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PURPOSE Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Uterine leiomyosarcoma (ULMS) is an aggressive malignancy for which hysterectomy is often the primary treatment approach. Due to the rarity of these tumors, the role of oophorectomy in the management of ULMS is not clearly established. This study aimed to describe the impact of oophorectomy and estrogen/progesterone (ER/PR) receptor status on clinical outcomes and survival.Women with ULMS treated between 1/2013 and 1/2018 were retrospectively identified. Clinical data was collected; descriptive statistics were performed and predictors of overall survival (OS) and event free survival (EFS) were analyzed using Cox regression and Kaplan-Meier methodology.189 patients were included. Median age was 53 years (20-84 years). The majority of patients had stage IB (58%) and grade 3 (94%) tumors. On pathologic analysis, ER/PR expression was positive in 41% and 33%, respectively. The majority of patients (179, 94.7%) underwent surgery as their primary treatment approach, of which 51 (28.5%) had ovarian conservation. 59.0% were treated with chemotherapy, while 9.9% received radiation therapy. 84.6% of patients experienced a recurrence, but there was no difference in EFS or OS by oophorectomy status, including among those with uterine confined disease. Additionally, ER/PR status was not independently associated with EFS/OS (p = 0.14, p = 0.07) nor did it impact survival among those with ovaries left in situ.Oophorectomy did not influence OS, even though many tumors were hormone receptor positive. ER/PR status was not independently associated with survival, including in the subset of women with uterine confined disease and those who had undergone oophorectomy.

To assess the impact of frailty in patients with ovarian cancer on surgical procedures and outcomes.A retrospective review of patients with stage II-IV ovarian cancer from April 2013 to September 2017 was performed. Patients were triaged by laparoscopy to determine primary resectability. The adjusted modified frailty index score (amFI) was calculated and amFI ≥2 classified as high frailty. Clinical outcomes, progression free survival (PFS) and overall survival (OS) were estimated.592 patients met inclusion criteria; amFI of 0, 1 and ≥ 2 was noted in 57%, 29%, and 14%, respectively. Patients with high frailty were less likely to be offered laparoscopic assessment for primary surgery (49% v. 43% v. 28% for amFI = 0, 1, and ≥ 2, p = 0.004), and more likely to have a Fagotti score ≥ 8 (58%, 48%, and 34%, p = 0.04). Only 17% of the high frailty cohort had primary tumor reductive surgery compared to 26% and 34% in patients with amFI = 1 and amFI = 0 (p = 0.02). Furthermore, patients with higher amFI were less likely to undergo any tumor reductive surgery (85% v. 74% v. 59%, p0.001). Postoperative complications were more frequent in patients with higher amFI (44% v. 56% v. 64%, p = 0.01). Death within thirty days of treatment initiation was significantly higher in patients with high frailty (0.4% v. 2% v. 9%, p = 0.005). In multivariate analysis, high frailty was associated with worse PFS (p = 0.02) and OS (p0.05).Postoperative morbidity, PFS, and OS were worse in patients with high frailty scores. Quantification of frailty may be useful for clinical decision making in patients with newly diagnosed advanced ovarian cancer.

Background:High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women.Methods:This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA).Results:324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia.Conclusions:Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer.Impact:These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

Supplementary Table from A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study

OBJECTIVE: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR. METHODS: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS). RESULTS: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI:1.14 – 11.05, p = 0.029). CONCLUSIONS: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively.

ImportanceDespite similar histologic appearance among high-grade serous ovarian cancers (HGSOCs), clinical observations suggest vast differences in gross appearance. There is currently no systematic framework by which to classify HGSOCs according to their gross morphologic characteristics.ObjectiveTo develop and characterize a gross morphologic classification system for HGSOC.Design, Setting, and ParticipantsThis cohort study included patients with suspected advanced-stage ovarian cancer who presented between April 1, 2013, and August 5, 2016, to the University of Texas MD Anderson Cancer Center, a large referral center. Patients underwent laparoscopic assessment of disease burden before treatment and received a histopathologic diagnosis of HGSOC. Researchers assigning morphologic subtype and performing molecular analyses were blinded to clinical outcomes. Data analysis was performed between April 2020 and November 2021.ExposuresGross tumor morphologic characteristics.Main Outcomes and MeasuresClinical outcomes and multiomic profiles of representative tumor samples of type I or type II morphologic subtypes were compared.ResultsOf 112 women (mean [SD] age 62.7 [9.7] years) included in the study, most patients (84% [94]) exhibited a predominant morphologic subtype and many (63% [71]) had a uniform morphologic subtype at all involved sites. Compared with those with uniform type I morphologic subtype, patients with uniform type II morphologic subtype were more likely to have a favorable Fagotti score (83% [19 of 23] vs 46% [22 of 48]; P = .004) and thus to be triaged to primary tumor reductive surgery. Similarly, patients with uniform type II morphologic subtype also had significantly higher mean (SD) estimated blood loss (639 [559; 95% CI, 391-887] mL vs 415 [527; 95% CI, 253-577] mL; P = .006) and longer mean (SD) operative time (408 [130; 95% CI, 350-466] minutes vs 333 [113; 95% CI, 298-367] minutes; P = .03) during tumor reductive surgery. Type I tumors had enrichment of epithelial-mesenchymal transition (false discovery rate [FDR] q-value, 3.10 × 10−24), hypoxia (FDR q-value, 1.52 × 10−5), and angiogenesis pathways (FDR q-value, 2.11 × 10−2), whereas type II tumors had enrichment of pathways related to MYC signaling (FDR q-value, 2.04 × 10−9) and cell cycle progression (FDR q-value, 1.10 × 10−5) by integrated proteomic and transcriptomic analysis. Abundances of metabolites and lipids also differed between the 2 morphologic subtypes.Conclusions and RelevanceThis study identified 2 novel, gross morphologic subtypes of HGSOC, each with unique clinical features and molecular signatures. The findings may have implications for triaging patients to surgery or chemotherapy, identifying outcomes, and developing tailored therapeutic strategies.

PURPOSE: An in-depth analysis of the tumor microenvironment of ovarian cancer is needed. The purpose of this study was to elucidate the architecture of the immune microenvironment of high-grade serous ovarian cancers (HGSCs) with and without BRCA1 and BRCA2 mutations. METHODS: A cohort of highly annotated HGSC patients with known germline BRCA1 and BRCA2 status was selected, and pretreatment tumor tissue specimens were analyzed with a multiplexed staining technique aimed at detecting lymphocytes, macrophages, and fibroblasts in the whole tumor area and in specific regions including epithelium, stroma, and perivascular areas. RESULTS: BRCA1- or BRCA2-mutated tumors showed a more immunogenic microenvironment, characterized by a higher abundance of CD8(+) and PD-L1(+) cells, than did tumors with wild-type BRCA1 and BRCA2. High numbers of PD-L1(+) and PD-L1(+)CD8(+) cells were prognostic for event-free survival (hazard ratio [HR]: 0.41, 95% CI: 0.21–0.79, p = 0.008 and HR: 0.49, 95% CI: 0.26–0.91, p = 0.025, respectively), as were high numbers of epithelial PD-L1(+) and FAP(+)PD-L1(+) cells (HR: 0.52, 95% CI: 0.28–0.96, p = 0.037 and HR: 0.27, 95% CI: 0.08–0.87, p = 0.029) and CD8(+) cells (HR: 0.51, 95% CI: 0.28–0.93, p = 0.027). CONCLUSIONS: This study reveals substantial differences between the immune microenvironment composition of germline BRCA-mutated and BRCA wild-type HGSC.

