Chemotherapy For Ovarian Cancer Research Articles

High-dimensional deconstruction of ovarian cancer at single-cell precision reveals HEBP2 that reshape the TIME and drive carboplatin resistance

BackgroundSingle-cell sequencing was employed to analyze the tumor immune microenvironment in ovarian cancer (OC) patients, exploring the evolutionary roles of various macrophage subgroups in OC progression and their correlation with fatty acid metabolism-related genes in contributing to drug resistance. MethodsThis study aimed to decipher the mechanisms underlying OC chemoresistance (OC-CR) and carboplatin resistance by integrating and analyzing multiple single-cell RNA sequencing datasets from OC patients. The tumor immune microenvironment in OC-CR patients exhibited notable alterations in cellular interactions and the proportions of different immune cell populations, in contrast to the cohort sensitive to OC chemotherapy. ResultsThe study demonstrates that the fatty acid-associated gene HEBP2 not only accelerates OC progression but also modifies the immune landscape of OC, driving the polarization from M0_TAM to M2_TAM. This shift results in a diminished efficacy of chemotherapy in OC. Furthermore, both in vitro and in vivo experiments underscored HEBP2′s role in boosting the proliferation of OC-resistant cell lines and suppressing apoptosis, thereby facilitating carboplatin resistance. ConclusionIn conclusion, the immune microenvironments of OC-CR significantly differ from those sensitive to chemotherapy, underscoring HEBP2′s role in fostering OC resistance. This establishes HEBP2 as a promising prognostic marker and a novel target for therapeutic strategies against OC resistance.

The Use of CA-125 KELIM to Identify Which Patients Can Achieve Complete Cytoreduction after Neoadjuvant Chemotherapy in High-Grade Serous Advanced Ovarian Cancer.

(1) Background: Neoadjuvant chemotherapy followed by interval debulking surgery is used in the treatment of advanced ovarian cancer. However, no tool can safely predict if complete cytoreduction after 3-4 cycles can be achieved. This study aims to investigate if the KELIM score can be a triage tool in the identification of patients that will be ideal candidates for interval debulking surgery (IDS). (2) Methods: We retrospectively analyzed the records of patients with high-grade serous advanced ovarian cancer that were treated in the 1st Department of Obstetrics-Gynecology, 2012-2022, with neoadjuvant chemotherapy followed by IDS. Patient characteristics, oncological outcome and follow-up information were collected. The primary outcome was the association of the KELIM score with residual disease. (3) Results: 83 patients were categorized into two groups: Group A (51 patients) with favorable (≥1) and Group B (32 patients) with unfavorable (<1) KELIM scores. A statistically significant correlation between KELIM and residual disease (p < 0.05) exists, showing that patients with a favorable KELIM score can achieve a complete IDS. Furthermore, there was a statistically significant difference in overall survival (p = 0.017), but no difference was observed in progression-free survival (p = 0.13); (4) Conclusions: KELIM seems to safely triage patients after neoadjuvant chemotherapy and decide who will benefit from IDS.

Abstract 6553: Targeting macrophages and regulatory T cells improves response to chemotherapy in high-grade serous ovarian cancer

Abstract Despite the initial response to chemotherapy, most high-grade serous ovarian cancer (HGSOC) patients will suffer disease relapse within two years of diagnosis with no currently successful immunotherapy options.We performed single-cell RNA sequencing (scRNAseq) on omental metastasis from HGSOC patients. Analysis of 64,097 immune cells showed that neoadjuvant chemotherapy (NACT) induced immunosuppressive mechanisms that counteracted its potentially positive effects. We showed that while NACT enhanced phagocytosis and antigen presentation, this was counterbalanced by upregulation of Stabilin1 (STAB1) in eight out of eleven macrophage subpopulations we identified. The NACT associated increase in macrophage STAB1 expression was validated in a separate cohort of eighty HGSOC patients at the protein level. STAB1 is a macrophage scavenger receptor that transports phagocytosed targets to undergo significant lysosomal degradation reducing the efficiency of antigen presentation. In vitro anti-stabilin1 antibody (anti-stab1 ab) -treated macrophages had significantly reduced antigen degradation and higher CD11C expression than isotype-treated ones. Furthermore, T cells co-cultured with anti-stab1 ab -treated macrophages had increased T cell proliferation and killing.We identified thirteen CD4 subpopulations by scRNAseq, five of which were Tregs. We showed that NACT significantly upregulated and activated Tregs. Tregs displayed a shared developmental trajectory with naïve and effector T cells suggesting that those are induced rather than natural Tregs. This was supported by TCR clonal sharing between Tregs and other effector cells. In vitro T cells treated with FOXP3 anti-sense oligonucleotide (ASO), AZD8701, had an anti-tumor cytokine profile and enhanced tumor cell killing. Analysis of 69,781 scRNAseq cells from control and chemotherapy-treated HGSOC syngeneic mouse model showed similar responses. In two HGSOC syngeneic mouse models (HGS2 and 30200), combinations of chemotherapy with anti-stab1 ab and/or Foxp3-ASO significantly increased median survival of mice with established peritoneal disease compared to chemotherapy alone. Bulk RNAseq of tumors treated with anti-stab1 ab were enriched with CXCL9 positive macrophages, while Foxp3-ASO treatment showed significant increase in T helper cell infiltration and activation. Potentially cured long-term survivors (300 days+) were resistant to tumor rechallenge.In a third HGSOC mouse model (60577), in which tumors relapsed after a good initial response to chemotherapy, combinations of chemotherapy with anti-stab1 ab and/or Foxp3-ASO significantly increased the post relapse survival compared to chemotherapy alone.We believe that modulating Tregs and STAB1 could improve response to chemotherapy and can have translational potential as each AZD8701 and a humanized anti-stab1 ab are in phase I clinical trials. Citation Format: Samar Elorbany, Chiara Berlato, Larissa Carnevalli, Simon Barry, Eleni Maniati, Jun Wang, Ranjit Manchanda, Julia Kzhyshkowska, Frances Balkwill. Targeting macrophages and regulatory T cells improves response to chemotherapy in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6553.

