Tumor Immune Microenvironment in Gynecologic Cancers.

Gynecologic cancers have varying response rates to immunotherapy due to the heterogeneity of each cancer's molecular biology and features of the tumor immune microenvironment (TIME). This article reviews key features of the TIME and its role in the pathophysiology and treatment of ovarian, endometrial, cervical, vulvar, and vaginal cancer. Knowledge of the role of the TIME in gynecologic cancers has been rapidly developing with a large body of preclinical studies demonstrating an intricate yet dichotomous role that the immune system plays in either supporting the growth of cancer or opposing it and facilitating effective treatment. Many targets and therapeutics have been identified including cytokines, antibodies, small molecules, vaccines, adoptive cell therapy, and bacterial-based therapies but most efforts in gynecologic cancers to utilize them have not been effective. However, with the development of immune checkpoint inhibitors, we have started to see the rapid and successful employment of therapeutics in cervical and endometrial cancer. There remain many challenges in utilizing the TIME, particularly in ovarian cancer, and further studies are needed to identify and validate efficacious therapeutics.

Unrestricted Ketogenic Diet Feeding Enhances Epithelial Ovarian Cancer Growth In Vivo.

The ketogenic diet (KD) is hypothesized to impact tumor progression by altering tumor metabolism. In this study, we assessed the impact of an unrestricted KD on epithelial ovarian cancer (EOC) tumor growth, gene expression, and metabolite concentration in a mouse model. ID8 EOC cells, which were syngeneic with C57Bl/6J mouse strain and transfected with luciferase (ID8-luc), were injectedand monitored for tumor development. Female mice were fed either a strict KD, a high fat/low carbohydrate (HF/LC) diet, or a low fat/high carbohydrate (LF/HC) diet (n = 10 mice per group) ad libitum. EOC tumor growth was monitored weekly, and tumor burden was determined based on luciferase fluorescence (photons/second). At the endpoint (42 days), tumors were collected and processed for RNA sequencing. Plasma and tumor metabolites were evaluated using LC-MS. The KD-fed mice exhibited a statistically significant increase in tumor progression in comparison to the HF/LC- and LF/HC-fed groups (9.1 vs. 2.0 vs. 3.1-fold, respectively, p < 0.001). The EOC tumors of the KD-fed mice exhibited significant enrichment of the peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid metabolism pathways based on the RNA sequencing analysis when compared to the LF/HC- and HF/LC-fed mice. Thus, unrestricted KD diet enhanced tumor progression in our mouse EOC model. KD was associated with the upregulation of fatty acid metabolism and regulation pathways, as well as enrichment of fatty acid and glutamine metabolites.

Comprehensive Care of Women With Genetic Predisposition to Breast and Ovarian Cancer.

Women at risk for hereditary breast and ovarian cancer syndromes are frequently seen in primary care and gynecology clinics. They present with a distinctive set of clinical and emotional needs that revolve around complex risk management discussions and decision making. The care of these women calls for the creation of individualized care plans that facilitate adjustment to the mental and physical changes associated with their choices. This article provides an update on comprehensive evidence-driven care of women with hereditary breast and ovarian cancer. The aim of this review is to aid clinicians in identifying those at risk for hereditary cancer syndromes and provide practical advice on patient-centered medical and surgical risk management. Topics of discussion include enhanced surveillance, preventive medications, risk-reducing mastectomy and reconstruction, risk-reducing bilateral salpingo-oophorectomy, fertility, sexuality, and menopausal management, with attention to the importance of psychological support. High-risk patients may benefit from a multidisciplinary team that provides realistic expectations with consistent messaging. The primary care provider must be aware of the special needs of these patients and the consequences of their risk management interventions.

Association between CT-based body composition assessment and patient outcomes during neoadjuvant chemotherapy for epithelial ovarian cancer.

