Abstracts of the 12th International Charité Mayo Conference on “Global Perspectives and Future Directions in Women’s Cancer”

FINAL OVERALL SURVIVAL AND LONG-TERM SAFETY IN THE ENGOT-OV16/NOVA PHASE 3 TRIAL OF NIRAPARIB IN PATIENTS WITH RECURRENT OVARIAN CANCER

FREDERIK MARMɹ, URSULA MATULONIS^2,3, JØRN HERRSTEDT^4,5, AMIT OZA⁶, SVEN MAHNER⁷, ANDRÉS REDONDO⁸, DOMINIQUE BERTON^9,10, JONATHAN S. BEREK¹¹, CHARLOTTE A. HASLUND¹², ANTONIO GONZÁLEZ-MARTÍN^13,14,15, STÉPHANIE BECOURT¹⁶, ANNA V. TINKER¹⁷, JONATHAN LEDERMANN^18,19, BENEDICT BENIGNO²⁰, GABRIEL LINDAHL²¹, NICOLETTA COLOMBO22, IZABELA A. MALINOWSKA²³, WENLEI LIU²³, MICHAEL H.A. SCHMITZ²⁴, BRADLEY J. MONK²⁵ and MANSOOR R. MIRZA^26,27

¹Medical Faculty Mannheim, Heidelberg University, University Hospital Mannheim, Germany;

²Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S.A.;

³Harvard Medical School, Boston, MA, U.S.A.;

⁴Department of Clinical Oncology and Palliative Care, Zealand University Hospital Roskilde, Roskilde, Denmark;

⁵Næstved University of Copenhagen, Copenhagen, Denmark; 6Division of Medical Oncology and Hematology, Cancer Clinical Research Unit at Princess Margaret Cancer Centre, Ontario, Toronto, Canada;

⁷Department of Obstetrics and Gynecology, University Hospital LMU Munich, Germany;

⁸Hospital Universitario La Paz - IdiPAZ, Madrid, Spain;

⁹Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), France;

¹⁰Institut de Cancerologie de l’Ouest, Centre René Gauducheau, Saint-Herblain, France;

¹¹Stanford Women’s Cancer Center, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, U.S.A.;

¹²Department of Oncology, Aalborg University Hospital, Aalborg, Denmark;

¹³Medical Oncology Department, Clínica Universidad de Navarra, Madrid, Spain;

¹⁴Program in Solid Tumours, CIMA, Pamplona, Spain;

¹⁵Grupo Español de Investigación en Cáncer de Ovario (GEICO), Pamplona, Spain;

¹⁶Department of Gynecological Oncology, Oscar Lambert Center, Lille, France;

¹⁷BC Cancer – Vancouver, Department of Medicine, University of British Columbia, Vancouver, Canada;

¹⁸Department of Oncology, UCL Cancer Institute, London, U.K.;

¹⁹UCL Hospitals, London, U.K.;

²⁰Ovarian Cancer Institute, University Gynecologic Oncology, Atlanta, GA, U.S.A.;

²¹Gynecology Section, Department of Oncology, University Hospital Linköping, Linköping, Sweden;

²²Department of Medicine and Surgery, University of Milano-Bicocca, Gynecology Oncology Program European Institute of Oncology, Milan, Italy;

²³GSK, Waltham, MA, U.S.A.;

²⁴GSK, Baar, Switzerland;

²⁵Division of Gynecologic Oncology, HonorHealth Research Institute, University of Arizona College of Medicine, Creighton University School of Medicine Phoenix, AZ, U.S.A.;

²⁶Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;

²⁷Nordic Society of Gynaecological Oncology-Clinical Trial Unit, Copenhagen, Denmark

Background/Aim: Primary results from the ENGOT-OV16/NOVA study showed that niraparib maintenance therapy significantly prolonged progression-free survival in patients with platinum-sensitive recurrent ovarian cancer (PSROC) regardless of germline BRCA DNA repair-associated gene mutation (gBRCAm) or homologous recombination deficiency (HRD) biomarker status. Here we report updated final overall survival (OS) and long-term safety results. Patients and Methods: NOVA was a randomized, double-blind, placebo-controlled, phase 3 trial. Patients with PSROC were enrolled into independent gBRCAm and non-gBRCAm cohorts. Patients were randomized 2:1 to 300 mg niraparib or placebo once daily. Missing survival data for 92 patients were retrieved for the updated analysis (data cutoff: March 31, 2021). Final OS was evaluated in both cohorts and by non-gBRCAm HRD status. Results: A total of 553 patients were randomized. Median follow-up at data cutoff was >75 months across both cohorts. Survival status was available for 97.6% of patients. Overall OS maturity was 77.9%. Median OS for patients treated with niraparib vs. placebo was 40.9 vs. 38.1 months (hazard ratio=0.85; 95% CI=0.61-1.20) for the gBRCAm cohort and 31.0 vs. 34.8 months (hazard ratio=1.06; 95% CI=0.81-1.37) for the non-gBRCAm cohort. For the non-gBRCAm cohort, median OS for patients treated with niraparib vs. placebo by HRD status was 35.6 vs. 41.4 months (hazard ratio=1.29, 95% CI=0.85-1.95) for patients with HRD, 27.9 months for both (hazard ratio=0.93, 95% CI=0.61-1.41) for homologous recombination-proficient patients, and 29.8 vs. 20.2 months (hazard ratio=0.62, 95% CI=0.29-1.36) for patients with unknown HRD status. No new safety signals were detected. Myelodysplastic syndromes/acute myeloid leukemia incidence rates for niraparib vs. placebo were 7.4% vs. 3.1% in the gBRCAm and 1.7% vs. 0.9% in the non-gBRCAm cohorts. Conclusion: NOVA was not powered to show an OS difference between arms, although the OS hazard ratio numerically favored niraparib in the gBRCAm cohort. No new safety signals were observed with long-term follow-up.

Key Words: Ovarian cancer, niraparib, maintenance therapy.

PRIMA/ENGOT-OV26/GOG-3012 STUDY: UPDATED LONG-TERM PROGRESSION-FREE SURVIVAL AND SAFETY

FLORIAN HEITZ^1,2, ANTONIO GONZÁLEZ-MARTÍN³, BHAVANA POTHURI⁴, IGNACE VERGOTE⁵, WHITNEY GRAYBILL⁶, MANSOOR R. MIRZA⁷, COLLEEN MCCORMICK⁸, DOMENICA LORUSSO⁹, GILLES FREYER¹⁰, FLOOR BACKES¹¹, KLAUS BAUMANN¹², ANDRÉS REDONDO¹³, RICHARD G. MOORE¹⁴, CHRISTOF VULSTEKE^15,16, ROISIN E. O’CEARBHAILL^17,18, IZABELA A. MALINOWSKA¹⁹, LUDA SHTESSEL¹⁹, NATALIE COMPTON¹⁹ and BRADLEY J. MONK²⁰

¹AGO Study Group and the Department for Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte, Essen, Germany;

²Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Gynaecology, Berlin, Germany;

³Grupo Español de Investigación en Cáncer de Ovario (GEICO), Medical Oncology Department, Clínica Universidad de Navarra, Madrid, Spain;

⁴Gynecologic Oncology Group (GOG), Department of Obstetrics/Gynecology, Perlmutter Cancer Center, NYU Langone Health, New York, NY, U.S.A.;

⁵Belgium and Luxembourg Gynaecological Oncology Group (BGOG), Department of Gynaecology and Obstetrics, Division of Gynaecologic Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium;

⁶GOG, Gynecologic Oncology, Medical University of South Carolina, Charleston, SC, U.S.A.;

⁷Nordic Society of Gynaecological Oncology (NSGO), Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark;

⁸GOG, Legacy Medical Group Gynecologic Oncology, Portland, OR, U.S.A.;

⁹Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Fondazione Policlinico Gemelli IRCCS National Cancer Institute of Milan, Milan, Italy;

¹⁰Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), HCL Cancer Institute Department of Medical Oncological, Lyon University, Lyon, France;

¹¹Division of Gynecologic Oncology, Ohio State University, Columbus, OH, U.S.A.;

¹²Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), Department of Gynecology and Obstetrics, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany;

¹³GEICO, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain;

¹⁴USOR, Division of Gynecologic Oncology, Wilmot Cancer Institute, Department of Obstetrics and Gynecology, University of Rochester, Rochester, NY, U.S.A.;

¹⁵BGOG, Department of Medical Oncology and Hematology, AZ Maria Middelares, Gent, Belgium;

¹⁶Department of Molecular Imaging, Pathology, Radiotherapy and Oncology, Center for Oncological Research, Antwerp University, Antwerp, Belgium;

¹⁷GOG, Gynecologic Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, U.S.A;

¹⁸Department of Medicine, Weill Cornell Medical College, New York, NY, U.S.A;

¹⁹GSK, Middlesex, U.K.;

²⁰Division of Gynecologic Oncology, University of Arizona College of Medicine, Phoenix Creighton University, Phoenix, AZ, U.S.A.

Background/Aim: Niraparib showed progression-free survival (PFS) benefit as first-line maintenance therapy in the primary analysis of the PRIMA study (data cut-off: 17th May 2019) regardless of biomarker status. Here we report updated long-term efficacy and safety data from the double-blind, placebo-controlled, phase 3 PRIMA study. Patients and Methods: Patients newly diagnosed with advanced ovarian cancer with complete or partial response to first-line platinum-based chemotherapy (CT) received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line CT regimen (complete/partial response), receipt of neoadjuvant CT (yes/no), and homologous recombination deficiency status [deficient (HRd) vs. proficient (HRp)/not determined]. Updated (ad hoc) PFS data (as of 17th November 2021) by investigator assessment are presented. Results: Of 733 randomized patients (niraparib, 487; placebo, 246), 51% were HRd (niraparib, 247; placebo, 126), and 34% were HRp (niraparib, 169; placebo, 80). Median follow-up for PFS was 3.5 years. Niraparib-treated patients continued to have a PFS benefit vs. those treated with placebo. Investigator-assessed PFS for patients treated with niraparib vs. placebo was 24.5 vs. 11.2 months [hazard ratio=0.52; 95% confidence interval (CI)=0.40-0.68] for HRd patients, 13.8 vs. 8.2 months (hazard ratio=0.66; 95% CI=0.56-0.79) for the overall population, and 8.4 vs. 5.4 months (hazard ratio=0.65; 95% CI=0.49-0.87) for HRp patients; results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4 years than placebo-treated patients (HRd: 38% vs. 17%; overall: 24% vs. 14%). The most common grade ≥3 treatment-emergent adverse events in niraparib-treated patients were thrombocytopenia (40%), anemia (32%), and neutropenia (21%). The incidence rate of myelodysplastic syndromes/acute myeloid leukemia was the same for niraparib-treated (1.2%) and placebo-treated (1.2%) patients. Overall survival data remain immature. Conclusion: Niraparib maintained clinically significant improvement in PFS with 3.5 years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of homologous recombination deficiency status. No new safety signals were identified. Encore Statement: Previously presented at the European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France. Final Publication Number: 530P. Antonio González-Martín et al. Reused with permission.

Key Words: Ovarian cancer, niraparib, maintenance therapy.