Abstract 980: Plasma tumor fraction is an independent prognostic marker of response to front line chemotherapy in high-grade serous epithelial ovarian cancer: The MITO-16a/MANGO-OV2a/clinical trial experience

Abstract Background. Although 80% of high grade serous ovarian cancer (HGSOC) patients are initially responsive to platinum (Pt)-based chemotherapy, the majority of them experience relapse with a progressive Pt-resistant disease. One of the most challenging issue that hampers the possibility to effectively treat relapsed disease is the lack of biological information about tumor recurrence. To date, the Pt-free interval (PFI), an empirical measure of the time lagging between the end of front-line chemotherapy and relapse, is the only and widely accepted parameter to predict patient outcome and sensitivity to Pt second-line chemotherapy. We have previously demonstrated that analysis of circulating tumor DNA (ctDNA) by low pass whole genome sequencing (sWGS) is a suitable tool to predict patient outcome and to intercept early signs of relapsed disease (Paracchini et al. PMID:33323403). In the present study, we quantified the percentage of tumor fraction (TF) in plasma of patients enrolled within the frame of a phase III clinical trial (MITO-16A/MaNGO-OV2A-EUDRACT number: NCT01706120) to demonstrate, at baseline, the prognostic value of untargeted ctDNA analysis. Methods. 172 eligible patients enrolled with the frame of the MITO-16A/MaNGO-OV2A clinical trial, for whom plasma sample was collected at chemotherapy before chemotherapy, were selected for the study. For each plasma sample, circulating-free DNA (cfDNA) was purified and whole genome libraries (HyperPlus, Roche) sequenced (mean coverage 0.5X). ichorCN algorithm was used to infer the percentage of TF, as previously published (Paracchini et al. PMID:33323403). Results. In 168 out of 172 plasma samples analyzed, the TF was detectable and it ranged from 2.4% to 47%. Cox-model univariate analysis with patients’ overall survival (OS) and Progression-Free Survival (PFS), indicates association of TF levels with both OS and PFS (p&amp;lt;0.001). The prognostic relevance of TF was also confirmed in multivariate analysis, where, considering CA-125, residual tumor, stage of disease, histology and age as co-variables, TF maintained its statistical significance in PFS (HR = 2.1, CI 95%, p-value &amp;lt; 0.003). Conclusion. Retrospective analysis of baseline plasma samples collected within the frame of the MITO-16A/MaNGO-OV2A clinical trial, demonstrated that the percentage of TF is an independent prognostic marker of relapse. This finding confirms the importance of liquid biopsy analysis based on untargeted sWGS tool as an innovative approach to predict response to front line therapy and patient’s outcome Citation Format: Sergio Marchini, Lara Paracchini, Laura Arenare, Giovanni Scambia, Carmela Pisano, Riccardo Zadro, Laura Mannarino, Annamaria Ferrero, Paolo Chiodini, Daniela Califano, Sandro Pignata, Maurizio D'Incalci. Plasma tumor fraction is an independent prognostic marker of response to front line chemotherapy in high-grade serous epithelial ovarian cancer: The MITO-16a/MANGO-OV2a/clinical trial experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 980.

Abstract 126: Effect of active cytomegalovirus infection on symptoms of fatigue, cancer-related cognitive impairment, and peripheral neuropathy in ovarian cancer survivors