OBJECTIVE: The aim of this study was to characterize the body composition of patients undergoing neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC), identify factors associated with sarcopenia at diagnosis, and evaluate the impact of pretreatment sarcopenia and changes in body composition parameters during therapy on perioperative and disease-related outcomes. METHODS: Patients undergoing NACT for EOC between 2008 and 2020 were identified. Pre-treatment and post-treatment contrast-enhanced CT scans were reviewed to determine skeletal muscle index (SMI) and visceral adipose tissue (VAT) area at the mid-fourth lumbar vertebral level. SMI and VAT were analyzed for association with clinical and treatment variables. RESULTS: 174 patients were identified. Mean pretreatment SMI and VAT were 38.3 cm2/m2 ± 7.9 and 51.2 cm2/m2 ± 34.3, respectively. Comparatively, mean post-treatment SMI and VAT were 37.8 cm2/m2 ± 7.9 and 43.7 cm2/m2 ± 29.7, respectively. Most patients exhibited an overall decrease in SMI from pretreatment to posttreatment scans. Caucasian race, older age, and lower body mass index at diagnosis were associated with lower pretreatment SMI. Lower pre-treatment SMI was associated with lower surgical complexity scores (p < 0.001) and estimated blood loss (p = 0.029). Decrease in SMI after NACT was associated with increased rates of ICU admissions and length of stay. While there was no association between SMI and overall survival (OS) or progression-free survival (PFS), >2% decrease per 100 days in VAT was significantly associated with worse OS. CONCLUSIONS: Patients with lower pretreatment SMI tend to undergo less complex surgery than those with higher SMI despite NACT. Decrease in VAT may be a potential indicator of worse OS. Information on body composition can aid in clinical decision making in patients with EOC.

Not all stage I and II endometrial cancers are created equal: Recurrence-free survival and cause-specific survival after observation or vaginal brachytherapy alone in all subgroups of early-stage high-intermediate and high-risk endometrial cancer.

OBJECTIVE: To evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and high-risk endometrial cancer (EC). METHODS: We identified patients with stage I HIR (GOG-249 criteria) and stage II endometrioid EC, and stage I and II non-endometrioid EC who underwent surgery at Mayo Clinic and Cleveland Clinic between 1999 and 2016. Three-year RFS and CSS after observation or VB only were estimated in 16 subgroups defined by risk factors. RESULTS: Among 4156 ECs, we identified 447 (10.8%) stage I endometrioid HIR, 52 (1.3%) stage II endometrioid, 350 (8.4%) stage I non-endometrioid, and 17 (0.4%) stage II non-endometrioid ECs; observation or VB alone was applied in 349 (78.1%), 24 (46.2%), 187 (53.4%), and 2 (11.8%) patients, respectively. After observation or VB, stage I HIR endometrioid EC subgroups with <2 factors among grade 3, LVSI, or stage IB had a 3-year CSS >95% (lower 95% confidence intervals limit: 89.8%), whereas subgroups with ≥2 factors had poorer outcomes. No EC-related deaths after 3 years were reported in 97 stage IA non-endometrioid ECs without myometrial invasion. Stage II ECs had poor outcomes regardless of histology. CONCLUSIONS: Observation or VB only may be sufficient in stage I endometrioid HIR ECs with <2 factors among grade 3, LVSI, or IB and in stage IA non-endometrioid ECs without myometrial invasion. Stratification of early-stage HIR and high-risk ECs into risk subgroups potentially alleviates the overtreatment and undertreatment risk and should be considered in future research.

Preoperative assessment using the five-factor modified frailty index: A call for standardized preoperative assessment and prehabilitation services in gynecologic oncology.

OBJECTIVE: To evaluate if the 5-factor modified frailty index (mFI) is associated with postoperative complications, readmissions or non-home discharge in gynecologic cancer patients undergoing surgery. METHODS: Patients with a diagnosis of gynecologic cancer (cervical, uterine, or ovarian cancer) who underwent surgery between 2014 and 2018 were identified through the National Surgical Quality Improvement Program (NSQIP) database. The 5-factor mFI was applied and patients classified into 6 categories (mFI groups 0,1,2, 3, 4 and 5). The incidence of 30-day complications, readmissions and non-home discharge was evaluated. Multivariable logistic regression models were used to determine the association between mFI category and readmissions/ complications. Adjusted probabilities of events were calculated based on patient characteristics. RESULTS: At total of 31,181 gynecologic cancer cases were included in the analysis: N = 2968 (9.4%) cervical, N = 20,862 (66.4%) uterine, and N = 7351 (23.4%) ovarian cancers. Of all patients, 46.1% were in category 0, 36.5% category 1, and 1% category 3-5. Factors associated with increased mFI included older age, African American race, laparoscopic surgery and obesity. A significant dose-response relationship between higher mFI and readmission and 30-day complications was noted on adjusted multivariable analysis (adjusted OR 2.37 (1.65-3.45) and 2.10 (1.59-2.75) for readmissions and complications, respectively, in mFI category 3-5). These associations were consistent within each cancer type. CONCLUSIONS: The 5-factor mFI universally predicts postoperative readmissions, 30-day complications and non-home discharge in patients with gynecologic cancer. Incorporation of mFI into routine preoperative assessment can identify patients for non-surgical treatments, prehabiliatation and short term home assessments.