TOLERANCE AND PRELIMINARY EFFICACY OF INTRAPERITONEAL NIVOLUMAB AFTER EXTENSIVE DEBULKING SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY IN PATIENTS WITH ADVANCED OVARIAN CARCINOMA: A PHASE I STUDY WITH AN EXPANSION COHORT (ICONIC)

PAULINE CORBAUX^1,2, BENOIT YOU³, VAHAN KEPENEKIAN⁴, NAOUAL BAKRIN⁴, AUDREY GELOT⁵, DAVID DAYDE⁵, CHRISTOPHE SAJOUS³, MICHÈLE LAMURAGLIA², JULIEN PÉRON³, OLIVIER GLEHEN⁴ and GILLES FREYER^2,3

¹EA UCBL/HCL 3738, Centre pour l’lnnovation en Cancérologie de Lyon (CICLY), Claude Bernard University, Lyon, France;

²Medical Oncology, Institut de Cancérologie et d’Hématologie Universitaire de Saint-Étienne (ICHUSE), Centre Hospitalier Universitaire de Saint-Etienne, Saint-Priest-en-Jarez, France;

³Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Centre Hospitalier Lyon-Sud, Lyon, France;

⁴Department of Surgical Oncology, Centre Hospitalier Lyon Sud, Lyon, France;

⁵Plateforme de Recherche de l’Institut de Cancérologie des Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France

Background/Aim: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) combination with intraperitoneal (i.p.) immunotherapy is likely to have a synergistic effect, through an increase of tumor antigen expression and mutational load. We assessed the safety of i.p. nivolumab after extensive debulking surgery (DS) and HIPEC in heavily pretreated patients with recurrent ovarian carcinoma (NCT03959761). Patients and Methods: Patients were treated at one center according to three dose levels of i.p. nivolumab following a 3+3 design (0.5, 1 and 3 mg/kg), starting 5-7 days after DS and HIPEC. Four i.p. nivolumab injections were planned, repeated every 2 weeks. The primary objective was to demonstrate the feasibility of i.p. nivolumab based on the dose-limiting toxicity (DLT). Secondary objectives were to assess changes in tolerance of DS, HIPEC and post procedural intravenous chemotherapy. Results: DLT was evaluable in 9/10 patients from the dose-escalation cohort (there was one peritoneal catheter disconnection after the second infusion). No DLTs were observed at either dose level according to an independent Data Safety Monitoring Board. Therefore, seven patients were included in an expansion cohort with 3 mg/kg i.p. nivolumab. Overall, six patients (35.3%) did not complete all planned cycles: Four due to peritoneal catheter complications (two due to painful injections, one due to disconnection and on due to infection) and two related to early disease progression. No procedure-related death occurred. Eleven patients (64.7%) experienced severe adverse events (SAEs), mainly related to surgery (9/11) and mainly represented by transitory grade 3-4 transaminase elevations (6/11). Four SAEs were related to the peritoneal catheter, one to i.p. chemotherapy (grade 3 hypokalemia), without any SAE being related to i.p. nivolumab. With a median follow-up of 16.4 months, median progression-free-survival was 10.5 months (95% confidence interval=6.3 months-not reached) in platinum-sensitive, and 6.5 months (95% confidence interval=3.9 months-not reached) in platinum-resistant disease. Conclusion: The ICONIC study is the first study showing the feasibility of i.p. nivolumab after DS and HIPEC in patients with advanced ovarian cancer in relapse.

Key Words: Ovarian cancer, intraperitoneal treatment, immunotherapy, hyperthermic intraperitoneal chemotherapy.

THE RELATIONSHIP BETWEEN THE NUMBER OF CYCLES IN NEOADJUVANT CHEMOTHERAPY FOR OVARIAN CANCER AND THE PATHOLOGIC RESPONSE OF THE TUMOR

JUMANA JOUBRAN¹, IDO LASKOV¹, ASAF AIZEK², NADAV MISHAAN¹, YAEL RAZ¹ and DAN GRISARU¹

¹Gynecologic-oncology Department, Tel-Aviv Medical Center, Tel Aviv, Israel;

²Pathology Department, Tel-Aviv Medical Center, Tel Aviv, Israel

Background/Aim: Neoadjuvant chemotherapy (NACT) for advanced ovarian carcinoma is the choice of treatment when primary surgery is not expected to achieve complete resection of the tumor. However, the optimal timing of surgery after a certain number of administered chemotherapy cycles is not unified nor anchored in guidelines. The chemotherapy response score (CRS) evaluated through omental specimen examination and reported in the interval debulking surgery pathology report has been related to surgical outcome and overall survival. In our study we examined the relationship between the number of NACT cycles and the reported CRS. Patients and Methods: Retrospectively from 2016 to 2022, at a single center, data regarding cases diagnosed with advanced serous ovarian carcinoma, who were referred to NACT and underwent surgery, were extracted from electronic records, and analyzed statistically. Results: A total of 116 women were divided into two groups according to the number of NACT cycles received: 3 vs. 4-6 cycles. There were no differences in the women’s age, body mass index, primary tumor site, stage, or DNA repair-associated gene status (Table I). The surgical and pathological results showed no statistical significance in the CRS but did show achieving complete debulking was significantly better in the group of patients treated with 3 cycles (88%) compared to the group treated with 4-6 cycles (69%) (p=0.026) (Table II). When examining the groups by CRS, there were no differences in the patients’ characteristics, including preoperative administration of bevacizumab, nor in the time interval between diagnosis and operation, the only significant difference was in the body mass index, it being higher in the group with CRS-3 (27.09±6.2 kg/m²) compared to CRS-2 (23.9±4.09 kg/m²) (p=0.021). In surgical results, patients with CRS-3 had a significantly higher rate of no evidence of disease when the abdomen was opened (43.4%) compared to the CRS-2 (10.5%) and CRS-1 (4%) groups (p<0.001), and in achievement of complete debulking (87%) compared to CRS-2 (84%) and CRS-1 (46%) groups (Table III). Conclusion: The number of NACT cycles was not associated with the CRS but did correlate with the rate of achieving complete debulking, being higher in those treated with 3 cycles compared to 4-6 cycles.

Key Words: Neoadjuvant chemotherapy, ovarian cancer, chemotherapy response score.

LABORATORY FINDINGS IN PREDICTING THROMBOTIC EVENTS FOR PATIENTS WITH OVARIAN CANCER

KAMILĖ LASKAUSKAITĖ¹, ARTŪRAS SUKOVAS² and MIGLĖ GEDGAUDAITĖ²

¹Faculty of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania;

²Obstetrics and Gynecology Department, Lithuanian University of Health Sciences, Kaunas, Lithuania

Background/Aim: Ovarian cancer is one of the leading causes of cancer-related deaths in women around the world. Patients with ovarian cancer are especially prone to thrombotic events that can lead to deteriorating wellbeing and poorer overall outcomes. The aim of the study was to evaluate how the hemoglobin level, leukocyte and thrombocyte count, and cancer antigen 125 (CA-125) level can help predict future risks for thrombotic events in patients with ovarian cancer. Patients and Methods: A comparative analysis was combined with a retrospective study of newly diagnosed patients with ovarian cancer from 2017 till 2021 (n=342). From The Hospital of Lithuanian University of Health Sciences Kauno Clinic archive, we gathered information about whether the patient had a low level of hemoglobin (<100 g/l), high leukocyte (>11×10⁹/l) and thrombocyte (>350×10⁹/l) counts, and what the CA-125 level was before cancer treatment. We observed whether the patient had any thrombotic events during that time (n=66) and compared laboratory results with patients who had no complications. Results: We found there was a significant risk for thromboembolism in patients with ovarian cancer that had a low hemoglobin level [odds ratio (OR)=2.742, 95% confidence interval (CI)=1.408-5.339, p<0.002], high leukocyte count (OR=4.587, 95% CI=2.192-9.598, p<0.001), high thrombocyte count (OR=4.963, 95% CI=2.777-8.867, p<0.001) in comparison with patients with no thrombotic complications. A CA-125 level higher than 522 U/ml was associated with higher risk for thrombosis (OR=5.200, 95% CI=2.751-9.830, p<0.001). Conclusion: Full blood count and CA-125 determination might help assess the risk of future possible thrombotic complications before a cancer treatment plan is made. By evaluating risk, anticoagulant therapy can be administered earlier and prolonged depending on the course of treatment.

Key Words: Ovarian cancer, thrombotic events, haemoglobin level, leukocyte count, thrombocyte count, CA-125 level.

REAL-WORLD CLINICAL AND PATIENT-REPORTED OUTCOME DATA OF PATIENTS WITH NEWLY DIAGNOSED, ADVANCED OVARIAN CANCER – THE GERMAN PROSPECTIVE, NON-INTERVENTIONAL SCOUT-1 STUDY (NOGGO ov54, NCT04830709)

TJADINA ARNDT^1,2, KLAUS PIETZNER^1,2, ELENA IOANA BRAICU^1,2, PAULINE WIMBERGER^1,3, MATTHIAS ROSE⁴ and JALID SEHOULI^1,2

¹North-Eastern German Society of Gynecological Oncology (NOGGO), Berlin, Germany;

²Department of Gynecology, European Competence Center for Ovarian Cancer, Charité Medical University, Berlin, Germany;

³Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany;

⁴Centre for Internal Medicine and Dermatology, Department of Psychosomatic Medicine, Charité Medical University, Berlin, Germany

Background/Aim: The current standard of care for advanced ovarian cancer (OC) consists of upfront debulking surgery, with the goal of complete macroscopic resection, followed by carboplatin-based chemotherapy for at least six cycles, and maintenance therapy with poly(ADPribose) polymerase inhibitors or bevacizumab as monotherapy or in combination (1). The primary objective of the prospective, non-interventional SCOUT-1 study (NOGGO ov54; NCT04830709) is the evaluation of the effectiveness of current standard of care treatment sequences by assessing progression-free survival according to investigator’s assessment. Patients and Methods: SCOUT-1 will evaluate clinical outcomes of patients newly diagnosed with histologically confirmed advanced (International Federation of Obstetrics and Gynecology stage III-IV) high-grade OC under real-world conditions in Germany with special focus on patient-reported outcomes regarding quality of life, symptoms, needs and expectations. Patients providing written informed consent, who have completed surgery (if applicable), are eligible for platinum-based chemotherapy, have been tested for mutations of BRCA DNA repair-associated 1/2 genes (solitary or within homologous recombination deficiency test) and willing/able to complete patient-reported outcomes electronically, will be enrolled and followed for up to 7 years. The primary objective is the evaluation of effectiveness of current standard of care treatment sequences by assessing progression-free survival according to investigator’s assessment. During the enrollment period, all initiated/active sites are asked once a year to provide the total number of patients with OC treated at the site in the previous year, independently of their eligibility for the study. Results: Until April 1st, 2022, data were provided by 47 sites. The majority (n=36, 77%) were full-service hospitals (university hospital, hospital with maximum or specialized care), three (6%) were base service hospitals, and eight (17%) were office-based (gyneco)oncological sites. Most sites declared they were (gyneco)oncological centers certified by the German Cancer Society. In 2021, they treated on average 28 patients newly diagnosed with OC, with a wide range of 4-127 patients. Conclusion: SCOUT-1 is expected to deliver substantial short- and long-term insights into outcomes of the current standard of care, patients’ quality of life, symptoms, needs and expectations under real-life conditions. Participating sites and first cumulative data showed the potential for enrolling a representative cohort of patients with advanced OC in the SCOUT-1 study. The study is ongoing and open for recruitment.

Key Words: Advanced ovarian cancer, BRCA, real-world conditions, standard of care, patient-reported outcomes.