Abstract Background: Fatigue, cancer-related cognitive impairment (CRCI) and neuropathy are among the most common and distressing side effects reported by individuals treated with chemotherapy for ovarian cancer. Cytomegalovirus (CMV) is a highly prevalent herpes virus infection worldwide, affects inflammation and immune function, and can reactivate with treatment for cancer. This study aimed to explore the associations between active CMV infection and patient-reported symptoms among ovarian cancer survivors who have completed front-line chemotherapy. Methods: We conducted a cross-sectional study among individuals with a history of a diagnosis of ovarian cancer, primary peritoneal cancer, or fallopian tube cancer from academic and community cancer clinics in Minnesota at any time point after completion of front-line chemotherapy. Participants completed a one-time survey and provided a blood sample. The exposure of interest was plasma CMV DNA level measured using digital PCR, with ≥100 copies/mL of plasma considered active infection (CMV+). We measured symptoms of fatigue (Fatigue Symptom Inventory), CRCI (PROMIS Cognitive Function 8a) and peripheral neuropathy (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity) using validated self-reported measures. Data were analyzed using descriptive statistics and compared by active CMV infection status (CMV+ vs. CMV-) in the full group and by treatment status (receipt of chemotherapy within 30 days prior to data collection) using t-tests. Results: A total of 160 participants were analyzed. Participants were median of 64.0 years old and 2.3 years from initial diagnosis. Most (75.2%) had advanced stage disease, 43.8% had experienced at least one recurrence, and 40.0% received chemotherapy within 30 days prior to participation. Overall, 40.0% were CMV+, with 40.6% CMV+ among those who received chemotherapy within 30 days and 39.6% CMV+ among those who had not. Participants who were CMV+, compared to those who were CMV-, had overall worse symptoms, with greater symptoms of neuropathy in the full group (11.9±9.2 vs. 9.1±7.8, p=0.04) and particularly greater symptoms of CRCI among those who had recently received chemotherapy (29.2±7.4 vs. 33.2±6.7, p=0.03). Conclusion: We identified that active CMV infection is common in this survivor population and found that worse symptoms of neuropathy and CRCI are associated with CMV+ status. These results are consistent with studies among other immune-compromised populations, and with further validation, provide a potential therapeutic path for reducing these symptoms. Citation Format: Xuan Li, Katherine Brown, Kate Honeyfield, Devon Hunter-Schlichting, Morgan Gruner, Deanna Teoh, Melissa Geller, Heather Nelson, Rachel I. Vogel. Effect of active cytomegalovirus infection on symptoms of fatigue, cancer-related cognitive impairment, and peripheral neuropathy in ovarian cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 126.

Abstract 639: Evaluation of individual drug response in tumor microenvironment to cisplatin treatment in precision-cut tumor slices of ovarian cancer

Abstract Ovarian cancer is a complex and heterogeneous disease and the major cause of death among women with gynecological cancers. While patients usually respond well to the platinum-based first-line chemotherapy, the disease often becomes increasingly resistant to the treatment. The tumor microenvironment (TME) plays an important role in tumor development and drug resistance. Characterizing the TME of ovarian cancer after drug treatment is essential to identify molecular mechanisms that allow residual tumor cells to survive chemotherapy in ovarian cancer. We have established a preclinical model using precision-cut tumor slices (PCTS) with 250 µm thickness which preserves the TME of solid tumors with their heterogeneous cell composition during cultivation. The tumor morphology, viability and heterogeneity in terms of tumor and stromal cells as well as the immune compartment are preserved within the system. Based on the PCTS model, we also established a method to perform single-cell RNA sequencing (scRNA-seq) of the PCTS after cultivation and drug treatment to characterize the cellular features and dynamic relationships of different cell populations in the TME after drug treatment. Over 20 cell subtypes including different clusters of epithelial cells, immune cells and fibroblasts can be identified in PCTS after cisplatin treatment through the scRNA-seq analysis. This enables further deeper analysis of each cell subgroup in the TME after drug treatment. In response to cisplatin treatment, patients PCTS showed an individual induction of PD-L1 in different cell types. Additionally, multiplex immunofluorescence (mIF) stainings of the PCTS were performed to spatially trace the response of the TME to drug treatment. The mIF staining allows the simultaneous detection of up to 6 different markers on one FFPE tissue section. Images were analyzed using a machine-learning based workflow, which allows the comparison of biomarker expression and immune cell spatial distribution in the PCTS stromal and tumor areas before and after treatment. Combining the PCTS as a preclinical model with scRNA-seq and mIF staining analysis allows us to bridge the cellular characteristics and cellular spatial distribution with treatment response in the TME of solid tumors. It enables the systematic analysis of residual cancer populations after cisplatin treatment within the complex TME and further identification of predictive markers and targets for an individualized combination of chemotherapy with compounds targeting these mechanisms. The individual drug response of patients can be deeply evaluated and efficacious therapies can be further developed. Citation Format: Julia Thiel, Adrian Kneer, Weimeng Yu, Bernd Winkler, Georg Sauer, German Ott, Walter E. Aulitzky, Thomas E. Mürdter, Matthias Schwab, Chunguang Liang, Meng Dong. Evaluation of individual drug response in tumor microenvironment to cisplatin treatment in precision-cut tumor slices of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 639.

Abstract 6785: KIYA-PREDICT™ XPDX: An ex vivo 3D spheroid platform for modeling in vivo responses to multiple classes of oncology therapeutics

