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To examine patients with confirmed endometrial cancer recurrence; evaluate patterns, presentation, and mode of diagnosis.A retrospective review of women with endometrial cancer diagnosis between 2014 and 2020. Disease recurrences were evaluated. Medical records were reviewed focusing on presentation at time of recurrence. Relationships were assessed using χ2, Fisher's exact test, t-test, and Wilcoxon test. The Kaplan-Meier product limit was used to estimate survival. Multiple logistic regression analysis was used to assess the impact of covariates.Endometrial cancer recurrence was identified in 201 (11.7%) patients. Sixty percent (120/201) of patients presented with symptoms. Pain was the most common presenting symptom (23.4%, 47/201) and bleeding was reported in14% (28/201). Patients with symptomatic presentation were less likely to be able to receive treatment for their recurrent disease (76.7% vs 91.3%, p = 0.005). Asymptomatic pelvic exam diagnosed recurrence in 13.4% (27/201) and was more common in patients initially diagnosed with early-stage disease (66.7% vs 34.5% p = 0.001) of endometrioid histology (66.7% vs 36.8%, p = 0.003) without prior adjuvant therapy (48.2% vs 17.9%, p = 0.001). More than1/3 of diagnoses were made by providers outside of the oncologic care team.The majority of women with recurrent endometrial cancer were symptomatic and pain is a common complaint associated with disease recurrence. Patients with symptomatic presentation of disease recurrence were less likely to receive treatment for recurrent disease but this did not result in an overall survival (OS) difference. Given the rising mortality rate of endometrial cancer further work is needed to develop multidisciplinary surveillance strategies that will enable meaningful treatment of disease recurrence.

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 following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Supplemental table S1 shows siRNA sequences. Table S2 shows primer sequences used for RTPCR. Figure S1 shows sensitivity of various cells to olaparib. Figure S2 shows the effect of olaparib on ALDHbr population. Figure S3 shows expression of ALDH isoforms at mRNA level. Figure S4 shows mRNA level of ALDH isoforms in PARPi-resistance cancer cells. Figure S5 shows the effect of ALDH1A1 expression on the sensitivity of EOC cells to olaparib. Figure S6 shows DNA repair ability in ALDH+ cells. Figure S7 shows the effect of ALDH1A1 on homologous recombination repair. Figure S8 shows the effect of NCT-501 on cell viability and ALDH activity. Figure S9 shows BRCA2 expression in various EOC cells. Figure S10 shows the combined effect of olaparib and NCT-501 on BRCA2-wt cells. Figure S11 shows the effect of NCT-501 on DNA repair in PARPi-resistant cells.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum-sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Here, we demonstrated that PARP inhibitor (olaparib)–resistant epithelial ovarian cancer (EOC) cells exhibited an elevated aldehyde dehydrogenase (ALDH) activity, mainly contributed by increased expression of ALDH1A1 due to olaparib-induced expression of BRD4, a member of bromodomain and extraterminal (BET) family protein. We also revealed that ALDH1A1 enhanced microhomology-mediated end joining (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein that promotes homologous recombination (HR) by using an intrachromosomal MMEJ reporter. Moreover, NCT-501, an ALDH1A1-selective inhibitor, can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. Given that MMEJ activity has been reported to be responsible for PARPi resistance in HR-deficient cells, we conclude that ALDH1A1 contributes to the resistance to PARP inhibitors via enhancing MMEJ in BRCA2−/− ovarian cancer cells. Our findings provide a novel mechanism underlying PARPi resistance in BRCA2-mutated EOC cells and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming PARPi resistance in EOC patients carrying BRCA2 mutation.

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Purpose:Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002.Patients and Methods:Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints.Results:Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28–0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23–0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03–0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34–0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25–0.97; P = 0.041). Toxicity was not different between arms.Conclusions:Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.