1 S3-Guideline on Diagnostics, Therapy and Follow-up of Malignant Ovarian Tumors, version 5.1. AWMF registration number 032/035OL. Available at: https://www.leitlinienprogramm-onkologie.de/fileadmin/user_upload/LL_Ovarialkarzinom_Langversion_5.1.pdf [Last accessed on April 20, 2023]

BEVACIZUMAB, OLAPARIB AND DURVALUMAB IN PATIENTS WITH RELAPSED OVARIAN CANCER (THE GINECO BOLD STUDY): PROGNOSTIC VALUE OF KELIM-B AND NANOSTRING^® TUMOR INFLAMMATION SIGNATURE

GILLES FREYER¹, CORIOLAN LEBRETON², OLIVIER TREDAN³, AURORE CARROT⁴, CAROLE LANGLOIS-JACQUES⁵, JONATHAN LOPEZ⁶, FRÉDÉRIC SELLE⁷, CYRIL ABDEDDAIM⁸, ALEXANDRA LEARY⁹, DIANA BELLO-ROUFFAI¹⁰, MICHEL FABBRO¹¹, LAURENCE GLADIEFF¹², MICHELE LAMURAGLIA¹³ and DAVID DAYDE¹⁴

¹Department of Medical Oncology, Lyon 1 University, GINECO and Cancer Institute Hospices Civils de Lyon, Lyon, France;

²Department of Medical Oncology – Gynecological Tumors, GINECO and Institut Bergonié, Bordeaux, France;

³Medical Oncology, GINECO and Centre Léon Bérard, Lyon, France;

⁴EMR 3738, UFR Lyon-Sud, Université Lyon 1, Lyon, France;

⁵Biostatistics and Bioinformatics Department, Hospices Civils de Lyon, Lyon, France;

⁶Department of Biochemistry and Molecular Biology, Hospices Civils de Lyon, Lyon, France;

⁷Department of Medical Oncology, GINECO and Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France;

⁸Gynecologic Oncology Department, GINECO and Centre Oscar Lambret, Lille, France;

⁹Oncology Department, GINECO and Institut Gustave Roussy, Villejuif, France;

¹⁰Medical Oncology, GINECO and Institut Curie Saint Cloud, Paris, France;

¹¹Department of Medical Oncology, GINECO and Institut du Cancer de Montpellier, Montpellier, France;

¹²Medical Oncology, GINECO and Institut Claudius Regaud IUCT-Oncopole, Toulouse, France;

¹³Medical Oncology, GINECO and Institut de Cancérologie du CHUSE, Saint-Etienne, France;

¹⁴Clinical Research, Cancer Institute Hospices Civils de Lyon, Lyon, France

Background/Aim: Strategies combining bevacizumab, olaparib, and durvalumab are anticipated to have synergistic activity. We evaluated this triple combination in platinum-resistant and platinum-sensitive relapse of advanced ovarian cancer. Patients and Methods: This open-label, multicenter phase 2 study assessed activity and safety of 1120 mg durvalumab once every 3 weeks (q3w), 15 mg/kg bevacizumab q3w, and 300 mg tolaparib twice daily, in patients with relapsed, high-grade epithelial, advanced ovarian cancer. Previous bevacizumab or poly (ADP-ribose) polymerase inhibitor was permitted. The primary endpoint was the rate of non-progression at 3 months for patients with platinum-resistant relapse or 6 months for those with platinum-sensitive relapse. Secondary endpoints included the modeled cancer antigen 125 (CA-125) elimination rate constant (KELIM-B) for longitudinal CA-125 kinetics over 100 days, and the Nanostring^® tumor inflammation signature at baseline. Results: Between March 2019 and January 2020, 74 patients were included (41 with platinum-resistant and 33 with platinum-sensitive disease). With a median follow-up of 15.4 months, non-progression rates were 69.8% [90% confidence interval (CI)=55.9-80.0%] at 3 months for those with platinum-resistant relapse, and 43.8% (90% CI=29.0-57.4%) at 6 months for those with platinum-sensitive relapse. Median PFS was 4.1 months (95% CI=3.5-5.9 months) for those with platinum-resistant relapse and 4.9 months (95% CI=2.9-7.0 months) for those with platinum-sensitive relapse. Median overall survival was 18.8 months (95% CI=9.6 months-not reached) and 18.5 months (95% CI=15.6 months-not reached), respectively. Higher (favorable) KELIM-B values were prognostic for improved PFS [median=6.2 months (95% CI=3.5-9.0 months) vs. 1.5 months (95% CI=0.7-6.2 months); p=0.03]. A higher tumor inflammation signature was associated with longer median PFS, notably for patients with platinum-sensitive relapse [6.9 months (95% CI=3.3-10.3) vs. 4.0 months (95% CI=1.4-5.7 months)]. No toxic deaths or major safety signals were observed. Conclusion: The chemotherapy-free triple combination of durvalumab, olaparib and bevacizumab was well tolerated, with encouraging efficacy in heavily pretreated patients with platinum-resistant relapse. Favorable KELIM-B and higher immune-related biomarkers are prognostic for survival. Further investigation of the triple combination is warranted.

Key Words: Ovarian carcinoma, poly (ADP-ribose) polymerase inhibitor, immunotherapy, bevacizumab.

MODEL OF RISK STRATIFICATION METHODS IN DIAGNOSIS OF ENDOMETRIAL CANCER

MAGDALENA BIZOŃ¹, PAMELA CZAJKA², MARIA FALIS³, ALEKSANDRA ZACNY⁴, JANTONI MIKULSKI⁴ and WŁODZIMIERZ SAWICKI⁵

¹Department of Gynecology and Gynecological Oncology, LUX MED Oncology, Św. Wincentego Hospital, Warsaw, Poland;

²Center of Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland;

³First Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland;

⁴Student’s Scientific Club, Chair and Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, Warsaw, Poland;

⁵Chair and Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, Warsaw, Poland

Background/Aim: Endometrial cancer is one of the most common gynecological cancers. There is no screening for early prediction of this disease. Symptoms are nonspecific because bleeding can also be associated with hormonal disorders. Hysteroscopy is a diagnostic procedure for further treatment. However, the symptoms and ultrasound view may be insufficient to perform hysteroscopy as quickly as possible. The aim of this study was to create a predictive model of endometrial cancer which will help to guide the diagnostic process. Patients and Methods: The analysis was based on 271 patients who underwent hysteroscopy. The population was divided into two groups: One group with a final histological diagnosis of endometrial cancer (124 patients, mean age ± standard deviation=65.57±10.81 years), and a control group with a nonmalignant diagnosis after hysteroscopy (147 patients, mean age 53.5±12.66 years). Indications for hysteroscopy were symptoms regarding suspicion of endometrial cancer such as irregular bleeding, postmenopausal bleeding, endometrial hyperplasia in ultrasound view and endometrial polyps. The predictive model was created based on symptoms and data from the blood count taken before the procedure because of anesthetic standards. The model was estimated using 20 different methods of machine learning: Linear discriminant analysis, quadratic discriminant analysis, naive Bayes classification, decision trees, random forests, logistic regression, and others. Results: The most specific method seemed to be that using a random forest, where accuracy was 90%, sensitivity 92.5% and specificity 86.5%. Post-hoc analysis revealed the more significant impact of blood count and clinical symptoms than age and blood count or age and symptoms in creation of the predictive model. Conclusion: Risk stratification methods are promising in endometrial cancer to improve the speed of the diagnostic process and not miss cases less suspected of endometrial cancer. Special calculators for estimating risk of endometrial cancer can be used in ambulatory practice.

Key Words: Endometrial cancer, diagnosis, predictive model, calculator.

THE PROGNOSTIC RELEVANCE OF THE LYMPH NODE RATIO IN PRIMARY ENDOMETRIAL CANCER

MARIUS LÖFFLER¹, MARIA FRIEDRICH¹, INNA SHEHAJ^2,3, MORVA TAHMASBI-RAD¹, BAHAR GASIMLI¹, THOMAS KARN¹, MAXIMILIAN FLEISCHMANN⁴, AHMED EL-BALAT¹, SVEN BECKER¹, JELENA BOEKHOFF⁵ and KHAYAL GASIMLI¹

¹Department of Obstetrics and Gynecology, JWG University, Frankfurt am Main, Germany;

²Department of Obstetrics and Gynecology, Jung-Stilling-Hospital, Siegen, Germany;

³Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany;

⁴Department of Radiotherapy and Radiation Oncology, JWG University, Frankfurt am Main, Germany;

⁵Department of Obstetrics and Gynecology, Philipps University Marburg, Marburg, Germany

Background/Aim: Endometrial cancer (EC) is the most common gynecologic malignancy in the Western world. According to the current European Society for Medical Oncology/European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology guidelines (1), removing lymph nodes determines the prognosis and identifies patients with advanced-stage disease. Currently, sentinel mapping is applied for lymph node staging in primary diagnosis. The lymph node ratio (LNR), i.e., the ratio of positive to excised lymph nodes, has already been examined in several gynecological and non-gynecological cancer types. This study aimed to investigate the prognostic role of LNR in patients with primary EC. Patients and Methods: In this multicenter retrospective analysis, 99 patients with primary EC, treated between 2010 and 2021, who underwent surgical treatment through hysterectomy, bilateral adnexectomy, and either pelvic or both pelvic and para-aortic lymph node dissection were included. The stepwise forward method was used for the Cox regression model and variable selection. A Cox model was calculated for any possible threshold in 1% steps to determine the cut-off value, and the model with the highest log-likelihood was selected. The cut-off value classified patients into groups with LNR ≤0.23 (n=65) and LNR >0.23 (n=34). The log-rank test and the Kaplan–Meier method analyzed the correlation between clinical factors and survival rate. A chi-square test was used for categorical variables and a t-test for continuous variables. Results: The median age of the cohort was 64 years (range=40-96 years). Most patients had endometrioid histology. LNR >0.23 was associated with more recurrences (26.4% vs. 13.8%, p=0.003) and higher death rates (52.9% vs. 20.0%, p=0.027). Multivariant analysis showed the following variables to be associated with reduced progression-free and overall survival: LNR >0.23 (p<0.001), pM1 (p<0.001), pV1 (p=0.003), higher Eastern Cooperative Oncology Group performance status (p<0.001) and level of lymph node excision (p=0.024). Regarding LNR, the 3-year PFS rates were 29.3% and 6.1% (p<0.001), and the 3-year overall survival rates were 36.4% and 8.1% (p<0.001), for the groups with low and high LNR, respectively. Conclusion: LNR predicts survival and might be a prognostic instrument in the treatment setting. However, further prospective and multicenter research is needed to validate these results.

Key Words: Endometrial cancer, lymph nodes metastases, lymph node ratio, survival, prognostic factors.

1 Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, Ledermann J, Bosse T, Chargari C, Fagotti A, Fotopoulou C, Gonzalez Martin A, Lax S, Lorusso D, Marth C, Morice P, Nout RA, O’Donnell D, Querleu D, Raspollini MR, Sehouli J, Sturdza A, Taylor A, Westermann A, Wimberger P, Colombo N, Planchamp F, Creutzberg CL: ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 31: 12–39, 2021. DOI: 10.1136/ijgc-2020-002230

METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE IS ASSOCIATED WITH CERVICAL STROMAL INVOLVEMENT IN PATIENTS WITH ENDOMETRIAL CANCER: A CROSS-SECTIONAL STUDY IN SOUTH CHINA

XITE LIN^1,2,3#, CHUNXIA CHEN^4#, TINGTING JIANG^1,2,3, JINCHENG MA^1,2,3, LIXIANG HUANG^1,2,3, LEYI HUANG^1,2,3, HUIFANG LEI¹, YAO TONG¹, GUANXIANG HUANG^1,2,3, XIAODAN MAO^1,2,3 and PENGMING SUN^1,2,3

¹Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics, Gynecology and Pediatrics, Fujian Medical University, Fuzhou, P.R. China;

²Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou, P.R. China;

³Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, P.R. China;

⁴Department of Imaging, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, P.R. China

^#These Authors contributed equally to this work.