OBJECTIVES: To evaluate the factors associated with response to neoadjuvant chemotherapy (NACT) and the ability to undergo interval tumor reductive surgery (iTRS) in patients with advanced ovarian cancer. METHODS: We performed a retrospective review from April 2013 to March 2019 of patients with advanced stage ovarian cancer triaged to NACT based on our standard triage algorithm. Clinicopathologic and treatment data were analyzed for factors associated with response to NACT, outcomes at iTRS, and their impact on progression-free survival (PFS). RESULTS: 562 patients met inclusion criteria and triaged to NACT following laparoscopy (n=132) or without laparoscopy (n=430). 413 patients underwent iTRS (74%). Factors that correlated with a patient reaching iTRS included increasing age (p1cm, p

ObjectiveEvaluate the association between time to diagnosis and treatment of advanced ovarian cancer with overall and ovarian cancer specific mortality using a retrospective cross sectional study of a population based cancer registry database.MethodsThe Surveillance, Epidemiology, and End Results–Medicare database was searched from 1992 to 2015 for women aged ≥66 years with epithelial ovarian cancer and abdominal/pelvic pain, bloating, difficulty eating, or urinary symptoms within 1 year of cancer diagnosis. Time from presentation to diagnosis and treatment were evaluated as outcomes and covariables. Cox regression models and adjusted Kaplan–Meier curves evaluated 5 year overall and cancer-specific survival.ResultsAmong 13 872 women, better survival was associated with longer time from presentation to diagnosis (overall survival hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.94 to 0.95; cancer specific survival HR 0.95, 95% CI 0.94 to 0.96) and diagnosis to treatment (overall survival HR 0.94, 95% CI 0.92 to 0.96; cancer specific survival HR 0.93, 95% CI 0.91 to 0.96). There was longer time from presentation to diagnosis in Hispanic women (relative risk (RR) 1.21, 95% CI 1.12 to 1.32) and from diagnosis to treatment in non-Hispanic black women (RR 1.36, 95% CI 1.21 to 1.54), with lower likelihood of survival at 5 years after adjustment for time to diagnosis and treatment among non-Hispanic black women (HR 1.15, 95% CI 1.05 to 1.26) compared with non-Hispanic white women. Gynecologic oncology visit was associated with improved overall (pConclusionLonger time to diagnosis and treatment were associated with improved survival, suggesting that tumor specific features are more important prognostic factors than the time interval of workup and treatment. Significant sociodemographic disparities indicate social determinants of health influencing workup and care. Gynecologic oncologist visits were associated with improved survival, highlighting the importance of appropriate referral for suspected ovarian cancer.

Objective The ideal number of neoadjuvant chemotherapy (NACT) cycles prior to interval tumor-reductive surgery (iTRS) for advanced ovarian cancer is poorly defined. We sought to assess survival stratified by number of NACT cycles and residual disease following iTRS in patients with advanced ovarian cancer with partial response (PR) or stable disease (SD) following 3–4 cycles of NACT. Methods We retrospectively identified patients with advanced high-grade ovarian cancer (diagnosed 2/1/2013 to 2/1/2018) who received at least 3 cycles of NACT and iTRS and had a PR or SD. The population was divided into four groups based on the number of NACT cycles prior to iTRS and residual disease status after (CGR [complete gross residual] or incomplete resection [any amount of residual disease]): 1) 3–4 NACT cycles/CGR, 2) 3–4 NACT cycles/incomplete resection, 3) > 4 cycles/CGR, and 4) >4 cycles/incomplete resection. Overall survival (OS) and progression-free survival (PFS) were estimated using a Kaplan-Meier product-limit estimator and modeled using univariable and multivariable Cox proportional hazards analysis. Results The cohort consisted of 265 patients with advanced high-grade ovarian cancer with a median age at diagnosis of 65 years. Most were White (87%), had serous histology (89%), and stage IV disease (57%), with an overall CGR rate of 81%. In a multivariable analysis receipt of >4 NACT cycles was not associated with worse PFS or OS (adjusted hazard ratio [aHR] 1.02, 95% CI 0.74–1.42; aHR 1.12, 95% CI, 0.73–1.72 respectively) than was receipt of 3–4 cycles. Any amount of residual disease was associated with worse PFS and OS regardless of the number of NACT cycles (aHR 1.56, 95% CI 1.09–2.22; aHR 2.38, 95% CI 1.52–3.72 respectively). Conclusions Residual disease was associated with worse survival outcomes regardless of the number of NACT cycles in patients with PR or SD after NACT for advanced high-grade ovarian cancer. These data suggest that the ability to achieve CGR should take precedence in decision-making regarding the timing of surgery.

ObjectiveA novel classification system of high-grade serous ovarian carcinoma based on gross morphology observed at pre-treatment laparoscopy was recently defined. The purpose of this study was to identify radiographic features unique to each morphologic subtype.MethodsThis retrospective study included 109 patients with high-grade serous ovarian cancer who underwent pre-operative computed tomography (CT) scanning and laparoscopic assessment of disease burden between 1 April 2013 and 5 August 2015. Gross morphologic subtype had been previously assigned by laparoscopy. Two radiologists independently reviewed CT images for each patient, categorized disease at eight anatomic sites, and assessed for radiographic characteristics of interest: large infiltrative plaques, mass-like metastases, enhancing peritoneal lining, architectural distortion, fat stranding, calcifications, and lymph node involvement. Demographic and clinical information was summarized with descriptive statistics and compared using Student's t-tests, χ² tests, or Fisher exact tests as appropriate; kappa statistics were used to assess inter-reader agreement.ResultsCertain radiographic features were found to be associated with gross morphologic subtype. Large infiltrative plaques were more common in type 1 disease (88.7% (47/53) vs 71.4% (25/35), p=0.04), while mass-like metastases were more often present in type 2 disease (48.6% (17/35) vs 22.6% (12/53), p=0.01). Additionally, radiographic presence of disease at the falciform ligament was more common in type 1 morphology (33.9% (19/56) vs 13.2% (5/38), p=0.02).ConclusionMorphologic subtypes of high-grade serous ovarian cancer were associated with specific CT findings, including the presence of large infiltrative plaques, mass-like metastases, and falciform ligament involvement.

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety. Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. NCT02693535 (26 February, 2016).

Low-grade serous carcinoma of the ovary/peritoneum (LGSC) is relatively chemoresistant in the adjuvant, neoadjuvant, and recurrent settings. We sought to expand our prior work and evaluate response rates of women with LGSC to neoadjuvant chemotherapy (NACT) compared to women with high-grade serous carcinoma of the ovary/peritoneum (HGSC).Thirty-six patients with LGSC who received NACT were matched to patients with HGSC. A single radiologist re-reviewed pre- and post-NACT imaging for response using RECIST 1.1. Pre- and post-NACT CA-125 values were compared using paired t-tests. Kaplan-Meier estimates of progression free survival (PFS) and overall survival (OS) were performed.All patients received neoadjuvant platinum-based regimens. LGSC patients received a median of 5 cycles (range 3-9), HGSC patients received a median of 4 cycles (range 3-9). Interval cytoreductive surgery was performed in 29/36 (81%) of LGSC and 32/36 (89%) HGSC patients. Complete cytoreduction was reported and achieved in 11/29 (38%) of LGSC patients and 24/32 (75%) of HGSC patients (p = 0.002). Median pre- and post-treatment CA-125 levels for LGSC patients were 295.5 U/mL and 144 U/mL (52% decrease) (p 0.001). The median pre- and post-treatment CA-125 levels for HGSC patients were 767.5 and 35.6 (96% decrease) (p 0.001). For LGSC patients, 4/36 (11%) had partial response (PR), 30/36 (83%) had stable disease (SD), and 2/36 (6%) had progressive disease (PD). In HGSC patients, 27/36 (75%) had PR, and 9/36 (25%) SD. Median PFS for LGSC patients was 18.5 months and median OS was 47.4 months.This study provides further evidence of relative chemoresistance of LGSC in patients treated with NACT.

IntroductionThe purpose of this study was to compare operative times, surgical outcomes, resource utilization, and hospital charges before and after the implementation of a sentinel lymph node (SLN) mapping algorithm in endometrial cancer.MethodsAll patients with clinical stage I endometrial cancer were identified pre- (2012) and post- (2017) implementation of the SLN algorithm. Clinical data were summarized and compared between groups. Total hospital charges incurred on the day of surgery were extracted from the hospital financial system for each patient and all charges were adjusted to 2017 US dollars.ResultsA total of 203 patients were included: 71 patients in 2012 and 130 patients in 2017. There was no difference in median age, body mass index, or stage. In 2012, 35/71 patients (49.3%) underwent a lymphadenectomy. In 2017, SLN mapping was attempted in 120/130 patients (92.3%) and at least one SLN was identified in 110/120 (91.7%). Median estimated blood loss was similar between groups (100 mL vs 75 mL, p=0.081). There was a significant decrease in both median operative time (210 vs 171 min, p=0.007) and utilization of intraoperative frozen section (63.4% vs 14.6%, pDiscussionImplementation of an SLN mapping algorithm for high- and low-risk endometrial cancer resulted in a decrease in both operative time and intraoperative frozen section utilization with no change in surgical morbidity. While hospital charges did not significantly change, further studies are warranted to assess the true cost of SLN mapping.

