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PURPOSE Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy. PATIENTS AND METHODS NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs). RESULTS Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, –2.0 to –0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed. CONCLUSION Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.

PURPOSE: Sparing active bone marrow (ABM) can reduce acute hematologic toxicity in patients undergoing chemoradiotherapy for cervical cancer, but ABM segmentation based on positron emission tomography/computed tomography (PET/CT) is costly. We sought to develop an atlas-based ABM segmentation method for implementation in a prospective clinical trial. METHODS AND MATERIALS: A multiatlas was built on a training set of 144 patients and validated in 32 patients from the NRG-GY006 clinical trial. ABM for individual patients was defined as the subvolume of pelvic bone greater than the individual mean standardized uptake value on registered (18)F-fluorodeoxyglucose PET/CT images. Atlas-based and custom ABM segmentations were compared using the Dice similarity coefficient and mean distance to agreement and used to generate ABM-sparing intensity modulated radiation therapy plans. Dose-volume metrics and normal tissue complication probabilities of the two approaches were compared using linear regression. RESULTS: Atlas-based ABM volumes (mean [standard deviation], 548.4 [88.3] cm(3)) were slightly larger than custom ABM volumes (535.1 [93.2] cm(3)), with a Dice similarity coefficient of 0.73. Total pelvic bone marrow V(20) and D(mean) were systematically higher and custom ABM V(10) was systematically lower with custom-based plans (slope: 1.021 [95% confidence interval (CI), 1.005-1.037], 1.014 [95% CI, 1.006-1.022], and 0.98 [95% CI, 0.97-0.99], respectively). We found no significant differences between atlas-based and custom-based plans in bowel, rectum, bladder, femoral heads, or target dose-volume metrics. CONCLUSIONS: Atlas-based ABM segmentation can reduce pelvic bone marrow dose while achieving comparable target and other normal tissue dosimetry. This approach may allow ABM sparing in settings where PET/CT is unavailable.

Purpose: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti–CTL antigen-4 (anti–CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment. Patients and Methods: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot. Results: Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival. Conclusions: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

Background Immune checkpoint inhibitors are being considered for locally advanced cervical cancer (LACC) together with standard-of-care pelvic chemoradiation (CRT). However, the safety of the combination and its optimal schedule are unknown. Defining the safety of the combination is a primary objective of a study examining concurrent and sequential schedules. This article presents a safety analysis that was fully accrued and met reporting requirements. Methods Pembrolizumab was given after CRT (arm 1) or during CRT (arm 2) according to a randomized phase 2 design. Patients who were 18 years old or older and had LACC (stages IB-IVA according to the 2009 International Federation of Gynecology and Obstetrics system) were randomized 1:1 to the treatment regimens. The CRT was identical in the 2 arms. Pembrolizumab was administered every 3 weeks for 3 doses; no maintenance was allowed. All patients receiving any treatment were evaluated for safety. Safety assessments included the incidence and severity of adverse events (AEs) and the occurrence of protocol-defined dose-limiting toxicity (DLT) through 30 days after the last pembrolizumab infusion. Results As of August 2019, 52 of the 88 planned patients had completed treatment and were evaluable for toxicity. Treatment-related grade 2 or higher toxicity was experienced by 88%; 11 had at least 1 grade 4 AE, and another 23 had at least 1 grade 3 AE. Grade 1 or higher diarrhea was reported in 34 patients (65%; 50% of these were grade 1), and there was no difference between arms (63% in arm 1 vs 68% in arm 2). Two patients experienced 3 DLTs. Most patients completed cisplatin (100% in arm 1 vs 82% in arm 2); 83% in both arms completed all pembrolizumab. Conclusions Preliminary results support the safety and feasibility of adding pembrolizumab to pelvic CRT concurrently or sequentially. Lay summary Pembrolizumab is a humanized antibody against programmed cell death protein 1 that is used in cancer immunotherapy. Preliminary data suggest that pembrolizumab can be safely combined with chemotherapy and pelvic radiation in the treatment of locally advanced cervical cancer. Future studies of the addition of immunotherapy to traditional chemoradiation are planned to determine the best way to deliver the treatment and whether any improvement is seen with the addition of immunotherapy to traditional therapy.

The sfRon kinase is an important therapeutic target in ovarian cancer that contributes to prominent tumor growth and disease progression. We reasoned that a multi-kinase inhibition of sfRon pathway might be an effective strategy to achieve a sustained anti-tumor response, while simultaneously preventing treatment resistance. We performed a detailed dissection of sfRon signaling in vitro and demonstrated that S6K1 is a key component of a multi-kinase targeting strategy in sfRon expressing ovarian tumors. We selected AD80 compound that targets several kinases within sfRon pathway including AKT and S6K1, and compared its efficacy with inhibitors that selectively target either sfRon or PI3 kinase. Using human ovarian xenografts and clinically relevant patient-derived xenografts (PDXs), we demonstrated that in vivo treatment with single agent AD80 shows superior efficacy to a standard-care chemotherapy (cisplatin/paclitaxel), or to the direct inhibition of sfRon kinase by BMS777607. Our findings indicate that ovarian tumors expressing sfRon are most effectively treated with multi-kinase inhibitors simultaneously targeting AKT and S6K1, such as AD80, which results in long-term anti-tumor response and prevents metastasis development.

Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.