Background/Aim: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant health issue closely associated with multiple extrahepatic cancers. The association between MAFLD and clinical outcomes of endometrial cancer (EC) remains unknown. Patients and Methods: We retrospectively included 824 patients with EC between January 2013 and December 2020. The odds ratios (ORs) for developing cervical stromal involvement (CSI) were calculated using logistic regression analyses. The hepatic steatosis index (HSI) was assessed for the best cut-off using the receiver operating characteristics (ROC) method and Youden index calculation. Patients with EC were dichotomized with the HSI cut-offs from the corresponding ROC curves. Results: Among patients with EC, the prevalence of MAFLD was 25.7% [205/797, 95% confidence interval (Cl)=20.5-28.5%]. MAFLD was significantly associated with CSI (OR=2.204, 95% CI=1.221-3.978; p=0.009). Moreover, MAFLD was significantly associated with CSI in the type I EC subgroup (OR=2.699, 95% Cl=1.322-5.510; p=0.006) but not in the type II EC subgroup (p=0.732). The ROC curve analysis showed that the calculated cut-off value was 34.37 among patients with EC (area under the curve=0.548, 95% CI=0.489-0.608). Further logistic regression analysis suggested that the HSI was significantly associated with CSI in non-obese (body mass index <25 kg/m²) patients with type I EC (p=0.036). Conclusion: About one-quarter of our cohort had MAFLD. MAFLD was associated with the risk of CSI in patients with EC; this association existed in patients with type I EC but not in those with type II EC. Furthermore, the HSI can help predict CSI in patients without obesity with type I EC.

Key Words: Metabolic dysfunction-associated fatty liver disease, endometrial cancer, cervical stromal involvement, hepatic steatosis index.

ERRα PROMOTES GLYCOLYTIC METABOLISM AND TARGETS NLRP3 TO REGULATE PYROPTOSIS IN ENDOMETRIAL CANCER

PINGPING SU^1#, XIAODAN MAO^1,2,3#, JINCHENG MA¹, LIXIANG HUANG¹, LIRUI YU¹, KELVIN STEFAN OSAFO¹, ELENA IOANA BRAICU^4,5, JALID SEHOULI⁵ and PENGMING SUN^1,2,3,6

¹Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics, Gynecology and Pediatrics, Fujian Medical University, Fuzhou, P.R. China;

²Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, P.R. China;

³Fujian Clinical Research Center for Gynecologic Oncology, Fujian Maternity and Child Health Hospital, Fujian Obstetrics and Gynecology Hospital, Fuzhou, P.R. China;

⁴Department of Gynecology with Center of Oncological Surgery, Charité Campus Virchow Clinic, University of Medicine, Berlin, Germany;

⁵Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, U.S.A.;

⁶Fujian Province Key Clinical Specialty for Gynecology, Fujian Maternity and Child Health Hospital, Fuzhou, P.R. China

^#These Authors contributed equally to this work.

Background/Aim: Tumor cells can survive chemotherapy-induced pyroptosis through metabolic reprogramming. Platinum resistance is a common phenomenon and results in cancer recurrence and metastasis, which remains a major problem in clinical practice. High estrogen-related receptor alpha (ERRα) expression indicates a more aggressive phenotype and is closely related to a poor clinical prognosis of the tumor. As a central regulator of cellular energy metabolism, there have been no reports about ERRα and tumor cellular pyroptosis. Materials and Methods: The protein interaction between ERRα and hypoxia-inducible factor-1 alpha (HIF1α) was verified using chromatin immunoprecipitation in cell lysates of ERRα-overexpressing HEC-1 cells. The transcriptional binding sites of ERRα and NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) were confirmed by dual-luciferase reporter assay. Flow cytometry, transmission electron microscopy, and extracellular acidification rate analysis were performed to investigate the effect of ERRα on the pyroptosis pathway and mitochondrial glycolytic metabolism. These experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis-associated genes was analyzed using The Cancer Genome Atlas database. Results: The results indicated that ERRα bound to the promoter of NLRP3, thereby reducing inflammasome activation and increasing pyroptosis resistance. Moreover, ERRα promoted mitochondrial glycolytic metabolism, resulting in cisplatin resistance. In EC-derived organoids, knock-down of ERRα increased the sensitivity of EC cells to cisplatin. The xenograft animal experiment verified that overexpression of ERRα enhanced the growth of EC xenograft tumor by inhibiting cell pyroptosis. The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in the progression of EC. Conclusion: ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells. ERRα may be a potential prognostic indicator for predicting cisplatin resistance in patients with EC.

Key Words: Endometrial cancer, pyroptosis, metabolic reprogramming, ERRα, platinum resistance.

PERIPHERAL BLOOD LYMPHOCYTES INFLUENCE HUMAN PAPILLOMAVIRUS INFECTION AND CLEARANCE: A RETROSPECTIVE COHORT STUDY

YE LI^1,2,3#, YEBIN FENG^4#, YANLIN CHEN^1,2,3#, WENYU LIN^1,2,3, HANGJING GAO^1,2,3, MING CHEN^1,2,3, KELVIN STEFAN OSAFO^1,2,3, XIAODAN MAO^1,2,3, YAFANG KANG^1,2,3, LEYI HUANG^1,2,3, DABIN LIU⁵, SHUXIA XU⁶, LIXIANG HUANG^1,2,3, YUXUAN HUANG^1,2,3, BINHUA DONG^1,2,3 and PENGMING SUN^1,2,3

¹Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, P.R. China;

²Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou, P.R. China;

³Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, P.R. China;

⁴Department of Pharmacy, Fujian Maternity and Child Health Hospital, Fuzhou, P.R. China;

⁵Department of Gynecology, Fujian Maternity and Child Health Hospital, Fuzhou, P.R. China;

⁶Department of Pathology, Fujian Maternity and Child Health Hospital, Fuzhou, P.R. China

^#These Authors contributed equally to this work.

Background/Aim: The purpose of this study was to determine which lymphocytes in peripheral blood influence human papillomavirus (HPV) infection and to identify whether peripheral blood lymphocyte (PBL) subsets might be used as biomarkers to predict HPV clearance in the short term. Patients and Methods: This study recruited 716 women who underwent colposcopy between January 2019 and December 2021. Logistic regression was used to analyze the association between PBLs and HPV infection. Cox regression analysis was performed to screen lymphocytes affecting HPV clearance. Risk scores were calculated based on the percentage of PBLs and their corresponding coefficients to construct prognosis models for predicting HPV clearance. Kaplan–Meier analysis and time-dependent receiver operating characteristic curves were used to evaluate the PBL prognosis model. The model was further internally validated by bootstrapping. Results: The presence of fewer CD4⁺ T-cells was associated with a higher risk of HPV, high-risk HPV, HPV18 and HPV52 infections, with corresponding odds ratios (95% confidence interval) of 1.58 (1.16-2.15), 1.71 (1.23-2.36), 2.37 (1.12-5.02), and 3.67 (1.78-7.54), respectively. A lower T-cell and CD8⁺ T-cell count, along with more natural killer (NK) cells, were unfavorable factors for natural HPV clearance (p<0.05). Optimal cut-off values (risk score cell percentage of 0.78-67.39 for T-cells, 0.53-22.65 for NK cells, and 0.95-21.75 for CD8⁺ Use of T-cells determined by PBL prognosis models allow for good triage for HPV clearance and HPV persistence (p<0.05). After internal validation with bootstrap resampling, the above conclusions still hold. Conclusion: The level of CD4⁺ T-cells was an important determinant of HPV infection. T-Cells, NK cells, and CD8⁺ T-cells can serve as potential biomarkers for predicting natural HPV clearance, which can aid in patient risk stratification, individualized treatment, and follow-up management.

Key Words: Human papillomavirus, peripheral lymphocyte subsets, HPV infection, HPV clearance, predictive model.

ASSESSING RISK FACTORS FOR DEVELOPMENT OF CERVICAL OR ENDOMETRIAL HIGH-GRADE LESION IN CHINESE WOMEN WITH AGC-FN: A COHORT STUDY

SHUXIA XU^#, TINGTING JIANG^#, XIAODAN MAO, LIANGZHI CAI, XITE LIN, YAO TONG, BINHUA DONG and PENGMING SUN

Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, P.R. China

^#These Authors contributed equally to this work.

Background/Aim: Papanicolaou smear sharing atypical glandular cells favor neoplastic (AGC-FN) can be related to premalignant and malignant cervical and endometrial lesions. However, there has been no effective proxy for triaging patients with AGC-FN. This study aimed to find the risk factors for AGC-FN and analyze the relationship between AGC-FN and high-grade lesions. Patients and Methods: A cohort study was performed using data from the Fujian Province Cervical Lesion Screening Cohorts. A total of 211 women diagnosed with AGC-FN based on the Bethesda 2001 classification system who were followed-up with colposcopy, biopsy, and endometrial curettage from January 2013 to July 2021 were enrolled. p-Values less than 0.05 (two-sided) were regarded as statistically significant. Results: In more than 200,000 cases from 2012 to 2021 who underwent cervical fluid-based cytology, the number of AGC-FNs was 241; 211 of these were enrolled. Of the 211 patients, 59 were diagnosed as cervical intraepithelial neoplasia (CIN) 2+ and 92 had histologically confirmed endometrial cancer and precancerous lesions. Older age, menopause, higher CA-125 and high-risk human papillomavirus (HR-HPV) infection were found in the patients with precancerous endometrial lesions and endometrial cancer (p<0.05). These indicators were reversed in women with HISL and cervical cancer. Notably, the odds ratio (OR) of HPV-16/18/58/59 infection [OR=40.043, 95% confidence interval (CI)=11.871-135.076; p<0.01] was second only to that of HPV-16/18 infection (OR=50.122, 95% CI=13.441-186.909; p<0.01) for those with HSIL/cervical cancer. Moreover, human epididymis protein was selected as a specific risk factor (OR=3.351, 95% CI=1.099-10.214) for precancerous endometrial lesions and endometrial cancer, and CA199 was a protective factor (OR=0.204, 95% CI=0.085-0.492) for HSIL/cervical cancer. Conclusion: CA-125 and HR-HPV play opposing roles in predicting the risk for high-grade lesions of the endometrium and cervix in women with AGC-FN. Besides HPV-16 and HPV-18, HPV-58 and HPV-59 should not be ignored in screening women with those with HSIL/cervical cancer. The findings of this study can optimize the triaging strategy for AGC-FN in the current guidelines.

Key Words: Screening, high-risk HPV, tumor biomarker, high-grade lesion.

