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High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061–induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

To present a recent clinical case of Skene's gland carcinoma and review all published literature of Skene's gland malignancy with associated treatment and outcomes.We review a new case of metastatic Skene's gland adenocarcinoma. We then performed a systematic search of PubMed and Ovid-Medline through December 2021 and retrieved English language articles for review. Peer-reviewed articles were deemed eligible if they included patients with Skene's gland malignancy. Reports were reviewed for pathologic accuracy, patient characteristics, clinical presentation, tumor pathology, treatment and outcome.We reviewed 211 articles and included 15 cases from 1974 to 2022. The median patient age was 71 years (range 46-88). The most common presentation was an asymptomatic periurethral or urethral lesion in five cases (33.3%), followed by hematuria or vaginal bleeding in three patients (20.0%). In eight cases, a prostate-specific antigen was measured and found to be elevated, range 0.8-60.8 ng/mL. Treatment approaches varied and included local excision in eight cases, radical surgical resection in two cases, radiation therapy in two cases, and adjunctive androgen deprivation therapy in one case. Pathology was consistent with adenocarcinoma resembling prostate in all cases. In all cases tested, prostate-specific antigen normalized after definitive therapy of any type. Median follow up was 11.5 months, and there were no cases of recurrence or mortality secondary to Skene's gland adenocarcinoma.There are 15 published cases of a Skene's gland malignancy, all adenocarcinoma resembling prostate. Local excision is most often utilized for treatment, with androgen deprivation therapy emerging as a new treatment consideration.

Fig. S1

High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061–induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.

Table S1

Sequencing outcomes and PPP2R1A hotspot mutation frequency for the Case Comprehensive Cancer Center Gynecologic Tumor Biobank

Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma–specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type Aα in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo. Furthermore, small molecule–mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo. These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations.Significance:This study characterizes a highly recurrent, disease-specific PP2A PPP2R1A mutation as a driver of endometrial carcinoma and a target for novel therapeutic development.See related commentary by Haines and Huang, p. 4009

Supplementary Figure Legends and Methods

High-Grade Serous Carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP-inhibitors (PARPi) have become the mainstay of HGSC targeted therapy, given that these tumors are driven by a high degree of genomic instability and Homologous Recombination (HR) defects. Nonetheless, only ∼30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a Small Molecule Activator of Protein Phosphatase 2A (PP2A) (SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in Patient-Derived HGSC cells and Xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for transformation (B56α,B56γ and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061 stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and -deficient cells and in patient-derived xenograft models. Our studies identify PP2A as novel regulator of HR and introduces PP2A activators as a potential treatment for HGSC tumors. Our studies further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 has presented benefits in overcoming PARPi-resistance driven by BRCA1/2 mutation reversions.

The NCCN Guidelines for Cervical Cancer provide recommendations for diagnostic workup, staging, and treatment of patients with the disease. These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to first- and second-line systemic therapy recommendations for patients with recurrent or metastatic disease, and emerging evidence on a new histopathologic classification system for HPV-related endocervical adenocarcinoma.

e13508 Background: The National Cancer Institute (NCI) estimates that approximately one-quarter of adults with cancer are parents to children less than 18 years. Further, it is estimated that 2.85 million minor children in the United States have a parent undergoing cancer treatment. Previous studies have demonstrated that parents with cancer experience significant stress and disruptions to familial life following a cancer diagnosis. In a study of women with breast, gynecologic cancer and other cancers undergoing cancer therapy, 48.7% of women endorsed needing help with childcare and 64.1% needing help with household management. Despite this evidence supporting both a need for childcare among patients with cancer, data regarding the availability of on-site childcare programs and resources at NCI-designated cancer centers is limited. The objective of this cross-sectional study was to assess the availability of childcare resources for parents who are undergoing cancer treatment at NCI-Designated Cancer Centers. Methods: The availability of childcare resources for parents undergoing cancer treatment at all 51 NCI-designated comprehensive cancer centers and 13 NCI-designated cancer was assessed in January 2021 and February 2021. Childcare resources were assessed via online search and telephone calls. Specifically, centers were queried regarding availability of daycare programs for children of patients undergoing treatment and whether resources were available to assist patients in need of childcare. Descriptive statistics were performed. Results: In total, only 1/64 (1.6%) of NCI-designated cancer centers currently offer childcare resources for patients undergoing cancer treatment. This center offers childcare for children ages 2–8, free of charge with multiple outpatient locations. One additional institution previously provided patients with access to daycare, but has closed due to the COVID-19 pandemic. Further, only 1/64 (1.6%) NCI-designated cancer center offers financial assistance grants to aid patients to subsidizing childcare costs during cancer treatment. Conclusions: Institution sponsored options for childcare for patients undergoing cancer treatments are highly limited, even in the best resourced cancer care settings. The COVID-19 pandemic has limited options further, and many hospitals now restrict visitors under the age of 18. Patient grants or institutionally sponsored childcare provider networks may represent an avenue for supporting parents who are facing a cancer diagnosis. Supporting families of patients with cancer has great potential to impact quality of life, economic and psychological stress.