Purpose We conducted a randomized phase III trial to determine whether adjuvant chemotherapy improves survival in women with uterine leiomyosarcoma. Methods Women with uterus-confined, high-grade leiomyosarcoma who were confirmed disease free by imaging were randomly assigned to four cycles of gemcitabine plus docetaxel, followed by four cycles of doxorubicin, or to observation. All were followed for evidence of recurrence. The primary end point was overall survival (OS). Results With international collaboration, 38 of the targeted accrual of 216 patients were enrolled, after which the study was closed by the National Cancer Institute for accrual futility. Twenty patients were assigned to chemotherapy, 18 to observation. Among the 17 patients treated with at least one cycle of chemotherapy, grade 3 or 4 toxicities were observed in 47%; among the 18 patients assigned to observation, one had grade 3 hypertension. There were six deaths (chemotherapy, n = 5; observation, n = 1), all due to disease. The restricted mean survival time for OS was estimated as 34.3 months (95% CI, 25.3 to 43.3 months) in the chemotherapy arm and as 46.4 months (95% CI, 43.6 to 49.1 months) in the observation arm. There were eight recurrences in each arm. The restricted mean survival time for recurrence-free survival was estimated as 18.1 (95% CI, 14.2 to 22.0) months in the chemotherapy arm and as 14.6 months (95% CI, 10.3 to 19.0 months) in the observation arm. Neither survival outcome comparison was considered statistically robust, due to the small sample size. Conclusion Despite international collaboration to test the role of adjuvant chemotherapy in uterine-confined leiomyosarcoma, this study was closed for accrual futility. Although the sample size precludes robust statistical comparison, observed OS and recurrence-free survival data do not show superior outcomes with adjuvant chemotherapy.

Purpose/Objective(s) Total neoadjuvant therapy (TNT) including chemotherapy (chemo) and concurrent chemo and radiotherapy (RT) is a promising strategy for rectal cancer. Characterizing tumor regression during TNT represents an important area of research. We report a prospective validation study of the Magnetic Resonance Tumor Regression Grade (MR-TRG) using MRIs from NRG-GI002, a phase II trial of TNT for rectal cancer. Materials/Methods This was the a priori designed imaging biomarker study of NRG-GI002 seeking to correlate the MR-TRG with the pathologic Neoadjuvant Rectal score (NAR) and pathologic complete response (pCR). 110 patients (pts) were needed with 2 MRI's, 1 pre-TNT and 1 post. Three diagnostic radiologists independently reviewed each MRI and completed a consensus read. Radiologists’ assessment of complete response (mriCR) was tested for its positive predictive value (PPV), negative predictive value (NPV), sensitivity (sen), and specificity (spec) with pCR. Chi-squared test was used for association of mriCR and pCR, and Wilcoxon-Mann-Whitney test was used for association of MR-TRG and pCR. Spearman Rho was used for association of MR-TRG/mriCR and NAR. P-values Results A total of 126 patients, from 76 institutions, had 2 MRI's (pre-TNT and post), 3 radiologists completed 756 MRI interpretations. Of 126 patients, 29% were female (N = 37), 85% white (N = 107) and median age was 55 (24-76). Individual and consensus MR-TRG scores were highly associated with pCR (P Conclusion MR-TRG is significantly correlated with pathologic NAR score. Binary assessment of CR, using MR-TRG and DWI, had near perfect agreement across readers. The addition of DWI to MR-TRG improved both the sen and spec, reflecting utility of DWI in this setting. Correlation of mriCR with pCR was statistically significant. Notably, PPVs here were limited, implicating the need for stronger biomarkers when planning a national rectal organ preservation study. NCT02921256.

Importance Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed. Objective To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. Design, setting, and participants In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020. Interventions Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. Main outcomes and measures The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety). Results A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found. Conclusions and relevance Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study. Trial registration ClinicalTrials.gov Identifier: NCT02921256.

INTRODUCTION: Endometrial carcinoma (EMC) is the most common gynecologic malignancy and is highly lethal in the metastatic setting with an overall survival of 1.5-2 years due to chemotherapy resistance. Uterine carcinosarcoma (UCS) is a rare but aggressive biphasic subtype that comprises only 3-4% of EMCs but accounts for greater than 16% of uterine cancer deaths. Sulfatase 2 (SULF2) is an extracellular enzyme that activates pro-tumorigenic growth factor signaling, including transforming growth factor β (TGFβ). SULF2 is overexpressed in many cancers and is associated with tumor progression and poor prognosis. TCGA data reveal that the SULF2 gene is commonly amplified or mutated in UCS (17.5%) and may be a viable therapeutic target. OKN-007, a disulfonyl derivative of phenyl-tert-butyl nitrone, interrupts the TGFβ pathway and decreases downstream markers of epithelial mesenchymal transition (EMT) through inhibition of SULF2 in the tumor extracellular matrix. As such, assessment of OKN-007 was undertaken in UCS and EMC.METHODS: The anticancer effect of OKN-007 was evaluated in a UCS cell line (CS99) and EMC cell lines (Ishikawa, AN3CA, Hec1A, and RL95-2A). Cell viability, migration, colony-formation, and protein expression of SULF2, TGFβ, and EMT markers were evaluated in 2D and 3D culture conditions in vitro. The effect of OKN-007 alone or in combination with chemotherapy (carboplatin and paclitaxel) on tumor growth was evaluated in an intraperitoneal UCS xenograft mouse model. In vivo tumor growth was monitored using magnetic resonance imaging. TGFβ, SULF2, and EMT markers were investigated by western blot. RESULTS: SULF2 was highly expressed in UCS and EMC cells in 2D and 3D conditions. Decreased cell viability, migration, and colony-forming ability were observed with OKN-007 treatment with differences observed in IC50 values in 2D vs 3D conditions. Mice treated with OKN-007 demonstrated no observable toxicity, had decreased mean tumor volume (p Citation Format: Anjalika Gandhi, Samrita Dogra, Rheal Towner, Bethany N. Hannafon, Katherine Moxley. OKN-007 suppresses uterine carcinosarcoma by inhibiting extracellular sulfatase 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB137.