Abstract Patient-derived xenografts (PDX) are a powerful and commonly used tool in preclinical drug development as they represent an in vivo platform for screening drug response in human tumors that recapitulate many molecular and histological features of the original patient tumor. However, these models are costly and time-intensive, necessitating the development of ex vivo platforms for assessing drug response to PDX-derived tumors to de-risk in vivo studies by aiding in model selection and reducing the number of animals and costs associated with in vivo experimentation. The KIYA-PREDICT™ platform is a clinically validated, ex vivo 3D cell culture platform with demonstrated ability to predict patient response to chemotherapy in high grade glioma and ovarian cancer. Here, we apply this platform to profiling XPDX from XenoSTART’s comprehensive library of well-characterized models as a tool for assessing drug response and mechanism of action ex vivo while also aiding in model selection for in vivo studies. Over 100 XPDX models have been profiled ex vivo for response to several classes of cancer therapeutics, including chemotherapy, targeted therapy, and antibody-drug conjugates (ADCs), demonstrating robust concordance with in vivo drug response. CDK4/6 inhibitors palbociclib and ribociclib evaluated ex vivo in breast XPDX display strong correlation to in vivo response and recapitulate palbociclib resistance. Similarly, G12C inhibitors sotorasib (AMG-510) and adagrasib (MRTX849) screened against a panel of non-small cell lung cancer XPDX ex vivo match in vivo response and drug resistance. Finally, ex vivo and in vivo responses to FDA approved ADC enfortumab vedotin were evaluated in a panel of bladder cancer PDX, with ex vivo and in vivo responses showing good concordance and expected modulation based on Nectin-4 expression levels. The combination of the KIYA-PREDICT™ platform with XenoSTART’s XPDX catalogue is a flexible and powerful tool that can be utilized for streamlining preclinical drug development for a wide range of therapeutic classes. Citation Format: Aaron L. Carlson, Natalie W. Dance, Kimberly J. Burgess, Danielle Y. Nadeau, Melissa Millard, Alyssa Simonson, Armando Diaz, Michael Wick, Teresa M. DesRochers. KIYA-PREDICT™ XPDX: An ex vivo 3D spheroid platform for modeling in vivo responses to multiple classes of oncology therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6785.

Peritumoral MRI Radiomics Features Increase the Evaluation Efficiency for Response to Chemotherapy in Patients With Epithelial Ovarian Cancer.

It remains unclear whether extracting peritumoral volume (PTV) radiomics features are useful tools for evaluating response to chemotherapy of epithelial ovarian cancer (EOC). To evaluate MRI radiomics signatures (RS) capturing subtle changes of PTV and their added evaluation performance to whole tumor volume (WTV) for response to chemotherapy in patients with EOC. Retrospective. 219 patients aged from 15 to 79 years were enrolled. 3.0 or 1.5T, axial fat-suppressed T2-weighted imaging (FS-T2WI), diffusion-weighted imaging (DWI), and contrast enhanced T1-weighted imaging (CE-T1WI). MRI features were extracted from the four axial sequences and six different volumes of interest (VOIs) (WTV and WTV + PTV (WPTV)) with different peritumor sizes (PS) ranging from 1 to 5 mm. Those features underwent preprocessing, and the most informative features were selected using minimum redundancy maximum relevance and least absolute shrinkage and selection operator to construct the RS. The optimal RS, with the highest area under the curve (AUC) of receiver operating characteristic was then integrated with independent clinical characteristics through multivariable logistic regression to construct the radiomics-clinical model (RCM). Mann-Whitney U test, chi-squared test, DeLong test, log-rank test. P < 0.05 indicated a significant difference. All the RSs constructed on WPTV exhibited higher AUCs (0.720-0.756) than WTV (0.671). Of which, RS with PS = 2 mm displayed a significantly better performance (AUC = 0.756). International Federation of Gynecology and Obstetrics (FIGO) stage was identified as the exclusive independent clinical evaluation characteristic, and the RCM demonstrated higher AUC (0.790) than the RS, but without statistical significance (P = 0.261). The radiomics features extracted from PTV could increase the efficiency of WTV radiomics for evaluating the chemotherapy response of EOC. The cut-off of 2 mm PTV was a reasonable value to obtain effective evaluation efficiency. 4 TECHNICAL EFFICACY: Stage 2.

Neoadjuvant chemotherapy for high-grade serous ovarian cancer: radiologic-pathologic correlation of response assessment and predictors of progression.

Neoadjuvant chemotherapy is often administered for high-grade serous ovarian carcinoma (HGSC) prior to cytoreductive surgery. We evaluated treatment response by CT (simplified peritoneal carcinomatosis index [S-PCI]), pathology (chemotherapy response score [CRS]), laboratory markers (serum CA-125), and surgical outcomes, to identify predictors of disease-free survival. For this retrospective, HIPAA-compliant, IRB-approved study, we identified 396 women with HGSC receiving neoadjuvant chemotherapy between 2010 and 2019. Two hundred and ninety-nine patients were excluded (surgery not performed; imaging/pathology unavailable). Pre- and post-treatment abdominopelvic CTs were assigned CT S-PCI scores 0-24 (higher score indicating more tumor). Specimens were assigned CRS of 1-3 (minimal to complete response). Clinical data were obtained via chart review. Univariate, multivariate, and survival analyses were performed. Ninety-seven women were studied, with mean age of 65years ± 10. Interreader agreement was good to excellent for CT S-PCI scores (ICC 0.64-0.77). Despite a significant decrease in CT S-PCI scores after treatment (p < 0.001), mean decrease in CT S-PCI did not differ significantly among CRS categories (p = 0.20) or between patients who were optimally versus suboptimally debulked (p = 0.29). In a survival analysis, lower CRS (more viable tumor) was associated with shorter time to progression (p < 0.001). A joint Cox proportional-hazard models showed that only residual pathologic disease (CRS 1/2) (HR 4.19; p < 0.001) and change in CA-125 (HR 1.79; p = 0.01) predicted progression. HGSC response to neoadjuvant therapy by CT S-PCI did not predict pathologic CRS score, optimal debulking, or progression, revealing discordance between imaging, pathologic, biochemical, and surgical assessments of tumor response.