Objectives To determine the progression free survival (PFS) of paclitaxel and carboplatin (PC) versus bleomycin, etoposide, and cisplatin (BEP) for treatment of newly diagnosed Stage IIA-IV or recurrent chemotherapy-naive ovarian sex cord-stromal tumors (SCST). Methods This study was a phase II, open-label, noninferiority trial. Eligible women with SCST were equally randomized to PC (6 cycles P 175 mg/m2 and C AUC=6 IV every 3 weeks), or BEP (4 cycles B 20 units/m2 IV push day 1, E 75 mg/m2 IV days 1–5, and cisplatin 20 mg/m2 IV days 1–5 every 3 weeks). The targeted 128 patient accrual and PFS hazard ratio (HR)=0.67 provided 85% power to exclude noninferiority margin HR=1.10. Results 63 patients were accrued at the interim futility analysis (31 PC and 32 BEP). Median age was 48 years. 87% had granulosa cell tumors. 37% had measurable disease. The DSMB closed the study early for futility of PC. The futility analysis was supported by 21/16 PFS events on the PC/BEP arms respectively, with an estimated HR=1.12 [95% CI: 0.58 to 2.16]. Median PFS was 27.7 months [7.4 to 41.0] for PC and 19.7 months for BEP [95% CI: 10.4–52.7]. PC patients had fewer grade 3 or higher adverse events (PC 77% vs BEP 90%). Differences included infections (0 vs 10%), low neutrophil count (65% vs 84%), and low WBC (22 vs 40%). One death NOS occurred on PC. Conclusions Compared to BEP, PC failed to improve PFS in ovarian SCSTs. PC showed a more favorable side effect profile.

The NCCN Guidelines for Cervical Cancer provide recommendations for diagnostic workup, staging, and treatment of patients with the disease. These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to first- and second-line systemic therapy recommendations for patients with recurrent or metastatic disease, and emerging evidence on a new histopathologic classification system for HPV-related endocervical adenocarcinoma.

BACKGROUND Adjuvant therapy choice for women with FIGO stage III endometrial carcinoma (EC) is controversial. We investigate the comparative benefit of adjuvant chemotherapy (CT) alone, radiation therapy alone (RT) or in combination (chemotherapy and radiation therapy [CRT]) with respect to recurrence-free survival (RFS) and overall survival (OS) in women with pelvis-limited (PL) EC (stage IIIA, IIIB, and IIIC1). MATERIALS AND METHODS A multi-institutional database of 270 surgically staged women with PLEC was analyzed. Univariate log-rank analyses and Cox regression multivariate analyses (MVA) were performed to identify factors associated with RFS and OS. RESULTS Median RFS and OS were 112 and 130 months, respectively, for the full cohort. Adjuvant treatment was CT in 21%, RT in 27%, and CRT in 47%. Age, year of treatment, grade, histology, and adjuvant treatment were significantly associated with RFS and OS on univariate analysis. PLEC patients receiving CT alone fared worse in terms of RFS (P=0.07 relative to RT and