With the goal of identifying diagnostic and prognostic biomarkers in endometrial cancer, miRNA-profiling was carried out with formalin-fixed paraffin embedded (FFPE) tissue samples from 49 endometrial cancer patients. Results using an 84-cancer specific miRNA panel identified the upregulation of miR-141-3p and miR-96-5p along with a downregulation of miR-26, miR-126-3p, miR-23b, miR-195-5p, miR-374a and let-7 family of miRNAs in endometrial cancer. We validated the dysregulated expression of the identified miRNAs in a panel of endometrial cancer cell-lines. Immunohistochemical analysis of the tissue micro array derived from these patients established the functional correlation between the decreased expression of tumor suppressive miRNAs and their target oncogenes: ERBB2, EGFR, EPHA2, BAX, GNA12, GNA13, and JUN. Comparative analysis of the samples from the patients with extended progression-free survival (PFS) ( > 21 months) versus the patients with the PFS of < 21 months indicated increased expression of tumor suppressive miR-142-3p, miR-142-5p, and miR-15a-5p in samples from extended PFS patients. In addition to defining a specific set of miRNAs and their target genes as potential diagnostic biomarkers, our studies have identified tumor suppressive miR-142 cluster and miR-15a as predictors of favorable prognosis for therapy response in endometrial cancer.

5527 Background: Treatment options for patients with recurrent cervical and endometrial cancer remain limited. Even with optimum care, median survival has stalled at 12-17 months. The PARP inhibitor rucaparib has demonstrated activity in both BRCA wild-type and mutant cancers. Furthermore, preclinical studies suggest a synergistic effect of PARP inhibitors and antiangiogenic agents. We hypothesized that the combination of rucaparib and the VEGF inhibitor bevacizumab would yield a clinically-significant anti-cancer effect in patients with persistent or recurrent cervical or endometrial carcinoma. Methods: NCT03476798 is a phase II trial of adults with histologically-documented carcinoma of the cervix or endometrium. Patients with evaluable lesions who had undergone at least one prior line of systemic therapy, had adequate performance status and organ function, with a life expectancy of at least three months were eligible. Biopsies were obtained prior to treatment initiation for assessment of baseline tumor biomarkers, including ARID1A mutation status. Each cycle comprised 21 days. Rucaparib was administered orally at 600 mg, twice daily. Bevacizumab was administered by IV at 15 mg/kg on day 1 of each cycle. The primary objective was to estimate the proportion of patients with persistent or recurrent cervical or endometrial cancer who survive progression-free for at least six months (PFS6). Kaplan-Meier analysis was used to estimate progression-free survival. Results: There were 28 evaluable patients; six had cervical and 22 had endometrial cancer. Median age was 60.5 years (range, 30-74). Self-reported patient races were White (82.1%), Black (10.7%), and Native American (7.1%). Self-identified Hispanic or Latina patients comprised 3.6% of the cohort. Twenty-two of 28 patients had progressive disease by six months [survival distribution function estimate = 0.214 (lower CI, 0.087; upper CI, 0.378)]. Of the six patients who achieved PFS6, one had cervical and five had endometrial cancer. Six patients had a mutation in the ARID1A gene and those patients achieved PFS6 at a rate of 66.7%. Conclusions: The study hypothesis was evaluated in a two-stage design, and the interim analysis occurred once 28 evaluable patients were enrolled. In order to move on to the second stage, at least seven patients needed to remain progression-free at six months, but only six did. Thus, the study was ended after the interim analysis. The combination of rucaparib and bevacizumab did not provide the expected clinical benefit in this cohort of patients, but may warrant further exploration in patients with ARID1A mutations. Clinical trial information: NCT03476798.

Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment.

The bottleneck in current vector-based cancer therapy is the targeted and controlled release of therapeutics in tumors. Exosomes are submicron-sized vesicles that are secreted by all cell types and are involved in communication and transportation of materials between cells. Analogous in size and function to synthetic nanoparticles, exosomes offer many advantages, rendering them the most promising candidates for targeted drug or gene delivery vehicles. Patient-specific customized therapeutic strategies can be engineered using exosomes derived from the patient's own healthy cells. Therefore, exosome-based cancer therapy has the potential to become an important part of personalized medicine. Interest in exosomes as carrier organelles is relatively recent. Knowledge about exosomal biology and its applications remains limited. The present review is an attempt to describe the current status of the application of exosomes to cancer therapy and the potential challenges associated with their use.

Background: Endometrial cancer is the most common gynecologic malignancy and incidence and mortality continue to increase. While active chemotherapy regimens are available, the median time to progression remains six to eight months and mortality in this setting is approaches 100%. Rapid progression and lack of response to systemic therapies are significant challenges in this disease and underscore the need for identification of molecular markers and targets of drug resistance. Alterations in non-coding micro-RNA (miRNA) have been shown to be necessary for cellular proliferation and differentiation in normal and malignant phenotypes. miRNA signatures unique to malignant, specifically treatment resistant cancers are described in many solid tumors; however, knowledge of these changes in resistant endometrial cancer is limited. Identification of molecular signatures unique to drug resistant endometrial cancer may inform novel therapeutic targets to predict and/or reverse resistance to chemotherapy. One source of tumor miRNA is in exosomes derived from tumor cells that transport tumor derived products including non-coding RNAs. They are readily identified in peripheral body fluids and are known to act at distant sites to facilitate tumor growth and metastasis. As such, exosomes are a potential source of tumor-specific genetic material that may characterize disease and predict drug response. Results: In characterized endometrial cancer cell lines, we determined chemo-sensitivity to platinum-based therapy. Exosomes were isolated and purified from the culture media and exosomal miRNA profiles were sequenced, aligned and cross-referenced with published datasets. Our preliminary data have identified a unique exosomal miRNA signature that differentiates chemotherapy sensitive and resistant endometrial cancer in vitro. Upregulation of oncomirs, miR155, miR98 and downregulation of tumor suppressor miRNAs, miR25, miR27a, miR200a were observed. Two unique miRNA candidates were also identified miR3125 and miR6068. The clinical expression of these candidate miRNAs was interrogated within the Kaplan Meier plotter RNAseq dataset and decreased overall survival was observed in samples exhibiting dysregulation of the candidate miRNA panel1. These results were confirmed in vitro with rtPCR. We have since isolated exosomes from the sera of 14 endometrial cancer patients with known clinical outcomes data. Seven patients exhibited rapid disease progression on standard chemotherapy while 7 demonstrated a complete clinical response of at least 6 months. The exosomal miRNA was isolated, quantified and sequencing is ongoing. Conclusions: Our data implicate a unique grouping of miRNAs in the endometrial cancer chemo-resistance. The clinical impact of these miRNAs remains unknown, but 5 are associated with a significant decrease in overall survival1. The ability to detect a unique miRNA profile in the body fluids of patients, provides an accessible resource for study before and during treatment. Such data could significantly impact treatment of endometrial cancer both as a predictive biomarker of response and source of novel therapeutic targets. The high rate of recurrence, inevitable development of a chemo-resistant disease and the clinical challenges associated with repeated tumor sampling, make exosomal miRNA a valuable candidate for exploration in this disease. Citation Format: Katherine M. Moxley. Exosomes in predicting response to chemotherapy in endometrial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1418.