Potential tools for predicting response to chemotherapy in OC: Assessment of immune dysbiosis, participant’s self-rated health and microbial dynamics

Epithelial ovarian cancer (OC) is the deadliest female reproductive cancer; an estimated 13,270 women will die from OC in 2023. Platinum-based chemotherapy resistance mechanisms contribute to poor OC 5-year survival rates. Peripheral inflammation is linked to various disease states and we previously identified unique peritoneal microbial features predictive of OC. We hypothesized that unique peripheral immune profiles and peritoneal microbial features may be predictive of disease-free interval (time to recurrence) and response to chemotherapy in participants with OC. We also investigated self-rated health (SRH) scores in the context of peripheral inflammation as a potential screening tool for OC. Blood and peritoneal fluid were collected from participants with OC or a benign adnexal mass (BPM). Lymphocyte populations were analyzed using Fluorescence Activated Cell Sorting, serum cytokine levels were analyzed using the Human Th17 Magnetic Bead Panel assay and peritoneal fluid microbial features were analyzed using Next Generation Sequencing (NGS). Participants completed a standardized questionnaire on self-rated physical and emotional health. Participants were classified into three chemotherapy response categories: platinum-refractory, platinum-resistant or platinum-sensitive. A significant positive correlation was found between elevated inflammatory status on the day of surgery and longer disease-free interval. SRH measures did not correlate with immune status in participants with OC or a BPM. We identified a correlation between peritoneal microbial features and chemotherapy response. We conclude that immune dysbiosis may be useful in predicting OC recurrence. The immune findings reported here set the framework for additional studies utilizing immune profiles to predict platinum-based chemotherapy responsiveness in OC.

Prospective validation of the role of PET/CT in detecting disease after neoadjuvant chemotherapy in advanced ovarian cancer.

The study aimed to compare the diagnostic accuracies of 2-[18F]FDG PET/CT and contrast-enhanced CT (ceCT) after neoadjuvant chemotherapy (NACT) in advanced ovarian cancer (OC). This study consisted historical observational cohort and prospective validation cohort. Patients with newly diagnosed stage III-IV OC scheduled for NACT were recruited, with imaging performed after three to six cycles of NACT before interval debulking surgery. Nineteen regions in the abdominopelvic cavity were scored for the presence and absence of disease, referenced to the intra-operative findings or histological specimens. Diagnostic metrics were compared using McNemar's test. In the historical cohort (23 patients, age 58 ± 13), 2-[18F]FDG PET had an overall accuracy (Acc) 82%, sensitivity (Sen) 38%, specificity (Spe) 97%, positive predictive value (PPV) 79% and negative predictive value (NPV) 82%; ceCT had an overall Acc 86%, Sen 64%, Spe 93%, PPV 75% and NPV 89%. In the prospective cohort (46 patients, age 59 ± 9), 2-[18F] FDG PET had an overall Acc 87%, Sen 48%, Spe 98%, PPV 84% and NPV 88%; ceCT had an overall Acc 89%, Sen 66%, Spe 95%, PPV 77% and NPV 91%. No significant difference was demonstrated between the two imaging modalities (p > 0.05). High false-negative rates were observed in the right subdiaphragmatic space, omentum, bowel mesentery and serosa. High omental metabolic uptake after NACT was associated with histological non-responders (p < 0.05). 2-[18F]FDG PET/CT had no additional value over ceCT with comparable diagnostic accuracy in detecting disease after NACT in advanced OC. 2-[18F]FDG PET/CT is not superior to contrast-enhanced CT in determining disease after neoadjuvant chemotherapy in advanced ovarian cancer; contrast-enhanced CT should be suffice for surgical planning before interval debulking surgery. • Additional value of 2-[18F]FDG PET/CT over contrast-enhanced CT is undefined in detecting disease after neoadjuvant chemotherapy. • 2-[18F]FDG PET/CT has comparable diagnostic accuracy compared to contrast-enhanced CT. • Contrast-enhanced CT will be suffice for surgical planning after neoadjuvant chemotherapy.

Oncological outcomes of intraperitoneal chemotherapy in advanced ovarian cancer: BRCA mutation role

IntroductionThe knowledge of BRCA status offers a chance to evaluate the role of the intraperitoneal route in patients selected by biomolecular profiles after primary cytoreduction surgery in advanced ovarian cancer. Materials and methodsWe performed a retrospective, multicenter study to assess oncological outcomes depending on adjuvant treatment (intraperitoneal [IP] vs intravenous [IV]) and BRCA status (BRCA1/2 mutated vs. BRCA wild type [WT]). The primary endpoint was to determine progression-free survival. The secondary objectives were overall survival and toxicity. ResultsA total of 288 women from eight centers were included: 177 in the IP arm and 111 in the IV arm, grouped into four arms according to BRCA1/2 status. Significantly better PFS was observed in BRCA1/2-mutated patients with IP chemotherapy (HR: 0.35; 95% CI, 0.16–0.75, p = 0.007), which was not present in BRCA1/2-mutated patients with IV chemotherapy (HR: 0.65; 95% CI, 0.37–1.12, p = 0.14). Significantly better OS was also observed in IP chemotherapy (HR: 0.17; 95% CI, 0.06–043, p < 0.0001), but was not present in IV chemotherapy in relation with BRCA mutation (HR: 0.52; 95% CI, 0.22–1.27, p = 0.15). For BRCA WT patients, worse survival was observed regardless of the adjuvant route used. The IP route was more toxic compared to the IV route, but toxicity was equivalent at the long-term follow-up. ConclusionThis retrospective study suggests that BRCA status can help to offer an individualized, systematic treatment after optimal primary surgery for advanced ovarian cancer, but is limited by the small sample size. Prospective trials are essential to confirm these results.