HLA-DPB2 RS4713607 AND RS3117039 DETECTION OPTIMIZE PRIMARY HPV SCREENING FOR CERVICAL CANCER

WENYU LIN^1,2,3, YAOJIA CHEN^1,2,3, YE LI^1,2,3 and PENGMING SUN^1,2,3

¹Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics, Gynecology and Pediatrics, Fujian Medical University, Fuzhou, P.R. China;

²Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou, P.R. China;

³Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, P.R. China

Background/Aim: New screening techniques may affect the optimal approaches for the prevention of cervical cancer. This study evaluated the diagnostic performance of single-nucleotide polymorphisms (SNPs) and human papillomavirus (HPV) testing to provide evidence for cervical cancer screening guidelines in China. Patients and Methods: The study was a multi-center study including 2,628 women from Fujian, and 1,999 women from Shenzhen. All participants underwent polymerase chain reaction (PCR)-reverse dot blot human papillomavirus genotyping test, and some patients underwent cytology and pathology testing. In addition, we used the competitive allele-specific PCR method to genotype selected SNPs of 4,627 participants [exocyst complex component 1 (EXOC1) rs13117307, major histocompatibility complex, class II, DP (HLA-DP) alpha 1 (HLA-DPA1) rs2116260; HLA-DPB1 rs4282438; HLA-DPB2 rs3117039, rs4713607, rs3129275 and rs3117008; COL11A2 rs9391756; microRNA 219a-1 (MIR219A1) rs213210; intergenic rs9277952; and gasdermin B (GSDMB) rs8067378]. Outcome indicators included the sensitivity, specificity, positive predicting value (PPV), negative predictive value (NPV), and cost of identifying cervical intraepithelial neoplasia of grade 2/3 or worse (CIN2+/CIN3+). Results: MIR219A1 rs213210, HLA-DPB2 rs4713607 and EXOC1 rs13117307 were associated with HPV infection (p<0.001). The presence of EXOC1 rs13117307 and MIR219A1 rs213210 were associated with lower risk of HPV infection [odds ratio (OR)=0.47, p<0.001; OR=0.63, p=0.002, respectively]. HLA-DPB2 rs4713607 was associated with a higher risk of HPV infection (OR=2.51, p<0.001) and cervical cancer (OR=1.61, p=0.02). HLA-DPB2 rs3117039 may be related to a lower risk of developing cervical cancer (OR=0.48, p=0.01). Moreover, HPV and SNP (HLA-DPB2 rs4713607 AA or rs3117039 AG/GG) testing gave a higher specificity and positive predictive value (PPV) compared to that of the HPV primary test in the detection of CIN2+ (specificity: 42.98% vs. 38.94%; PPV: 41.23% vs. 39.71%, respectively) and CIN3+ (specificity: 37.17% vs. 33.63%; PPV: 22.15% vs. 21.22%, respectively). Conclusion: HLA-DPB2 rs4713607 and HLA-DPB2 rs3117039 contribute to cervical cancer, while EXOC1 rs13117307 and MIR219A1 rs213210 were protective against HPV infection. HPV and SNP in primary testing may provide higher specificity and PPV as a triage test for CIN2+ and CIN3+.

Key Words: SNP, HPV, cervical cancer, screening, HLA.

THE NON-APOPTOTIC FUNCTION OF CASPASE-8 IN NEGATIVELY REGULATING THE CDK9-MEDIATED SER2 PHOSPHORYLATION OF RNA POLYMERASE II IN CERVICAL AND OVARIAN CANCERS LEADS TO ENHANCED METASTASIS AND DRUG RESISTANCE

KHAYAL GASIMLI¹, RANADIP MANDAL¹, MONIKA RAAB¹, FRANZ RÖDEL^2,3,4, ANDREA KRÄMER¹, IZABELA KOSTOVA¹, SAMUEL PENA-LLOPIS^5,6,7, GIOELE MEDICI^1,8,9, BJÖRN HÄUPL^3,4,7,10, THOMAS OELLERICH^3,4,7,10, MOURAD SANHAJI¹, SVEN BECKER¹ and KLAUS STREBHARDT^1,3

¹Department of Gynecology, University Hospital, Frankfurt am Main, Germany;

²Department of Radiotherapy and Oncology, University Hospital, Frankfurt am Main, Germany;

³German Cancer Consortium (DKTK), Frankfurt am Main, Germany;

⁴Frankfurt Cancer Institute (FCI), Goethe University, Frankfurt am Main, Germany;

⁵Translational Genomics in Solid Tumors, West German Cancer Center, University Hospital, Essen, Germany;

⁶German Cancer Consortium (DKTK), Essen, Germany;

⁷German Cancer Research Center (DKFZ), Heidelberg, Germany;

⁸Laboratory of Molecular Neuro-Oncology, Department of Neurology and Brain Tumor Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland;

⁹Clinical Neuroscience Center and Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland;

¹⁰Medizinische Klinik 2 Haematology/Oncology, University Hospital, Frankfurt am Main, Germany

Background/Aim: Ovarian and cervical cancers are among the deadliest gynecological cancers worldwide. More than 70% of ovarian cancer cases are diagnosed at an advanced stage and are usually untreatable due to resistance to standard platinum-based therapy. Moreover, between 15% and 61% of cervical cancer cases metastasize and develop chemoresistance, which reduces 5-year survival. It is, therefore, critical to unravel the mechanisms contributing to treatment resistance and metastasis to develop more effective targeted therapies against both diseases. Materials and Methods: HeLa, OVCAR-3, and OVCAR-8 cell lines were obtained from ATCC and cultured according to instructions. The expression of the CASP8 gene was stably knocked out in the HeLa cells by targeting two distinct regions within its Exon 1. Positive clones were confirmed through sequencing. Transcription and proteome analysis was performed from non-synchronized (NS), and S/G2-phase synchronized HeLa cells. To identify caspase-8 interacting proteins, caspase-8 was immunoprecipitated (IP) from non-synchronized (NS) and S/G2-phase synchronized HeLa cells. Co-immunoprecipitates (Co-IP) were loaded in a 12% SDS-PAGE gel. After Coomassie staining, the lanes in the gel were excised into individual fragments and prepared for liquid chromatography-mass spectrometric (LC-MS) analysis. For IHC staining, a total of 69 patients with uterine cervix squamous cell carcinoma treated with definitive chemoradiotherapy/brachytherapy (CRT/BT) at the Department of Radiotherapy and Oncology of the University Hospital Frankfurt, who provided informed consent and after an institutional review board approval. Results: Our study identified a novel mechanism where nuclear caspase-8 directly interacts with and inhibits the activity of cyclin dependent kinase 9 (CDK9), thereby modulating RNA polymerase IIA (RNAPII)-mediated global transcription, including those of cell-migration- and cell-invasion-associated genes, such as stomatin (STOM), transglutaminase-2 (TGM2), and Na+/H+ exchange regulatory factor 1 (NHERF1) as confirmed by transcriptomic analysis. Furthermore, low caspase-8 expression in cervical and ovarian cancer patients leads to poor prognosis, higher CDK9 phosphorylation at Thr186, and increased RNAPII activity in cervical cancer cell lines and patient biopsies. In addition, caspase-8 knock-out cells were also more resistant to the small-molecule CDK9 inhibitor BAY1251152 in both 2D- and 3D-culture conditions. However, combining BAY1251152 with cisplatin synergistically overcame the chemoresistance of caspase-8-deficient cervical cancer cells. Finally, we found that the loss of caspase-8 enhances metastasis in vivo in ovarian cancer orthotopic mouse model. Conclusion: Our investigation has uncovered a novel and crucial role for caspase-8 in mediating transcription elongation by modulating the enzymatic activities of CDK9 and RNAPII. These findings suggest that the protein expression profile of caspase-8 could serve as a predictive biomarker for cervical cancer patients. Notably, caspase-8’s anti-metastatic function appears to be independent of its role in apoptosis, instead relying on transcriptional regulation. Further analysis of primary cervical cancer patient-derived tissues confirmed a significant correlation between high Caspase-8 expression and low CDK9 Thr186 phosphorylation, as well as low RNAPII Ser2 phosphorylation. In conclusion, our study supports the evaluation of CDK9 inhibitors in advanced and resistant cervical and ovarian cancer, emphasizing the importance of rigorously assessing caspase-8 expression and patient stratification to guide successful clinical implementation of CDK9-based targeted strategies in various cancer types.

Key Words: Caspase-8, non-apoptotic function, transcription, CDK9, RNAPII, chemoresistance, metastasis.

METASTATIC BREAST CANCER: PROGNOSTIC FACTORS OF SURVIVAL AND THE DIFFERENCE BETWEEN DE NOVO AND RECURRENT DISEASE

KIM ROMMEL, JOHANNES ETTL, MARION KIECHLE and HOLGER BRONGER

Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University Munich (TU), Munich, Germany

Background/Aim: The objective of this retrospective study was to determine whether there are differences in survival between patients with de novo, early and late recurrent metastatic breast cancer (MBC). Patients and Methods: A total of 538 women with MBC undergoing treatment at the hospital of the Technical University Munich between 1993 until 2020 were identified and analyzed based on initial presentation and course of the disease. Overall survival (OS) was estimated using Kaplan–Meier method and log-rank test was used to compare OS across the groups. Cox proportional hazards model was used to determine the prognostic impact of metastatic site, fist-line therapy and adjuvant therapy. Results: Overall, 229 women had de novo MBC and 309 had recurrent MBC, including 70 women with early recurrent MBC (metastatic-free survival ≤2 years) and 239 women with late recurrent MBC. Median OS among patients with de novo, early and late recurrent MBC were 3.5, 1.3 and 4 years, respectively (p<0.001). In the multivariable model, women with endocrine therapy as first-line therapy had a reduced risk of death compared to those not receiving such therapy (hazard ratio=0.54, p=0.002). Median progression-free survival (PFS) was observed to be 1.1 years among all patients. Among women with PFS ≤1.1 and PFS >1.1 years, OS was estimated to be 1.5 and 5.7 years, respectively (p<0.001). Conclusion: Patients with early recurrent MBC and short PFS had a significantly worse OS. Thus, patients with de novo MBC, late recurrent MBC, and patients with a long PFS in first-line therapy had a better prognosis. This large cohort study provides a valuable tool in future prognosis assessments and treatment decisions.

Key Words: De novo metastatic breast cancer, recurrent metastatic breast cancer, survival, prognostic factors, site of metastasis.

DEEP-LEARNING-BASED LOCALIZATION OF BREAST BIOPSY MARKER IN ULTRASOUND DATA

RAHUL KODARAPU¹, TORSTEN FASSBENDER¹, MATTEA REINISCH², PAULA SUDIKATUS², JAN RIEGER¹ and SHERKO KÜMMEL²

¹Aura Health Technologies GmbH, Berlin, Germany;

²Kliniken Essen Mitte, Essen, Germany

Background/Aim: Breast biopsy markers (BBMs) are placed after image-guided breast biopsy of a suspicious imaging finding per standard of care. A technology that would support BBM localization in standard ultrasound would accelerate the search for BBMs in follow-up procedures and would enable intraoperative localization of lesions during breast-conservative surgery. The aim of this study was to investigate the ability to perform automated localization and highlighting of BBMs in ultrasound data in real time. Patients and Methods: We collected ultrasound data from ~100 breast biopsy patients and manually annotated the position of the BBM in the reconstructed b-mode images. The data were split 80:20 into training and testing datasets. Established algorithms for image-based object detection were implemented and their suitability for automatic localization of BBMs in ultrasound-data was tested. To achieve the best possible accuracy, extensive hyperparameter tuning was performed in combination with transfer-learning, and variable regularization procedures were applied. The procedures are intended to be used for intra-operative navigation and therefore must be able to provide the result in real time. To achieve this, runtime optimization was achieved using different methods for parameter reduction and quantization. Quantitative evaluation metrics were average false-positives per image (FPPI), sensitivity, and average frames per second rate. Results: A sensitivity of 0.62 at an FPPI of 0.001 was achieved; the marker was detected and localized correctly in 62% of the annotated test frames, with on average only one false-positive detection per 1,000 frames. The software was tested on an Intel^® Core™ i7-10510U with an Intel^® UHD Graphics Processor where it ran at 50 frames per second and so is usable in a scenario with real-time requirements. Conclusion: This research demonstrates that machine learning-based detection of BBMs in ultrasound images is possible. Algorithms developed for object detection in camera images can be adapted to ultrasound data and successfully used to detect and localize BBMs.

Key Words: Breast-conserving therapy, intraoperative ultrasound, localization, biopsy marker, machine learning.