Background: Ovarian cancer is the fifth leading cause of cancer death in the United States in large part because more than 85% of patients present with metastatic disease. The majority of these are epithelial of high-grade serous (HGSOC) histology where the 5-year overall survival remains poor despite advances in chemotherapy and improved understanding of molecular tumor biology. As a heterogeneous, p53-driven malignancy, HGSOC employs a variety of molecular and metabolomic changes that promote preferential tumor growth within the peritoneal cavity. The miliary spread patterns of ovarian cancers within the peritoneal cavity create distinct clinical challenges, particularly in the preoperative assessment of surgical resectability. Therefore, it is clinically imperative to develop better imaging modalities capable of accurately predicting location, volume, and consistency of tumor implants that will inform treatment planning without exposing the patient to unnecessary harm. To this end, recent research efforts have focused on identifying novel clinical and imaging biomarkers capable of predicting optimal surgical resection, tumor response, and disease specific outcomes. Unfortunately, the clinical utility of such markers in individualizing patient specific treatment strategies remains limited. In the absence of unique molecular biomarkers, the use of advanced quantitative imaging features that utilize novel computer-aided detection (CAD) algorithms and can train artificial intelligence platforms will improve the accuracy with which current imaging modalities predict surgical outcome in HGSOC. Results: Using an established imaging platform established at Tempus Labs, Inc. we evaluated preoperative images of women undergoing cytoreductive surgery for advanced epithelial ovarian cancer. The CT images of forty-five retrospectively collected cases, with complete clinical outcomes data, are undergoing analysis. Lesions have been identified, contoured from CT images, and approved by a trained radiologist. Over 2,000 quantitative imaging (radiomic) features will be extracted from these images, and using the Tempus proprietary imaging platform, feature selection will be performed to identify factors predictive of surgical resectability and compare them to those that do not correlate with surgical outcome. These selected features will be used to model surgical outcomes data. Conclusions: Prior research has demonstrated the utility of quantitative CT image analysis in predicting response to chemotherapy and platinum sensitivity. This same technology, however, has not been applied to the surgical management of women with advanced HGSOC. In this study, we assessed the utility of similar “radiomics algorithms” in order to establish a set of radiomic features that characterize tumors amenable to optimal (R0) surgical resection. The selected features identified in this retrospective training cohort are now be tested in a larger prospective cohort of metastatic HGSOC cancer patients. Citation Format: Paul A. DiSilvestro, Jessica DiSilvestro, Jonathan S. Ball, Stephen Yip, Anna Schwarzbach, Katherine M. Moxley. Analysis of advanced quantitative computed tomography imaging features in predicting the surgical resectability of advanced epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A12.

Background: Ovarian cancer is the fifth leading cause of cancer death in the United States, with an anticipated 13,000 deaths in the United States in 2017. High-grade serous (HGSOC) sub-type is both the most common and the most lethal histopathology. As more than 85% of patients present with metastatic disease, the 5-year overall survival remains dismal at only 30%. It is known that human cancers are initiated and maintained by self-renewing stem cells. Cancer stem cell related protein Doublecortin-like kinase 1 (DCLK1) is a major regulator of stemness and EMT, promoting drug resistance, tumor dormancy, progression, and metastasis in solid tumors. The molecular mechanisms of DCLK1 in tumorigenesis and drug resistance remain limited but DCLK1 expression is increased in cancer, especially in the drug-resistant setting. Results: Our lab has made the discovery that DCLK1 is overexpressed in HGSOC where it regulates tumor progression, tumor stemness, and EMT via noncoding RNA regulation of downstream oncogenic pathways. Our study involved assessment of DCLK1 expression in tissue culture and xenografts created from primary patient-derived cell lines (PDACs). Expression of the DCLK1 protein was assessed by immunoblot analysis in lysates of cell lines representing HGSOC and PDACs obtained from the ascites of patients at the University of Oklahoma at the time of diagnosis, prior to initiation of chemotherapy. FTE-187, FTE-188, and OSE cells were used as normal controls. Elevated levels of DCLK1 expression were observed in the panel of HGSOC cell lines and in PDAC lines. Our in vitro studies confirmed DCLK1 upregulation in the tissue and stroma of PDAC lines and our in vivo studies with PDAC xenografts revealed that siRNA knockdown of DCLK1 negatively regulated tumor suppressor miRNAs including mi-143/145, let-7a, and miR-200a-c resulting in downregulation of pluripotency, EMT, and proangiogenic markers including OCT4, SOX2, KLF4, NANOG, LIN28B, NOTCH, KRAS, and c-MYC. This was most pronounced in the setting of platinum resistance. For this, lysates from paired cells lines with known platinum-sensitive and platinum-resistant variants were assessed (Tyk-nu/Tyk-nu CPR and A2780/A2780.cp). An increase in DCLK1 expression was observed in both of the platinum-resistant lines compared to the platinum-sensitive lines. This was confirmed in PDACs where clinical platinum status correlated with DCLK1 expression, suggesting the role of DCLK1 in inherent platinum-resistant tumor clones. Conclusions: Our data implicate DCLK1 in ovarian cancer pathogenesis and platinum resistance and indicate that DCLK1 knockdown via may suppress malignant progression and resensitize tumors to platinum chemotherapy. These data could have a significant impact on future therapeutic strategies involving DCLK1 inhibitors in treating platinum-resistant patients. Given the high recurrence rate and inevitable development of platinum-resistant disease, such compounds have high potential to impact clinical outcomes in this lethal malignancy. Citation Format: Katherine M. Moxley, JiHee Ha, Daniel Andrade, Courtney Houchen, Danny Dhanasekaran. DCLK1 mediates tumor stemness and platinum resistance in high-grade serous epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A55.