Abstract A062: Untargeted analysis of plasma tumor fraction is an independent prognostic marker of response to front line chemotherapy in high-grade serous epithelial ovarian cancer: the MITO-16A/MANGO-OV2A clinical trial experience

Abstract Background: Although 80% of high grade serous ovarian cancer (HGSOC) patients are initially responsive to platinum (Pt)-based chemotherapy, the majority of them experience relapse with a progressive Pt-resistant disease. One of the most challenging issues that hampers the possibility to effectively treat relapsed disease is the lack of biological information about tumor recurrence. To date, the Pt-free interval (PFI), an empirical measure of the time lagging between the end of front-line chemotherapy and relapse, is the only and widely accepted parameter to predict patient outcome and sensitivity to Pt second-line chemotherapy. We have previously demonstrated that analysis of circulating tumor DNA (ctDNA) by low pass whole genome sequencing (sWGS) is a suitable tool to predict patient outcome and to intercept early signs of relapsed disease (Paracchini et al. PMID:33323403). In the present study, we quantified the percentage of tumor fraction (TF) in plasma of patients enrolled within the frame of a phase III clinical trial (MITO-16A/MaNGO-OV2A-EUDRACT number: NCT01706120) to demonstrate, at baseline, the prognostic value of untargeted ctDNA analysis. Methods: 172 eligible patients enrolled with the frame of the MITO-16A/MaNGO-OV2A clinical trial, for whom plasma sample was collected at baseline before chemotherapy, were selected for the study. For each plasma sample, circulating-free DNA (cfDNA) was purified and whole genome libraries (HyperPlus, Roche) sequenced (mean coverage 0.5X). ichorCN algorithm was used to infer the percentage of TF, as previously published (Paracchini et al. PMID:33323403). Results: In 168 out of 172 plasma samples analyzed, the TF was detectable, and it ranged from 2.4% to 47%. Cox-model univariate analysis with patients’ overall survival (OS) and Progression-Free Survival (PFS), indicate association of TF levels with both OS and PFS (p&amp;lt;0.001). The prognostic relevance of TF was also confirmed in multivariate analysis, where, considering CA-125, residual tumor, stage of disease, histology and age as co-variables, TF maintained its statistical significance in PFS (HR = 2.1, CI 95%, p-value &amp;lt; 0.003). Conclusion: Retrospective analysis of baseline plasma samples collected within the frame of the MITO-16A/MaNGO-OVtrialnical trial, demonstrated that the percentage of TF is an independent prognostic marker of relapse. This finding confirms the importance of liquid biopsy analysis based on untargeted sWGS tool as an innovative approach to predict response to front line therapy and patient’s outcome. Citation Format: Sergio Marchini, Lara Paracchini, Laura Arenare, Giovanni Scambia, Carmela Pisano, Riccardo Zadro, Laura Mannarino, Annamaria Ferrero, Paolo Chiodini, Daniela Califano, Piergiacomo Di Gennaro, Sandro Pignata, Maurizio D'Incalci. Untargeted analysis of plasma tumor fraction is an independent prognostic marker of response to front line chemotherapy in high-grade serous epithelial ovarian cancer: the MITO-16A/MANGO-OV2A clinical trial experience [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A062.

Abstract B077: Spatial patterns of immune cell states are associated with poor response to neoadjuvant chemotherapy in high-grade serous ovarian cancer

Abstract The composition and functional state of the tumor microenvironment (TME) play a crucial role in determining the response to neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSC) patients. Understanding these complex interactions is essential for patient stratification and the development of novel combination therapies. With the advent of spatial transcriptomics technologies, studying the TME in terms of not only quantitative, qualitative, but also spatial aspects have become possible. This study aimed to investigate the spatial distribution and functional states of different cell types within the HGSC TME and their association with NACT response. We utilized 10 publicly available post-NACT HGSC 10x Visium spatial transcriptomics samples comprising patients with good (n=3), partial (n=2), and poor (n=5) responses to NACT. Each spot on Visium hematoxylin and eosin (H&amp;E) slides have been manually annotated by a pathologist as tumor, mixed (both tumor and stroma morphology), stroma or other. Three zones of stroma in the tumor-stromal interface (TSI) were defined based on proximity to tumor/mixed spots (TSI1 closest to the tumor, followed by TSI2 and TSI3). Differential gene expression (DGE) analysis followed by overrepresentation analysis (ORA) was performed to characterize transcriptional pathway activity variations between tumor, TSI, and stromal spots. Notably, differential activity was observed in crucial pathways such as epithelial-mesenchymal transition, tumor necrosis factor alpha (TNF-α) signaling, and estrogen response both within spot types and across different NACT responses. Additionally, analysis of cell type distribution within the zones was conducted. UCell scores for HGSC TME cell type signatures were calculated for each spot, and cell type deconvolution was performed using the FindTransferAnchor method from the Seurat R package. Comparisons of mean UCell and deconvolution scores across spot types revealed substantial spatial variations in cell type composition, particularly for macrophages, fibroblasts, and plasma cells. Notably, these spatial distributions showed significant changes with the NACT response. For instance, macrophage scores were markedly higher in good responders and decreased with distance from the tumor. Fibroblast signatures were significantly elevated in good responders but only in proximity to the tumor, while plasma cell scores were notably elevated exclusively within tumor and mixed spots of good responders. Furthermore, selected functional properties of these cell types were examined by computing UCell scores for crucial pathways governing their biology. Collectively, our findings highlight substantial differences in TME composition depending on proximity to the tumor and NACT response. Macrophages, fibroblasts, and plasma cells exhibited the most prominent spatial patterns. These results underscore the importance of studying the TME within a spatial context to gain deeper insights into these intricate interactions, so important to the NACT response. Citation Format: Iga Niemiec, Essi Kahelin, Zhihan Liang, Erdogan P. Erkan, Anna Vähärautio, Anni Virtanen, Anniina Färkkilä. Spatial patterns of immune cell states are associated with poor response to neoadjuvant chemotherapy in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B077.