The chemotherapy response score (CRS) is used to score histopathologic response to neoadjuvant chemotherapy (NACT) of patients with extrauterine high-grade serous carcinoma. This study was undertaken to determine if the CRS in the omentum, adnexa or when combined correlates with (1) progression-free survival (PFS) or overall survival (OS), (2) laparoscopic score of abdominal disease, (3) Cancer antigen 125 levels, (4) BRCA status, and (5) platinum-resistant disease. A total of 158 cases were retrospectively collected that received NACT between April 2013 and February 2018 at a single institution. The 3-tier Bohm CRS system was applied to the omentum and adnexa. Survival outcomes between scored subgroups were analyzed using Cox proportional hazards regression. Spearman rank correlation analyses were used to assess CRS and clinical data. A total of 119 cases were treated only with carboplatin/paclitaxel. Omental CRS was: 1 (23 cases, 19.3%), 2 (65 cases, 54.6%), and 3 (31 cases, 26.1%), whereas adnexal CRS was: 1 (50 cases, 42%), 2 (48 cases, 40.3%) and 3 (21 cases, 17.6%). The omental CRS was significantly associated with PFS as a 2-tier score (hazard ratio [HR]=0.612, 95% confidence interval [CI]: 0.378-0.989, P=0.045) but not associated with the PFS using the 3-tier score or with OS using either system. Adnexal CRS was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.49, 95% CI: 0.263-0.914, P=0.025) and 2-tier scores (HR=0.535, 95% CI: 0.297-0.963, P=0.037). The combined score was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.348, 95% CI: 0.137-0.88, P=0.026) and 2-tier scores (HR=0.364, 95% CI: 0.148-0.896, P=0.028). No CRS system used associated with laparoscopic assessment of disease. CRS in the omentum had no significant association with platinum resistance; however, the adnexal CRS 1/2 were 3 times as likely to develop platinum resistance compared with CRS 3 (relative risk=3.94, 95% CI: 1.03-15.09, P=0.046). The CRS, when used on the omentum, adnexa, and as a combined score, was significantly associated with PFS but not with OS. Adnexal CRS 1/2 are more likely to develop platinum-resistant disease. Therefore, the use of this pathology parameter may be useful for clinical management.

Objectives We aimed to compare clinical and survival outcomes in high grade ovarian cancer (HGOC) stratified by homologous recombination deficiency (HRD) status undergoing frontline and/or maintenance therapy. Methods We performed a retrospective analysis of HGOC from April 2013 to June 2019. Clinical outcomes were analyzed by (1) germline BRCA+ (2) germline BRCA - and somatic BRCA/HRD+, or (3) BRCA-/HRD-. Progression free (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods and modeled via Cox proportional hazards regression. Results 187 patients met inclusion criteria. 106 patients had germline BRCA mutation, 26 somatic BRCA/HRD+, and 55 BRCA/HRD-. Multivariate analysis for PFS revealed that age (HR 1.02, 95% CI 1.00–1.04), p=0.01), stage (HR 5.7, 95% CI 1.39–23.4, p=0.02), R0 resection at TRS (HR 0.41, 95% CI 0.21–0.83, p=0.01), and BRCA/HRD- status (HR 1.63, 95% CI 1.07–2.48, p=0.02) were significant factors impacting PFS. Multivariate analysis for OS revealed age (HR 1.07, 95% CI 1.03–1.10, p Conclusions Germline BRCA-mutant, somatic BRCA/HRD+ HGOC was associated with improved PFS and OS regardless of primary TRS or NACT. BRCA-/HRD- was a negative prognostic factor for survival in HGOC. PARPi maintenance therapy was associated with improved PFS in Germline BRCA-mutant, somatic BRCA/HRD+ HGOC

Objective We reviewed our institutional data to evaluate toxicity and efficacy outcomes of pembrolizumab/lenvatinib in recurrent endometrial cancer in a “real-world” clinical setting and to compare the impact of reduced lenvatinib starting dose on outcomes. Methods Retrospectively, we reviewed toxicity, treatment responses, and survival outcomes of patients with recurrent endometrial cancer who received ≥1 cycle of pembrolizumab/lenvatinib. We compared subgroups based on lenvatinib starting dose (recommended [20 mg] vs reduced [ Results We analyzed 70 patients (recommended dose cohort, n = 16; reduced dose cohort, n = 54). The most common starting dose was 14 mg daily. Compared to the reduced dose cohort, the recommended dose cohort had a significantly higher mean number of lenvatinib dose reductions due to side effects (1.1 vs. 0.4; p = 0.003) and significantly shorter median time to treatment toxicity (1.3 vs. 3.7 days; p = 0.0001). Response rates did not differ significantly between the recommended and reduced dose cohorts (28.6% vs. 38.3%, respectively; p = 0.752). Two patients, both in the reduced dose cohort, had complete responses. Patients with carcinosarcoma histology had response and clinical benefit rates of 25% (3 of 12) and 58.3% (7 of 12), respectively. There were no differences between the 2 dose cohorts with respect to progression-free (p = 0.245) or overall survival (p = 0.858). Conclusion In clinical practice, a lower starting dose of lenvatinib (14 mg daily) in combination with pembrolizumab was safe and efficacious in recurrent endometrial cancer. The combination produced responses in endometrial carcinosarcomas. Larger studies are required to validate these findings.

OBJECTIVE: To determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment. METHODS: Patients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response. RESULTS: Median age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn’t meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53–81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (P

Background The identification of extrauterine disease is critical to the management of patients with high-risk endometrial cancer. The purpose of the current study was to determine the accuracy of preoperative positron emission tomography (PET)/computed tomography (CT) in the detection of extrauterine disease. Methods Women with high-risk endometrial cancer were enrolled prospectively and underwent preoperative PET/CT followed by surgery, including sentinel lymph node biopsy and lymphadenectomy. Primary tumor factors on PET/CT were correlated with lymph node pathology. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the detection of lymphadenopathy and peritoneal disease by PET/CT. Results A total of 112 patients were enrolled and underwent PET/CT between April 2013 and May 2016, 108 of whom were evaluable. On PET/CT, 21 patients (19.4%) were found to have extrauterine disease, 18 (17%) had positive lymph nodes, and 8 (7%) had peritoneal disease. A total of 108 patients underwent surgery, 103 of whom (95%) underwent lymphadenectomy. The sensitivity of PET/CT to detect positive lymph nodes was 45.8%, with a specificity of 91.1%, positive predictive value of 61.1%, and negative predictive value of 84.7%. The false-negative rate was 54.2%. There was no difference in primary tumor characteristics on imaging noted between patients with positive and negative lymph nodes. The sensitivity of PET/CT to detect peritoneal disease was 37.5%, with a specificity of 97.8%, positive predictive value of 75%, and negative predictive value of 90.0%. The false-negative rate was 62.5%. Conclusions Preoperative PET/CT did not reliably predict the presence of extrauterine disease in women with high-risk endometrial cancer. Given the high false-negative rates, PET/CT should not be used in the preoperative treatment planning of these patients.