6003 Background: Combination cediranib (C) and olaparib (O) improved progression-free survival (PFS) in patients (pts) with relapsed platinum (plat)-sensitive high-grade ovarian cancer (ovca) compared to O alone in a Phase 2 trial (NCT01116648). We conducted this randomized, open-label Phase 3 trial (NCT02446600) to assess whether combination C+O, or O alone, was superior to standard of care (SOC) plat-based therapy in relapsed plat-sensitive ovca. Methods: Eligible pts had recurrent plat-sensitive [ > 6-month plat-free interval (PFI)] high-grade serous or endometrioid, or BRCA-related, ovca. One prior non-plat therapy and unlimited prior plat-therapies were allowed; prior anti-angiogenics in the recurrent setting or prior PARP inhibitor were exclusions. Pts were randomized 1:1:1 to SOC (carboplatin/paclitaxel; carboplatin/gemcitabine; or carboplatin/liposomal doxorubicin), O (300mg twice daily), or C+O (C 30mg daily + O 200mg twice daily). Randomization was stratified by g BRCA status, PFI (6-12 vs > 12 months), and prior anti-angiogenic therapy. Target sample size was 549 pts; primary analysis occurred 2 years after the last pt enrolled. The primary endpoint was PFS. Type 1 error = 0.025 was controlled by a gatekeeping hierarchy that assessed C+O vs SOC, then O alone vs SOC, and finally C+O vs O. All maintenance therapy was prohibited. Results: Between 4FEB2016 and 13NOV2017, 565 pts enrolled (187 SOC, 189 O, 189 C+O), and 528 pts initiated treatment (166 SOC, 183 O, 179 C+O). 23.7% of patients had g BRCAmut. Median follow-up was 29.1 months. 53 pts on SOC initiated non-protocol therapy (predominantly PARP inhibitor maintenance) before disease progression. The hazard ratio (HR) for PFS was 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail) between C+O and SOC and 1.20 (95% CI 0.93-1.54) between O and SOC, with median PFS of 10.3, 8.2, and 10.4 months for SOC, O, and C+O, respectively. Response rates were 71.3% (SOC), 52.4% (O), and 69.4% (C+O). In gBRCA pts, HR for PFS was 0.55 (95% CI 0.73-1.30) for C+O vs SOC, and 0.63 (95% CI 0.37-1.07) for O vs SOC. In non-g BRCA pts, HR for these comparisons was 0.97 (95% CI 0.73-1.30) and 1.41 (1.07-1.86). No OS differences between arms were observed at 44% events. Pts receiving C+O (vs SOC) had more frequent Grade 3 or higher gastrointestinal (30.1% vs 8.4%), hypertension (31.7% vs 1.8%), and fatigue events (17.5% vs 1.8%). Conclusion: C+O demonstrated similar activity to SOC in relapsed plat-sensitive ovca but did not meet the primary endpoint of improved PFS. Clinical trial information: NCT02446600.

6087 Background: SAP (TAK-228, MLN0128) is a selective dual inhibitor of mammalian target of rapamycin complexes 1 and 2. In endometrial tumor xenograft models, SAP+PAC exhibited stronger antitumor efficacy than PAC alone. Methods: Female pts with histologic/cytologic diagnosis of endometrial cancer were randomized to receive SAP 4 mg by mouth (days [d] 2–4, 9–11, 16–18, 23–25) plus PAC 80 mg/m2 intravenously (d 1, 8, 15), or PAC alone, in 28-day cycles until unacceptable toxicity or disease progression. Randomization was stratified by histologic subtype, lines of prior chemotherapy (1 vs. 2), and prior taxane therapy. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR; ORR + stable disease), and safety. Additional treatment arms of SAP alone (weekly dosing) and SAP+TAK-117 were closed after futility analyses. Results: 180 pts were randomized to SAP+PAC (n=90) or PAC (n=90); 86 and 87 pts received SAP+PAC and PAC, respectively; 3 pts from each arm were ongoing on treatment at data cut (30 July 2019). Baseline characteristics were balanced between arms. After a median follow-up of 17.2 vs. 14.4 mos with SAP+PAC vs. PAC, median PFS was 5.6 mos vs. 3.7 mos (hazard ratio [HR] 0.82; 95% CI 0.58–1.15). In pts with endometrioid histology (n=116), median PFS was 5.7 mos with SAP+PAC vs 3.3 mos with PAC (HR 0.66; 95% CI 0.43–1.03). In pts with nonendometrioid histology (n=64), median PFS was 3.6 mos with SAP+PAC vs. 5.4 mos with PAC (HR 1.09; 95% CI 0.62–1.90). Median OS was 13.7 mos with SAP+PAC vs. 14.6 mos with PAC (HR 1.01; 95% CI 0.67–1.53). Confirmed ORR was 24% with SAP+PAC vs. 18% with PAC (endometrioid, 23% vs. 16%; nonendometrioid, 28% vs. 22%); CBR was 80% vs. 58% (endometrioid, 84% vs. 55%; nonendometrioid, 72% vs. 63%). Median number of cycles received was 5 (range 1–23) with SAP+PAC and 4 (range 1–37) with PAC. Rates of grade ≥3 treatment-emergent adverse events (TEAEs) were 90% with SAP+PAC vs. 54% with PAC; the most common included anemia (21% vs.12%), neutropenia (12% vs. 3%), fatigue (12% vs. 5%), hypophosphatemia (12% vs. 1%), and pulmonary embolism (11% vs. 3%). Conclusions: Median PFS was longer with SAP+PAC vs. PAC in pts with endometrial cancer but did not reach statistical significance. PFS was particularly longer in the endometrioid subtype but again was not significant, and further studies are warranted. Incidence of grade ≥3 TEAEs was higher with SAP+PAC vs. PAC, but SAP+PAC toxicity was manageable, with no new safety signals. Clinical trial information: NCT02725268.

Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein α-subunit Gαi2 disrupted LPA-stimulated aerobic glycolysis. LPA stimulated a pseudohypoxic response via Rac-mediated activation of NADPH oxidase and generation of reactive oxygen species, resulting in activation of HIF1α. HIF1α in turn induced expression of glucose transporter-1 and the glycolytic enzyme hexokinase-2 (HKII). Treatment of mice bearing ovarian cancer xenografts with an HKII inhibitor, 3-bromopyruvate, attenuated tumor growth and conferred a concomitant survival advantage. These studies reveal a critical role for LPA in metabolic reprogramming of ovarian cancer cells and identify this node as a promising therapeutic target in ovarian cancer. Significance: These findings establish LPA as a potential therapeutic target in ovarian cancer, revealing its role in the activation of HIF1α-mediated metabolic reprogramming in this disease. Cancer Res; 78(8); 1923–34. ©2018 AACR.

Exosomes have great potential to serve as a source of diagnostic and prognostic biomarkers for endometrial cancer (EC). Urine-derived exosomes from patients with EC and patients with symptoms of EC, but without established EC, were used to evaluate a unique miRNA expression profile. Of the 84 miRNA studied, 57 were amplified in qPCR, suggesting the differential packaging of miRNA in exosomes. Further, hsa-miR-200c-3p was identified to be enriched the most. Various bioinformatics and in silico tools were used to evaluate the biological significance of hsa-miR-200c-3p in EC. We conclude that differential miRNA in exosomes can be utilized for discovery of biomarker signatures and EC diagnosis; hsa-miR-200c-3p is one such candidate. Urine-derived exosomes pave the way for the development of non-invasive biomarkers.

Background The polycomb group protein, BMI1 plays important roles in chromatin modification, stem cell function, DNA damage repair and mitochondrial bioenergetics. Such diverse cellular functions of BMI1 could be, in part, due to post-translational modifications, especially phosphorylation. To date, AKT has been reported as a kinase that by site specific phosphorylation of BMI1 modulates its oncogenic functions. Methods Immunoprecipitation in conjunction with kinase assay and mass spectrometry was used to determine association with and site specific phosphorylation of BMI1 by CK2α. Functional implications of the BMI1/CK2α axis was examined in cancer cells utilizing siRNA and exogenous gene expression followed by biochemical and phenotypic studies. Correlations between expression of CK2α and BMI1 were determined from cell lines and formalin fixed paraffin embedded tissues representing the normal fallopian tube epithelium and high grade serous ovarian cancer samples. Results Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. In ovarian cancer cell lines, expression of CK2α correlated with the phospho-species, as well as basal BMI1 levels. Preventing phosphorylation of BMI1 at Serine 110 significantly decreased half-life and stability of the protein. Additionally, re-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function. Clinically, compared to normal fallopian tube epithelial tissues, the expression of both BMI1 and CK2α were significantly higher in tumor tissues obtained from high-grade serous ovarian cancer patients. Among tumor samples, the expression of BMI1 and CK2α positively correlated (Spearman coefficient = 0.62, P = 0.0021) with each other. Conclusion Taken together, our findings establish an important regulatory role of CK2α on BMI1 phosphorylation and stability and implicate the CK2α/BMI1 axis in ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0617-8) contains supplementary material, which is available to authorized users.

BACKGROUND: The 5-year survival rate of patients with recurrent epithelial ovarian cancer is only 30%, in part due to relapse and resistance to first-line platinum-based chemotherapy. Even with marked progress toward understanding ovarian cancer biology, the translation of research findings into new therapies is still an enormous barrier to progress. Recent data suggests a 90% failure rate for new oncology drugs in the clinic. Development and preclinical testing of new cancer therapies has been limited by the availability of clinically relevant models that recapitulate the molecular and phenotypic characteristics of primary ovarian cancers. To overcome this barrier, we have initiated collaborative project between Stephenson Cancer Center (SCC) and Oklahoma Medical Research Foundation (OMRF) with the goal to generate a biobank of patient-derived xenograft (PDX) models derived directly from ovarian cancer patients undergoing therapy. RESULTS: PDX tumor models are generated in the Patient-Derived Xenograft and Preclinical Therapeutics (PDX-PCT) Core at OMRF and used to improve preclinical evaluation of new drugs towards more personalized medicine. We have collected blood samples and tumor tissues from consenting patients having primary debulking surgery at Stephenson Cancer Center since 2015 (>140 unique patients). Fresh tumor tissue is minced into small tumor chunks (~2 mm) and implanted into immunocompromised mice. PDXs are expanded for 3-4 passages and characterized based on tumor type, histology and molecular characteristics. Immunohistochemical and molecular analysis showed that histology of the original patient tumors as well as the expression of commonly used markers for high-grade serous ovarian cancer such as cytokeratin, PAX8 and WT1 are perfectly maintained in the derivative PDX lines. Genotyping of patients' tumors and their corresponding PDXs using Illumina's Exome Array revealed that single nucleotide polymorphism (SNP) profile found in the original tumors is perfectly maintained in PDX lines. One of the PDX limitations is that human tumor stromal and immune cells are being replaced with mouse equivalents upon in vivo propagation of PDXs, which negatively affects quality of genomic or proteomic analyses. To overcome this challenge, we optimized a method to deplete mouse cells from PDX tumors by magnetic cells separation. Our data showed that ovarian cancer PDXs contain around 28-54% of human tumor cells, where the rest are mouse cells. We also optimized protocols to utilize pure population of human tumor cells isolated from PDXs to transduce these with lentiviral vectors expressing GFP and/or luciferase to generate luciferized PDXs. Luciferized ovarian PDXs are excellent models used for non-invasive orthotopic tumor growth and drug response monitoring. CONCLUSIONS: Collection of our PDXs illustrates heterogeneity and diversity of human ovarian tumors. However, each PDX maintains essential molecular features of the original patients' tumor. Our goal is to generate clinically faithful ovarian tumor models that will provide a platform to learn more about cancer biology and to screen these for new better therapies. Citation Format: Magdalena Cybula, Katherine Moxley, Lin Wang, Luyao Wang, Magdalena Bieniasz. UTILIZATION OF PATIENT-DERIVED TUMOR XENOGRAFT (PDX) MODELS IN ONCOLOGY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-021.