Abstract B094: A combined RAD51 and phosphorylated replication protein assay predict response to platinum chemotherapy in high-grade serous ovarian cancer

Abstract B094: A combined RAD51 and phosphorylated replication protein assay predict response to platinum chemotherapy in high-grade serous ovarian cancer

Cost-effectiveness and drug wastage of bevacizumab biosimilar with or without chemotherapy for platinum-resistant recurrent ovarian cancer

ABSTRACT Introduction The cost-effectiveness of adding bevacizumab biosimilar with or without chemotherapy (CT) and drug wastage in treating platinum-resistant recurrent ovarian cancer (PRrOC) was assessed. Methods A three-state partitioned-survival model to compare the clinical and economic outcomes in the treatment of patients with PRrOC from a Taiwan healthcare prospective, extrapolated to two years based on data obtained from the JGOG3023 clinical trial. The primary outcomes of the model were incremental cost-effectiveness ratios (ICERs). Results In the base-case scenario, using vials of bevacizumab biosimilar (Bevbiol) plus chemotherapy, the ICER was (new Taiwan dollar) NT$ 4,555,878 per QALY gained. The incremental cost savings of an incremental 2.02 QALYs were NT$ 1,605,828 if weight-based Bevbiol plus chemotherapy were used, but the ICER remained high at the willingness-to-pay (WTP) threshold. If the cost of Bevbiol were reduced to 50% per vial, adding it to CT would be cost-effective at an acceptable WTP threshold of NTD 2,994,200, with an ICER of NT$ 2,975,484. Conclusions Bevacizumab biosimilars in mg/kg dosage form with chemotherapy are still not cost-effective in Taiwan, but using weight-based dosing will reduce drug waste and save treatment costs.

Response and Clinical Outcome of Locally Advanced Epithelial Ovarian Cancer to Neoadjuvant Chemotherapy with Paclitaxel and Carboplatin

This is a single institutional study of stage 3 and 4 epithelial ovarian cancer treated with neoadjuvant chemotherapy, paclitaxel and carboplatin during 2018- 2020 and underwent interval cytoreduction and was done to evaluate the pathological response in patients treated with neoadjuvant chemotherapy (NACT) for unresectable advanced-stage ovarian cancer

STING inhibitors sensitize platinum chemotherapy in ovarian cancer by inhibiting the CGAS-STING pathway in cancer-associated fibroblasts (CAFs)

Chemotherapy resistance in ovarian cancer hampers cure rates, with cancer-associated fibroblasts (CAFs) playing a pivotal role. Despite their known impact on cancer progression and chemotherapy resistance, the specific mechanism by which CAFs regulate the tumor inflammatory environment remains unclear. This study reveals that cisplatin facilitates DNA transfer from ovarian cancer cells to CAFs, activating the CGAS-STING-IFNB1 pathway in CAFs and promoting IFNB1 release. Consequently, this reinforces cancer cell resistance to platinum drugs. High STING expression in the tumor stroma was associated with a poor prognosis, while inhibiting STING expression enhanced ovarian cancer sensitivity. Understanding the relevance of the CGAS-STING pathway in CAFs for platinum resistance suggests targeting STING as a promising combination therapy for ovarian cancer, providing potential avenues for improved treatment outcomes.

Tropomyosin1 isoforms underlie epithelial to mesenchymal plasticity, metastatic dissemination, and resistance to chemotherapy in high-grade serous ovarian cancer

