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Purpose: Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations., Methods: We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression., Results: DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel., Conclusions: Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy., Competing Interests: Declaration of Competing Interest Dr. Arend participates in Data Safety Monitoring/Advisory Boards (DSMB) for Astra Zeneca, Caris Life Sciences, Clovis, Merck, Seagen, Sutro, Glaxo Smith Kline, VBL Therapeutics. Dr. Matulonis reports relationships with the Med Learning Group and participates in DSMB for: Allarity, NextCure, Alkermes, Symphogen, Trillium, Agenus, Immunogen, Novartis, Boerhinger Ingelheim, Rivkin Foundation, Ovarian Cancer Research Alliance, Clearity Foundation, and Morphosys. Dr. Kagey and Dr. Sirard are employed by and own stock in Leap Therapeutics. Dr. Hamilton reports consulting or advisory for: Pfizer (Inst), Genentech/Roche (Inst), Lilly (Inst), Puma Biotechnology (Inst), Daiichi Sankyo (Inst), Mersana (Inst), Boehringer Ingelheim (Inst), AstraZeneca (Inst), Novartis (Inst), Silverback Therapeutics (Inst), Black Diamond (Inst). Dr. Sachdev participates in DSMB for Pfizer, Immunomedics, AstraZeneca, Tempus, and Ipsen; discloses stock/options in Biosplice Therapeutics; and is employed by Biosplice Therapeutics. Dr. Duska reports royalties from JB Learning, consulting fees from UpToDate, serves as an expert law review, and participates in DSMB for Regeneron and Inovio. She reports leadership in SGO, ASCO, the NCI, and the British Journal of OBGYN. Dr. ElNaggar reports employment and stock/options with Natera. Ms. Liu and Ms. Piper were employed by LEAP Therapeutics during manuscript preparation. Dr. O'Malley participates in DSMB for: AbbVie, AdaptImmune, Agenus, Arquer Diagnostics, Arcus Biosciences, AstraZeneca, Atossa Therapeutics, Boston Biomedical, Cardiff Oncology, Celcuity, Clovis Oncology, Corcept Therapeutics, Duality Biom, Eisai, Elevar, Exelixis, Genentech, Genelux, GlaxoSmithKline, GOG Foundation, Hoffman-LaRoche, ImmunoGen, Imvax, InterVenn, INXMED, IOVANCE Biotherapeutics, Janssen, Laekna, Leap Therapeutics, Luzsana Biotechnology, Merck, Merck Sharp & Dohme, Mersana, Myriad, Novartis, NovoCure, OncoC4, Onconova, Regeneron, RepImmune, R Pharm, Roche, SeaGen, Sorrento, Sutro, Tarveda, Toray, Trillium, Umoja, Verastem, VBL Therapeutics, Vincerx, Xencor, Zentalis. All other authors report no disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC., Methods: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m 2 on days 1 and 8 of a 21 day cycle, with or without paz 800 mg QD, stratified by platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS., Results: 148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p < 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p < 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%)., Conclusions: The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab., Competing Interests: Declaration of competing interest Dr. Duska has served on advisory boards for Astra Zeneca, Genentech, Merck, Tesaro, Morphotek. She serves on the DSMC for an Inovio trial. She has received research funding from GSK/Novartis (current trial) and Merck. Her instition has received research funding from multiple pharmaceutical companies. Dr. Secord reports research funding from pharmaceutical companies outside the submitted work; and a grant from the National Cancer Trial Network outside the submitted work. She also reports honoraria/advisory boards from Alexion, Aravive, Astex Pharmaceuticals Inc., Astra Zeneca, Clovis, Janssen/Johnson & Johnson, Merck, Mersana, Myriad, Oncoquest, Roche/Genentech, and Tesaro outside of the submitted work. Dr. Moore has served on advisory boards for Astra Zeneca, Advaxis, Clovis, Immunogen, Tesaro, Genentech/Roche, Janssen, Pfizer, Merck, Aravive, Samumed, Oncomed, VBL Therapeutics and Eisai. She serves on steering committees (not compensated) for Astra Zeneca, Tesaro, VBL Therapeutics. She has received research funding from PTC Therapeutics, Lilly, Genentech/Roche and Clovis. Dr. Brown reports personal fees from Tesaro, personal fees from Clovis, from Tempus, personal fees from AstraZeneca, personal fees from Genentech, personal fees from Olympus, personal fees from Advanced Surgical Concepts, personal fees from OncLive, outside the submitted work. The following authors report no financial interests: Dr. McGuire, Dr. Petroni, Ms Varhegyi, Dr. Barroilhet, Dr. Jelovac, Dr. Darus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Transfusion related immune modulation associated with red blood cell (RBC) transfusion is thought to result in decreased cancer survival. Results in epithelial ovarian cancer (EOC) have been mixed however most suggest worse oncologic outcomes in patients who were transfused at the time of debulking surgery. The impact of restrictive transfusion strategies on this patient population is currently not known., Methods: We conducted a retrospective study of women with EOC. The study population was divided into two groups based on whether they were transfused RBCs during the peri-operative period or not. Clinical characteristics and prognosticators were compared between groups. Overall survival was compared between groups based on transfusion status and other known prognostic factors. Cox proportional hazard modeling was used to examine the association between the prognostic factors and the study endpoint., Results: Sixty-six percent of women were transfused. Transfusion was associated with CA125, the use of neoadjuvant chemotherapy (NACT), surgical blood loss, and anemia. The mean pre-transfusion Hgb was 7.8 + 0.6 g/dL and 94% had a hemoglobin level greater than the transfusion threshold of 7 g/dL. RBC transfusion, suboptimal debulking, anemia, and NACT were associated with decreased survival. Only RBC transfusion and suboptimal debulking status remained significant in a multivariate model., Conclusions: Peri-operative RBC transfusion compromises survival in ovarian cancer supporting the need to minimize the use of transfusion at the time of debulking surgery. Adherence to evidence-based transfusion guidelines offers an opportunity to reduce transfusion rates in this population with a resulting positive influence on survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: For women who have completed childbearing, the treatment of choice for adenocarcinoma in situ (ACIS) of the cervix is hysterectomy. In women who desire future fertility, however, conservative therapy is an acceptable alternative. In this study we compare the outcomes for young women who underwent loop conization or were treated with cold knife conization., Methods: We performed a retrospective analysis in 112 patients with ACIS, age 30 or younger, treated with cold knife conization or loop conization between 1998 and 2010. Decision to perform office loop conization was based on the size of the cervix and the colposcopic lesion. Main outcomes were negative margins after the procedure and recurrence of ACIS., Results: Fifty-eight patients (52%) were treated with cold knife conization and 54 (48%) underwent loop conization. The odds ratio for cold knife conization to achieve negative cone margins compared with loop conization was 1.4 (95% CI 0.6-3.5). We observed no difference in residual or recurrent ACIS between patients treated with loop conization versus cold knife conization., Conclusions: In select young patients who desire future fertility, loop conization and cold knife conization have equivalent rates of negative margins and negative follow-up. For optimal results, patients must have a lesion which can be removed in one pass of a loop, confirmed by expert colposcopy. Loop excision should be considered the treatment of choice in this specific group of patients., (Copyright © 2011. Published by Elsevier Inc.)