// Marilyne Labrie 1 , Tae-Beom Kim 2 , Zhenlin Ju 2 , Sanghoon Lee 3 , Wei Zhao 3 , Yong Fang 1 , Yiling Lu 3 , Ken Chen 2 , Pedro Ramirez 4 , Michael Frumovitz 4 , Larissa Meyer 4 , Nicole D. Fleming 4 , Anil K. Sood 4 , Robert L. Coleman 4 , Gordon B. Mills 1 , 3 and Shannon N. Westin 4 1 Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA 2 Department of Bioinformatics and Computational Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA 3 Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA 4 Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Shannon N. Westin, email: swestin@mdanderson.org Keywords: poly (ADP-ribose) polymerase inhibitor; combination therapy; adaptive response; ovarian cancer; targeted therapy Received: March 12, 2019 Accepted: May 02, 2019 Published: May 28, 2019 ABSTRACT Poly (ADP-ribose) polymerase inhibitor (PARPi)-based combination therapies are demonstrating efficacy in patients, however, identifying the right combination for the right patient remains a critical challenge. Thus, it is urgent to develop approaches able to identify patients likely to benefit from specific combination therapies. Several groups, including ours, have demonstrated that targeting adaptive responses induced by PARPi increases depth and duration of response. In this study, we instituted a talazoparib (PARPi) monotherapy window of opportunity trial to identify informative adaptive responses in high grade serous ovarian cancer patients (HGSOC). Patients were treated for 7 to 14 days with PARPi monotherapy prior to surgery with tissue samples from multiple sites being collected pre- and post-treatment in each patient. Analysis of these samples demonstrated that individual patients displayed different adaptive responses with limited interlesional heterogeneity. Ability of combination therapies designed to interdict adaptive responses to decrease viability was validated using model systems. Thus, assessment of adaptive responses to PARPi provides an opportunity for patient-specific selection of combination therapies designed to interdict patient-specific adaptive responses to maximize patient benefit.

Background: Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (CGR) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have response enabling interval cytoreductive surgery. Through comprehensive omics analyses, we previously characterized molecular and cellular profiles of highly clinically defined HGSC from patients who had CGR versus those triaged to NACT. However, clinically useful predictive biomarkers for such distinctions are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. Here, we performed extensive molecular characterization of serum-derived EVs and correlated them with therapeutic outcomes in patients with HGSC. Methods: Serum-derived medium/large size EVs from patients with HGSC treated under a systematic surgical algorithm were isolated following standard methods of the International Society for Extracellular Vesicles. Patients had either complete gross resection after primary surgery (R0, n=3); poor response to NACT (NACT-PR, n=4), or excellent response to NACT with carboplatin and paclitaxel (NACT-ER, n=3); tissue and matched germline blood samples have already been comprehensively analyzed (Lee et al, Cell Reports, 2020). The isolated EV-DNA and EV-RNA were subjected to whole-genome sequencing and RNA sequencing, respectively. Results: We identified somatic EV-DNA alterations in cancer hallmark genes, including FAT1 and KMT2D as the most frequent mutated genes. Interestingly, we found alterations in ovarian cancer-related genes, including BRCA2 and RAD51 in R0; BRCA2 in NACT-ER; TP53, CDK13, CDK12, BRAF, AKT2, and ARID1A in NACT-PR patients. We also identified 26,338 genes expressed in the EV-RNA transcriptomic profiles. The analysis of the enrichment of cancer hallmark pathways showed that the R0 group was more enriched in the interferon α/γ, PI3K/AKT/mTOR signaling, and DNA repair pathways. Interestingly, we also identified 6,757 differentially expressed genes (DEGs) in the CGR versus the NACT groups (absolute log2-fold change ≥2 and adjusted p-value Conclusions: Taken together, our preliminary data suggest that molecular characteristics of EVs could provide an accurate prediction of patients with HGSC who can undergo CGR with surgery and respond to chemotherapy. Citation Format: Li Zhao, Shaolin Ma, Nicole D. Fleming, Joseph Celestino, Mark S. Kim, Richard A. Hajek, Nicholas B. Jennings, Erika J. Thompson, Hongli Tang, Shannon N. Westin, Amir A. Jazaeri, Jianhua Zhang, P Andrew Futreal, Anil K. Sood, Sanghoon Lee. Distinct molecular profiles of serum-derived extracellular vesicles in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5106.

Background: High-grade serous ovarian cancer (HGSC) is the most aggressive epithelial ovarian cancer, exhibiting tumor heterogeneity, molecular abnormality, and variable clinical outcomes. The heterogeneity and apparent adaptability of the HGSC genome under selective pressure by chemotherapy likely explain the high rates of drug resistance in HGSC. However, the underlying mechanisms of drug resistance are not well understood. Following our previous findings of significant distinct molecular and cellular characteristics in pre-treatment tumor samples from highly clinically annotated HGSC patients who received neoadjuvant chemotherapy (NACT), we examined post-treatment transcriptomic changes associated with excellent or poor responders to NACT in HGSC patients. Methods: Thirty tumor tissues (pre- and post-treatment) after 3 to 4 cycles of NACT were collected from HGSC patients at interval cytoreductive debulking surgery from the following groups: excellent response to NACT with carboplatin/paclitaxel (post-ER, n=8); poor response to NACT (post-PR, n=8). Primary or metastatic sites for each patient were obtained (n=13, post-ER; n=17, post-PR) and subjected to RNA sequencing. The downstream bioinformatics analysis was then performed and compared with the data from the matched pre-NACT samples from the same patients (Lee et al., Cell Reports, 2020). Results: We identified a total of 9,764 upregulated and 2,762 downregulated differentially expressed genes (DEGs, absolute log2FC >=2, adj-p Conclusions: Our transcriptomic analysis revealed distinct transcripts changes in post-NACT vs pre-NACT tumor tissues from HGSC patients with excellent or poor response to the NACT. These findings could enhance treatment decision-making and rationale for developing alternative therapies for patients with HGSC. Citation Format: Sanghoon Lee, Li Zhao, Nicole D. Fleming, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Yan Liu, Shannon N. Westin, Amir A. Jazaeri, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood. Transcriptomic profiles of response to neoadjuvant chemotherapy in patients with high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5738.

Background: Despite high rates of remission after frontline management, most patients with advanced stage ovarian cancer recur. Second look laparoscopy (SLL) can provide more sensitive detection of minimal residual disease (MRD) allowing for more individualized prognostication and possible therapeutic intervention. It may also assess tumor biology and microenvironment associated with undetectable chemoresistant MRD phase of ovarian cancer. The objective of this study was to determine SLL feasibility, and clinicopathologic and molecular characteristics of MRD after frontline therapy in ovarian cancer. Methods: SLL was offered to patients with stage III-IV high grade epithelial ovarian cancer who achieved complete response after frontline surgery and 6 cycles of carboplatin and paclitaxel chemotherapy. Patients were offered standard of care or investigational management options based on homologous recombination deficiency (HRD) and MRD status at SLL. Preliminary translational studies included RNAseq for comparison of serial, matched tumor from primary or interval TRS and SLL derived MRD+ biopsies at the time of SLL. In addition, Nanostring analyses of SLL surgical biopsies both with and without residual tumor were performed. Molecular profiling employed hierarchical clustering, principle component analysis, non-parametric testing, and pathway analyses. Results: Between 4/2017- 7/2021, 39 patients underwent SLL. The majority had stage III disease (74%), high grade serous histology (90%) and underwent neoadjuvant chemotherapy with interval tumor reductive surgery (TRS; 54%). MRD was present in 49% (n=19) of patients and was more frequent among neoadjuvant chemotherapy recipients (73% vs 26%, P=0.015) and patients with homologous recombination proficient tumors (81% vs 25%, P=0.01). Most patients without MRD were dispositioned to observation; 4 patients with HRD received a PARP inhibitor per standard of care. All other patients with MRD received bevacizumab as part of a clinical trial, except for one patient who received a PARP inhibitor. Median follow-up was 6.74 months (range 0.66 - 28.62). Presence of MRD was associated with worse PFS (HR 3.7, 95% CI 1.3- 10.9; 5.5 vs 24.6 months; P= 0.02). Based on transcriptional signature, MRD are immunologically distinct from untreated tumors or those collected at interval TRS (after 3 cycles of chemo) but also displayed heterogeneity with two distinct subclusters. Conclusions: SLL to assess for MRD has potential to further individualize post-frontline therapy, and identify patients at high risk for progression for early intervention clinical trials. Transcriptional profiling suggests that MRD phase of ovarian cancer is characterized by a distinct, heterogeneous, and evolving tumor and immune microenvironment. Citation Format: Roni Nitecki, Minghao Dang, Sanghoon Lee, Bryan Fellman, J Alejandro Rauh-hain, Jolyn Taylor, Lois Ramondetta, Michaela Grinsfelder, Lauren Cobb, David M. Boruta, Pamela T. Soliman, Aaron Shafer, Nicole D. Fleming, Shannon N. Westin, Anil K. Sood, Chris Tanguma, Pedro T. Ramrez, Karen H. Lu, Linghua Wang, Amir A. Jazaeri. Initial clinicopathologic and molecular characterization of minimal residual disease detected by second look laparoscopy after completion of frontline surgery and chemotherapy in patients with advanced stage ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4135.