Phenotypic plasticity, defined as the ability of individual cells with stable genotypes to exert different phenotypes upon exposure to specific environmental cues, represent the quintessential hallmark of the cancer cell en route from the primary lesion to distant organ sites where metastatic colonization will occur. Phenotypic plasticity is driven by a broad spectrum of epigenetic mechanisms that allow for the reversibility of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions (EMT/MET). By taking advantage of the co-existence of epithelial and quasi-mesenchymal cells within immortalized cancer cell lines, we have analyzed the role of EMT-related gene isoforms in the regulation of epithelial mesenchymal plasticity (EMP) in high grade serous ovarian cancer. When compared with colon cancer, a distinct spectrum of downstream targets characterizes quasi-mesenchymal ovarian cancer cells, likely to reflect the different modalities of metastasis formation between these two types of malignancy, i.e. hematogenous in colon and transcoelomic in ovarian cancer. Moreover, upstream RNA-binding proteins differentially expressed between epithelial and quasi-mesenchymal subpopulations of ovarian cancer cells were identified that underlie differential regulation of EMT-related isoforms. In particular, the up- and down-regulation of RBM24 and ESRP1, respectively, represent a main regulator of EMT in ovarian cancer cells. To validate the functional and clinical relevance of our approach, we selected and functionally analyzed the Tropomyosin 1 gene (TPM1), encoding for a protein that specifies the functional characteristics of individual actin filaments in contractile cells, among the ovarian-specific downstream AS targets. The low-molecular weight Tpm1.8/9 isoforms are specifically expressed in patient-derived ascites and promote invasion through activation of EMT and Wnt signaling, together with a broad spectrum of inflammation-related pathways. Moreover, Tpm1.8/9 expression confers resistance to taxane- and platinum-based chemotherapy. Small molecule inhibitors that target the Tpm1 isoforms support targeting Tpm1.8/9 as therapeutic targets for the development of future tailor-made clinical interventions.

[Antitumor effects of redox-responsive nanoparticles containing platinum（Ⅳ）in ovarian cancer].

Objectives: To explore the antitumor effects of redox-responsive nanoparticles containing platinum(Ⅳ)-NP@Pt(Ⅳ) in ovarian cancer. Methods: Redox-responsive polymer carriers were synthesized. Polymer carriers and platinum(Ⅳ)-Pt(Ⅳ) can self-assemble into NP@Pt(Ⅳ). Inductively coupled plasma mass spectrometry was performed to detect the platinum release from NP@Pt(Ⅳ) in reducing environment and the platinum content in ovarian cancer cells ES2 treated with cisplatin, Pt(Ⅳ) and NP@Pt(Ⅳ). The proliferation ability of the ovarian cancer cells were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular apoptosis was assessed by flow cytometry. Collection of primary ovarian cancer tissues from patients with primary high-grade serous ovarian cancer who were surgically treated at the Cancer Hospital of the Chinese Academy of Medical Sciences from October to December 2022. The high-grade serous ovarian cancer patient-derived xenograft (PDX) mice were intravenously injected with Cy7.5 labeled NP@Pt(Ⅳ) followed by in vivo imaging system. Mice were treated with PBS, cisplatin and NP@Pt(Ⅳ). Tumor volume and weight were measured in each group. Necrosis, apoptosis and cell proliferation of tumor tissues were detected by hematoxylin-eosin (HE) staining, TUNEL fluorescence staining and Ki-67 immunohistochemistry staining. Body weight and HE staining of heart, liver, spleen, lung and kidney of mice in each group were measured. Results: The platinum release of NP@Pt(Ⅳ) after 48 hours in reducing environment was 76.29%, which was significantly higher than that of 26.82% in non-reducing environment (P<0.001). The platinum content in ES2 cells after 4 hours and 7 hours of treatment with NP@Pt(Ⅳ) (308.59, 553.15 ng/million cells) were significantly higher than those of Pt(Ⅳ) (100.21, 180.31 ng/million cells) and cisplatin (43.36, 50.36 ng/million cells, P＜0.05). The half inhibitory concentrations of NP@Pt(Ⅳ) in ovarian cancer cells ES2, A2780, A2780DDP were 1.39, 1.42 and 4.62 μmol/L, respectively, which were lower than those of Pt(IV) (2.89, 7.27, and 16.74 μmol/L) and cisplatin (5.21, 11.85, and 71.98 μmol/L). The apoptosis rate of ES2 cells treated with NP@Pt(Ⅳ) was (33.91±3.80)%, which was significantly higher than that of Pt(Ⅳ) [(16.28±2.41)%] and cisplatin [(15.01±1.17)%, P＜0.05]. In high-grade serous ovarian cancer PDX model, targeted accumulation of Cy7.5 labeled NP@Pt(Ⅳ) at tumor tissue could be observed. After the treatment, the tumor volume of mice in NP@Pt(IV) group was (130±98) mm3, which was significantly lower than those in control group [(1 349±161) mm3, P<0.001] and cisplatin group [(715±293) mm3, P=0.026]. The tumor weight of mice in NP@Pt(IV) group was (0.17±0.09)g, which was significantly lower than those in control group [(1.55±0.11)g, P<0.001] and cisplatin group [(0.82±0.38)g, P=0.029]. The areas of tumor necrosis and apoptosis in mice treated with NP@Pt(Ⅳ) were higher than those in mice treated with cisplatin. Immunohistochemical staining revealed that there were low expressions of Ki-67 at tumor tissues of mice treated with NP@Pt(Ⅳ) compared with cisplatin. The change in body weight of mice in NP@Pt(Ⅳ) group was not significantly different from that of the control group [(18.56±2.04)g vs.(20.87±0.79)g, P=0.063]. Moreover, the major organs of the heart, liver, spleen, lung, and kidney were also normal by HE staining. Conclusion: Redox-responsive NP@Pt(Ⅳ), produced in this study can enhance the accumulation of cisplatin in ovarian cancer cells and improve the efficacy of ovarian cancer chemotherapy.