Background There is a paucity of literature regarding outcomes following vulvar excision for non-malignant lesions. This is a common procedure among gynecologists (GYN) and gynecologic oncologists (GO), and a body of evidence is warranted to guide clinical care and future research. Objectives This study aimed to estimate the rate of wound complications following simple vulvar excision and to identify risk factors for these outcomes. Our secondary objectives were to determine rates of 1) positive margins and 2) occult carcinoma in cases of vulvar dysplasia. Study design We conducted a single-institution, retrospective cohort study of patients who underwent simple vulvar excision procedures for suspected premalignant or benign lesions between June 2016 and February 2020. Our primary outcome was the rate of composite wound complication including wound separation or breakdown, infection, or hematoma. Our secondary outcomes were the incidence of 1) margins positive for residual dysplasia and 2) occult minimally invasive carcinoma. Fisher's exact tests and Chi-squared tests were used to compare categorical variables and logistic regression models and independent student t tests were used for continuous variables, as appropriate. Multivariate stepwise selection and multiple logistic regression was performed to evaluate risk factors for complication and generate odds ratios. Results Three-hundred thirty-eight patients were included and 143 (42.3%) experienced wound complication. The majority of these were wound separation or breakdown (n=134, 39.6%), followed by infection (n=22, 6.5%) and hematoma (n=4, 1.2%). On multivariate analysis, the presence of high-grade vulvar dysplasia (aOR 1.83, 95% CI 1.06-3.15), longer specimen diameter (aOR 1.03, 95% CI 1.01-1.05), and lesion location on the perineum (aOR 2.25, 95% CI 1.38-3.66) were independent risk factors. With high-grade vulvar dysplasia, the rate of positive margins was 50.2% (114/227) and occult microinvasive carcinoma was 17.2% (39/227). Notably the primary and secondary outcomes were similar between GO and GYN. Conclusions Wound complications following vulvar excision for non-malignant lesions are common. Select groups may benefit from anticipatory counseling and future interventional studies to prevent complication. The incidence of positive surgical margins and occult minimally invasive carcinoma is also high reflecting the challenging nature of treating vulvar disease.

Uterine cancers are associated with a high risk of venous thromboembolism. The American Society of Clinical Oncology practice guidelines recommend all patients undergoing pelvic surgery for cancer receive extended pharmacological thromboprophylaxis with the duration dependent on risk. However, risk stratification for patients with uterine cancer is not clearly defined. The Caprini score is the most widely used risk assessment model but it has been found to have limited utility in the gynecologic oncology population. A modified Caprini score has been explored in other populations. The Khorana score is an additional risk assessment model which has not been studied in this context.Our objective was to evaluate the ability of a modified Caprini model as well as the Khorana score to risk stratify patients with uterine cancer for postoperative venous thromboembolism within 90 days of surgery.Following IRB approval, a retrospective cohort study was performed and all patients with uterine cancer who underwent a hysterectomy over a 4-year period were included. The Caprini and Khorana scores were calculated for each patient. The Caprini score cutoff for highest risk was evaluated at ≥7, ≥8 and ≥9 ("modified Caprini") and the Khorana score cutoff was evaluated at ≥2 and ≥3. To determine the prognostic utility of each score as well as other clinico-pathologic criteria on development of venous thromboembolism, univariate analysis was performed using independent t test, chi-square test or Fisher's exact test; multivariate analysis was performed using logistic regression.A total of 954 patients were included, the rate of venous thromboembolism was 1.7% (16/954). Minimally invasive surgical approach was utilized in 90.5% (863/954) of patients. The mean Caprini score of patients with venous thromboembolism was 10.3 compared to 8.1 for the patients without (p0.0001, 95%CI 1.17-3.33). The mean Khorana score of the venous thromboembolism group was 2.4 versus 1.9 (p=0.03, 95%CI 0.04-0.82). Both the Caprini and Khorana scores were found to be associated with venous thromboembolism, but only a Caprini score with cutoff ≥8 or ≥9 was statistically significant (RR 31.25, 95%CI 1.88-519.49; RR 4.59, 95%CI 1.49-14.13 respectively), with high accuracy based on area under the curve (0.75 and 0.68, respectively). Of the minimally invasive subgroup, 11.7% (101/863) had same-day discharge with no postoperative thromboprophylaxis; none of these patients developed venous thromboembolism. Despite laparotomy patients receiving extended prophylaxis (30 days), the rate of venous thromboembolism was more than three times that of the minimally invasive group (5.49% vs 1.7%). Advanced stage and leukocytosis were noted to be independent risk factors for venous thromboembolism.Our study suggests that using a modified Caprini score could help identify the highest risk patients who would benefit from prolonged thromboprophylaxis, reduce the incidence of postoperative venous thromboembolism as well as minimize the cost and harm of overtreatment. These findings need to be validated in a prospective manner and further research is needed to determine the optimal duration of therapy.

In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease have continued to rise; from 1987 to 2014 there has been a 75% increase in cases and almost 300% increase in endometrial cancer deaths. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer with increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress.The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Publications Committee, and the SGO board members prior to submission for publication. The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines [1] using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.

In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. This manuscript, Part II in a two-part series, includes specific recommendations on treatment of recurrent disease, post treatment surveillance and survivorship, considerations for younger women, and special situations. Part I covered histopathology and molecular pathology, risk factors, presentation and diagnostic approach, surgical approach and adjuvant therapy.

Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging from 9 to 33%. Hormonal treatment options take advantage of the estrogen-dependent molecular pathways in endometrial cancers. Current options for hormonal therapies include progesterone therapy (medroxyprogesterone acetate and megestrol acetate) as a single agent or in combination and agents that target the estrogen pathway. Aromatase inhibitors have had modest single-agent activity, but synergistic effects have been found when used in combination with targeted therapy including mTOR inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Molecular profiling of endometrial cancers has begun to help individualize treatments. This review will report on existing data and ongoing trials investigating novel hormonal therapy agents.