5545 Background: Epithelial ovarian cancer is genetically heterogeneous, both among and within histologic subtypes. Advances in next-generation sequencing have made it feasible to ascertain the somatic genetic signature of each patient, however, critical analysis of population-level sequencing results is required to maximize the potential of this technology. Here, we aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in a large cohort of patients with high-grade epithelial ovarian cancer. Methods: Our study population comprised patients with high-grade serous (n = 972), clear cell (n = 33), endometrioid (n = 28), mucinous (n = 4), and mixed (n = 34) or unspecified (n = 21) epithelial ovarian carcinoma diagnosed between April 2013 and September 2021. tbNGS results were identified within the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected for patients who had undergone tbNGS. Progression-free survival (PFS) and overall survival (OS) were calculated from date of first treatment to date of first recurrence and date of death, respectively. Data were analyzed using descriptive statistics, univariate and multivariate Cox regression models, and clustering analyses. Results: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results identified. Nearly all (96.1%) revealed one or more genetic aberrations. Most patients (74.6%) had an actionable mutation, defined as relaying eligibility for a targeted treatment or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations; and CCNE1 amplification. Ten different targeted institutional and commercial panels were employed, covering a range of 35 to 600+ gene loci. The median time from diagnosis to testing was 14.5 months, likely corresponding to time of recurrence. Though no standalone alterations were significantly related to survival, multivariate and clustering analyses identified several genetic patterns which corresponded to patient outcomes. Mutation of BRAF, PIK3R1, NOTCH3, MET, and/or ATR was correlated with shorter PFS (HR 1.84, p = 0.001); mutation of ATM, RB1, CDKN2A, FGFR1, and/or FGFR2 was associated with improved PFS (HR 0.64, p = 0.04), as was mutation of NBN and/or ATRX (HR 0.54, p < 0.05). MYC, NOTCH3, and/or CREBBP mutations were significantly correlated with worse OS (HR 1.95, p = 0.02). In our population, 40 patients (9.78%) were enrolled in genotypically-relevant clinical trials. Conclusions: tbNGS is prevalent at our institution, and often yields actionable information. We identified several mutational patterns that correlate to patient survival. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools.

5522 Background: Neoadjuvant chemotherapy has demonstrated limited activity in low-grade serous carcinomas (LGSOC) of the ovary, fallopian tube, and peritoneum, with objective response rate of 11% and complete gross resection (CGR) rate of 38% at the time of interval cytoreductive surgery (ICS). LGSOC has many similarities to hormone receptor positive (HR+) breast cancer, including clinical benefit from endocrine therapies in the recurrent and maintenance settings. Based on the activity of antiestrogen plus CDK4/6 inhibitor combination therapy in HR+ breast cancer, we conducted a phase II pilot study to assess the clinical benefit of neoadjuvant treatment with fulvestrant and abemaciclib for women with advanced LGSOC. Methods: Women with unresectable, untreated stage III or IV LGSOC of the ovary, fallopian tube or peritoneum were eligible. Patients received fulvestrant (500 mg IM on day 1 and 15 of the first 28-day cycle, followed by day 1 of subsequent cycles) and abemaciclib 150 mg orally BID. Pre/perimenopausal patients also received goserelin 10.8 mg subcutaneously every 12 weeks for ovarian suppression. Patients continued treatment until deemed resectable by the treating surgeon with imaging re-assessment every 8 weeks using RECIST 1.1. Following ICS, patients receive 4 cycles of adjuvant fulvestrant and abemaciclib and then transition to maintenance letrozole. Patients with progressive disease (PD) were removed from study and received standard of care chemotherapy. Primary endpoint is clinical benefit rate (CBR). Results: Fifteen patients were enrolled and evaluable. At data cutoff date (January 20, 2022), 7 of 15 patients (47%) had partial response (PR) (one patient with radiologic PR had a pathologic complete response at ICS), 5 of 15 (33%) had stable disease (SD), and 3 of 15 (20%) had progressive disease (PD), resulting in a CBR of 80%. Of the 7 patients with PR, 3 have had ICS with CGR, 3 have not yet had ICS, and 1 underwent resection of supraclavicular disease with small volume residual disease in the chest. Of the 5 patients with SD, one underwent ICS with CGR, and two have been on treatment for 8 and 16 weeks with reduction in measurable disease but not yet deemed to be candidates for surgery. Four of the 5 patients (80%) who had ICS, had CGR. Median time on study prior to surgery was 24 weeks. Adverse events (grade 3 or 4) possibly related to abemaciclib occurred in 2 patients (13.3%) and included acute kidney injury (6.7%) and neutropenia (6.7%). Conclusions: Neoadjuvant treatment with fulvestrant and abemaciclib was tolerable and demonstrated unprecedented response and CGR rates in this pilot study. These results compare favorably to published outcomes of neoadjuvant chemotherapy in LGSOC. Further studies are planned to explore this new treatment option in a larger study population. Clinical trial information: NCT03531645.

e24034 Background: Active Living After Cancer (ALAC) is a 12-week evidence-based program funded by the Cancer Prevention and Research Institute of Texas (CPRIT) to provide physical activity and survivorship education to cancer survivors. Given the limited data evaluating the effects of physical activity educational programs in gynecologic cancer survivors, we aim to assess the effects of the ALAC intervention in this patient population. Methods: A retrospective analysis was performed on gynecologic cancer survivors who participated in ALAC from 2017 to 2021. The 12-week ALAC program included weekly meetings (in-person or virtual) led by a facilitator providing physical activity behavioral skills training, leading 10 minutes of exercise, and discussing topics related to cancer survivorship. Surveys and functional testing assessments were collected pre- and post-program which included: The Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ) and 30-second sit-to-stand. A patient-reported outcomes survey was used to assess patient perceived benefits and program satisfaction. Results: Thirty-two patients participated in ALAC and 22 completed pre- and post-program assessments. The mean age of participants was 60.2 years (range 50.7-69.7 years) and mean number of classes attended was 8 (range 0-12 classes). Prior cancer diagnoses included 14 cervical, 11 uterine, and 7 ovarian cancers. A significant improvement was seen pre- and post-ALAC in moderate-intensity physical activity minutes (n = 17, 97 vs 252 minutes, p = 0.007) by GSLTPAQ and 30-second sit-to-stand test (n = 16, 12.3 vs 15.8 repetitions, p = 0.003) in our cohort. The post-ALAC patient reported outcome survey (n = 22) revealed improvement in emotional well-being (90%), physical well-being (91%), physical activity level (100%), comfort speaking openly in a group (85%), and willingness to discuss their cancer journey (66%). Overall, 95.3% of participants were satisfied with the ALAC program and 100% of participants would recommend the ALAC program to other cancer survivors. Conclusions: Educational physical activity-based programs like ALAC improve physical functioning and moderate-intensity physical activity in gynecologic cancer survivors. Further studies on the long-term health benefits of structured educational programs which promote active lifestyles in gynecologic cancer survivors are needed in larger patient cohorts.