The article examines current treatment options in patients with endometrial carcinoma, the role of drug resistance, and the rationale for the use of epothilones in treating this disease., Adenocarcinoma of the endometrium represents the most common gynecologic malignancy in developed countries. Although early-stage cancers are effectively treated surgically, commonly without adjuvant therapy, the treatment of high-risk and advanced disease is more complex. Chemotherapy has evolved into an important modality in high-risk early-stage and advanced-stage disease, and in recurrent endometrial cancer. Taxane-based therapy consistently demonstrates the highest response rates in the first-line and salvage settings of endometrial cancer. Unfortunately, response to chemotherapy is modest and strategies are needed to predict chemotherapy-responsive and chemotherapy-resistant populations. Chemotherapy resistance mediated by overexpression of drug efflux pump proteins and mutations in β-tubulin isoforms in both primary and recurrent disease represent unique treatment challenges and highlight the need for new agents that are less susceptible to these known resistance pathways. Epothilone B analogs are novel cytotoxic agents with activity in solid tumors, including advanced/recurrent endometrial carcinoma, and may have unique properties that can overcome resistance in some settings. These agents alone and in combination represent a new therapeutic opportunity in endometrial carcinoma.

5589Background: Protocol GOG-258 randomized Cis-RT+CP or CP for 6 cycles to patients (pts) with stage III/IVA endometrial carcinoma (Matei et al, ASCO 2017). Recurrence-free survival was the primar...

5505Background: We conducted a phase III trial to determine whether adjuvant chemotherapy with gemcitabine-docetaxel followed by doxorubicin improves survival compared to observation in women with ...

5505 Background: Patients with stage III/IVA uterine cancer (UC) carry high risk of systemic and local recurrence. Chemotherapy was shown to reduce systemic recurrence, however the risk of local failure remains high. Methods: The primary endpoint of this open label, randomized phase III trial was to determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for 4 cycles (C-RT, experimental arm) reduces the rate of recurrence or death (i.e., increases recurrence-free survival, RFS) when compared to carboplatin and paclitaxel for 6 cycles (CT, control arm) in patients with stages III-IVA ( grd 3 toxicity events in the C-RT arm and 227 (63%) in the CT arm. The most common > grd 3 events were myelosupression (40% vs. 52%), gastrointestinal (13% vs. 4%), metabolic (15% vs. 19%), neurological (7% vs. 6%), infectious (4% vs. 5%). Treatment hazard ratio for RFS was 0.9 (C-RT vs. CT; CI 0.74 to 1.10). C-RT reduced the incidence of vaginal (3% vs. 7%, HR = 0.36, CI 0.16 to 0.82), pelvic and paraaortic recurrences (10% vs. 21%, HR=0.43, CI 02.8 to 0.66) compared to CT, but distant recurrences were more common with C-RT vs. CT (28% vs. 21%, HR 1.36, CI 1 to 1.86). The analysis is premature for OS comparison. Conclusions: Although C-RT reduced the rate of local recurrence compared to CT; the combined modality regimen did not increase RFS in optimally debulked, stage III/IVA UC. Clinical trial information: NCT00942357.

Purpose Women with abnormal cervical cancer screening results are referred to colposcopy and biopsy for diagnosis of cervical cancer precursors (high-grade squamous intraepithelial lesions [HSILs]). Colposcopy with a single biopsy can miss identification of HSILs. No systematic study has quantified the improved detection of HSIL by taking multiple lesion-directed biopsies. Methods The Biopsy Study was an observational study of 690 women referred to colposcopy after abnormal cervical cancer screening results. Up to four directed biopsies were taken from distinct acetowhite lesions and ranked by colposcopic impression. A nondirected biopsy of a normal-appearing area was added if fewer than four directed biopsies were taken. HSIL identified by any biopsy was the reference standard of disease used to evaluate the incremental yield and sensitivity of multiple biopsies. Results In the overall population, sensitivities for detecting HSIL increased from 60.6% (95% CI, 54.8% to 66.6%) from a single biopsy to 85.6% (95% CI, 80.3% to 90.2%) after two biopsies and to 95.6% (95% CI, 91.3% to 99.2%) after three biopsies. A significant increase in sensitivity of multiple biopsies was observed in all subgroups. The highest increase in yield of HSIL was observed for women with a high-grade colposcopic impression, HSIL cytology, and human papillomavirus (HPV) type 16 positivity. Only 2% of all HSILs diagnosed in the participants were detected by biopsies of normal-appearing transformation zone. Conclusion Collection of additional lesion-directed biopsies during colposcopy increased detection of histologic HSIL, regardless of patient characteristics. Taking additional biopsies when multiple lesions are present should become the standard practice of colposcopic biopsy.

Objective This study aims to assess the role of polymorphisms in DNA repair genes, excision repair cross-complementation group 1 ( ERCC1 ) and methyl-methanesulfonate sensitivity 19 ( MMS19 ), in tumor response to platinum-based chemotherapy and survival in advanced epithelial ovarian cancer (EOC). Methods Single nucleotide polymorphism (SNP) analysis was performed on the paraffin-embedded tumor tissue of women with advanced EOC, treated with platinum-based chemotherapy at the University of Oklahoma Health Sciences Center. Polymorphisms from two ERCC1 (codon-118 and C8092A) and three MMS19 (rs2211243, rs2236575 and rs872106) gene loci were evaluated by real time PCR Allelic Discrimination Assay. Results Genotyping was performed in 107 patients, 45 platinum-sensitive and 62 platinum-resistant. ERCC1 , codon-118 and C8092A genotyping was evaluable in 98 and 106 patients respectively and in all 107 patients for MMS19 polymorphisms. No differences were observed in genotype between platinum-sensitive and platinum-resistant patients. Polymorphisms in the ERCC1 , codon-118 and MMS19 genes did not correlate with overall survival (OS), although a trend toward improved progression free survival (PFS) was observed in patients expressing the minor (GG) alleles of the rs872106 MMS19 gene. Women homozygous for the ERCC1 -C8092A minor (AA) alleles had a significant increase in PFS compared to AC and CC patients and both AA and AC genotypes conferred improved survival over the major (CC) genotype. Conclusions Polymorphisms in ERCC1 , codon-118 and MMS19 genes are not associated with clinical response to platinum or survival. The ERCC1 -C8092A genotypes containing an "A" allele were associated with significant improvement in PFS and OS strengthening the value of this specific genotype in survival.