Objective Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV. Methods 341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13–12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified. Results Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total). Conclusions Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.

With the increasing rates of same-day discharge following minimally invasive surgery for endometrial cancer, the need for and value of routine postoperative testing is unclear.This study aimed to determine whether routine postoperative laboratory testing following minimally invasive hysterectomy for endometrial cancer leads to clinically significant changes in postoperative care.This was a single-institution retrospective cohort study of patients undergoing minimally invasive hysterectomy for endometrial cancer by a gynecologic oncologist between June 2014 and June 2017. Patient demographics, preoperative comorbidities, operative and postoperative data, and pathologic findings were manually extracted from the patients' medical records. The financial burden of laboratory testing was computed using hospital-level cost data.Of the 649 women included in the analysis, most (91.4%) were White, with a mean age of 61 years, and mean body mass index of 38.0 kg/mRoutine postoperative laboratory tests are unlikely to lead to significant changes in management for women undergoing minimally invasive hysterectomy for endometrial cancer, and may increase cost without providing a discernible clinical benefit. In the setting of strict postoperative guidelines, laboratory tests should be ordered when clinically indicated rather than as part of routine postoperative management for women undergoing minimally invasive hysterectomy for endometrial cancer.

The laparoscopic hysterectomy readmission score (LHRS) was created to identify patients for whom same day discharge (SDD) after minimally invasive hysterectomy (MIH) may not be advisable and includes diabetes, chronic obstructive pulmonary disease, disseminated cancer, chronic steroid use, bleeding disorder, length of surgery, and any postoperative complication prior to discharge. We evaluated the performance of the score at predicting readmission in a gynecologic oncology population, and additionally sought to determine if any factors known prior to surgery could replace those that are not known until the time of surgery (operative time and postoperative complication).This was a single-institution retrospective cohort study of women undergoing robotic hysterectomy by a gynecologic oncologist in 2018. Associations between pre-operative, operative and post-operative factors and 30-day readmission, SDD and postoperative complications were assessed using logistic regression.The 30-day readmission rate among the 423 women in the cohort was 4.5% and 1.9% in those undergoing SDD. Readmission rates by LHRS were: score 1 (4.9%), score 2 (7.8%), score 3 (13.6%), score 4 (16.7%). Patients with a LHRS of ≥3 had higher odds of readmission compared to those with a lower score (OR 4.20, p = 0.02). Infectious morbidity accounted for the majority of postoperative complications, emergency room visits and readmissions. We did not identify preoperative factors to replace the intra- and post-operative factors used in the score.The readmission rate following MIH is low, and a LHRS of ≥3 is associated with increased risk of readmission. Our findings support the applicability of the LHRS to a gynecologic oncology population; addressing risk factors for postoperative infection or closer follow up for patients with a LHRS ≥3 could reduce postoperative readmissions.

Background Endometrial cancer (EC) is the most common gynecologic cancer in the U.S. The objective of this cohort study was to characterize the clinical and pathologic features that are associated with endometrial cancer–specific death for women cared for at a single National Cancer Institute–designated comprehensive cancer center. Patients, Materials, and Methods This is a retrospective cohort from 2014 to 2017 including all women who had a hysterectomy for EC. Charts were reviewed for clinical and pathologic data, focusing on survival outcomes. Results Seven hundred seventy-one patients with EC underwent hysterectomy with 760 informative for outcomes. Seventy-six (10%) deaths were related to their EC; 62 women died from recurrent EC. Nonendometrioid histology and advanced stage were predictors of recurrence and EC death. Among patients with endometrioid ECs, mismatch repair status was significantly associated with EC-specific survival (relative risk = 4.8; 95% confidence interval, 2.3–10.3; p < .0001). Most patients with EC who recurred died of their disease 62/83 (74.7%). Nearly half of the patients that recurred (27/62) had no additional therapy at the time of recurrence. Overall survival was significantly longer for those women who had additional treatment at the time of recurrence; however, the improvement in overall survival with therapy at recurrence was largely attributable to effects in those women who were adjuvant therapy naïve. Conclusion Although there is benefit of treatment at the time of recurrence for treatment-naïve women; only approximately half of patients were able to receive therapy. There is an urgent need for continued efforts for more effective EC therapy in both the front-line and recurrent setting as well as early identification of cancer diagnosis and recurrence. Implications for Practice Approximately 10% of patients died of their endometrial cancer. Most deaths were from recurrent disease; however, almost 20% of endometrial cancer deaths were within 120 days of surgery. Although treatment at the time of recurrence improves overall survival, only approximately half of patients will receive therapy at the time of recurrence. Traditional prognostic features like histology and stage remain important to predict risk of recurrence, and newer biomarkers, such as mismatch repair status, may improve risk stratification and targeted therapy. There remains an urgent need for improved therapy and early detection of diagnosis and recurrence.