6574 Background: Advanced care planning (ACP) involves sharing of knowledge related to prognosis, treatment options, and patient values/goals, among the patient, their caregivers, and the clinical care team. These goals of care (GOC) discussions are critical at different time points during the care of a cancer patient, but are not performed or documented consistently in most oncology practices. The American Society of Clinical Oncology recommends that documentation of advance directive discussions, a component of ACP, take place by the third office visit for patients with newly diagnosed invasive cancer. We implemented a quality improvement initiative to improve ACP discussion and documentation in our large gynecologic oncology practice. Methods: As part of an institution-wide effort called “Mind the Gap: bridging the gap between patients’ perception of their oncologic situation and the reality thereof”, we identified 3 critical timepoints for which a GOC discussion and ACP documentation was recommended in the outpatient setting. These time points included: (1) by the 3rd visit for new patients with an invasive cancer, (2) preoperative (within 30 days of surgery), and (3) at time of treatment/chemotherapy change. Providers were educated on the key components of ACP documentation including surrogate decision maker and goals of cancer treatment. Standard templates were used to document these discussions for easy identification in the electronic health record. Metrics for each faculty team were shared monthly with the entire department. The department goal was to reach a cumulative goal > 60% completion for all patients in each of the 3 clinical time points within 6 months. Results: The proposed plan and education on ACP standard documentation was presented to 22 gynecologic oncologists during a faculty retreat in 10/2020. Baseline data from 8/2020 was shared revealing that ACP documentation was completed in 24% of new patients, 1% of preoperative, and 19% at treatment change. At the 6-month assessment (5/2021), ACP documentation was completed in 83.6% of new patients, 79.8% of preoperative, and 63% of patients at the time of treatment change. At one year (10/2021), ACP documentation was completed on 88.6% of new patients, 70.3% of preoperative, and 59% of patients at the time of treatment change. There was variability among providers in documentation of ACP for new patients (range 50-100%), preoperative (range 0-100%) and treatment change (range 12.5-100%). Conclusions: Through a departmental initiative, we were able to successfully encourage more frequent goals of care discussions and their standardized documentation, which was maintained at 1 year. We are currently evaluating the impact of this program on end-of-life quality metrics including chemotherapy within 14 days, ICU stay within 30 days and multiple hospital admissions within 30 days of end of life.

Objectives: The androgen receptor (AR) is more widely expressed than the estrogen or progesterone receptor in endometrial cancer (EC), including up to 90% of endometrioid type. Enzalutamide binds to the AR thereby nuclear translocation of receptors and blocking the association of the AR with DNA. We sought to evaluate the efficacy of paclitaxel, carboplatin and enzalutamide in a phase II study of advanced or recurrent endometrioid EC. Methods: Women with chemo-naive, advanced-stage or recurrent endometrioid EC with measurable disease and adequate end organ function were eligible. Documented AR expression was not required. A safety lead in of the triplet was performed to confirm dose. In phase II, patients received 28 days of enzalutamide (160mg daily) as a single agent before starting triplet therapy. Pre- and post-treatment biopsies were obtained during the single agent lead in for evaluation of molecular markers including AR receptor expression and activation, expression of AR-related genes/proteins, and DNA copy number alterations and mutations. Patients then received carboplatin (AUC 6 IV Q3wk), paclitaxel (175 mg/m2), and enzalutamide (160mg daily). Response per RECIST 1.1 was assessed every 3 cycles for a maximum of 9 cycles. Evaluable patients received at least 6 cycles of triplet therapy. Progression free survival (PFS) was calculated from date of treatment initiation to earliest date of progression, death, or last contact. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Astellas Pharma Global Development, Inc. Results: A total 81 patients were screened with 49 patients treated to date (safety lead in n=7; phase II n=42). Median age was 64 years (range 41-81) and the majority of patients had grade 2 histology (53.1%) and recurrent disease (81.6%). There were no dose-limiting toxicities observed during the safety lead in. Patients received a median of 9 cycles of triplet therapy (range 0-9). 8 patients (16.3%) did not receive chemotherapy due to rapid progression during single agent enzalutamide (n=3), unrelated death (n=2), withdrawal (n=2), and unrelated stroke (n=1). PFS for the entire cohort was 11.47 months (95% CI 9.86 - 17.94; Figure 1a) and 6-month PFS probability was 0.77 (95% CI 0.61-0.87). Among 35 evaluable patients, confirmed objective response rate was 71% (95% CI 54–85%), 6 months PFS probability was 0.83 (95% CI 0.66-0.92) and median PFS was 14.42 months (95% CI 11.2-25.5; Figure 1B). The most common adverse events were as expected for chemotherapy alone, including neutropenia (20%), anemia (18%), fatigue (18%), neuropathy (10%), hyperglycemia (14%), nausea (8%), and thrombocytopenia (8%). Download : Download high-res image (41KB) Download : Download full-size image Conclusions: The combination of enzalutamide, carboplatin, and paclitaxel was tolerable and had promising clinical outcomes in chemo-naive advanced or recurrent endometrioid EC. Further analyses are ongoing regarding predictors of response and resistance to androgen-inhibitor therapy. Clinical Trials Registration: NCT02684227.

Objectives: We aimed to assess the impact of frailty in ovarian cancer patients on surgical procedures and outcomes. Methods: A retrospective review of a prospectively collected database from April 2013 to September 2017 was performed. Patients with advanced disease were triaged by laparoscopy to determine primary resectability. The modified frailty index score (mFI) was calculated based on the sum of 10 items: chronic obstructive pulmonary disease or recent pneumonia, congestive heart failure, myocardial infarction, coronary artery disease, diabetes, hypertension, peripheral vascular disease, cerebrovascular disease (CVA), CVA with neurologic deficit, and Eastern Cooperative Oncology Group (ECOG) status 3 or 4, with each item receiving a score of 1 if present. Patients with an mFI ≥2 were classified as high frailty. Clinical outcomes were assessed and compared by mFI using t-test or Fisher's exact test. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: A total of 591 patients met inclusion criteria. A total of 57% of patients had an mFI of 0, 29% mFI of 1, and 14% mFI ≥2. There was no difference in stage by mFI (p=0.984). Patients with high frailty were less likely to be offered a laparoscopic surgery to determine primary resectability than those with an mFI of 1 or 0 (27.63% vs 42.77% vs 48.58%, respectively, p=0.004). If laparoscopy was performed, the modified Fagotti score was more likely to be ≥8 in patients with a higher frailty score (58%, 48%, and 34% for a score of ≥2, 1, and 0, respectively, p=0.038), leading to only 17% of the high frailty cohort proceeding with primary debulking surgery, compared to 26% and 34% in patients with mFI = 1 and mFI = 0 (p=0.015). Furthermore, patients with a higher frailty score were less likely to undergo any tumor reductive surgery (TRS), whether primary or interval (59% vs 74% vs 85% for a score of ≥2, 1, and 0, respectively, p Conclusions: Frailty is associated with bulkier disease, decreased surgical intervention, and worse clinical outcomes.

Objectives: Pembrolizumab/lenvatinib demonstrated impressive response rates in advanced/recurrent endometrial cancer (EC) in a recent phase II clinical trial, leading to its accelerated FDA approval. However, tolerability of the recommended 20 mg starting dose of lenvatinib may pose clinical challenges. To comprehend how this regimen translates into daily clinical practice, we evaluated our preliminary data regarding toxicity and efficacy of pembrolizumab/lenvatinib in the treatment of advanced/recurrent EC at the University of Texas MD Anderson Cancer Center. Methods: In this single-institution, retrospective cohort study, we evaluated recurrent/advanced EC patients who received ≥1 cycle of pembrolizumab/lenvatinib treatment. Toxicity was evaluated through rates of hospitalization and treatment interruptions or discontinuations, as well as number of dose reductions. Clinical efficacy was evaluated by best radiologic response to treatment. Clinical benefit was defined as having stable disease or partial/complete response. Results: From October 2019 to July 2020, 83 EC patients were identified but 16 were excluded for unconfirmed administration of pembrolizumab/lenvatinib or lack of toxicity or response data. Thus, 67 EC patients were included in the analysis with a median follow-up of 5 months (range 1 - 11). The median age and number of prior lines of therapy were 67 (range 31–77) and 2 (range 1–9), respectively. The majority had an ECOG performance status of 0 to 1 (91%). The predominant histologic subtype was endometrioid and serous (n=19 each) followed by carcinosarcoma (n=13), mixed (n=8), clear cell (n=4), and other (n=4). The most common starting dose of lenvatinib was 14 mg (n=43; 64.2%), followed by 20 mg (n=15; 22.4%). Treatment-related hospitalizations occurred in 26.9% of patients but did not differ between lenvatinib dosage groups (p=0.37). Compared to those with a lower starting dosage level, patients started on 20 mg doses had significantly higher treatment discontinuations (100% vs 69.2%, p=0.01) and numbers of lenvatinib dose reductions (1.0 vs 0.38, p=0.004), with a trend of higher treatment interruptions (93.3% vs 73.1%, p=0.09). Among the 56 patients with evaluable radiologic response, there were 21 (37.5%) patients with either a partial (n=18) or complete response (n=3), while 18 patients (32.1%) had stable disease. Of the patients with complete response, all patients had a starting lenvatinib dose of 14 mg. Based on a starting lenvatinib dose of 20 mg vs Conclusions: In treatment of recurrent/advanced EC, lower starting dosage of lenvatinib was associated with fewer treatment interruptions/discontinuations and dose de-escalations compared to the FDA recommended 20 mg dosage level while maintaining equivalent response and clinical benefit rates. Furthermore, patients with carcinosarcoma histology also appeared to benefit from pembrolizumab/lenvatinib. While larger studies are needed to validate these safety and efficacy findings, our preliminary data supports starting a lower dosage of lenvatinib in clinical practice.