TiLOOP^® BRA POCKET SUPPORTED PRE-PECTORAL BREAST RECONSTRUCTION: 12 MONTHS FOLLOW-UP RESULTS FROM A PROSPECTIVE OBSERVATIONAL STUDY

STEFAN PAEPKE¹, EVELYN KLEIN¹, ANNE ANDRULAT², CHRISTINE ANKEL³, LELIA BAUER⁴, ANDREE FARIDI⁵, VISNJA FINK⁶, CLAUDIA GERBER-SCHÄFER⁷, DAPHNE GSCHWANTLER-KAULICH⁸, JOERG HEIL⁹, SHERKO KÜMMEL¹⁰, RALF OHLINGER¹¹ and MARC THILL¹²

¹Klinikum rechts der Isar, Klinik und Poliklinik für Frauenheilkunde, Technische Universität München, Munich, Germany;

²Interdisziplinäres Brustzentrum Rotkreuzklinikum, Munich, Germany;

³DRK-Kliniken Berlin, Berlin, Germany;

⁴GRN Klinik Weinheim, Zertifiziertes Brustzentrum Weinheim, Weinheim, Germany;

⁵Abteilung für Senologie mit zertifiziertem Brustzentrum, Universitätsklinikum Bonn, Bonn, Germany;

⁶Brustzentrum Universitätsklinikum Ulm, Ulm, Germany;

⁷Vivantes Klinikum am Urban, Brustzentrum, Berlin, Germany;

⁸Ordinationszentrum PK Döbling, Vienna, Austria;

⁹Brustzentrum Heidelberg, Klinik St. Elisabeth, Heidelberg, Germany;

¹⁰Brustzentrum Kliniken Essen Mitte, Essen, Germany;

¹¹Interdiziplinäres Brustzentrum Universitätsmedizin Greifswald, Greifswald, Germany;

¹²Brustzentrum Agaplesion Markus Krankenhaus, Frankfurt/Main, Germany

Background/Aim: Safety and breast aesthetics of direct-to-implant techniques are well recognized. Pre-pectoral techniques add a new dimension supported by the next generation of titanized mesh-pockets with high biocompatibility. Patients and Methods: A prospective international, multicenter observational investigation (PRO-Pocket-Trial clinicaltrials.gov: NCT03868514) is performed in 12 clinical centers in Germany and Austria. Patient reported outcome after TiLOOP^® Bra Pocket supported prepectoral breast reconstruction is assessed by the Breast-Q questionnaire. Furthermore, complications are documented. The results of the 12 months follow-up are presented. Results: From 06/2019 until 02/2021, 311 (age 23-80) patients with TiLOOP^® Bra Pocket supported breast reconstructions were included. The mean BMI was 24.6±4.5 kg/m². The most frequent indication for surgery was invasive ductal carcinoma followed by increased breast cancer risk. Breast-Q data are available for 261 patients. The mean score of the scales “satisfaction with breasts” and “psychosocial well-being” increased by 8.0±28 and 7.1±22.1 points, respectively, from prior surgery to 12 months follow-up. The mean score for “sexual well-being” increased by 3.3±23.0 points, while the mean score for “physical well-being chest” decreased by 2.1±15.3 points. Currently, 6.8% seroma, 5.2% capsular fibrosis, 3.6% wound healing disorders, 3.4% infections, 2.3% necroses, and 2.5% bleedings (needing revision) are documented. Conclusion: Use of TiLOOP^® Bra Pocket enables a new standard of pre-pectoral reconstructive techniques preserving the natural anatomy, thereby avoiding adverse effects associated with submuscular reconstruction and minimizing postoperative pain. Patient-reported outcome showed postoperative increased satisfaction with breast and psychosocial well-being.

Key Words: Pre-pectoral reconstructive techniques, patient-reported outcome, satisfaction.

THE SIGNIFICANCE OF THE LASER SHOCK-WAVE DESTRUCTION METHOD IN THE TREATMENT OF DYSTROPHIC DISEASES OF THE VULVA

MADINA UMAKHANOVA, ELENA POLUCHOVA, VICTOR YEZHOV, LAURA BOLOTAEVA and NATALYA AGNAEVA

A. I. Yevdokimov Moscow State Medical University of Medicine and Dentistry, Moscow, Russian Federation

Background/Aim: Vulva diseases, particularly dystrophic changes, correspond to the most sophisticated and least explored area of gynecology. The search of effective treatment methods of dystrophic diseases is one of the priorities in modern gynecology and is conditioned by the unsatisfactory results of treatment, and the long, recurrent course of disease, leading to social maladaptation and life quality decrease. This study aimed to estimate the effectiveness and significance of the shock-wave destruction method for treatment of dystrophic diseases of the vulva. Patients and Methods: The examination and treatment of 110 patients aged 28-78 years with dystrophic diseases of the vulva were analyzed. The diagnosis of planocellular hyperplasia in all cases was confirmed by means of morphological changes of the biopsy materials. The treatment was applied using the laser set ‘Lasermed 10-01’ (Russian Federation) combined with photoactivating gel. Innovational characteristics of the method are based on the selective possibility of the local layerwise destruction of the bio-tissue with adaptive dosing according to the width and depth of the destructive exposure. Results: The disease duration among all the tested women reached values from 1 to 6 years (average value 2.4 years). The main complaints were: itchiness (permanent) in 90%, dyspareunia in 95%, vulvodynia in 80%, dysuric disorders in 75% of cases. The majority of the patients were admitted with two or more symptoms, which led to a significant decrease in quality of life. All the patients had treatment using laser shock-wave destruction of the vulva. As a result, all 110 patients had full disappearance of the basic symptoms (itchiness in the vulva area and vulvodynia). Seventy-eight patients (70.9%) had stable remission of the disease 24 months after treatment. This method has many advantages: absence of injuries on the surrounding unexposed tissues, fast epithelization, shortening of the rehabilitation period, good cosmetic effect, and low recidivation frequency. Conclusion: The use of the laser shock-wave destruction showed its high effectiveness and significance in the treatment of patients with planocellular hyperplasia of the vulva.

Key Words: Dystrophic diseases of vulva, laser shock-wave destruction method.

NEOADJUVANT CHEMOTHERAPY IN THE COMPLEX TREATMENT OF PATIENTS WITH STAGE IIIC – IV OVARIAN CANCER

ANNA KRYZHANIVSKA^1,2, IRYNA DJAKIV^1,2 and ROMAN HRYTSYK¹

¹Ivano Frankivsk National Medical University, Ivano-Frankivsk, Ukraine;

²Prykarpatski Clinical Oncological Center of Ivano-Frankivsk Redional Council, Ivano-Frankivsk, Ukraine

Background/Aim: To compare the results of interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT) with those of primary debulking surgery (PDS) in patients diagnosed with stage IIIC-IV ovarian cancer (OC) and to determine the recurrence-free survival and overall survival of patients. Patients and Methods: A total of 114 patients with stage IIIC and IV OC treated with NACT/IDS or PDS between 2017 and 2021 were retrospectively reviewed. Patients were divided into two groups: NACT/IDS (n=48) and PDS group (n=66). Characteristics of the patients are shown in Table I. Postoperative characteristics are shown in Table II. Results: NACT followed by IDS does not affect the recurrence-free and overall survival of patients with locally advanced OC compared to patients who underwent PDS. However, NACT provides the opportunity to achieve optimal and suboptimal cytoreduction in patients with more advanced OC lesions. Conclusion: In patients with stage IIIC-IV OC, the NACT/IDS group does not have significantly better recurrence-free survival compared to patients in the PDS group.

HIGH-GRADE SEROUS OVARIAN CANCER PATIENT-DERIVED ORGANOIDS APPLICABLE FOR IN VIVO MODELS OF EMERGENCE OF RESISTANCE TO ANTI-VEGF TREATMENT

LILIIA HLADCHENKO, MIRJANA KESSLER, FABIAN TRILLSCH, ALEXANDAR BURGES, BASTIAN CZOGALLA, FABIAN KRAUS, SVEN MAHNER and ANCA CHELARIU-RAICU

Department of Obstetrics and Gynecology, CCC Munich, LMU University Hospital, Munich, Germany

Background/Aim: Standard first-line treatment for ovarian cancer includes carboplatin-based chemotherapy to which the majority of the patients are highly responsive, followed by maintenance therapy with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and/or poly (ADP-ribose) polymerase inhibitors (PARPi). MACC1 is a transcriptional regulator reported to be involved in tumor angiogenesis. In this study, we utilized high-grade serous ovarian cancer (HGSOC) patient-derived organoids (PDOs) to develop a model that potentially could be used for studying the role of MACC1 in the emergence of resistance to anti-VEGF therapy. Materials and Methods: Ovarian cancer cell lines and phenotypically and genotypically validated PDOs from primary tumor deposits of HGSOC, were used as a model to study bevacizumab response in vitro by combining reverse transcription–polymerase chain reaction, western blotting, and tube formation assay. Selected cell lines, including CAOV3 and WiDr, and PDOs were chronically exposed (2 and 3 months) to bevacizumab in vitro to develop bevacizumab-adapted cell lines and PDOs. Subsequently, we collected conditioned medium from the above-mentioned ovarian cancer cell lines and PDOs and used it in angiogenesis assays. Human umbilical vein endothelial cells were isolated by a collagenase treatment from the umbilical vein. Results: Expression of MACC1 was downregulated in the bevacizumab-adapted cells after 2 and 3 months of exposure to bevacizumab. In contrast, bevacizumab-adapted PDOs showed that MACC1 was upregulated after 2 and 3 months of chronic exposure to bevacizumab. MACC1 in bevacizumab-adapted cell lines and PDO was correlated to total tube length, the number of nodes, and junctions evaluated by tube formation assays. Conclusion: Chronic exposure of HGSOC PDOs to bevacizumab increased the expression of MACC1, while the opposite was observed in ovarian cancer cell lines. Our study shows that PDOs are reliable models to study the emergence of resistance to anti-VEGF therapy.

THE CLINICAL RELEVANCE OF FRACTIONAL CURETTAGE IN pT2 STAGE PRIMARY ENDOMETRIAL CANCER

MARIA LAURA FRIEDRICH¹, MARIUS LÖFFLER¹, INNA SHEHAJ^2,3, BAHAR GASIMLI¹, THOMAS KARN¹, MOURAD SANHAJI¹, SVEN BECKER¹, MORVA TAHMASBI-RAD¹ and KHAYAL GASIMLI¹

¹Department of Obstetrics and Gynecology, JWG University, Frankfurt am Main, Germany;

²Department of Obstetrics and Gynecology, Jung-Stilling-Hospital, Siegen, Germany;

³Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany

Background/Aim: Hysteroscopy and fractional curettage are standard in diagnosing abnormal postmenopausal bleeding and histological confirmation of primary endometrial cancer (EC) in Germany. This study examined the clinical usefulness of obtaining preoperative endocervical tissue in parallel with corpus fractions by fractional curettage. Patients and Methods: Eighty-four patients with T1-stage EC and 55 patients with T2-stage EC who underwent primary surgery between 2011 and 2021 in the University-Hospital Frankfurt or Jung-Stilling-Hospital Siegen were included in this retrospective study. Postoperative T2-stage EC patients were divided into two groups: preoperative endocervical curettage negative versus positive in fractional curettage. For the comparison of categorical and continuous variables, the Pearson-Chi-square test was applied, and for the multivariate analyses and the regression models, the Kaplan–Meier method and Cox regression models were used, respectively. Results: The median age of pT2-stage patients was 64 years (range=38-85 years), and most patients had an endometrioid subtype of EC (90.9%). The comparison analysis for groups indicated significantly more laparotomies (p=0.002) in patients with preoperatively detected endocervical involvement. Other clinicopathological factors showed no significant difference. Sensitivity and specificity to identify endocervical involvement with fractional curettage were 70.9% and 73.8%, respectively. In multivariate analysis, age at diagnosis (p=0.004), endocervical invasion in preoperative cervix curettage (p=0.006), grading (p=0.006), and FIGO (p=0.024) were prognostic factors for overall survival (OS). Prognostic factors for progression-free survival were age at diagnosis (p=0.035), endocervical invasion in preoperative cervix curettage (p=0.049), and grading (p=0.042). A statistically significant difference for OS (p=0.013) was found between preoperative endocervical curettage positive and negative patients. Conclusion: Preoperative determination of endocervical involvement of primary T2-stage EC could be used as a prognostic indicator in decision-making for the treatment of EC. Performing a separate endocervical curettage is a financial burden on the healthcare system with its lack of therapeutic consequences.