Optimization of preoperative nutritional status has been recommended and associated with improved outcomes for other oncologic procedures, but has not been studied in patients undergoing pelvic exenteration.A retrospective chart review of 199 patients was conducted. Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate analysis was performed with Cox proportional hazards.199 patients underwent PE with 61 (31%), 78 (40%) and 58 (29%) patients having colorectal, gynecologic and urologic histological diagnoses, respectively. Median OS following PE was 25 months. Preoperative serum albumin3.5 g/dL was associated with worsened OS (HR 1.661; 95% CI 1.052-2.624) as well as increased incidence of any postoperative complication (85.9% vs 72.3%, p = 0.034), but was not associated with 90-day mortality (11.3% vs 7.9%, p = 0.457).Poor preoperative nutritional status is associated with increased complications and decreased OS. Surgeons should maximize preoperative nutritional status to improve perioperative outcomes and long-term survival.

To evaluate surgical complexity scores (SCS) and minimally invasive surgery (MIS) at interval debulking surgery (IDS) in advanced epithelial ovarian cancer (EOC) patients receiving neoadjuvant chemotherapy (NACT).A multi-institutional study of NACT with IDS for advanced EOC was conducted. Demographic data were abstracted and SCS assigned based on IDS findings. Disease-specific overall survival (DSS) was defined as the time from completion of adjuvant chemotherapy to death due to disease. Cox proportional hazards regression models were used for univariate and multivariate survival analyses.282 patients were identified; 80.5% had high-grade serous histology and 54.6% were75 (median 63.9; range 34.1-84.8). Approximately 84% were optimally cytoreduced (61% R0; 23%1 cm). In multivariate analyses, age 75+ (p ≤ 0.001), residual disease (1 cm; p = 0.03), and SCS ≥ 3 (p = 0.04) were significantly predictive of worse DSS when morbidity and ASA score were also in the model. When optimally debulked was defined as R0, only age 75+ (0.001) was significantly associated with decreased DSS. In the R0 cohort, SCS did not significantly predict DSS. However, subset analysis defining optimal ≤1 cm, revealed higher SCS was associated with a 1.6-fold increased risk of death (p = 0.02). Fifty-one patients underwent laparoscopic IDS. Twenty-four (47%) were converted to laparotomy to achieve optimal debulking in 21 patients (87.5%); while 25 had laparoscopic optimal cytoreduction (19/25 [76%] R0).In women with advanced EOC treated with NACT, older age, SCS ≥ 3, and residual disease1 cm at IDS were predictors of worse survival. MIS appears safe and feasible with acceptable optimal cytoreduction rates.

Background The objective of this study was to assess the correlation between mismatch repair (MMR) status, disease recurrence patterns, and recurrence-free survival (RFS) in patients with high-intermediate-risk (HIR) endometrioid endometrial cancer (EEC). Methods A single-institution chart review for consecutive patients who were diagnosed with ECC between 2007 and 2016 was undertaken. Tumor MMR status was determined for all patients based on reported findings for mutL homolog 1 (MLH1), postmeiotic segregation (PMS2), mutS homolog 2 (MSH2), and MSH6 immunohistochemistry; and defective MMR (dMMR) status was defined as the lack of expression of at least 1 of these proteins. Patients were classified with HIR EEC according to criteria used for Gynecologic Oncology Group study 249. The factors associated with recurrence were assessed by logistic regression. RFS and associated factors were assessed by Kaplan-Meier survival analysis and Cox proportional-hazards models. Results In total, 197 patients who had HIR EEC (64 with dMMR and 133 with intact MMR [iMMR]) were identified, of whom 32 (16.2%) developed recurrent disease. The median follow-up was 54 months. The recurrence rate for women who had dMMR was 28% compared with 10.5% for those who had iMMR (P = .002), independent of the type of adjuvant therapy they received. The increase in distant recurrences among patients who had dMMR was even more pronounced (14.1% vs 3%; P = .003). The estimated 5-year RFS was 66% for women who had dMMR compared with 89% for those who had iMMR (P = .001). Excluding isolated vaginal recurrences, the difference in 5-year RFS was 73.5% versus 95%, respectively (P = .0004). Conclusions Patients who had HIR EEC with dMMR had increased rates of recurrence and decreased RFS compared with those who had HIR EEC with iMMR, despite the receipt of similar adjuvant treatment. The current findings highlight the need for alternative treatment options and the importance of MMR status as a biomarker for patients with HIR EEC.