Development and validation of a comprehensive clinical risk-scoring model for prediction of overall survival in patients with endometrioid endometrial carcinoma.

OBJECTIVE: To develop and validate a comprehensive overall survival (OS) risk-scoring model in women with endometrioid endometrial cancer (EC). METHODS: Patients with EC diagnosed from 2004 to 2013 were identified through the National Cancer Database (NCDB). Patients with known lymphovascular space invasion (LVSI) status who were treated surgically (with or without adjuvant therapy) were included. Cox proportional hazards analysis was used to identify prognostic factors for OS. This model was used to assign points based on hazard ratios for risk factors and a risk score was obtained. Recursive partitioning analysis (RPA) was used to categorize patients into risk groups. Results were internally validated in a cohort of patients from our institution (CCF cohort). Risk scores were calculated and assessed in a Cox regression model, and Harrell's c-index was calculated to assess model fit. RESULTS: Among 349,404 women with EEC during the study period, 42,107 fulfilled inclusion criteria. Factors associated with worse OS were age ≥ 60, African American race, Charlson-Deyo score 1 or 2+, higher grade, LVSI, tumor size ≥2 cm, and no lymphadenectomy performed. Six risk groups were identified (scores 0-30) and OS estimated for each risk group. Risk score per 1-point increase in HR were comparable between NCDB and CCF cohorts (HR 1.21 (1.20-1.22 p < 0.001 vs 1.18 (1.12-1.25), p < 0.001), and c-index 0.80 (0.79-0.81) vs. 0.77 (0.68-0.86). Similar analysis was done in stage IA and IB. Adjuvant therapy had a beneficial effect on survival in the majority of stage IB patients, but only one of the six risk groups in stage IA EC. CONCLUSIONS: We report a comprehensive validated OS risk-scoring model for patients with.

Stereotactic body radiotherapy for the treatment of oligometastatic gynecological malignancy in the abdomen and pelvis: A single-institution experience.

PURPOSE/OBJECTIVES: Metastasis-directed therapy with stereotactic body radiotherapy (SBRT) in the setting of oligometastatic disease is a rapidly evolving paradigm given ongoing improvements in systemic therapies and diagnostic modalities. However, SBRT to targets in the abdomen and pelvis is historically associated with concerns about toxicity. The purpose of this study was to evaluate the safety and efficacy of SBRT to the abdomen and pelvis for women with oligometastases from primary gynecological tumors. MATERIALS/METHODS: From our IRB-approved registry, all patients who were treated with SBRT between 2014 and 2020 were identified. Oligometastatic disease was defined as 1 to 5 discrete foci of clinical metastasis radiographically diagnosed by positron emission tomography (PET) and/or computerized tomography (CT) imaging. The primary endpoint was local control at 12 months. Local and distant control rates were estimated using the Kaplan-Meier method. Time intervals for development of local progression and distant progression were calculated based on follow up visits with re-staging imaging. Acute and late toxicity outcomes were determined based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: We identified 34 women with 43 treated lesions. Median age was 68 years (range 32-82), and median follow up time was 12 months (range 0.2-54.0). Most common primary tumor sites were ovarian (n=12), uterine (n=11), and cervical (n=7). Median number of previous lines of systemic therapy agents at time of SBRT was 2 (range 0-10). Overall, SBRT was delivered to 1 focus of oligometastasis in 29 cases, 2 foci in 2 cases, 3 foci in 2 cases, and 4 foci in 1 case. All patients were treated comprehensively with SBRT to all sites of oligometastasis. Median prescription dose was 24 Gy (range 18-54 Gy) in 3 fractions (range 3-6) to a median prescription isodose line of 83.5% (range 52-95). Local control by lesion at 12 and 24 months was 92.5% for both time points. Local failure was observed in three treated sites among two patients, two of which were at 11 months in one patient, and the other at 30 months. Systemic control rate was 60.2% at 12 months. Overall survival at 12 and 24 months was 85% and 70.2%, respectively. Acute grade 2 toxicities included nausea (n=3), and there were no grade > 3 acute toxicities. Late grade 1 toxicities included diarrhea (n=1) and fatigue (n=1), and there were no grade > 2 toxicities. CONCLUSION: SBRT to oligometastatic gynecologic malignancies in the abdomen and pelvis is feasible with encouraging preliminary safety and local control outcomes. This approach is associated with excellent local control and low rates of toxicity during our follow-up interval. Further investigations into technique, dose-escalation and utilization are warranted.

Controversies in Hereditary Cancer Management.

Personalized management of patients at risk ideally should involve a multidisciplinary team of not only genetic counselors and surgeons, but also women's health or menopause specialists, knowledgeable psychologists, and primary care providers or obstetrician-gynecologists aware of the risks and fears "previvors" (survivors of a predisposition to cancer who have not had the disease) face as well as the issues that are common postoperatively. Identification of patients at risk for hereditary cancer, understanding of current genetic testing modalities and potential results, knowledge about screening and prevention including timing of surveillance, preventive medication and risk-reducing surgeries, understanding limitations and comorbidities associated with these risk management strategies and long-term psychological support are all important in hereditary cancer management. We describe issues surrounding the identification of the high-risk patient, universal testing in breast and ovarian cancer, and testing in special populations. We describe a simplified approach to understanding and communicating genetic testing results and nuances of testing including direct-to-consumer testing. We highlight concerns surrounding breast cancer screening during pregnancy and lactation. A framework for practical management and counseling of women who opt for risk-reducing salpingo-oophorectomy or risk-reducing mastectomy or both is provided. We provide an in-depth discussion of questions that arise in relation to timing of surgery, fertility preservation, management of menopausal symptoms, and surgical technique. Alternative choices in women who choose to delay bilateral salpingo-oophorectomy are reviewed. Finally, the psychosocial effects of carrying a genetic mutation and the issues that women face when undergoing to risk-reducing surgery including adjustment, sexuality issues, and cosmesis are addressed.

Clinicopathologic characteristics and outcomes of endometrial Cancer patients with mismatch repair deficiency in the era of universal Lynch syndrome screening.

OBJECTIVE: To evaluate clinicopathologic characteristics and survival impact associated with mismatch repair (MMR) deficient subgroups of endometrial cancer (EC) in patients undergoing universal screening for Lynch Syndrome. METHODS: A retrospective cohort study using a prospectively maintained gynecologic oncology registry of patients who underwent surgery for EC was conducted. All pathology specimens underwent tumor testing using immunohistochemistry for MMR deficiency with reflex MLH1 promotor methylation testing. Tumors were classified as MMR-I (intact MMR expression), MMR-DM (MMR deficient due to MLH1 methylation), and MMR-DU (MMR deficient without MLH1 methylation). Univariate and multivariate analysis performed to determine factors associated with MMR-DM. Progression-free survival (PFS) and overall survival (OS) analyzed by stage and endometrioid subgroup. RESULTS: From 2012 to 2016, 1018 EC patients were identified and screened. Overall, 71.6% were classified as MMR-I, 23.8% MMR-DM, and 4.6% MMR-DU. In comparison to MMR-DU, MMR-DM tumors were associated with older age, postmenopausal status, lymphovascular space invasion, and pure endometrioid histology. Compared to MMR-I, MMR-DM tumors were associated with older age, endometrioid histology, lymphovascular space invasion, and higher grade on multivariable analysis. There was no difference in PFS and OS between the three groups overall. In patients with endometrioid EC, MMR-DM tumors were associated with lower PFS vs. MMR-I (HR:2.51, CI:1.54, 4.10, P < 0.001). This effect persisted for stage I/II endometrioid EC (HR 2.66, CI:1.34, 5.26 p = 0.005). No difference in PFS or OS was noted among stage III/IV endometrioid tumors. CONCLUSION: MMR deficiency is associated with adverse prognostic factors and worse PFS among endometrioid tumors, particularly in early stage EC. MMR testing outside of LS screening has prognostic value, warranting consideration for inclusion as a biomarker in prospective clinical trials.

Diet and gut microbiome interactions in gynecologic cancer.

Over the last decade, there has been a dramatic surge in research exploring the human gut microbiome and its role in health and disease. It is now widely accepted that commensal microorganisms coexist within the human gastrointestinal tract and other organs, including those of the reproductive tract. These microorganisms, which are collectively known as the "microbiome", contribute to maintaining host physiology and to the development of pathology. Next generation sequencing and multi-'omics' technology has enriched our understanding of the complex and interdependent relationship that exists between the host and microbiome. Global changes in the microbiome are known to be influenced by dietary, genetic, lifestyle, and environmental factors. Accumulating data have shown that alterations in the gut microbiome contribute to the development, prognosis and treatment of many disease states including cancer primarily through interactions with the immune system. However, there are large gaps in knowledge regarding the association between the gut microbiome and gynecologic cancers, and research characterizing the reproductive tract microbiome is insufficient. Herein, we explore the mechanisms by which alterations in the gut and reproductive tract microbiome contribute to carcinogenesis focusing on obesity, hyperestrogenism, inflammation and altered tumor metabolism. The impact of the gut microbiome on response to anti-cancer therapy is highlighted with an emphasis on immune checkpoint inhibitor efficacy in gynecologic cancers. We discuss dietary interventions that are likely to modulate the metabolic and immunologic milieu as well as tumor microenvironment through the gut microbiome including intermittent fasting/ketogenic diet, high fiber diet, use of probiotics and the metabolic management of obesity. We conclude that enhanced understanding of the microbiome in gynecologic cancers coupled with thorough evaluation of metabolic and metagenomic analyses would enable us to integrate novel preventative strategies and adjunctive interventions into the care of women with gynecologic cancers.

Time to surgery and its impact on survival in patients with endometrial cancer: A National cancer database study.

OBJECTIVE: To determine patient and facility-specific factors associated with time to surgery (TTS) in patients with endometrial cancer (EC), and define the impact of delay in TTS >6 weeks on overall survival (OS) by tumor histology and stage. METHODS: The National Cancer Database (NCDB) was queried to identify patients with EC who underwent definitive primary surgical treatment between 2004 and 2013. Patients were stratified by EC histology into type I (endometrioid) and type II (non-endometrioid). TTS (number of days from diagnosis to definitive surgery) was calculated and trends in TTS during the study period were analyzed. Poisson regression was used to identify factors associated with TTS for patients with type I and type II EC, respectively. Cox regression was used to assess the impact of delay in TTS > 6 weeks on OS by tumor histology and stage. RESULTS: Out of 284,499 patients included in the study, 83% had type I EC and 17% had type II EC. Median (interquartile range; IQR) TTS for type I and II EC was 27 days (10-41) and 26 days (13-40), respectively. TTS increased over the study period in both groups. In Type I EC, delay in TTS was associated with worse OS in patients with early stage (I-II) EC only. In type II EC, delay in TTS had no significant impact on OS in stage I-III EC, while a paradoxical relationship between TTS > 6 weeks and improved OS was observed for stage IV EC. CONCLUSION: TTS increased over the study period. TTS >6 weeks was negatively associated with OS in early stage type I EC. Interventions to reduce TTS in specific stages and settings for EC are necessary given this impact on mortality.

Perioperative Management of Women Undergoing Risk-reducing Surgery for Hereditary Breast and Ovarian Cancer.

Carriers of genetic mutations that predispose to cancer syndromes are often faced with complex decisions. For women with hereditary breast and ovarian cancer in particular, the decision to undergo risk-reducing mastectomy or bilateral salpingo-oophorectomy is burdensome from a physical and psychological perspective. Although risk-reducing surgery is the most effective preventative measure in reducing a genetic mutation carrier's risk of breast or ovarian cancer, the success of these procedures requires a multidisciplinary approach that centers on careful counseling regarding the risks and benefits of risk-reducing surgery. The physical and psychological distress associated with risk-reducing surgery often makes a combined surgical approach attractive to some patients. In this review, we present the evidence surrounding the comprehensive surgical care of women with hereditary breast and ovarian cancer syndromes and evaluate the perioperative factors that influence surgical management.

Predicting non-home discharge in epithelial ovarian cancer patients: External validation of a predictive model.

OBJECTIVE: To externally validate a model predicting non-home discharge in women undergoing primary cytoreductive surgery (CRS) for epithelial ovarian cancer (EOC). METHODS: Women undergoing primary CRS via laparotomy for EOC at three tertiary medical centers in an academic health system from January 2010 to December 2015 were included. Patients were excluded if they received neoadjuvant chemotherapy, had a non-epithelial malignancy, were not undergoing primary cytoreduction, or lacked documented model components. Non-home discharge included skilled nursing facility, acute rehabilitation facility, hospice, or inpatient death. The predicted probability of non-home discharge was calculated using age, pre-operative CA-125, American Society of Anesthesiologists (ASA) score and Eastern Cooperative Oncology Group (ECOG) performance status as described in the previously published predictive model. Model discrimination was calculated using a concordance index and calibration curves were plotted to characterize model performance across the cohort. RESULTS: A total of 204 admissions met inclusion criteria. The overall rate of non-home discharge was 12% (95% CI 8-18%). Mean age was 60.8 years (SD 11.0). Median length of stay (LOS) was significantly longer for patients with non-home discharge (8 vs. 5 days, P < 0.001). The predictive model had a concordance index of 0.86 (95% CI 0.76-0.93), which was similar to model performance in the original study (CI 0.88). The model provided accurate predictions across all probabilities (0 to 100%). CONCLUSIONS: Non-home discharge can be accurately predicted using preoperative clinical variables. Use of this validated non-home discharge predictive model may facilitate preoperative patient counseling, early discharge planning, and potentially decrease cost of care.

Intestinal Surgery in Gynecologic Oncology: Are We Training for the Future?

OBJECTIVE: The objective of this study was to assess the scope of intestinal surgery training across gynecologic oncology fellowships in the United States and identify factors associated with perceived preparedness to perform intestinal surgery independently. MATERIALS/METHODS: An institutional review board-approved survey was distributed to Society of Gynecologic Oncology fellows and candidate members within the first 3 years of practice. Questions addressed demographics, operative experience, preparedness and plans for performing intestinal surgery, and attitudes toward gynecologic oncologists (GOs) performing intestinal surgery. Responses were analyzed using descriptive statistics as well as univariate and multivariate analyses. RESULTS: Of 374 Society of Gynecologic Oncology members invited, 108 (29%) responded, including 38 fellows (35%) and 53 recent graduates (49%). Fifteen (14%) reported more than 3 years of practice and were excluded. Most participants (96%) received intestinal surgery training from GOs, and 64% reported that all faculty routinely performed intestinal surgery. Most participants (81%) believed GOs should perform intestinal procedures, whereas only 58% felt prepared and 59% planned to perform intestinal procedures independently. Fellows who performed more than 10 intestinal diversion procedures, participated directed in intestine-related intraoperative consultations, or reported that all faculty performed intestinal surgery were more likely to feel prepared to perform intestinal surgery independently. Sex, training region, intended practice environment, and fellowship curriculum were not associated with preparedness to perform intestinal surgery. CONCLUSIONS: Almost half of gynecologic oncology fellows and recent graduates in the United States do not feel prepared to perform intestinal procedures independently after fellowship. Increased volume and direct involvement of fellows in intestinal surgery may improve preparedness for performing intestinal surgery after fellowship.

In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma.

OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo. METHODS: Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naïve PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting. RESULTS: Five PDX models were evaluated in vivo. Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2-deficient PDX. CONCLUSIONS: Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition.

Development of an Endometrial Ablation Model in New Zealand White Rabbits.