Key Words: Endometrial cancer, pT2-stage, fractional curettage, preoperative diagnostic, endocervical invasion, prognostic indicator.

CERVICAL CANCER BEYOND HPV: NEUROENDOCRINE-NEUROECTODERMAL PHENOTYPE

MARTA CIAURRIZ GORTARI, LAURA LOPEZ MARÍN, BLANCA GIL IBÁÑEZ, CLAUDIA SANCHEZ-AREVALO CRESPO and GREGORIO LOPEZ GONZÁLEZ

Gynecology and Obstetrics Department, Hospital October 12, Madrid, Spain

Background/Aim: Neuroectodermal tumors (NETs) arise from neural crest cells. NET of the uterine cervix is a rare entity, with less than 30 cases described at present. The aim of this presentation is to report a clinical case of NET of the cervix and to discuss its presentation, diagnosis, and therapeutic management. Case Report: A 45-year-old woman consulted for persistent vaginal bleeding of two-month duration. Physical examination revealed a 5 cm friable exophytic mass on the anterior lip of the cervix, with biopsy results showing a high-grade malignant neoplastic proliferation of undifferentiated round blue cells. The woman was HPV negative. Imaging tests (transvaginal ultrasound, MRI, and PET/CT) were performed, reaching the diagnosis of neuroendocrine tumor of the cervix of neural type, radiological stage IIIC1 (Figure 1). Hysterectomy, double adnexectomy and bilateral pelvic lymphadenectomy were performed, with debulking of the lymphadenopathy over the left common iliac artery and minor lymph nodes (Figure 2). The definitive study of the surgical specimen confirmed the diagnosis of a poorly differentiated high-grade malignant neoplasm of the cervix with a neuroendocrine-neuroectodermal phenotype, with all the suspicious lymphadenopathies showing metastasis. A PET/CT scan was performed prior to the start of adjuvant therapy, showing tumor recurrence in the iliac lymph node chains, liver, and bone pelvis. Chemotherapy (6 cycles) and pelvic and para-aortic radiotherapy were completed. The patient is currently in remission and without active treatment. Conclusion: Neuroectodermal tumor of the cervix is rare but should be included in the differential diagnosis of pelvic masses of cervical origin. Diagnosis and treatment are challenging, and a multidisciplinary approach is important. The long-term prognosis is poor, especially in patients with advanced disease at diagnosis.

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Figure 1.

Sagital abdomino pelvic magnetic resonance imaging.

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Figure 2.

Surgical specimen.

Key Words: Cervical cancer, neuroectodermal, neuroendocrine.

THE INFECTION OF HPV IN MALES IS RELATED TO THE ACQUISITION OF HPV EVENTS IN FEMALES IN HETEROSEXUAL COUPLES

YUXUAN HUANG#, YAFANG KANG#, YE LI, LIANGZHI CAI, QIBIN WU, DABIN LIU, XIAODAN MAO, LEYI HUANG, KELVIN STEFAN OSAFO, YAN ZHANG, SHUXIA XU, BINHUA DONG and PENGMING SUN

Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, P.R. China

^#These Authors contributed equally to this work.

Background/Aim: Few studies have focused on the impact of human papillomavirus (HPV) infection in male partners on female HPV infection and cervical lesions. The purpose of this study was to evaluate the impact of the HPV infection pattern of male partners on cervical HPV infection and lesions in females. Patients and Methods: We conducted a cross-sectional survey of genital HPV infection in 251 monogamous couples who attended the outpatient department of Fujian Maternal and Child Health Hospital from 2013 to 2021. HPV type analysis was performed on exfoliated cells of the female cervix and male urethra by the PCR-reverse dot blot method. Subsequently, the risk of HPV infection in male partners for females was analyzed. Results: In 251 couples, the most commonly detected high-risk HPV (HR-HPV) genotypes were 52, 51, 16, and 58 for males and 52, 16, 18, and 58 for females. Females with HPV-positive partners had higher infection rates for most HR-HPV genotypes. HR-HPV infection in males was a risk factor for the development of cervical lesions in females (OR=2.250, p=0.014). Both single-type (OR=2.085, p=0.040) and multiple-type (OR=2.751, p=0.036) infections in males promote the female partner’s susceptibility to non-HR-HPV and the progression of cervical lesions. Conclusion: Male HPV infection increases the burden of non-HR-HPV infection and the risk of cervical lesions in females. This is a significant public health information. It may provide a reference for cervical cancer prevention in females and HPV vaccination in males.

Key Words: Human papillomavirus, heterosexual couples, prevalence, concordance, sexually transmitted infection.

UPDATE IN ENDOCRINE AND TARGETED THERAPY IN ESTROGEN-RECEPTOR POSITIVE, HER2 NEGATIVE BREAST CANCERS

IZQUIERDO DE LA FUENTE JOANA, GIL IBAÑEZ BLANCA, CONTI NUNO, BEATRICE, BELTRÁN PARRA LAURA, LIZANA FERNANDEZ GUILLERMO, ARAGON SANCHEZ SOFIA and SANZ FERRANDEZ MARIA CONSUELO

Department of Obstetrics and Gynecology, Hospital 12 October, Madrid, Spain

Background/Aim: 70% of all breast cancers belong to the estrogen receptor positive – also known as luminal - subtype of tumors. Their treatment in early stages is based on Tamoxifen or aromatase-inhibitors (AI) therapy. Most of these cancers acquire resistance to such treatments, causing disease progression. Advances in molecular biology have led to a revolutionary development of new treatments, improving the prognosis of both pre- and post-menopausal women. The objective of this study was to introduce the new drugs that have been approved for the treatment of luminal breast cancers in different settings. Materials and Methods: A bibliographical research via PubMed was performed, using as keywords the following: hormone receptor + breast cancer and targeted therapy. The most relevant studies were included in this review (Table I). Results: Different target agents such as mTOR, PIK3 inhibitors, and CDK4/6 inhibitors have been approved for their use in metastatic stages of breast cancer. The latest studies have shown that treatment with PIK3 inhibitors, such as Alpelisib, with Fulvestrant or Exemestane increased the overall survival (OS) and progression-free survival (PFS) in postmenopausal patients. Moreover, CDK4/6 inhibitors have changed the natural history of this disease; Palbociclib, Ribociclib, and Abemaciclib in association with endocrine therapy have improved the OS, PFS, and life quality in both pre- and post-menopausal patients, showing minimal side effects. Currently there are phase II and III clinical trials exploring the usefulness of Ribociclib as neoadjuvant therapy in order to diminish the need for chemotherapy. Conclusion: CDK4/6 inhibitors and other treatments have been demonstrated to be effective as adjuvant therapies for breast cancer. However, protocolized first- and second-line treatment strategies depending on the stage of the disease should be established.

Key Words: Target therapy, luminal breast cancer, Ribociclib, Abemaciclib, CDK4/6 inhibitors.

PRIMARY TUMOR SURGERY IN METASTATIC BREAST CANCER: SURVIVAL ANALYSIS

FERNANDEZ LIZANA GUILLERMO, GIL IBAÑEZ BLANCA, IZQUIERDO DE LA FUENTE JOANA, CONTI NUNO BEATRICE, BELTRÁN PARRA LAURA, SANZ FERRANDEZ MARIA CONSUELO, ARAGON SANCHEZ SOFIA and ALVARO VALIENTE LAURA

Department of Obstetrics and Gynecology, Hospital 12 October, Madrid, Spain

Background/Aim: Six percent of women with breast cancer present metastases at the time of diagnosis. The aim of this study was to analyze the impact of loco-regional surgery on survival in women with metastatic breast cancer at diagnosis. Patients and Methods: This was an observational, descriptive, and retrospective study. Results: The number of women diagnosed with metastatic (early) breast cancer who underwent surgery in our center between 2011 and 2021 was 32. The median overall survival was 55.50 months and disease-free survival was 16 months. Regarding immunohistochemistry: 37% were luminal B tumors, 17% HER2-luminal, 17% luminal A, 17% pure HER2, and 12% triple negative. 29.2% underwent conservative surgery and 70.8% underwent radical surgery, ensuring free margins in 91.7% of the women. Statistically significant differences were found according to tumor phenotype (Log Rank test p=0.015). However, no statistically significant differences were found according to the location of the metastases (bone vs. visceral +/− bone; Log Rank test p=0.508) or the age of the patients (younger vs. older than 50 years; Log Rank test p=0.925). Conclusion: Surgery of the primary tumor in metastatic breast cancer at the time of diagnosis is a topic of interest, as retrospective studies published to date have observed an increase in survival. Randomized clinical trials are needed to support these results and the therapeutic approach to women should remain individualized and discussed in a multidisciplinary committee.

Key Words: Metastatic breast cancer, loco-regional surgery, tumor phenotype.

A RARE CASE OF OVARIAN FIBROSARCOMA IN A YOUNG LADY WITH COMPLETE REMISSION

BETHEL DEREJE and WONDIMU GUDU

Department of Obstetrics and Gynecology Saint Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia

Background: Ovarian fibrosarcoma is an extremely rare malignant sex cord-stromal tumor. It is common in menopausal and postmenopausal women and is associated with an extremely poor prognosis. Case Report: A 25-year-old nulliparous woman presented to our hospital with abdominal swelling and pain. On physical examination, a 30 cm by 25 cm sized cystic, mobile, non-tender abdominopelvic mass was identified. On bimanual examination, the mass could not be felt separate from the uterus. Tumor markers were: Cancer antigen-125=32.68 iu, carcinoembryonic Antigen=0.7 iu, lactate dehydrogenase=400 iu, and urine human chorionic gonadotrophin was negative. Computed tomography (CT) scan revealed a heterogeneous mass measuring 19×10×7 cm with central blood flow. Laparotomy was then performed. Intraoperative findings were: a 28 cm sized left ovarian mass with fine adhesion with the uterus, bladder, and small ascites. Left salpingo-oophorectomy was performed. The histopathological diagnosis was ovarian fibrosarcoma; fluid cytology was negative. After 5 months of disappearance from follow up she presented with abdominal pain. Computed tomography (CT) scan showed nodular solid masses in Douglas pouch and right adnexal mass measuring 1.8×3.9 cm and perihepatic nodular metastasis measuring 1.3×3.0 cm with ascites. A second surgery was decided and total abdominal hysterectomy, right salpingo-oophorectomy, pelvic mass resection, total omentectomy, subdiaphragmatic mass resection, and para-aortic lymph node sampling were performed. Histopathology report of the pelvic mass was consistent with ovarian fibrosarcoma. Other samples were negative for malignancy. She then completed 6 cycles of paclitaxel and Ifosphamide and has been under surveillance for the past 4 years. She is currently asymptomatic, and a repeat abdominopelvic CT scan performed a year ago showed no evidence of disease. Conclusion: Advanced ovarian fibrosarcoma in a young woman is extremely rare. Maximal surgical effort with adjuvant chemotherapy is associated with improved oncologic outcomes.

Key Words: Ovary, fibrosarcoma, complete remission.