Objectives To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer. Methods Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria. Results 26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness. Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months. Conclusions The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development.

This article will discuss the recent data on the prognostic significance of molecular classification of endometrial carcinoma, as well as its impact on directing treatment decisions. Molecular classification has emerged as a complement to the current paradigm of endometrial cancer (EC) risk stratification. POLE mutations appear to portend favorable prognoses, but data are insufficient to indicate withholding treatment based on this signature. Copy number high (CNH) EC carries a worse prognosis and may benefit from more aggressive therapy. MMRd tumors are likely to have other prognostic features that indicate adjuvant treatment and many recurrences respond favorably to pembrolizumab. Progression of molecular profiling may allow further discrimination of the no specific molecular profile (NSMP) group. Treatment for this group remains largely based on conventional risk factors. For both the NSMP and the CNH groups, treatment with lenvatinib and pembrolizumab is an attractive contemporary option for recurrence management. Molecular classification is a useful adjunct to conventional risk stratification paradigms for both prognostic counseling and treatment selection. Clinical trials incorporating molecular signatures in assigning treatment strategies may further elucidate the value of this classification system.

Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor α (ERα) and β (ERβ). Given that ERα is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERβ shows a protective effect against the development and progression of tumors, the activation of ERβ by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERβ using a newly developed ERβ agonist, OSU-ERb-12, can impede ovarian cancer cell expansion and tumor growth in an ERα-independent manner. More interestingly, we found that OSU-ERb-12 also reduces the cancer stem cell (CSC) population in ovarian cancer by compromising non-CSC-to-CSC conversion. Mechanistically, we revealed that OSU-ERb-12 decreased the expression of Snail, a master regulator of the epithelial-to-mesenchymal transition (EMT), which is associated with de novo CSC generation. Given that ERα can mediate EMT and facilitate maintenance of the CSC subpopulation and that OSU-ERb-12 can block the transactivity of ERα, we conclude that OSU-ERb-12 reduces the CSC subpopulation by inhibiting EMT in an ERα-dependent manner. Taken together, our data indicate that the ERβ agonist OSU-ERb-12 could be used to hinder tumor progression and limit the CSC subpopulation with the potential to prevent tumor relapse and metastasis in patients with ovarian cancer.

BackgroundCombining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.Patients and methodsIn this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored.ResultsMedian PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009).ConclusionsAdding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

Objectives: To report on the incidence of ovarian metastasis in patients with high grade neuroendocrine tumors of the cervix (NEC) who underwent surgical resection. Methods: This was a single institution retrospective chart review. The electronic medical record was searched for all patients with a diagnosis of NEC at The Ohio State University from January 2010 to March 2020. Patients without complete pathologic records were excluded. Results: From January 2010 to March 2020, 43 patients were identified with NEC. Of those patients, 16 had undergone surgical resection including hysterectomy, bilateral salpingectomy and oophorectomy, and lymph node dissection. Of the 16 patients, zero had evidence of metastatic disease to their ovaries. The median age of patients in our cohort was 35.5 years with a mean age of 40.5 (28-70y). 13 of the 16 patients were considered pre-menopausal at the time of their surgery (defined as age 50 or younger). Of the 16 patients who underwent surgical management, 2 had adjuvant chemotherapy alone, 7 had adjuvant chemotherapy with adjuvant radiotherapy, 2 had adjuvant chemoradiotherapy, and 3 had adjuvant radiation therapy. Of the 16 patients in the study, 13 received neoadjuvant chemotherapy as part of their treatment. For those who had chemotherapy as part of their treatment plan, the most commonly used regimen was cisplatin with etoposide with a median of 3 cycles neoadjuvant and 3 cycles in the adjuvant setting. Based on the FIGO 2018 staging classifications, 6 patients had stage I disease (1 1A2, 2 IB1, 1 IB2, 2 IB3). 10 of the 16 patients had advanced stage disease defined as IIB through IVB (2 IIB, 1 IIIB, 3 IIIC1, 2 IIIC2, 2 IVB). Conclusions: The incidence of ovarian metastasis in patients with NEC has not been reported in the literature. Here we demonstrate in our limited series that ovarian metastasis in NEC of the cervix is rare. Current practice of ovarian retention in NEC is based on expert opinion and is not standard of care across the field of gynecologic oncology. Our data support that ovarian retention in NEC is safe. Previously published data from our institution demonstrate that 82% of patients with stage I disease had no evidence of disease at time of their last follow up with the use of a multimodality treatment approach (McCann 2013). In our cohort, radiation therapy is often employed in the treatment of NEC. Ovarian retention with transposition out of the radiated field may be a reasonable option for women who would benefit from preservation of ovarian function. Commonly used chemotherapeutic agents were cisplatin with etoposide, both with limited gonadotoxicity. Given the low incidence of ovarian metastasis in NEC, ovarian cryopreservation or oocyte harvesting is a reasonable option for patients who desire the ability to have offspring with the assistance of a surrogate in the future. Further studies with a multi-institutional collaboration to better define the incidence of NEC metastasis to the ovary is necessary.