Objective To assess whether the addition of oncolytic reovirus (Reolysin®) to weekly paclitaxel prolonged progression-free survival (PFS) in the treatment of women with recurrent or persistent ovarian, tubal or primary peritoneal cancer. Patients and methods Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to paclitaxel (80mg/m 2 intravenously days 1, 8, and 15 every 4weeks) or the combination of paclitaxel (80mg/m 2 intravenously days 1, 8, and 15) plus reovirus 3×10 10 TCID 50 /day intravenously on days 1–5, both every 4weeks until disease progression or toxicity. The primary end point was PFS. The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. Results The study accrued 108 patients, 100 of whom were evaluable for toxicity. Median PFS was 4.3months for paclitaxel and 4.4months for paclitaxel plus reovirus (hazard ratio, 1.11; 90% two-sided CI, 0.78 to 1.59; one-sided P=0.687). The proportion responding (overall response rate) to paclitaxel was 20% among 45 patients with measurable disease receiving paclitaxel alone, and 17.4% among the 46 patients treated with the combination. The asymptotic relative probability of responding was 0.87 (90% CI, 0.42 to 1.79). Severe adverse events were more common in the combination regimen than in paclitaxel arm for severe neutropenia (grade≥4, 12% versus 0%), and severe respiratory adverse events (grade≥3, 25% versus 2%). No deaths were considered treatment related. Conclusion The addition of reovirus to weekly paclitaxel in the treatment of women with recurrent or persistent ovarian, tubal or peritoneal cancer did not sufficiently reduce the hazard of progression or death to warrant further investigation.

Background. To determine the prognostic significance of pretreatment levels of circulating lymphocyte (CLC), neutrophil (CNC), and monocyte (CMC) counts in patients with locally advanced cervical carcinoma (CC) treated with definitive radiation.Methods. A retrospective, dual-institution review of patients with Stage IB2-IVA CC from 2005 to 2015. Progression-free (PFS) and Overall Survival (OS) were determined for high and low CLC, CNC, and CMC groups. Multivariate analysis was used to confirm prognostic value of baseline leukocyte counts.Results. 181 patients were included. Median follow-up time was 26 (3–89) months. CNC had no effect on PFS or OS. PFS was similar between CMC groups; however, OS was significantly improved for patients with low CMC (62.5 versus 45.3 months,p=0.016). High CLC was associated with improved PFS (48.5 versus 27.8 months,p=0.048) and OS (58.4 versus 34.9 months,p=0.048). On multivariate analysis, high CNC was associated with increased relapse risk (HR 1.12,p=0.006) and low CLC was associated with increased mortality risk (HR 0.67,p=0.027).Conclusion. This study demonstrates that leukocyte values can provide prognostic information in CC. These hypothesis-generating findings warrant further prospective investigations.

Gestational trophoblastic neoplasia (GTN), a subset of gestational trophoblastic disease (GTD), occurs when tumors develop in the cells that would normally form the placenta during pregnancy. The NCCN Guidelines for Gestational Trophoblastic Neoplasia provides treatment recommendations for various types of GTD including hydatidiform mole, persistent post-molar GTN, low-risk GTN, high-risk GTN, and intermediate trophoblastic tumor.

Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.

Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma–specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type Aα in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo. Furthermore, small molecule–mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo. These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations. Significance: This study characterizes a highly recurrent, disease-specific PP2A PPP2R1A mutation as a driver of endometrial carcinoma and a target for novel therapeutic development. See related commentary by Haines and Huang, p. 4009

Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

Purpose/Objective(s): Stage IIIC endometrial carcinoma (EC) represents pathologically heterogenous patients with single/multiple pelvic (stage IIIC1) or paraaortic (stage IIIC2) lymph nodes (LNs). There is an increasing trend to offer adjuvant chemotherapy (CT) +/− radiation (RT) uniformly to these patients, regardless of substage. We investigate the prognostic significance of positive LN (pLN) number, ratio (%pLN), location (IIC1 vs. IIC2), and adjuvant treatment on patterns of failure and survival in a large collaborative multi-institutional series. Materials and Methods: Clinical data for stage III EC patients such as patient characteristics, surgery/pathologic details, adjuvant therapies (including CT, RT, and chemotherapy and radiation), and outcomes (including pelvic control [PC], disease-free survival [DFS], distant DFS, and overall survival [OS]) were collected from 3 academic institutions. Log-rank analyses, Cox regression univariate and multivariate analyses were performed. Results: Of the 264 patients queried for stage III disease, 237 (73%) had pLN, and complete LN sampling for analysis. The mean number of pLN in the combined data were 3.9, with 26.1% of all LN sampled positive; 121 patients (51%) staged IIIC1, and 116 patients (49%) staged IIIC2. There was a significant difference in number of pLN (P=0.0006) and total LN sampled by institution (range, 13 to 35; P=0.0004), without a difference in %pLN (P=0.35). Ninety-seven of 220 (44.1%) have ≥20% pLN. While controlling for substage and institution, a decrease in DFS (hazard ratio [HR], 1.1; P=0.007), and OS (HR, 1.1; P=0.01) was observed with every increase of 10% in the pLN ratio. There was a significant difference in DFS (HR, 1.8; P=0.003), PC (HR, 1.9; P=0.004), and distant DFS (HR, 1.6; P=0.03), as well as a trend for decreased OS (HR, 1.6; P=0.08) for substage IIIC2 versus IIIC1 disease; 5 years DFS 40% versus 45%, OS 50% versus 57%. Patients received no adjuvant therapy (10%), CT alone (27%), RT alone (16%), or chemotherapy and radiation (47%). There was no significant difference in PC, DFS, or OS between the various treatment regimens. On univariate analysis, while pLN was significant, treatment type did not impact DFS or OS. On multivariate analysis for DFS, patient age, race, and IIIC1 versus IIIC2 substage retained significance (HR, 0.56; P=0.01). Conclusions: Stage III EC patients with substage IIIC2 disease have a significantly increased risk of local and distant disease recurrence and death from EC. A decrease in DFS and OS was observed with every increase of 10% in the pLN ratio. Stage IIIC2 patients represent a high-risk subpopulation for whom clinical trials, or targeted regimens should be explored to achieve improved oncologic outcomes.

Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations.

Purpose To evaluate the role of 3T-MRI–guided adaptive high-dose-rate (HDR) combined intracavitary and interstitial brachytherapy for cervical cancer using a novel intracavitary split-ring (ICSR) applicator adapter. Methods and Materials We retrospectively reviewed all HDR brachytherapy cases from 2013 to 2015 using an ICSR applicator. Initial optimization was performed using 3T multiparametric MRI (mpMRI) series with an applicator in place. The mpMRI series were discretionarily acquired before subsequent fractions for possible target adaptation. When necessary, interstitial needles (ISNs) were inserted through a novel ICSR adapter or freehand. Dosimetric parameters, clinical outcomes, and toxicities were compared between groups. Results Seventeen patients were included, with a mean followup of 32 months. An mpMRI series preceded each initial fraction and 52.9% of patients underwent ≥1 additional pretreatment mpMRI. Among these subsequent fractions, the high-risk clinical target volume was reduced in 80% vs. 41% without pretreatment mpMRI. Five patients had ISN placement (seven insertions) to improve extracervical target coverage. Mean D90 (Gy) per fraction to the high-risk clinical target volume and intermediate-risk clinical target volume with and without an ISN were 7.51 ± 1.07 vs. 6.14 ± 0.52 (p = 0.028) and 6.35 ± 0.75 vs. 5.21 ± 0.49 (p = 0.007), respectively. Mean fractional D2cc (Gy) for organs at risk was comparable. No Grades 3–4 toxicity was reported. Disease-free survival and local control for the ICSR-ISN and ICSR-alone groups were 29.8 months/80.0% and 31.2 months/83.3%, respectively. Conclusions The mpMRI acquisition with ICSR applicator in place immediately before HDR brachytherapy for cervical cancer guided successful adaptive treatment optimization and delivery. Our initial experience with a novel interstitial adapter for the split-ring applicator demonstrated excellent target coverage without compromising organs at risk, resulting in good local control and disease-free survival.