INTRAOPERATIVE FROZEN SECTION IN GYNECOLOGIC ONCOLOGY SURGERIES: INDICATIONS, FINDINGS, AND ACCURACY: EXPERIENCE FROM A NOVICE CENTER IN ETHIOPIA

WONDIMU GUDU, BEREKET BERHANE, BETHEL DEREJE and TADESSE URGIE

Department of Obstetrics and Gynecology, Saint Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia

Background/Aim: Intraoperative frozen section analysis provides surgeons with information that guides appropriate treatment. The aim of the study was to describe the pathologic findings of frozen section specimens & determine their accuracy in the first ever national experience of the practice at a teaching hospital in Ethiopia. Materials and Methods: This cross-sectional study was conducted from September 2021 to May 2022. Data were analyzed using SPSS 23.1 software. Overall accuracy, sensitivity, and specificity of frozen sections were calculated. Results: Intraoperative frozen section samples were obtained from 76 patients during the study period. The age of the patients was between 18 and 72 years (average 41 years). Most (56%) were parous. The average turnaround time was 25 min and more than 30 min in 39% of the cases. The samples were adnexal in 86%; uterine in four, and lymph nodes in three. Among the ovarian samples, most (78.5%) had a diagnosis of benign, followed by malignancy (27.6%). Four (4/65) had a frozen report of borderline. The most common benign pathology reported was serous cyst adenoma (41%), followed by dermoid cyst (15.7%), while serous cyst adenocarcinoma was the commonest (73%) malignancy reported. The overall accuracy of frozen sections for the detection of benign, borderline, and malignant neoplasms was 90%. The sensitivity and specificity of the detection of benign tumors was 94% and 90%, respectively; whereas it was 75% and 94% for borderline and 89% and 95% for malignant tumors, respectively. Conclusion: The overall accuracy of the frozen section at this novice center was comparable to reports from most international centers. Hence, it can be used for intraoperative decision making in the facility. Expanding the scope of the practice to other gynecologic indications and improving the turnaround time are imperative.

Key Words: Frozen section, intraoperative, gynecology, surgery, accuracy.

TUCATINIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC HER2+++ BREAST CANCER WHO RECEIVED AT LEAST TWO PRIOR ANTI-HER2 TREATMENT REGIMENS: STUDY DESIGN OF THE NON-INTERVENTIONAL STUDY TRACE IN GERMANY AND AUSTRIA

NADIA HARBECK¹, RUPERT BARTSCH², VOLKMAR MÜLLER³, MARIJA BALIC⁴, DANIEL EGLE⁵, EVA SCHUMACHER-WULF⁶, MORITZ ANGERER⁷, ARND NUSCH⁸, CHRISTOPH ULEER⁹, MANFRED WELSLAU¹⁰, JULIA RADOSA¹¹, DENISE WROBEL¹², REBECCA DE BUHR¹³, MARTIN GLASSTETTER¹³, JOHANNA HANSELMANN¹³, CATHRIN HOGREFE¹³, NORBERT MARSCHNER¹³, KATJA GRATZKE¹³ and ANJA WELT¹⁴

¹Klinikum der Universität München, München, Germany;

²Medizinische Universität Wien, Wien, Austria;

³Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany;

⁴LKH-Univ. Klinikum Graz, Graz, Austria;

⁵Medizinische Universität Innsbruck, Innsbruck, Austria;

⁶Mamma Mia – Die Krebsmagazine, atp Verlag GmbH, Köln, Germany;

⁷Schwerpunktpraxis Hämatologie & Internistische Onkologie, Fürth, Germany;

⁸Praxis für Hämatologie und internistische Onkologie, Ratingen, Germany;

⁹Praxisgemeinschaft Gynäkologische Onkologie & Spezielle Operative Gynäkologie, Hildesheim, Germany;

¹⁰MVZ am Klinikum Aschaffenburg GmbH, Aschaffenburg, Germany;

¹¹Universitätsklinikum des Saarlandes, Homburg (Saar), Germany;

¹²Sozialstiftung Bamberg Klinik für Frauenheilkunde und Geburtshilfe, Bamberg, Germany;

¹³iOMEDICO AG, Freiburg im Breisgau, Germany;

¹⁴Universitätsklinikum Essen, Essen, Germany

Background/Aim: Tucatinib (TUC), a highly selective HER2 tyrosine kinase inhibitor, in combination with trastuzumab (TRAS) and capecitabine (CAPE) has demonstrated in the pivotal HER2CLIMB trial a significant overall and progression-free survival benefit compared to placebo+TRAS+CAPE (1, 2) and has been approved in Europe for HER2+++ advanced breast cancer (ABC) patients (pts) after at least two prior anti-HER2 treatment regimens. TRACE will systematically collect data of pts treated with tucatinib according to the SmPC in two cohorts: a) pts treated in 1st/2nd and b) pts treated in 3rd/4th ABC treatment line. TRACE will gather information on patients underrepresented or excluded from the pivotal trial like elderly pts or pts treated with TUC+ TRAS+ CAPE in early ABC treatment lines. Additionally, TRACE will collect for the first-time data on treatment with TUC+TRAS+CAPE in pts after prior therapy with Trastuzumab-Deruxtecan in clinical routine. Patients and Methods: This non-interventional trial will enroll 300 pts with HER2+++ ABC scheduled to receive TUC+TRAS+CAPE according to SmPC in Germany and Austria (60 and 10 sites respectively). One hundred and fifty pts each (up to 30 Austrian pts each) will be enrolled into the 1st/2nd line and 3rd/4th line cohorts. Primary endpoint is time to deterioration of patient-reported global quality of life in EQ-5D-5L, EORTC QLQ-C30, and QLQ-BR23 questionnaires. Furthermore, all changes in the functional and symptom subscores in relation to baseline value will be analyzed. Another focus lies on effectiveness and safety. Physician decision making, details on TUC treatment, therapy management, and treatment sequences will be analyzed by descriptive statistics. TRACE will be accompanied by an international steering committee. Conclusion: TRACE will provide important real-world insights into TUC+TRAS+CAPE treatment of HER2+++ ABC pts with focus on quality of life. Effectiveness and safety will be assessed, and preplanned subgroup analyses will fill important knowledge gaps between the pivotal trial and routine clinical practice.

Key Words: HER2+++ breast cancer, ABC, anti-HER2 treatment, non-interventional, real-world, tucatinib, Germany, Austria.

1 Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W and Winer EP: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382(7): 597-609, 2020. DOI: 10.1056/NEJMoa1914609

2 Curigliano G, Mueller V, Borges V, Hamilton E, Hurvitz S, Loi S, Murthy R, Okines A, Paplomata E, Cameron D, Carey LA, Gelmon K, Hortobagyi GN, Krop I, Loibl S, Pegram M, Slamon D, Ramos J, Feng W and Winer E: Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol 33(3): 321-329, 2022. DOI: 10.1016/j.annonc.2021.12.005

DEVELOPMENT OF AN ONLINE PERSONALISED RESOURCE FOR THOSE IMPACTED BY GYNAECOLOGICAL CANCER IN PARTNERSHIP WITH PUBLIC AND PATIENT INVOLVEMENT

HELENA C. BARTELS¹, YVONNE O’MEARA^2,3, SHARON O’TOOLE³, NAOMICOONEY⁴ and DONAL J. BRENNAN^1,2

¹University College Dublin Gynaecological Oncology Group (UCD-GOG), Mater Misericordiae University Hospital and St Vincent’s University Hospital, Dublin, Ireland;

²Living Well Cancer Programme, School of Medicine, Catherine McAuley Research Centre, Mater Misericordiae University Hospital, Dublin, Ireland;

³Irish Society of Gynaecological Oncology Patient and Public Involvement, Dublin, Ireland; 4Placenta Accreta Ireland, Dublin, Ireland

Background/Aim: Early patient and public involvement (PPI) aims to ensure that research focusses on relevant issues; however, it is often biased by personal recollection and small sample sizes. We sought to develop an online personalized resource with relevant and reliable information to improve the health and wellbeing of women impacted by gynecological cancer in Ireland with PPI involvement from inception to completion. Patients and Methods: To ensure the PPI voice was present throughout the project, two separate PPI groups were approached and invited to take part in a series of workshops. Volunteers were sought through the Irish Society of Gynecological Oncology PPI group, inviting women with a history of gynecological cancer to partake. Secondly, in order to gain the perspective of those not impacted by gynecological cancer but have an understanding and experience of a life-threatening condition, a focus group was held with members of Placenta Accreta Ireland. Workshops were recorded, transcribed, and analyzed for thematic content. Results: PPI from those with the lived experience of gynecological cancer highlighted topics they found relevant, which focused on providing accurate scientific information. This included discussion and information on side effects of treatments at the time of diagnosis, details of clinical trials, and psychological support. Information on nutrition and exercise, menopausal symptoms, and fertility were also highlighted as central topics. However, the PPI workshop with Placenta Accreta Ireland focused more on the design and user-interaction of the online resource. There was emphasis on creating a resource that was warm and welcoming. A preference was voiced for animations instead of photos of people, to avoid alienating women at the time of their diagnosis. Conclusion: The exploratory workshops with the PPI groups facilitated a sharing of knowledge, resulting in an online personalized platform co-created by PPI and healthcare providers. The women’s voices and experiences were at the center of design and development, ensuring the resources are in keeping with the values and needs of the those impacted by gynecological cancer. PPI involving women without a personal history of gynecological cancer can help shape projects and provide key insights for project development.

Key Words: Public and patient involvement, education, gynecological cancer, survivorship.

VULVAR MELANOMA: REPORT OF A CLINICAL CASE

LAURA BELTRAN PARRA, BLANCA GIL IBAÑEZ, JOANA IZQUIERDO DE LA FUENTE, BEATRICE CONTI NUNO, GUILLERMO LIZANA FERNANDEZ, GLORIA GONZALEZ TRISTANTE, MARÍA CONSUELO SANZ FERRANDEZ, REYES OLIVER PEREZ and ÁLVARO TEJERIZO GARCÍA

Department of Obstetrics and Gynecology, Hospital 12 October, Madrid, Spain

Background/Aim: Gynecological melanomas are rare but aggressive tumors; the estimated 5-year overall survival is around 50%. The most common clinical presentation is a brown bleeding lump located in the vulvar area. The aim of this study was to determine the clinical, diagnostic, and therapeutical features of vulvar melanoma. Case Report: We present a 65-year-old woman with no relevant clinical background seeking consultation for the appearance of a 1 cm lump on the left labia minora. With an initial presumptive diagnosis of lichen sclerosus, a biopsy of the lesion was undertaken, revealing an anatomopathological (AP) diagnosis of “Clark level III lentiginous melanoma, 1.2 mm Breslow thickness”. Dissemination to other locations was ruled out by imaging techniques. Partial vulvectomy and sentinel lymph node biopsy were performed, with a final AP diagnosis of stage IIIC vulvar melanoma with micrometastases in both lymph nodes that were biopsied. BRAF and KIT were found to be wild-type, and thus a targeted therapy based on Nivolumab was initiated. Six months after the primary therapy – surgery – a tumor recurrence was detected in the cervix (Figure 1), with satellite lesions in the vagina. Radical surgery (hysterectomy + bilateral adnexectomy) was then attempted, followed by intracavitary brachytherapy. One year later, the patient was diagnosed with multiple lung and cerebral metastases, changing the treatment to Imatinib. Due to progression of the disease, Ipilimumab in association with palliative chemotherapy and holo-cranial radiotherapy were initiated, followed by the decease of the patient, 3 years after the initial diagnosis. Conclusion: The diagnosis of gynecological melanomas is based on anatomopathological features, requiring imaging techniques to determine the stage of the disease. Due to their aggressiveness, the approach should be multidisciplinary. The treatment of choice is surgery. In advanced stages, a mutational study is recommended, as well as adjuvant immunotherapy.

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Figure 1.

Recurrent melanoma of the uterine cervix.

Key Words: Vulvar melanoma, gynecological melanoma, immunotherapy.