Objectives: Despite similar histologic appearance amongst high-grade serous ovarian cancers (HGSOC), anecdotally there are differences in gross appearance. However, no systematic framework to classify morphologic differences exists. Therefore, we aimed to determine whether high-grade serous ovarian cancers (HGSOC) can be reliably divided into distinct gross morphologic subtypes and to assess clinical outcomes and molecular features of these subtypes. Methods: A retrospective review was performed of video-recordings from patients who underwent laparoscopic assessment of disease burden prior to primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT). Video recordings were reviewed by at least 2 physicians. A total of 4 sites (diaphragm, omentum, peritoneum, and pelvis) were assessed and classified as type I (deep, infiltrative disease with distortion of surrounding tissue) or type II (superficial, exophytic disease bordered by normal tissue). Tumor tissues from 16 of these chemotherapy-naive patients were analyzed by multi-platform omics (RNA sequencing, proteomics). Clinical outcomes were assessed utilizing a prospectively collected database and compared by morphology using t-test or Fisher's exact test. Results: Of the 99 evaluable patients, 60 exhibited uniform morphology at all involved metastatic sites (65% type I and 35% type II), and 81 exhibited a predominating morphology (58% type I and 42% type II). A total of 164 images were reviewed by a third physician with 83.5% inter-rater concordance (κ=0.6446). Patients with uniform type 1 (n=34)tumor morphology were more likely to exhibit an excellent response to NACT (defined as radiologic or CA-125 complete response) than those with type II (n=16) tumor morphology (47% vs 18%, p=0.13). Patients with type II predominant tumor morphology had a significantly higher estimated blood loss at the time of interval debulking surgery (p=0.008) as well as longer operative time (p=0.03) compared with type I tumor morphology. Patients with complete type II morphology were more likely to have a modified Fagotti score of Conclusions: There are at least two distinct gross morphological patterns of HGSOC with unique molecular differences and responses to chemotherapy. These findings could have major clinical implications for tailored therapeutic strategies. Download : Download high-res image (97KB) Download : Download full-size image

Objectives: To compare out-of-pocket cost between apixaban and enoxaparin for prevention of postoperative venous thromboembolism (VTE) in gynecologic oncology patients. Current guidelines recommend low molecular weight heparin for thromboprophylaxis following gynecologic cancer surgery, but new evidence suggests that oral apixaban may provide another safe and effective alternative. Recent publications have suggested apixaban more cost-effective, however these data do not evaluate out-of-pocket cost. Methods: This retrospective study was approved by the institutional QIAB. Patients undergoing open surgery for gynecologic malignancy qualified for this study. Test claims for apixaban 2.5 mg by mouth twice daily and enoxaparin 40 mg subcutaneously daily for 28 days were submitted for each patient prior to surgery. Patient copays, number of patients requiring prior authorization, and number of patients without prescription insurance were collected. Results: A total of 86 consecutive patients had test claims sent for both apixaban and enoxaparin thromboprophylaxis between July 2020 and October 2020. The average patient out-of-pocket cost to complete 28 days of apixaban prophylaxis was $73.95 (median $42.84, range $0-448.45). The average patient cost to complete 28 days of enoxaparin prophylaxis was $38.08 (median $10, range $0-260.91). Partial fills were allowed for 4 of 5 enoxaparin prescriptions that required prior authorization. A total of 5 apixaban prescriptions (5.8%) required prior authorization for full 28 days. A total of 5 patients (5.8 %) did not have prescription insurance. Cash price for enoxaparin was nearly double the cash price of apixaban. A total 6 patients’ (7 %) insurance was not contracted with our pharmacy. A single patient (1.2%) required enoxaparin via specialty pharmacy. A total of 2 patients (2.3 %) were enrolled in the institution's financial assistance per the institution. Download : Download high-res image (65KB) Download : Download full-size image Conclusions: Patients prescribed extended-duration venous thromboembolism prophylaxis may face higher out-of-pocket costs with apixaban than with enoxaparin. Prior authorizations can often take 48 to 72 hours for approval. Sending test claims prior to surgery can help identify prescriptions that will need prior authorizations so prescriptions can be sent earlier to avoid discharge delays and patient nonadherence. There may not be a one size fits all solution and individualized patient care should be considered. Future research areas should evaluate patient adherence with a twice daily oral pill vs a once daily injection.

Simple Summary Epithelial ovarian cancer is one of the most lethal cancers in women and is typically diagnosed at an advanced-stage. Historically, primary tumor reductive surgery was attempted followed by postoperative chemotherapy in most patients diagnosed with advanced ovarian cancer. However, neoadjuvant chemotherapy followed by interval tumor reductive surgery is an alternative approach for patients with advanced-stage ovarian cancer where primary tumor reductive surgery is not feasible. Here, we review proposed models that can assist in selecting patients who would benefit most from neoadjuvant chemotherapy followed by surgery. Abstract Epithelial ovarian cancer remains a leading cause of death amongst all gynecologic cancers despite advances in surgical and medical therapy. Historically, patients with ovarian cancer underwent primary tumor reductive surgery followed by postoperative chemotherapy; however, neoadjuvant chemotherapy followed by interval tumor reductive surgery has gradually become an alternative approach for patients with advanced-stage ovarian cancer for whom primary tumor reductive surgery is not feasible. Decision-making about the use of these approaches has not been uniform. Hence, it is essential to identify patients who can benefit most from neoadjuvant chemotherapy followed by interval tumor reductive surgery. Several prospective and retrospective studies have proposed potential models to guide upfront decision-making for patients with advanced ovarian cancer. In this review, we summarize important decision-making models that can improve patient selection for personalized treatment. Models based on clinical factors (clinical parameters, radiology studies and laparoscopy scoring) and molecular markers (circulating and tumor-based) are useful, but laparoscopic staging is among the most informative diagnostic methods for upfront decision-making in patients medically fit for surgery. Further research is needed to explore more reliable models to determine personalized treatment for advanced epithelial ovarian cancer.

Summary In patients with high-grade serous ovarian cancer (HGSC), it is unclear which genomic features are related to complete gross resection (R0), which is typically associated with better clinical outcomes, or response to neoadjuvant chemotherapy (NACT). In this study, we evaluated T cell receptor (TCR) repertoire diversity in primary and metastatic tumor samples (n = 90) from clinically well-annotated patients with HGSC who achieved R0 or received NACT with excellent or poor response based on a laparoscopic triage algorithm. TCR sequencing followed by an integrative analysis with comprehensive multi-omics data identified higher TCR diversity (e.g., higher number of unique productive sequences and less clonal relatedness) in the R0 than NACT groups. We found enrichment of specific TCRβ genes usage, distinct mutual exclusiveness and co-occurrence pattern of TCRβ genes among the groups. We also found significantly positive correlations between clonal relatedness and neoantigens, copy number variations, and mutation load in the groups., Graphical abstract, Highlights • Higher TCR repertoire diversity in the R0 versus neoadjuvant chemotherapy groups • Enrichment of specific TCRβ genes usage was noted among HGSC subgroups • Distinct mutual exclusiveness of TCRβ genes was noted among HGSC subgroups • Positive correlations between clonal relatedness and copy number variations, Biological Sciences; Immunology; Cancer

BackgroundRadiographic triage measures in patients with new advanced ovarian cancer have yielded inconsistent results.ObjectiveTo determine the correlation between surgeon radiology assessment and laparoscopic scoring by disease sites in patients with newly diagnosed advanced stage ovarian cancer.MethodsFourteen gynecologic oncology surgeons from a single institution performed a blinded review of pre-operative contrast-enhanced CT imaging from patients with advanced stage ovarian cancer. Each of the patients had also undergone laparoscopic scoring assessment, between April 2013 and December 2017, to determine primary resectability using the validated Fagotti scoring method, and assigned a predictive index value score. Surgeons were asked to provide expected predictive index value scores based on their blinded review of the antecedent CT imaging. Linear mixed models were conducted to calculate the correlation between radiologic and laparoscopic score for surgeons individually, and as a group. Once the model was fit, the inter-class correlation and 95% CI were calculated.ResultsRadiology review was performed on 20 patients with advanced stage ovarian cancer who underwent laparoscopic scoring assessment. Surgeon faculty rank included assistant professor (n=5), associate professor (p=4), and professor (n=5). The kappa inter-rater agreement was −0.017 (95% CI −0.023 to −0.005), indicating low inter-rater agreement between radiology review and actual laparoscopic score. The inter-class correlation in this model was 0.06 (0.02–0.21), indicating that surgeons do not score the same across all the images. When using a clinical cut-off point for the predictive index value of 8, the probability of agreement between radiology and actual laparoscopic score was 0.56 (95% CI 0.49 to 0.73). Examination of disease site sub-scales showed that the probability of agreement was as follows: peritoneum 0.57 (95% CI 0.51 to 0.62), diaphragm 0.54 (95% CI 0.48 to 0.60), mesentery 0.51 (95% CI 0.45 to 0.57), omentum 0.61 (95% CI 0.55 to 0.67), bowel 0.54 (95% CI 0.44 to 0.64), stomach 0.71 (95% CI 0.65 to 0.76), and liver 0.36 (95% CI 0.31 to 0.42). The number of laparoscopic scoring cases, tumor reductive surgery cases, or faculty rank was not significantly associated with overall or sub-scale agreement.ConclusionsSurgeon radiology review did not correlate highly with actual laparoscopic scoring assessment findings in patients with advanced stage ovarian cancer. Our study highlights the limited accuracy of surgeon radiographic assessment to determine resectability.

IntroductionThe surgical approach for interval debulking surgery after neoadjuvant chemotherapy has been extrapolated from primary tumor reductive surgery for high-grade ovarian cancer. The study objective was to compare pathologic distribution of malignancy at interval debulking surgery versus primary tumor reductive surgery.MethodsPatients with a diagnosis of high-grade serous or mixed, non-mucinous, epithelial ovarian, fallopian tube or primary peritoneal cancer who underwent neoadjuvant chemotherapy or primary tumor reductive surgery and had at least 6 months of follow-up were identified through tumor registry at a single institution from January 1995 to April 2016. Pathologic involvement of organs was categorized as macroscopic, microscopic, or no tumor. Statistical analyses included Mann-Whitney and Fisher’s exact tests.ResultsOf 918 patients identified, 366 (39.9%) patients underwent interval debulking surgery and 552 (60.1%) patients underwent primary tumor reductive surgery. Median age was 62.3 years (range 25.3–92.5). The majority of patients in the interval debulking surgery group were unstaged (261, 71.5%). In the patients who had a primary tumor reductive surgery, 406 (74.6%) had stage III disease. In both groups, the majority of patients had serous histology: 325 (90%) and 435 (78.8%) in the interval debulking and primary tumor reductive surgery groups, respectively. There was a statistically significant difference between disease distribution on the uterus between the groups; 31.4% of the patients undergoing interval debulking surgery had no evidence of uterine disease compared with 22.1% of primary tumor reductive surgery specimens (pConclusionIn patients undergoing interval debulking surgery, there was less macroscopic involvement of tumor in the uterus, adnexa and bowel compared with patients undergoing primary cytoreductive surgery.

ObjectiveThis retrospective study examined the clinicopathologic features of adenosarcoma patients to determine potential prognostic factors and retrospectively evaluated overall survival (OS), disease-free survival (DFS), and local recurrence-free survival (LRFS) after primary treatment of adenosarcoma including surgery, radiation, and chemotherapy.MethodsOne hundred sixty-five patients with adenosarcoma were identified from the MD Anderson Cancer Center tumor registry between 1982 and 2014. Clinical data were collected retrospectively. Pathologic characteristics were examined by sarcoma pathologists. We used the Kaplan-Meier method to estimate OS, DFS, and LRFS. The log-rank test was performed to test the difference in survival between groups. Multivariate regression analyses of survival data were conducted using the Cox proportional hazards model.ResultsMedian OS and DFS for all patients were 8.5 and 4.7 years, respectively. Pathologic characteristics that influence OS and DFS were sarcomatous overgrowth (SO), myometrial invasion (MI), lymphovascular invasion (LVI), tumor size, number of mitosis, estrogen receptor, progesterone receptor, International Federation of Gynecology and Obstetrics (FIGO) stage, age, and resection status. Median OS for adenosarcoma patients with SO was 5.2 versus 14.5 years for patients without SO (P < 0.0001). Median OS for adenosarcoma patients with MI was 5.8 years versus not reached for patients without MI (P = 0.0005). Median OS for adenosarcoma patients with LVI was 1.0 versus 8.9 years for patients without LVI (P = 0.0021). On Cox analysis for OS and DFS and LRFS, only SO, MI, LVI, age, resection status, and FIGO stage remained significant. There was no difference in OS or LRFS for adjuvant radiation versus no adjuvant radiation (P = 0.17, P = 0.076).ConclusionsThis study highlights the importance of LVI as a prognostic factor and confirms the prognostic significance of SO, MI, age, resection status, and FIGO stage for adenosarcoma. Furthermore, this study suggests that there is no additional benefit to adjuvant radiation. The standard-of-care treatment for adenosarcoma should remain total abdominal hysterectomy bilateral salpingo-oophorectomy +/− lymphadenectomy and no adjuvant radiation.

Objectives: Uterine leiomyosarcoma (ULMS) is a rare tumor with limited therapeutic options and no clearly established best treatment sequence strategy. The objective of this study was to evaluate treatment sequencing for ULMS following primary surgical management and determine predictors of survival. Methods: Women with a diagnosis of ULMS between 1/2013 and 1/2018 were identified. Clinical data was collected; for this analysis, only women treated with primary surgical management were included. Descriptive statistics were performed and predictors of overall survival (OS) and progression free survival (PFS) were analyzed using Cox regression and Kaplan-Meier methodology. Results: 179 patients were included. Median age was 52 years (20-78), 94% had grade 3 tumors, and over half the total population were treated with adjuvant chemotherapy (n=100, 56%). In the subset of patients with early stage disease (126), 49% were treated with surgery only while 51% received adjuvant chemotherapy. There was no difference in PFS between early stage patients who did or did not receive adjuvant chemotherapy (p=0.60). For the overall cohort, the most common adjuvant therapy regimens were gemcitabine/docetaxel (gem/doce, 40.9%) or ifosphamide/doxorubicin (ifos/doxo, 11.4%).137 patients (76.5%) experienced recurrence, progression or death during their follow up. The median PFS was 1.76 years (95% CI: 1.27- 2.08). The median survival for those treated with surgery alone was 1.79 years, for those treated with gem/doce was 1.27 years, and other chemotherapy regimen was 0.43 years. Median survival was not estimated for the ifos/doxo regimen due to small patient number. Upfront therapy regimen significantly impacted PFS (Figure 1, p=0.003), but was not significantly associated with OS (p=0.069). The one-year PFS probability was 0.58 for gem/doce (95% CI 0.45-0.68) compared with 0.80 for ifos/doxo (95% CI 0.54-0.91). Download : Download high-res image (94KB) Download : Download full-size image Conclusions: Median PFS was 1.76 years, despite many women undergoing adjuvant therapy after surgery, most commonly with either gem/doce or ifos/doxo regimens. Primary treatment with ifos/doxo was associated with higher one-year PFS. This finding warrants additional evaluation to determine the optimal adjuvant therapy for these women.