5524 Background: To assess if PET-CT improves accuracy of CT to detect lymph node (LN) metastasis in high risk endometrial cancer. Methods: This was a prospective HIPAA compliant ACRIN/GOG multicen...

5594 Background: Angiogenesis has a role in endometrial cancer (EC) progression and prognosis. Single agent bevacizumab had a response rate (RR) of 13% and 6 month progression-free survival of 40% ...

Background: TP53 is commonly mutated in ovarian cancer. As potential agents targeting TP53 mutant or wt are under development, the efficiency and accuracy for determination of TP53 mutations in a clinical trial was evaluated. Methods: Eligible patients, including relapsed, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer, underwent pre-screening for a clinical trial with MK1775, eligibility for which was determined by the presence of functional TP53 mutations (Brana I et al, ASCO 2013). Single base substitution and single base deletion mutations in exons 2 - 11 and the flanking splice junction in the TP53 gene were analyzed using AmpliChip p53 Assay (Roche Molecular Diagnostics, California) on archival tumor specimens. Results: Seventy-five women were screened for eligibility based on TP53; 43 had TP53 mutations, 27 were TP53 wild-type (wt), and 5 undetermined (Table 1). No clustering of mutations to define hot spots was evident. The most commonly mutated region was exon 5 (11 mutations). Missense mutations were the most common mutation type (69.7%); although, nonsense (14 %), splice (14 %), and frame shift mutations (2.3%) were also observed (Table 1). Most of the missense mutations were in exons 5 to 8 (90%). The mean turnaround time from sample reception to final TP53 status report was 3 days (range 1:14). Conclusions: The TP53 mutational status has been successfully determined in 93.3% of patients with a short turnaround time, supporting the feasibility of TP53 determination in the clinical setting. In our patient population, 57.3% had a TP53 mutation. Potential geographic differences in the incidence TP53 mutations cannot be evaluated due to the limited sample size; this hypothesis should be further evaluated in a larger patient population Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B181. Citation Format: Irene Brana, Kathleen Moore, Stephen Welch, Ronnie Shapira-Frommer, Darlene Gibbon, Hal Hirte, Saul Rivkin, Robert Coleman, Gerry Prendergast, Katherine M. Moxley, Ying-Ming Jou, Michelle Marinucci, Tomoko Freshwater, Sharon McCarthy, Mark Lee Anthony, Shelonitda Rose, Amit M. Oza. TP53 mutation screening in patients with recurrent platinum-sensitive ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B181.

Introduction: Cytology-based screening for and treatment of cervical precancers has led to substantial reduction of cervical cancer incidence and mortality worldwide. Current screening approaches have limited accuracy, however, and lead to misclassification of cervical precancer at the levels of primary screening, colposcopic evaluation, and histological evaluation. We designed the Biopsy Study to systematically evaluate the extent of misclassification of cervical precancer at colposcopy. Methods: Previously-untreated women referred to the University of Oklahoma colposcopy clinic for abnormal screening results were enrolled. Before colposcopy, a specimen was taken for liquid-based cytology, HPV genotyping, and biomarker studies. During colposcopy, a digital image of the cervix was taken and annotated for observed lesions and biopsy sites. Up to four colposcopically directed biopsies were taken from distinct lesions; if less than four targeted biopsies were obtained, a random biopsy was added. All biopsies were ranked by severity based on visual impression and evaluated individually in histology. Three cervical cancer screening tests, Pap cytology, HPV DNA testing, and p16/ki67 cytology, were evaluated against disease endpoints based on the most severely appearing biopsy (representing the current clinical standard) and based on the worst histology result from all four biopsies. Results: To date, more than 450 women have been enrolled in the study; 86% of women had at least three, and 64% had four biopsies taken. For 377 women, a histological diagnosis was available. Forty-one of 377 women (10.8%) had CIN3, 119 (31.6%) had CIN2, 82 (35.3%) had CIN1, and 84 (22.3%) had benign changes or normal results as worst histological result. In 70.7% of women, the precancer was detected in the first biopsy, in 22.0% it was found at the second biopsy and in 7.3% it was detected in the third or fourth biopsies. Cervical cancer screening tests were evaluated in a subset of 241 women. The specificity of HPV DNA, Pap cytology, and p16/ki67 for the detection of CIN2+ increased by 6%, 7.5%, and 11.8%, respectively when the improved gold standard was applied. Meanwhile, the sensitivity of all screening tests was not reduced. Discussion: Current colposcopy-biopsy protocols have limited sensitivity in detecting prevalent cervical precancer. In our study, we quantified the incremental benefit of taking multiple biopsies to detect cervical precancer. In the interim analysis, adding a second targeted biopsy improved disease detection by over 20%. The improved sensitivity of colposcopy resulted in decreased misclassification of cervical disease and a more accurate evaluation of cervical cancer screening tests. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3189. doi:10.1158/1538-7445.AM2011-3189

Erratum to “Induction of death receptor ligand-mediated apoptosis in epithelial ovarian carcinoma: The search for sensitizing agents” [Gynecol. Oncol. 115 (2009) 438–442] Katherine Marie Moxley , Shylet Chengedza , Doris Mangiaracina Benbrook a,b,⁎ a Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA b Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA