Prognostic value of isolated tumor cells in sentinel lymph nodes in low risk endometrial cancer: results from an international multi-institutional study.

OBJECTIVE: The prognostic significance of isolated tumor cells (≤0.2 mm) in sentinel lymph nodes (SLNs) of endometrial cancer patients is still unclear. Our aim was to assess the prognostic value of isolated tumor cells in patients with low risk endometrial cancer who underwent SLN biopsy and did not receive adjuvant therapy. Outcomes were compared with node negative patients. METHODS: Patients with SLNs-isolated tumor cells between 2013 and 2019 were identified from 15 centers worldwide, while SLN negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018. Only low risk patients (stage IA, endometrioid histology, grade 1 or 2) who did not receive any adjuvant therapy were included. Primary outcomes were recurrence free, non-vaginal recurrence free, and overall survival, evaluated with Kaplan-Meier methods. RESULTS: 494 patients (42 isolated tumor cells and 452 node negative) were included. There were 21 (4.3%) recurrences (5 SLNs-isolated tumor cells, 16 node negative); recurrence was vaginal in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). Median follow-up among those without recurrence was 2.3 years (interquartile range (IQR) 1.1-3.0) and 2.6 years (IQR 0.6-4.2) in the SLN-isolated tumor cell and node negative patients, respectively. The presence of SLNs-isolated tumor cells, lymphovascular space invasion, and International Federation of Obstetrics and Gynecology (FIGO) grade 2 were significant risk factors for recurrence on univariate analysis. SLN-isolated tumor cell patients had worse recurrence free survival (p<0.01) and non-vaginal recurrence free survival (p<0.01) compared with node negative patients. Similar results were observed in the subgroup of patients without lymphovascular space invasion (n=480). There was no difference in overall survival between the two cohorts in the full sample and the subset excluding patients with lymphovascular space invasion. CONCLUSIONS: Patients with SLNs-isolated tumor cells and low risk profile, without adjuvant therapy, had a significantly worse recurrence free survival compared with node negative patients with similar risk factors, after adjusting for grade and excluding patients with lymphovascular space invasion. However, the presence of SLNs-isolated tumor cells was not associated with worse overall survival.

Safety and efficacy of topical artesunate for the treatment of vulvar intraepithelial neoplasia 2/3.

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3. METHODS: Participants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation. RESULTS: Fifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance. CONCLUSIONS: Topical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial.

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.

Impact of comorbidities and extent of lymphadenectomy on quality of life in endometrial cancer patients treated with minimally invasive surgery in the era of sentinel lymph nodes.

OBJECTIVE: To identify predictors of quality of life (QoL) among patients who undergo surgical staging with sentinel lymph node (SLN) biopsy or lymphadenectomy for endometrial cancer. METHODS: Patients who underwent minimally invasive surgery for primary endometrial cancer at the Mayo Clinic from October 2013 to June 2016 were mailed a 30-item QoL in Cancer survey (QLQ-C30) and a validated 13-item lower extremity lymphedema screening questionnaire. Patients who answered <50% of the items or had a pre-operative history of lymphedema were excluded. Multivariable linear regression models were fit to evaluate predictors of QoL using inverse-probability of treatment weighting to adjust for differences at the time of the surgery between the lymphadenectomy and SLN groups. RESULTS: The 221 patients included in the analysis were stratified into two groups: patients who underwent (1) bilateral lymphadenectomy as 'backup' after SLN mapping (lymphadenectomy group; n=101) or (2) SLN removal with or without side-specific lymphadenectomy (SLN group; n=120). On multivariable analysis, obesity, lower extremity lymphedema, and kidney disease had significant (p<0.05) and clinically meaningful negative impacts on global QoL. Declines in average adjusted global QoL scores were marked (19.7 points lower) in patients with BMI ≥40 kg/m2 and lower extremity lymphedema compared with non-obese patients without lower extremity lymphedema. In contrast, there was only a 2.9 point difference in the adjusted average global QoL score between the SLN and lymphadenectomy groups. CONCLUSIONS: Lower extremity lymphedema coupled with obesity predicts poorer QoL in patients who undergo surgical staging for endometrial cancer. In this population, reduction of lower extremity lymphedema by performing SLN instead of lymphadenectomy and earlier targeted interventions may improve patients' QoL. Future research focusing on targeted interventions is needed.

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.

Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: An international multi-institutional study.

OBJECTIVE: To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded. RESULTS: Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%-85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2-41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50-9.99; P < .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45-7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44-9.54; P = .007) were independent predictors of recurrence. Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months). CONCLUSIONS: In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.

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.

Impact of treatment modality on overall survival in women with advanced endometrial cancer: A National Cancer Database analysis.

OBJECTIVE: To evaluate overall survival (OS) in women with advanced endometrial cancer (EC) following chemotherapy alone (CT), neoadjuvant chemotherapy and interval debulking surgery (NACT + IDS) or primary cytoreductive surgery and chemotherapy (PCS + CT). METHODS: The National Cancer Database (NCDB) was queried for patients with stage III/IV EC from 2004 to 2015. Univariable and multivariable Cox proportional hazards analyses assessed the impact of treatment modality upon OS. RESULTS: Of 48,179 women identified, 5531 received CT (11.5%), 2614 NACT + IDS (5.4%) and 40,034 PCS + CT (83.1%). Median OS was 11.1 months for CT, 25.1 months for NACT + IDS and 60.9 months for PCS + CT (p < 0.001). On multivariate analysis, NACT + IDS (HR 0.44 (0.40, 0.49); p < 0.001) and PCS + CT (HR 0.32 (0.30, 0.35); p < 0.001) were associated with improved OS vs. CT alone. Age, African American race, income, higher Charlson comorbidity index and grade were predictors of worse OS (p < 0.001). On subgroup analysis by stage (III/IV) and histology (Type I/II), PCS + CT improved OS for all patients, compared to NACT + IDS (p < 0.001) and CT (p < 0.001). NACT + IDS was associated with improved OS vs. CT in stage III type I (HR 0.50; 95% CI 0.38, 0.67; p < 0.001), stage IV type I (HR 0.43; 95% CI 0.35, 0.52; p < 0.001), and stage IV type II EC (HR 0.43; 95% CI 0.36, 0.51; p < 0.001), but not stage III type II EC (HR 0.76; 95% CI 0.56, 1.03; p = 0.08). CONCLUSIONS: In women with advanced EC, PCS + CT is associated with improved OS compared to NACT + IDS or CT alone, regardless of stage or histology. Additionally, NACT + IDS is associated with superior OS in stage III type I and all stage IV EC compared to CT alone. Where feasible, surgery should be incorporated into treatment planning in women with advanced EC.

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.

Use of Transabdominal Ultrasound for the detection of intra-peritoneal tumor engraftment and growth in mouse xenografts of epithelial ovarian cancer.

OBJECTIVE: To evaluate intraperitoneal (IP) tumor engraftment, metastasis and growth in a pre-clinical murine epithelial ovarian cancer (EOC) model using both transabdominal ultrasound (TAUS) and bioluminescence in vivo imaging system (IVIS). METHODS: Ten female C57Bl/6J mice at six weeks of age were included in this study. Five mice underwent IP injection of 5x106 ID8-luc cells (+ D- luciferin) and the remaining five mice underwent IP injection of ID8-VEGF cells. Monitoring of tumor growth and ascites was performed weekly starting at seven days post-injection until study endpoint. ID8-luc mice were monitored using both TAUS and IVIS, and ID8-VEGF mice underwent TAUS monitoring only. Individual tumor implant dimension and total tumor volume were calculated. Average luminescent intensity was calculated and reported per mouse abdomen. Tumor detection was confirmed by gross evaluation and histopathology. All data are presented as mean +/- standard deviation. RESULTS: Overall, tumors were successfully detected in all ten mice using TAUS and IVIS, and tumor detection correlated with terminal endpoint histology/ H&E staining. For TAUS, the smallest confirmed tumor measurements were at seven days post-injection with mean long axis of 2.23mm and mean tumor volume of 4.17mm3. However, IVIS imaging was able to detect tumor growth at 14 days post-injection. Ascites formation was detected in mice at 21 days post-injection. CONCLUSIONS: TAUS is highly discriminatory for monitoring EOC in pre-clinical murine model, allowing for detection of tumor dimension as small as 2 mm and as early as seven days post-injection compared to IVIS. In addition, TAUS provides relevant information for ascites development and detection of multiple small metastatic tumor implants. TAUS provides an accurate and reliable method to detect and monitor IP EOC growth in mouse xenografts.

Endometrial cancer in young women: prognostic factors and treatment outcomes in women aged ≤40 years.

OBJECTIVE: Endometrial cancer in pre-menopausal patients aged ≤40 years is rare and poses both diagnostic and management challenges. The goal of this study was to investigate the clinical and pathologic factors associated with endometrial cancer in this group and their impact on survival. METHODS: Patients with endometrial cancer treated between January 2004 and August 2016 were retrospectively reviewed. Patients who underwent either primary surgical treatment or fertility-sparing therapy were included. Exclusion criteria were age >60 years and patients who received neoadjuvant chemotherapy or primary radiation. Age at diagnosis was used to classify patients into two groups: ≤40 and 41-60 years. Clinical and pathologic variables were compared between the groups. Progression-free survival and overall survival were estimated using Cox proportional hazards. RESULTS: A total of 551 patients were evaluated, of which 103 (18.7%) patients were ≤40 years and 448 (81.3%) were 41-60 years. Age ≤40 years was associated with higher body mass index (38.8 vs 35.8 kg/m2, p=0.008), non-invasive cancers (54.2% vs 32.6%, p<0.001), lower uterine segment involvement (27.2% vs 22.5%, p<0.001), and less lymphovascular space invasion (16.8% vs 29.1%, p=0.015). The rate of synchronous ovarian cancer was 9.2% vs 0.7% in age 41-60 years (p<0.001), and 19% of women with endometrial cancer aged ≤40 years underwent fertility-sparing therapy. Grade, stage, myometrial invasion, lymphovascular space invasion, and lymph node status were associated with survival, and fertility-sparing therapy adversely affected the recurrence rate of the age ≤40 years cohort. Among all patients aged ≤60 years, mismatch repair deficiency due to MLH1 methylation was associated with worse progression-free survival, 48.6% vs 83.3% (HR 1.98, 95% CI 1.06 to 3.17, p=0.032), and overall survival, 56.5% vs 90.0% (HR 2.58, 95% CI 1.13 to 5.90, p=0.025). CONCLUSIONS: Patients aged ≤40 years with endometrial cancer have more favorable prognostic factors and higher rates of synchronous tumors. Fertility-sparing therapy was associated with higher recurrence rates. The prognostic value of MLH1 methylation in this population warrants further investigation.

Impact of vaginal brachytherapy on survival in stage I endometrioid endometrial carcinoma.

OBJECTIVE: To evaluate trends in use of radiation therapy and its impact on overall survival in low- and high-grade stage I endometrioid endometrial carcinoma. METHODS: Patients with stage I endometrial cancer who underwent hysterectomy from 2004 to 2013 were identified through the National Cancer Database and classified as: stage IA G1/2, stage IA G3, stage IB G1/2, and stage IB G3. Trends in use of vaginal brachytherapy and external beam radiation therapy were assessed. Overall survival was measured from surgery and estimated using the Kaplan-Meier method. The effect of radiation therapy on overall survival was assessed within each stage/grade group using Cox proportional hazards analysis in propensity-matched treatment groups. RESULTS: A total of 132 393 patients met inclusion criteria, and 81% of patients had stage IA and 19% had stage IB endometrial cancer. Adjuvant therapy was administered in 18% of patients: 52% received vaginal brachytherapy, 30% external beam radiation therapy, and 18% chemotherapy ±radiation therapy. External beam radiation therapy use decreased from 9% in 2004 to 4% in 2012, while vaginal brachytherapy use increased from 8% to 14%. Stage IA G1/2 patients did not benefit from either external beam radiation therapy or vaginal brachytherapy, while administration of vaginal brachytherapy improved overall survival in stage IB G1/2 compared with no treatment (p<0.0001). In stage IB G1/2 and stage IA G3, vaginal brachytherapy was superior to external beam radiation therapy (p=0.0004 and p=0.004, respectively). Stage IB G3 patients had improved overall survival with either vaginal brachytherapy or external beam radiation therapy versus no treatment but no difference in overall survival was seen between vaginal brachytherapy and external beam radiation therapy (p=0.94). CONCLUSIONS: The delivery of adjuvant radiation therapy in patients with stage IA G1/2 endometrial carcinoma is not associated with improvement in overall survival. Patients with stage IB G1/2 and G3 as well as stage IA G3 are shown to benefit from improved overall survival when adjuvant radiation therapy is administered. These findings demonstrate potential opportunities to reduce both overtreatment and undertreatment in stage I endometrial cancer patients.