even after adjusting for other confounders (OR, 0.9; 95% CI, 0.7-1.1; P = 0.26 and OR, 1.1; 95% CI, 0.7-1.6; P = 0.70, respectively). Obese and morbidly obese patients were more likely to have diabetes, hypertension requiring medications, cardiac morbidities, higher American Society of Anesthesiologists class, and leukocytosis and less likely to have weight loss before surgery. CONCLUSIONS: With appropriate control for confounding comorbidities, the 30-day morbidity and mortality rates for the obese and morbidly obese patients undergoing surgery for OC do not seem to differ. Therefore, reported inferior long-term survival for these patients is likely related to a different phase of their disease and treatment process and is deserving of further investigation.

Risk of Venous Thromboembolism After Laparoscopic Surgery for Gynecologic Malignancy.

STUDY OBJECTIVE: To determine the incidence of venous thromboembolism (VTE) after laparoscopic surgery for gynecologic cancer. DESIGN: Retrospective analysis of the ACS-NSQIP database (Canadian Task Force Classification II.1). SETTING: Academic and community healthcare institutions across the United States. PATIENTS: Women who underwent at least 1 major laparoscopic surgery for uterine, ovarian, and cervical cancers. INTERVENTION: Data were collected on surgical procedures, patient demographic variables, type of malignancy and VTE, and mortality outcomes within 30 days of surgery. MEASUREMENTS AND MAIN RESULTS: VTE was defined as deep venous thrombosis requiring therapy and pulmonary embolism confirmed by imaging or autopsy within 30 days of surgery. Of the 2219 patients included in the final analysis, 15 patients (.7%) were diagnosed with VTE within 30 days after surgery. Six patients (.3%) were diagnosed before discharge, and 9 patients (.4%) were diagnosed after discharge. The median time from surgery to diagnosis was 6 days (range, 0-28 days). Although most patients included in the study had uterine cancer (86%, n = 1913), no difference was noted based on the site of cancer (.5% for cervical cancer, .7% for endometrial cancer, and .8% for ovarian cancer; p = .95). There was no difference in rate of VTE when stratified by age (p = .10), body mass index (p = .68), diabetes (p = .22), smoking (p = .60), respiratory morbidities (p = .55), cardiac disease (p = .22), hypertension (p = .13), preoperative blood transfusion (p = .90), or American Society of Anesthesiologists class (p = .10). There was a trend toward higher risk of VTE among patients with disseminated cancer compared with those with early cancers (3.6% vs .6%, p = .05). No difference was found in the risk of VTE based on operative time (.7% for <2 hours, .6% for 2-3 hours, and .7% for >3 hours; p = .96). No difference was noted in the risk of VTE among those who underwent lymphadenectomy compared with those who did not (.9% vs .5%, p = .35). In multivariable logistic regression analysis adjusting age (p = .12), body mass index (p = .90), operative time (p = .71), and lymphadenectomy (p = .30), none of these variables was significantly associated with risk of VTE. In multivariable analysis adjusting for other confounders, VTE within 30 days was a significant predictor of higher 30-day mortality (OR, 26.0; 95% CI, 2.2-306.9; p = .01). CONCLUSION: The rate of VTE is low after major laparoscopic surgery for gynecologic cancers but is associated with increased 30-day mortality. Universal or extended thromboprophylaxis does not appear to be indicated for all patients. Further studies are needed to identify patients at high risk for postoperative VTE who may benefit from pharmacologic prophylaxis.

Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study.

BACKGROUND: Endometrial cancer has been recognized only recently as a major component of Cowden syndrome (CS). Germline alterations in phosphatase and tensin homolog (PTEN; PTEN_mut+), succinate dehydrogenase B/C/D (SDHB-D; SDHx_var+), and killin (KLLN_Me+) cause CS and Cowden syndrome-like (CSL) phenotypes. This study was aimed at identifying the prevalence and clinicopathologic predictors of germline PTEN_mut+, SDHx_var+, and KLLN_Me+ in CS/CSL patients presenting with endometrial cancer. METHODS: PTEN and SDHB-D mutation and KLLN promoter methylation analyses were performed for 371 prospectively enrolled patients (2005-2011). PTEN protein was analyzed from patient-derived lymphoblast lines. The PTEN Cleveland Clinic (CC) score is a weighted, regression-based risk calculator giving the a priori risk for PTEN_mut+. Demographic and clinicopathologic features were correlated with the specific gene. RESULTS: Germline PTEN_mut+, SDHx_var+, and KLLN_Me+ were found in 7%, 9.8%, and 10.5% of informative samples, respectively. Predictors of PTEN_mut+ included an age ≤ 50 years (odds ratio [OR] for an age < 30 years, 6.1 [P = .015]; OR for an age of 30-50 years, 4.4 [P = .001]), macrocephaly (OR, 14.4; P < .001), a higher CC score (OR for a 1-U increment, 1.35; P < .001), a PTEN protein level within the lowest quartile (OR, 5.1; P = .039), and coexisting renal cancer (OR, 5.7; P = .002). KLLN_Me+ patients were on average 8 years younger than KLLN_Me- patients (44 vs 52 years, P = .018). Predictors of KLLN_Me+ were a younger age and a higher CC score. On the other hand, no clinical predictors of SDH_var+ were found. CONCLUSIONS: Clinical predictors of PTEN and KLLN alterations, but not SDHx_var+, were identified. These predictors should alert the treating physician to potential heritable risk and the need for referral to genetic professionals. High-risk cancer surveillance and prophylactic surgery of the uterus may be considered for KLLN_Me+ patients similarly to PTEN_mut+ patients.

Impact of age on 30-day mortality and morbidity in patients undergoing surgery for endometrial cancer.

OBJECTIVES: To investigate the impact of age on postoperative mortality and morbidity for women undergoing surgery for endometrial cancer. METHODS: Patients with endometrial cancer who had a hysterectomy were identified in the 2005-2011 National Surgical Quality Improvement Program database. Patient characteristics and outcomes were compared between age groups. Multivariable logistic regression models were used. RESULTS: 4000 patients met inclusion criteria. Octogenarians (n=328) were less likely to undergo laparoscopic surgery (p<0.001) but there was no difference in surgical complexity among age groups (p=0.54). In multivariate analysis, ages 60-69 (OR 0.9, 95% CI 0.3-2.8, p=0.82), 70-79 (OR 1.4, 95% CI 0.4-4.3, p=0.60) and ≥80 years (OR 2.4, 95% CI 0.7-8.1, p=0.17) were not associated with increased mortality compared to age<60 years. Significant predictors of mortality were respiratory or renal disease, dependent functional status, and hypoalbuminemia. Octogenarians were more likely to have non-surgical complications (8% vs. 3-5%, p=0.001) but there was no difference in surgical complications (p=0.89). In multivariate analysis, ages 60-69 (OR 1.2, 95% CI 1.0-1.6, p=0.09), 70-79 (OR 1.3, 95% CI 1.0-1.8, p=0.05) and ≥80 years (OR 1.3, 95% CI 0.9-2.5, p=0.14) were not associated with increased complications compared to age<60 years. Significant predictors of complications were higher ASA class, anemia, and thrombocytosis. CONCLUSIONS: Older patients should not be denied surgery for endometrial cancer based on age alone as they do not have higher rates of 30-day morbidity or mortality after adjusting for other factors. An increased effort should be made to perform minimally invasive surgery in octogenarians.