Objectives: To describe results of tumor testing among women with ovarian cancer and to identify associations with oncologic outcomes according to genetic variant status. Methods: Institutional review board (IRB)-approved, retrospective review of tumor genomic results obtained within a single Gynecologic Oncology division. Genomic results, oncologic outcomes and other clinicopathologic data points were abstracted from medical records. Platinum sensitivity and response to PARP inhibitors were compared between patients with: germline BRCA (gBRCA) pathogenic variants (PV), somatic BRCA (sBRCA) PVs and no gBRCA PVs, and loss of heterozygosity (LOH)/genome instability and no gBRCA or sBRCA PVs. These groups are referred to as “gBRCA,” “sBRCA,” and “LOH,” respectively. Results: A total of 261 patients with epithelial ovarian/fallopian tube/primary peritoneal cancer had tumor testing between 2017 and 2020. There were 26 (10%) gBRCA PV carriers [15 BRCA1, 11 BRCA2] identified, 48/261 (18%) tumors with only sBRCA PVs and 13/261 (5%) tumors with LOH and no gBRCA or sBRCA PVs. There were no significant differences in histologies between groups. Of the patients with gBRCA and sBRCA respectively, 85% and 69% were primary platinum sensitive and 8% and 17% were primary platinum resistant, respectively (p=0.40). The average number of platinum-based regimens used before platinum resistance developed was 2.67 for gBRCA (N=6), 2.18 for sBRCA (N=11), 3.2 for LOH (N=5). These groups were not significantly different (p=0.17).23/26 (88%) gBRCA, 32/48 (67%) sBRCA, and 10/13 (77%) LOH patients received PARP inhibitors (PARPi) for treatment. 3 gBRCA and 4 sBRCA patients received PARPi more than once. Median PFS for PARPi use in the frontline was 6 months compared to 5 months in the recurrent setting. There were no significant differences between PFS on PARPi in the upfront or recurrent setting. PFS for PARPi used in the recurrent setting for gBRCA was 8 months (95% CI: 4.6-11.5) and 6.5 months (95% CI: 3.4-9.6) for sBRCA compared to 4 months for LOH (95% CI: 0.74-7.26; p=0.33). Download : Download high-res image (97KB) Download : Download full-size image Conclusions: Twenty-eight percent of ovarian cancer patients had a gBRCA or sBRCA PVs. Platinum sensitivity is similar between patients with gBRCA, sBRCA and LOH groups, however, patients with gBRCA and LOH received slightly more lines of platinum than those with sBRCA. There was a trend towards lower PFS for PARPi used in the recurrent setting in the LOH group compared to gBRCA or sBRCA. These outcomes should be evaluated in a larger population to determine the reliability of LOH assays for predicting functional homologous recombination deficiency and susceptibility to PARPi in the primary or recurrent setting.

Objectives: Preclinical data demonstrated a synergistic and additive effect between rucaparib and taxanes in human sporadic ovarian and endometrial cancer cell lines, with cell line data demonstrating that RNA expression of FOLR1 (folate receptor alpha) positively correlates with BRCA mutation status and with being LOH high. The objective was to estimate the maximally tolerated dose (MTD) and to describe toxicities associated with MIRV and rucaparib in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer. Methods: Patients had to have evidence of folate receptor α (FRα) expression by IHC (≥25% of tumor staining at ≥2+ intensity) on archival tissue or recent biopsy. Using a 3+3 design patients were given MIRV (4, 5, or 6 mg/kg IV every 3 weeks) and rucaparib PO BID (400 mg, 500 mg, or 600 mg) depending on the dose level. A total of 6 additional patients are being enrolled to the expansion cohort. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging every 3rd cycle, using RECIST v1.1 criteria. Results: A total of 88 patients were screened for FRα expression. A total of 16 patients have been enrolled to date; 12 with ovarian cancer and 4 with endometrial cancer, all had high grade serous carcinoma. Median age was 64.5 (range 57-82) with 3 (range 1-9) prior lines of treatment (including 5 with prior PARP inhibitor). Six patients completed DL2 (5/500), however, 2 DLTs with both grade 3 fatigue, and no DLTs at DL1, let us to establish the phase 2 dose at DL1 (MIRV 5 mg/kg IV every 3 weeks and rucaparib 400 mg PO BID). Treatment related toxicities (all grades) occurring in ≥25% of patients included fatigue (73%), nausea (67%), blurred vision (60%), anemia (47%), anorexia (47%), mucositis (40%), ALT/AST elevated (40%), dry eyes (33%), vomiting (27%), thrombocytopenia (27%), weight loss (27%), leukopenia (27%), dysgeusia (27%). Grade ≥3 toxicities were fatigue (20%), pneumonitis (13%), anemia (13%), diarrhea (7%), cataract (7%), lymphopenia (7%), thrombocytopenia (7%), weight loss (7%), hypokalemia (7%). A total of 12 patients are currently evaluable for response (updated results will be presented if accepted); 5 (33%) partial response, 1 (7%) unconfirmed partial response, 6 (40%) stable disease. The ORR was 6/12 (50%). 44% (4/9) in ovarian cancer and 67% (2/3) in endometrial cancer. Median FRα expression was 80% (70 for PR, 95 for SD; range 30-100). Median PFS is 6.3 months with 95% CI (0.7, 13.8) months. Among 6 responses, 1 progressed, 1 died, 4 are censored, thus the median duration of response is not reached. Conclusions: Combination rucaparib and MIRV was tolerable with mostly manageable side effects. Encouraging activity was seen in this heavily pretreated population (including prior PARPi) of both endometrial and ovarian cancer. Notably, two patients developed pneumonitis (AESI for both agents) grade ≥3 after 14 and 24 cycles of treatment, respectively, each with a prolonged PR. Close monitoring for delayed side effects remains critically important especially in those with prolonged therapy.

Purpose: Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002. Patients and Methods: Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints. Results: Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28–0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23–0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03–0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34–0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25–0.97; P = 0.041). Toxicity was not different between arms. Conclusions: Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.

BACKGROUND Robotic prostatectomy and robotic hysterectomy require steep Trendelenburg positioning. Many authors documented significant increases in intraocular pressure (IOP) during steep Trendelenburg. However, the long-term biological effect of a significant increase in IOP on the structural and functional ocular system is unknown. This study examines the effect of a significant increase in IOP on the visual acuity, retinal nerve fiber layer thickness (RNFLT), and ganglion cell complex (GCC) thickness in 52 patients without preexisting ocular disease of both genders before and 3 months after their procedures. METHODS This was a prospective cohort study. The total number of patients included was 56, then 3 females and 1 male case were excluded, totaling 28 robotic hysterectomies and 24 robotic prostatectomies were performed. Patients underwent complete eye examination before the procedure and 3 months after, measuring the main outcome of RNFLT and the secondary outcomes of GCC thickness, foveal threshold (FT), mean deviation (MD), and pattern standard deviation (PSD). These outcomes were analyzed using linear mixed-effects models. On the day of surgery, we examined the IOP after induction of anesthesia, at the end of steep Trendelenburg, and in the recovery room. RESULTS There were significant differences in IOP values at the end of steep Trendelenburg versus after induction and 45-60 minutes post-awakening (P < .001 for both groups). No difference between IOP 45 and 60 minutes post-awakening and IOP after induction was observed in either group. The highest IOPs occurred at the end of the steep Trendelenburg time point for both groups. The mean duration of steep Trendelenburg in robotic prostatectomy was 184.6 minutes (standard deviation [SD] = 30.8), while the mean duration in robotic hysterectomy was 123.0 minutes (SD = 29.8). All ophthalmologic examinations were normal preoperatively and 3 months postoperatively. The ocular parameters in the retina and optic disk did not differ significantly before surgery and 3 months after. CONCLUSIONS There is a significant increase in IOP during steep Trendelenburg positioning. There was no significant difference in the ocular parameters examined 3 months after the procedure in this cohort.

FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

Objective A pathologic chemotherapy response score (CRS) is used to grade ovarian cancer response to neoadjuvant chemotherapy (NACT). We evaluated the prognostic significance of the CRS in a single institution cohort. Methods A retrospective review of all consecutive epithelial ovarian cancer patients undergoing interval debulking surgery (IDS) after NACT from 2016 to 2017 were included. Clinical, pathologic, surgical, outcomes, and genetic data were abstracted from medical records. CRS was assigned by pathology based on a section of omentum as follows: 1 = minimal response, 2 = moderate response, and 3 = near complete response. Results Among the 50 subjects, 14 (28%) were classified as CRS1, 29 (58%) as CRS2, and 7 (14%) as CRS3. The majority of patients were diagnosed with high grade serous histology (94%). Most women in this cohort underwent either an optimal or complete cytoreduction to no gross residual disease (96%). Women in the CRS2 group were most likely to have a pathogenic variant (51.7%) while those in the CRS1 were least likely (7.1%). Most women recurred regardless of CRS. CRS was not associated with progression-free survival (log-rank p = 0.82) or overall survival (log-rank p = 0.30). Conclusions Though previous data support the use of CRS as a prognostic indicator, we failed to show a correlation between CRS and survival in our continuous single institution cohort. The high rate of optimal debulking across all CRS groups in this study may mitigate the prognostic significance of the scoring system. Nevertheless, tumors that respond poorly to traditional chemotherapy should remain of avid interest for potential novel therapies.