Background Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients. Methods Study subjects comprised 4374 participants of the NRG Oncology/Gynecology Oncology Group 210 Study with endometrial carcinoma who completed a presurgical questionnaire that assessed history of regular prediagnostic NSAID use and endometrial cancer risk factors. Recurrences, vital status, and causes of death were obtained from medical records and cancer registries. Fine-Gray semiproportional hazards regression estimated adjusted subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations of NSAID use with endometrial carcinoma-specific mortality and recurrence. Models were stratified by endometrial carcinoma type (ie, type I [endometrioid] vs type II [serous, clear cell, or carcinosarcoma]) and histology. Results Five hundred fifty endometrial carcinoma-specific deaths and 737 recurrences occurred during a median of five years of follow-up. NSAID use was associated with 66% (HR = 1.66, 95% CI = 1.21 to 2.30) increased endometrial carcinoma-specific mortality among women with type I cancers. Associations were statistically significant for former and current users, and strongest among former users who used NSAIDs for 10 years or longer (HR = 2.23, 95% CI = 1.19 to 4.18, two-sided P trend = .01). NSAID use was not associated with recurrence or endometrial carcinoma-specific mortality among women with type II tumors. Conclusions In this study, use of NSAIDs was associated with increased endometrial carcinoma-specific mortality, especially in patients with type I tumors. Barring a clear biologic mechanism by which NSAIDs would increase the risk of cause-specific mortality, cautious interpretation is warranted.

A large proportion of cervical cancer patients have a lower socioeconomic background and barriers to clinical trial participation. We hypothesized that patients participating in a clinical trial would have better outcomes compared to those not enrolled in a trial. This was a retrospective cohort study of women treated for recurrent cervical cancer on versus off clinical trial. We found that the progression free and overall survival between women treated with chemotherapy on or off trial for cervical cancer survival is similar. Introduction: A large proportion of patients with cervical cancer have a lower socioeconomic background with inherent barriers to clinical trial participation. The present authors hypothesized that patients participating in a clinical trial would have better outcomes compared with those not enrolled in a trial. The objective was to review the clinical outcomes of women with recurrent cervical cancer treated on a clinical trial versus those treated off trial. Patients and Methods: This was a retrospective cohort study of women treated for recurrent cervical cancer on versus off clinical trial between 1998 and 2010. Women participating in Gynecologic Oncology Group clinical trials for recurrent cervical cancer were identified and matched 1:1 with women treated off trial based on age within 10 years, ethnicity, stage at initial diagnosis, histology, primary treatment, and baseline renal function. Results: A total of 60 women with recurrent cervical cancer were identified; 30 were treated for their recurrence on a clinical trial and were matched to 30 treated off trial. The median number of salvage regimens was 1.0 for the trial group (range, 1-5) and 1.5 for the off-trial group (range, 1-5) (P ¼ .74). There was no significant difference in the number of cycles of chemotherapy completed on versus off trial (7.5 vs. 5.9; P ¼ .44). There was also no significant difference in progression-free and overall survival from time of recurrence on trial and off trial (4.2 vs. 3.1 months (P ¼ .75) and 15.0 vs. 13.8 months (P ¼ .64), respectively). Conclusion: This study found that the progression-free survival and overall survival are similar between women treated with chemotherapy on or off trial for cervical cancer.

To evaluate the impact of adjuvant post-operative therapy in women with early stage uterine carcinosarcoma.After IRB approval was obtained at all sites, a multi-center retrospective study of women with FIGO stage I-II uterine carcinosarcoma diagnosed from 1997 to 2007 was conducted. Post-operative treatment included observation (OBS), radiation (RT), chemotherapy (CT) alone or with RT (CT+RT). Data analyzed included demographic and pathologic factors, adjuvant therapy outcomes, and time-to-event information. The Kaplan-Meier method was used to estimate time-to-event functions. Cox regression modeling was used to examine the impact of selected covariates on progression free survival (PFS), and overall survival (OS).111 women were identified: 94 (85%) had stage I and 17 (15%) had stage II uterine carcinosarcoma. Forty-four women (40%) did not receive adjuvant therapy (OBS), 29 (26%) women had adjuvant CT, 23 (20%) women underwent RT and 15 (14%) women underwent RT+CT. Seventy-three patients were alive without disease and 38 had progressed or died at the close of data collection. In multivariate analysis, CT (p=0.003), LVSI (p0.0001) and a pre-existing cancer (p=0.004) were most predictive of PFS. LVSI was predictive of shortened OS (p=0.01).In women with FIGO stage I-II uterine carcinosarcoma, adjuvant chemotherapy is associated with improved PFS compared to radiation or observation alone. Ongoing clinical trials will clarify the role of chemotherapy in women with this disease.