OBJECTIVE: To develop an animal model for radiofrequency endometrial ablation (EA) and evaluate histopathologic outcomes of EA in New Zealand White (NZW) rabbits. STUDY DESIGN: A pilot study was conducted. A radiofrequency EA device was developed and a variety of EA settings were tested on euthanized NZW rabbits. An algorithm was developed to determine target EA parameters. Bilateral radiofrequency EA was performed via laparotomy using 5.2 mm, 6.1 mm, or 7.1 mm diameter x 100 mm bipolar probes on 10 live NZW rabbits. All rabbits were screened for endometrial cancer (EC). Rabbits were euthanized 3 weeks following EA, and histopathologic analysis of postablation hysterectomy specimens was performed. RESULTS: Bilateral radiofrequency EA was successful in rabbits that were candidates for the procedure, and uterine assessment was feasible in all rabbits. One case of EC was detected. Uterine anatomy was variable among rabbits. The optimal EA setting was 4.5 W/cm2 x 20 seconds, which provided consistent thermal destruction to the endometrium and inner myometrium as verified by histology. CONCLUSION: Use of a radiofrequency EA algorithm tailored to individual NZW rabbits produces consistent thermal destruction of the endometrium and inner myometrium. This animal model can be used to study the long-term consequences of EA and the association with EC.

Risk-adjusted outcomes in elderly endometrial cancer patients: implications of the contrasting impact of age on progression-free and cause-specific survival.

OBJECTIVE: To reexamine the tenet that advanced age independently impacts progression-free and cause-specific survival in patients with endometrial cancer (EC). METHODS: Patients undergoing surgery for stages I-IIIC EC between 1999 and 2008 were stratified by age (<70 vs ≥70years). Three propensity score (PS) methods were utilized to adjust for confounding risk factors. The PS, or conditional probability of being ≥70years old, given a patient's baseline covariates, was derived using logistic regression. The Cox proportional hazards models were fit to estimate the effect of age≥70years on outcomes. RESULTS: Of 1182 eligible patients, 822 (69.5%) were <70 and 360 (30.5%) were ≥70. Patients ≥70 were more likely to have multiple adverse risk factors. The total standardized difference of these factors was reduced by 74% and 81%, respectively, using PS-stratification and PS-matching analyses. The nonsignificant trend toward an association between progression-free survival and age≥70 in an unadjusted analysis (hazard ratio [HR], 1.40; 95% CI, 0.95-2.04) was further attenuated in the 3 PS analyses. The unadjusted HR for the association between age≥70 and cause-specific survival was 2.03 (95% CI, 1.32-3.13). HRs were attenuated in PS analyses but retained significance (except for PS matching), potentially reflecting differences in salvage therapies (P<.001), including a 3-fold greater use of chemotherapy in those <70. CONCLUSION: When risk-adjusted for the higher prevalence of adverse prognostic factors in elderly EC patients, progression-free survival after primary therapy is not age dependent but the less favorable cause-specific survival in this cohort may reflect age-related postrecurrence treatment differences.

Distribution and volume of extrauterine disease in uterine serous carcinoma: is minimally invasive surgery a suitable approach?

OBJECTIVE: Minimally invasive surgery (MIS) is the preferred technique for managing endometrial cancer. Given that uterine serous carcinoma (USC) has a predilection for multiquadrant peritoneal dissemination, our objective was to estimate the potential risk for overlooking occult peritoneal spread with the use of MIS. METHODS: A single-institution, retrospective review was conducted of patients who underwent primary surgical staging for endometrial cancer via laparotomy between 1999 and 2008. Patterns of metastases were analyzed to estimate the potential risk for understaging via MIS. RESULTS: A total of 202 USC cases met inclusion criteria. Pelvic and para-aortic nodes were positive in 59 (36%) of 166 and 43 (31%) of 138, respectively. Stage IVb disease was diagnosed in 77 (38%) of 202 patients. The majority (86%, 66/77) harbored bulky and/or multisite macroscopic abdominal implants. Isolated microscopic peritoneal disease was present in 5 of 77 cases (6% of stage IV, 2% of the entire cohort) but, in all cases, was limited to the omentum; 6 of 77 cases (8% of stage IV, 3% of the cohort) harbored a single implant in the context of a negative omentum but, in all cases, were macroscopic (locations included the ileum, the diaphragm, and the base of the mesentery). CONCLUSIONS: For providers who aim to remove all visible disease in patients with USC, the rate of extrauterine disease escaping detection using MIS is low (<3%) provided an omentectomy is performed together with staging.