Objective Stage is a critical determinant of prognosis and treatment for endometrial cancer (EC) patients. Women who have had a tubal ligation for sterilization have improved EC survival, secondary to lower stage at presentation, suggesting that transtubal spread may represent an important route of metastasis. We evaluated detection of intraluminal tumor cells (ILTCs) in relation to tumor characteristics and survival. Methods One pathologist retrospectively evaluated hematoxylin and eosin sections of routinely collected fallopian tubes for ILTCs from 295 EC patients, masked to outcome. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic (age, race) and clinical [FIGO 2009 stage, lymphovascular space invasion (LVSI), histological subtype] characteristics and ILTCs. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations between ILTCs and recurrence-free survival (RFS) and EC-specific survival, overall and stratified by histological subtype or stage. Results In univariable logistic regression models, age (55–64 vs. ≥65: OR = 3.41, 95% CI = 1.48–7.84), stage (stage IV vs. stage I OR = 14.58, 95% CI = 5.27–40.35), LVSI (OR = 2.93, 95% CI = 1.42–6.04), and histological subtype (serous vs. low-grade endometrioid OR = 3.21, 95% CI = 1.08–9.58), were associated with ILTCs. Only age and stage remained significantly associated with ILTCs in adjusted models. ILTCs were significantly associated with lower EC-specific survival among women with serous EC or stage I disease; however, adjustment for age, stage, and histology attenuated these associations. Conclusion Our findings suggest that ILTCs are associated with adverse EC prognostic features and reduced survival in cases of early stage or serous histology.

To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors.Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC).The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors.The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.

Objectives The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification. Methods Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations , and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods. Results Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53–3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10–7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04–4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status. Conclusions A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.

Highlights • Biopsies of a large mass are prone to sampling errors and may lead to an incorrect diagnosis. • MRI imaging of vulvar tumors can aid in surgical planning. • Large sarcomas of the vulva require a multi-disciplinary approach.

Objectives: To describe challenges with applying tumor genomic testing among women with ovarian cancer to clinical practice in a large division with >90% germline genetic testing compliance. Methods: Institutional review board (IRB)-approved, retrospective review of tumor genomic results obtained within a single Gynecologic Oncology division. Clinicopathologic data were abstracted from medical records and tumor genomic results were evaluated for congruency and discrepancies between different labs. Results: A total of 261 patients with epithelial ovarian/fallopian tube/primary peritoneal cancer had tumor testing between 2017 and 2020. A total of 4 commercial labs with CLIA-approved testing were primarily used over the study period (Figure 1). A total of 15 patients had tumor tests at more than one clinical laboratory, with 4/15 (27%) found to have Loss of Heterozygosity (LOH) on the second test (LOH testing was not performed on the first test). An additional 4 patients (27%) had discrepant somatic BRCA (sBRCA) results. A single patient had a somatic large rearrangement in BRCA2 not detected through her first sBRCA test. For 3 patients, a sBRCA alteration was reported from a testing laboratory that subsequently changed testing/reporting practices that negated the original reports. Secondary sBRCA testing at a different laboratory revealed no sBRCA alterations in all three patients.26 (10%) had germline BRCA (gBRCA) PVs [15 BRCA1, 11 BRCA2]. All 26 gBRCA carriers had somatic testing. 5 of those somatic tests included LOH tests and 5/5 demonstrated LOH-high scores. 10/26 (38%) tumor tests were ordered at the time of initial surgery and before the first line of chemotherapy was completed. There were 48 tumors with sBRCA PVs and no gBRCA PV. LOH testing with a score was provided for 6 patients, 5/6 (83%) had LOH-high scores. Excluding the sBRCA results from the lab that later negated reports, there were 18 tumors with 20 sBRCA variants confirmed. One patient's sBRCA variant was also found through germline testing and was classified as a variant of uncertain significance by the germline testing lab. Download : Download high-res image (52KB) Download : Download full-size image Conclusions: Classification of somatic variants differs from germline variants. Whether all somatic BRCA variants indicate homologous recombination deficiency and sensitivity to PARP inhibitors is not known. Discrepancies between labs and the availability of novel test components (i.e. LOH testing) highlight that repeating tumor testing can be valuable and may allow additional treatment options. Tumor testing is rapidly changing; the test ordered and timing of testing need to be carefully considered for each patient. In retrospect, the addition of tumor testing in the upfront setting did not alter management in patients who were found to carry gBRCA PVs. For gBRCA PV carriers, it may be higher yield to reserve tumor testing for the recurrent disease setting.