BackgroundObesity is a known risk factor and poor prognostic factor for many comorbidities including cancer. However, the influence of body mass index (BMI) on ovarian cancer outcomes is inconclusive. Therefore, the objective of this study was to evaluate the impact of BMI and weight changes on survival in patients with advanced ovarian cancer after primary treatment.MethodsAll patients with a diagnosis of advanced epithelial ovarian cancer from January 2000 to December 2007 undergoing primary cytoreductive surgery and adjuvant chemotherapy were identified. Patients were divided into 3 categories: underweight/normal weight (BMI, 2), overweight (BMI, 25–30 kg/m2), and obese (BMI, >30 kg/m2). Adjusted hazard ratios for progression-free survival (PFS) and overall survival (OS) were calculated via Cox proportional hazards models.ResultsOne hundred ninety-eight patients met the inclusion criteria. For all patients, the mean BMI was 26 kg/m2 (range, 16.4–49.1 kg/m2), with 43% of patients being classified as normal weight, 29% overweight, and 28% as obese. Median 5-year OS was 48.2 months (95% confidence interval, 16.4–49.1 months), and no differences in OS were noted between BMI groups. Unadjusted median PFS for patients with normal weight was 13.7 months, compared with 15.5 and 17.9 months for the overweight and obese groups. Adjusted analysis of BMI over time indicates a trend of increased risk for patients who gain weight in the 6 months after primary therapy on disease progression (hazard ratio, 1.68; 95% confidence interval, 0.87–3.26).ConclusionsAfter adjustment for confounders, such as stage, grade, histology, age, and debulking status, data suggest a trend toward a shorter PFS in patients with a normal BMI. However, OS was not significantly related to BMI, and weight change in the 6 months after completion of treatment had no effect on PFS or OS. Further research should be directed at elucidating relationships between weight and cancer biology.

Background Black women with endometrial cancer are more likely to die of their disease compared with white women with endometrial cancer. These survival disparities persist even when disproportionately worse tumor characteristics among black women are accounted. Receipt of less complete adjuvant treatment among black patients with endometrial cancer could contribute to this disparity. Objective We assessed the hypothesis that black women with endometrial cancer are less likely than their white counterparts to receive adjuvant treatment within subgroups defined by tumor characteristics in the NRG Oncology/Gynecology Oncology Group 210 Study. Study Design Our analysis included 615 black and 4283 white women with endometrial cancer who underwent hysterectomy. Women completed a questionnaire that assessed race and endometrial cancer risk factors. Tumor characteristics were available from pathology reports and central review. We categorized women as low-, intermediate-, or high-risk based on the European Society for Medical Oncology definition. Adjuvant treatment was documented during postoperative visits and was categorized as no adjuvant treatment (54.3%), radiotherapy only (16.5%), chemotherapy only (15.2%), and radiotherapy plus chemotherapy (14.0%). We used polytomous logistic regression to estimate odds ratios and 95% confidence intervals for multivariable-adjusted associations between race and adjuvant treatment in the overall study population and stratified by tumor subtype, stage, or European Society for Medical Oncology risk category. Results Overall, black women were more likely to have received chemotherapy only (odds ratio, 1.40; 95% confidence interval, 1.04–1.86) or radiotherapy plus chemotherapy (odds ratio, 2.01; 95% confidence interval, 1.54–2.62) compared with white women in multivariable-adjusted models. No racial difference in the receipt of radiotherapy only was observed. In tumor subtype-stratified models, black women had higher odds of receiving radiotherapy plus chemotherapy than white women when diagnosed with low-grade endometrioid (odds ratio, 2.04; 95% confidence interval, 1.06–3.93) or serous tumors (odds ratio, 1.81; 95% confidence interval, 1.07–3.08). Race was not associated with adjuvant treatment among women who had been diagnosed with other tumor subtypes. In stage-stratified models, we observed no racial differences in the receipt of adjuvant treatment. In models that were stratified by European Society for Medical Oncology risk group, black women with high-risk cancer were more likely to receive radiotherapy plus chemotherapy compared with white women (odds ratio, 1.41; 95% confidence interval, 1.03–1.94). Conclusion Contrary to our hypothesis, we observed higher odds of specific adjuvant treatment regimens among black women as compared with white women within specific subgroups of endometrial cancer characteristics.

Background: Black women diagnosed with endometrial cancer (EC) experience worse outcomes compared with white women. Differences in receipt of treatment are postulated to contribute to this disparity. While underuse of surgical treatment among black women is well documented, we know less about racial differences in adjuvant treatment. We therefore examined receipt of adjuvant treatment among black and white women in the NRG Oncology/Gynecology Oncology Group (GOG) 210 Study, a large prospective cohort of women with EC who received uniform surgical treatment but varying adjuvant therapy regimens. Methods: Our analysis included 615 black and 4,283 white women with EC who underwent either an abdominal hysterectomy or laparoscopic-assisted vaginal hysterectomy with bilateral salpingo-oophorectomy and lymph node dissection. At study enrollment, women completed a questionnaire that assessed race as well as risk factors for EC. Tumor characteristics were available from surgical pathology reports and a centralized review by pathologists with expertise in gynecologic cancers. Adjuvant treatment was documented at the time of the postoperative clinical visits and was categorized as none (54.3%), radiotherapy only (16.5%), chemotherapy only (n=15.2%), and radiotherapy and chemotherapy (14.0%). We used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between race and receipt of adjuvant therapy in the overall study population and stratified by tumor subtype (combination of histology and grade) adjusted for age, income, education, and stage. Results: Black compared with white women had higher odds of receiving combination radiotherapy and chemotherapy compared to no adjuvant therapy (OR=1.35, 95% CI=1.01-1.79) but no difference in receipt of radiotherapy only (OR=0.95, 95% CI=0.72-1.25) or chemotherapy only (OR=0.88 (0.64-1.20) was observed. In tumor-subtype stratified models, black women diagnosed with low-grade endometrioid (OR=2.04, 95% CI=1.06-3.93) or serous tumors (OR=1.81, 95% CI=1.07-3.08) had higher odds of receiving radiotherapy and chemotherapy than white women, but race was not associated with receipt of radiotherapy and chemotherapy for women with high-grade endometrioid, carcinosarcoma, mixed-cell, or clear-cell tumors. Moreover, the tumor-subtype stratified analyses revealed no racial differences in receipt of radiotherapy-only or chemotherapy-only regimens. Conclusions: In this study of women with EC who received uniform surgical treatment, we observed racial differences in receipt of some adjuvant treatment regimens but not others. Among women with indolent (i.e., low-grade endometrioid) or aggressive (i.e., serous) tumors, black women had higher odds of receiving radiotherapy and chemotherapy compared to white women. Radiotherapy and chemotherapy treatment is potentially contraindicated for women with indolent tumors, which suggests a need to understand the reasons why clinicians might overprescribe these therapies for black women. Overall, our results suggest racial differences in receipt of radiotherapy and chemotherapy, but not for other regimens. Citation Format: Ashley Felix, David Cohn, Theodore Brasky, David Mutch, William Creasman, Premal Thaker, Joan Walker, Richard Moore, Shashikant Lele, Saketh Guntupalli, Levi Downs, Christa Nagel, John Boggess, Michael Pearl, Olga Ioffe, Wei Deng, Marcus Randall, Louise Brinton. Receipt of adjuvant endometrial carcinoma treatment according to race: An NRG Oncology/Gynecologic Oncology Group 210 Study [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A85.

Large‐scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome‐scale, gain‐of‐function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor‐suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA‐mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease.