High-grade Serous Epithelial Ovarian Cancer Research Articles

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial

Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200mg/day for patients with bodyweight <77kg and/or platelet count <150×103/μL at baseline and 300mg/day otherwise. OS was a secondary endpoint. Totally, 265 patients were randomised to receive niraparib (n=177) or placebo (n=88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Abstract 3403: Disentangling the obesity paradox in high-grade serous epithelial ovarian cancer

Abstract Background: Previously published evidence suggests an 'obesity paradox' in epithelial ovarian cancer, where excess adiposity is linked to better survival. However, prior studies did not jointly consider skeletal muscle, a key prognostic factor in cancer. Addressing this gap, our study examines the combined effects of adiposity and muscle phenotypes on mortality in high-grade serous epithelial ovarian cancer (HGSOC), offering novel insights into the role of body composition in patient outcomes. Methods: 343 HGSOC patients from the Body Composition and Epithelial Ovarian Cancer (BComES) Cohort at Roswell Park were included in this analysis. Body composition was derived from sliceOmatic software using computed tomography images obtained prior to chemotherapy. Body composition was quantified as surface area (cm2) at L3 for intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), total adipose tissue (TAT), and skeletal muscle index (SMI). SMI&amp;lt;38.5 cm2/m2 was defined as low SMI, a proxy for sarcopenia. For each adipose depot, phenotypes were categorized as: 1) low adiposity/high SMI (optimal/referent); 2) high adiposity/high SMI; 3) high adiposity/low SMI (e.g., sarcopenic obesity); and 4) low adiposity/low SMI (e.g., cancer cachexia). Multivariable Cox models adjusted for age, tumor stage, and surgical debulking status were used to estimate Hazard Ratios (HR) and 95% Confidence Intervals (CI) representing associations of each body composition phenotype with mortality. Results: High IMAT and VAT were associated with increased mortality in patients with high SMI (HR=1.80, 95% CI: 1.18-2.74 and HR=1.96, 95% CI: 1.27-3.04, respectively) and low SMI (HR=1.65, 95% CI: 1.05-2.61 and HR=1.70, 95% CI: 1.04-2.80). High SAT and TAT were also associated with increased mortality in patients with high SMI (HR=1.74, 95% CI: 1.14-2.67 and HR=2.04, 95% CI: 1.31-3.18), but associations were shy of significance for patients with low SMI (HR=1.37, 95% CI: 0.85-2.23 and HR=1.58, 95% CI: 0.95-2.61). Lastly, low SMI and low adiposity was associated with increased mortality for VAT (HR= 1.65, 95% CI: 1.01-2.70), SAT (HR=1.88, 95% CI: 1.14-3.10), TAT (HR=1.97, 95% CI:1.19-3.26) and IMAT (HR=1.46, 95% CI: 0.85-2.53). Conclusions: In this study, we observed no support for an obesity paradox. Rather, we observed compelling evidence linking high adiposity phenotypes with striking increases in HGSOC mortality, regardless of SMI. Notably, as the cachectic phenotype was also linked to substantial increases in mortality, unwittingly assigning patients with low adiposity and low muscle to a reference group in adiposity research could falsely induce an ‘obesity paradox’. Importantly, as body composition can be modified through diet and exercise, our data establishes it as a potential therapeutic target alongside chemotherapy to improve outcomes in this deadly disease. Citation Format: Evan W. Davis, Nancy Barone, Charles Roche, Gyorgy Paragh, André Klein, Rikki Cannioto. Disentangling the obesity paradox in high-grade serous epithelial 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 3403.

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 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.

Prognostic value of HE4 in advanced-stage, high-grade serous ovarian cancer: Analysis of HE4 kinetics during NACT, predicting surgical outcome and recurrence in comparison to CA125

ObjectivesTo assess the prognostic value of human epididymis protein 4 (HE4) kinetics during and after neoadjuvant chemotherapy (NACT) cycles compared with cancer antigen 125 (CA-125), in predicting the surgical outcomes of interval debulking surgery (IDS) in patients with advanced-stage, high-grade serous ovarian cancer. MethodsThis retrospective cohort study was conducted at Severance Hospital in Seoul, South Korea and involved 123 women with high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who were diagnosed between April 2015 and July 2020. Three outcomes were considered: the chemotherapy response score (CRS) by omentum, residual disease after IDS, and recurrence. Other clinical, imaging, and biological parameters at baseline, during NACT cycles, and pre- and postoperative time were collected and analyzed. ResultsWe observed a substantial and gradual decrease in both CA-125 level (median from 1612 to 85.55 U/mL; p < 0.001) and HE4 level (514.7 to 87.7 pmol/L; p < 0.001) during NACT cycles, while pre-to-postoperative reduction was only significant for HE4 (median from 77.3 to 62.0 pmol/L (p < 0.001)). Of the total patients, 4.1% showed no response to NACT (chemoresistance) and 65.9% had a partial response. Residual disease was observed in 55 (44.7%) patients. Recurrence occurred in 90 patients (73.2%), with a median progression-free survival of 15.28 months. The percent reduction in CA-125 level– but not HE4 – during NACT was significantly associated with CRS (by omentum); the reduction in CA-125 during NACT cycles was higher when the CRS was found to be 3 and 2 (median = 96.4 [IQR = 8.3] and 93.7 [12.2] respectively) compared to score 1 (68.3 [34.1]), and the difference was statistically significant (p = 0.004). However, no significant association was observed between the percent reduction in CA-125 or HE4 levels during NACT and residual disease or recurrence. The normalization of HE4 – but not CA-125 – before surgery was predictive for surgery outcome; that is, an abnormal preop HE4 level was associated with a residual disease risk ratio of 2.72 (95% CI = 1.27–5.79). ConclusionMonitoring HE4 or CA-125 levels has low prognostic value in patients with advanced-stage, high-grade serous ovarian cancer who are treated with NACT followed by IDS. However, the preoperative level of the HE4 biomarker may be useful in identifying patients at higher risk for suboptimal cytoreductive surgery or who may require more extensive surgery. Further prospective studies are warranted to explore the prognostic utility of eventual combinations of clinical, radiological, and biological parameters, notably by using artificial intelligence-based models.

Real-world Study on the Effect of PARPi as Maintenance Therapy on Platinum Sensitivity after First- and Second-line Chemotherapy in Patients with Recurrent High-grade Serous Epithelial Ovarian Cancer.

This study investigated the effect of poly(ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy after first- and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). This study retrospectively analyzed 172 patients with rHGSOC treated at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital between January 2017 and December 2021. The 1st-PARPi group comprised patients who received a PARPi as maintenance therapy after first-line chemotherapy (n=23), and the 1st-control group comprised those who did not (n = 105). Similarly, the 2nd-PARPi group comprised patients not given a PARPi in their first-line treatment (n = 30), and the 2nd-control group comprised those who were given a PARPi (n = 89). Among the 23 patients in the 1st-PARPi group and the 105 patients in the 1st-control group, nine and 99 were platinum-sensitive, and 14 and six were platinum-resistant, respectively (hazard ratio [HR]: 14.46, P < 0.0001). Among the 30 patients in the 2nd-PARPi group and 89 patients in the 2nd-control group, 10 and 71 were platinum-sensitive, and 20 and 18 were platinumresistant, respectively (HR: 4.37, P < 0.0001). Age, stage, residual tumor, the courses of platinumbased chemotherapy, and breast cancer susceptibility gene mutations were not associated with platinum sensitivity when using a PARPi as maintenance therapy after first- and second-line chemotherapy. Patients with rHGSOC using a PARPi were more likely to be platinum-sensitive and develop platinum resistance independent of PARPi duration. Care should be taken when using a PARPi as maintenance therapy after first- and second-line chemotherapy.

Prevalence of viral DNA in high-grade serous epithelial ovarian cancer and correlation with clinical outcomes.

Currently 11 infectious agents are classified as carcinogenic but the role of infectious agents on outcomes of epithelial ovarian cancer is largely unknown. To explore the association between infectious agents and ovarian cancer, we investigated the prevalence of viral DNA in primary ovarian cancer tumors and its association with clinical outcomes. Archived tumors from 98 patients diagnosed with high-grade serous epithelial ovarian cancer were collected between 1/1/1994 and 12/31/2010. After DNA extraction, Luminex technology was utilized to identify polymerase chain reaction-amplified viral DNA for 113 specific viruses. Demographic data and disease characteristics were summarized using descriptive statistics. We used logistic regression and Cox proportional hazards model to assess associations between tumor viral status and disease outcome and between tumor viral presence and overall survival (OS), respectively. Forty-six cases (45.9%) contained at least one virus. Six highly prevalent viruses were associated with clinical outcomes and considered viruses of interest (VOI; Epstein-Barr virus 1, Merkel cell polyomavirus, human herpes virus 6b, and human papillomaviruses 4, 16, and 23). Factors independently associated with OS were presence of VOI (HR 4.11, P = 0.0001) and platinum sensitivity (HR 0.21, P<0.0001). Median OS was significantly decreased when tumors showed VOI versus not having these viruses (22 vs 44 months, P<0.0001). Women <70 year old with VOI in tumors had significantly lower median OS versus age-matched women without VOI (20 vs 57 months, P = 0.0006); however, among women ≥70 years old, there was no difference in OS by tumor virus status. The presence of a VOI was significantly associated with a lower OS. These findings may have implications for clinical management of ovarian cancer but require additional studies.

The Prognostic Value of the Circulating-Tumor DNA in High-Grade Serous Epithelial Ovarian Cancer: Experience From MITO-16a/MANGO-OV2a/ Clinical Trial

The Prognostic Value of the Circulating-Tumor DNA in High-Grade Serous Epithelial Ovarian Cancer: Experience From MITO-16a/MANGO-OV2a/ Clinical Trial

Economic impact of olaparib on maintenance treatment of patients with BRCA-mutation positive, platinum-sensitive relapsing high-grade serous epithelial ovarian cancer in Spain

ObjectiveTo estimate the economic impact of the introduction of olapa- rib in the Spanish National Health System as maintenance monotherapy in patients with BRCA-mutation positive high-grade serous ovarian cancer. Method: A budget impact model was developed from the Spanish NHS perspective and a time horizon of 5 years for four treatment lines. The model included prevalent and incident patients estimated according to Spanish epidemiological data. Patients moved between treatment lines according to the progression-free survival and overall survival curves obtained from the respective clinical trials. Only direct costs (€2017) were considered: pharmacological, administration, adverse effects and genetic tests. The robustness of the model was verified by a univariate sensitivity analysis. ResultsThe use of olaparib meant that, after 5 years, 6% fewer patients progressed to later lines compared to scenario without olaparib, remaining longer in the second line and delaying the initiation of subsequent lines. The total estimated budgetary impact ranged between € 1.6 and € 5.4 million (1-5 years). The economic impact associated to the introduction of olaparib is partially offset by the lower cost of chemotherapy, related adverse events, and palliative care in patients with olaparib than in patients without it. ConclusionsOlaparib as maintenance treatment in patients with BR- CA-mutation positive high-grade serous ovarian cancer increases progression-free survival and delays the use of subsequent chemotherapy, with an budgetary impact for the Spanish National Health System of 5.4 million euros after 5 years.

High serum levels of inflammatory markers are associated with early recurrence in patients with high-grade serous ovarian cancer after platinum therapy

ObjectiveTo determine if inflammatory biomarkers can predict the long-term outcome of platinum therapy in patients with high-grade serous ovarian cancer. MethodsWomen diagnosed with high-grade serous epithelial ovarian cancer (n = 70) at a single institution were enrolled in a prospective serum collection study between 2005 and 2020. Seventeen markers of inflammation and oxidative stress were measured in serum samples on a chemistry analyzer. Association was tested for serum levels with progression-free survival (PFS), time to recurrence (TTR), overall survival (OS), and time to death (TTD) using Cox proportional hazards and Kaplan-Meier curves. Patient survival was censored at 10 years. ResultsHigher serum levels of LDH were associated with worse PFS (HR 2.57, p = 0.028). High serum levels of BAP (HR 0.38, p = 0.025), GSP (HR 0.40, p = 0.040), HDL-c (HR 0.27, p = 0.002), and MG (HR 0.36, p = 0.017) were associated with improved PFS. Higher expression of LDH was associated with worse OS (HR 2.16, p = 0.023). Higher levels of CK.nac (HR 0.39, p = 0.033) and HDL-c (HR 0.35, p = 0.029) were associated with improved OS. Similar outcomes were found with TTR and TTD analyses. ConclusionGeneral inflammatory biomarkers may serve as a guide for prognosis and treatment benefit. Future studies needed to further define their role in predicting prognosis or how these markers may affect response to therapy.

Recovery of the Decreased Phagocytic Function of Peripheral Monocytes and Neutrophil Granulocytes following Cytoreductive Surgery in Advanced Stage Epithelial Ovarian Cancer.

(1) Monocytes and neutrophil granulocytes are the phagocytic cells of the innate immune system, playing a crucial role in recognizing and eliminating tumor-transformed cells. Our objective was to assess the impact of advanced-stage epithelial ovarian cancer (EOC) and cytoreductive surgery on the phagocytic function of peripheral monocytes and neutrophil granulocytes. We aimed to compare the pre- and postoperative phagocytic function of these immune cells in EOC patients with healthy control women. Additionally, we aimed to examine the influence of surgery on phagocytic function by comparing pre- and postoperative samples from patients with benign gynecological tumors. (2) We examined peripheral blood samples from 20 patients with FIGO IIIC stage high-grade serous EOC and 16 patients with benign gynecological tumors as surgical controls, collected before and seven days after tumor removal surgery, and from 14 healthy women. After separation, the cells were incubated with Zymosan-A particles, and the phagocytic index (PI) was assessed using immunofluorescence microscopy. One-way ANOVA, the Kruskal-Wallis H-test, and the paired samples t-test were used for the statistical analysis of the data. A significance level of p < 0.05 was applied. (3) Peripheral monocytes and neutrophils from EOC patients exhibited significantly lower preoperative PI values compared to healthy controls (p < 0.001; p < 0.001, respectively). Following cytoreductive surgery, the PI values of immune cells in EOC patients significantly increased by the 7th postoperative day (p < 0.001; p < 0.001), reaching levels comparable to those of healthy controls (p = 0.700 and p = 0.991). In contrast, there was no significant disparity in the PI values of cells obtained from pre- and postoperative blood samples of surgical controls when compared to healthy women (monocytes: p = 0.361 and p = 0.303; neutrophils: p = 0.150 and p = 0.235). (4) EOC and/or its microenvironment may produce factors that reduce the phagocytic function of monocytes and neutrophils, and the production of these factors may be reduced or eliminated after tumor removal.

Critical Analysis of Advanced High-Grade Serous Epithelial Ovarian Cancer in Women: An Experience of 100 Cases from a Regional Cancer Center in Northeast India.

Debabrata BarmonOvarian cancer is the sixth most common cancer in women worldwide. Patients with ovarian carcinoma mostly present at an advanced stage with serous type of epithelial ovarian cancers, which is the most lethal of all pelvic malignancies. This study aims to critically analyze high-grade serous epithelial ovarian carcinomas in women from the Northeastern region of India and compare our data with Western literature to modify treatment strategies and improve survival outcomes. This hospital-based retrospective analysis involved data from the records of 100 women with high-grade epithelial ovarian cancer treated primarily with neoadjuvant chemotherapy followed by interval debulking surgery in the department of gynecologic oncology at a tertiary level regional cancer institute from January 2018 to December 2019. The demographic, clinical and pathological profile, and survival outcome were evaluated using descriptive statistics. The overall survival of the study population was calculated using Kaplan-Meier curves using SPSS software (version 24). The majority of women belonged to 41 to 55 years age group. At first presentation to the hospital, 89 and11% patients were in stage III and stage IV of disease, respectively. Clinically, 95% of women had ascites, and 18% had metastasis to lymph nodes. Distant metastasis to lungs and liver was present in 10 and 3% of cases, respectively. A substantial percentage (98%) of women had raised serum Ca125 > 1000 at baseline, ranging from 1,745 to 10,987 IU/mL. Almost two-thirds of the cases had partial-to-complete response to neoadjuvant chemotherapy (78%). In most of the women (72%), there was no residual disease at interval debulking surgery (R0), though 28% women had R1& R2 resection. The median overall survival time was 36 months. High-grade serous ovarian cancer is commonly seen in older age group, but its occurrence in younger population has also been observed. Early diagnosis is crucial in decreasing morbidity and mortality among these patients. Therefore, efforts should be made to identify risk factors for malignancy. Assessing each parameter of statistical information reflecting its own profile may be important for calculating the risk for the development of ovarian cancer, which can help in implementing preventive measures in the future.

Immune profile of primary and recurrent epithelial ovarian cancer cases indicates immune suppression, a major cause of progression and relapse of ovarian cancer

BackgroundOvarian cancer is the third most prevalent cancer in Indian women. Relative frequency of High grade serous epithelial ovarian cancer (HGSOC) and its associated deaths are highest in India which suggests the importance of understanding their immune profiles for better treatment modality. Hence, the present study investigated the NK cell receptor expression, their cognate ligands, serum cytokines, and soluble ligands in primary and recurrent HGSOC patients. We have used multicolor flow cytometry for immunophenotyping of tumor infiltrated and circulatory lymphocytes. Procartaplex, and ELISA were used to measure soluble ligands and cytokines of HGSOC patients.ResultsAmong the enrolled 51 EOC patients, 33 were primary high grade serous epithelial ovarian cancer (pEOC) and 18 were recurrent epithelial ovarian cancer (rEOC) patients. Blood samples from 46 age matched healthy controls (HC) were used for comparative analysis. Results revealed, frequency of circulatory CD56Bright NK, CD56Dim NK, NKT-like, and T cells was reduced with activating receptors while alterations in immune subsets with inhibitory receptors were observed in both groups. Study also highlights differential immune profile of primary and recurrent ovarian cancer patients. We have found increased soluble MICA which might have acted as “decoy” molecule and could be a reason of decrease in NKG2D positive subsets in both groups of patients. Furthermore, elevated level of serum cytokines IL-2, IL-5, IL-6, IL-10, and TNF-α in ovarian cancer patients, might be associated with ovarian cancer progression. Profiling of tumor infiltrated immune cells revealed the reduced level of DNAM-1 positive NK and T cells in both groups than their circulatory counterpart, which might have led to decrease in NK cell’s ability of synapse formation.ConclusionsThe study brings out differential receptor expression profile on CD56BrightNK, CD56DimNK, NKT-like, and T cells, cytokines levels and soluble ligands which may be exploited to develop alternate therapeutic approaches for HGSOC patients. Further, few differences in the circulatory immune profiles between pEOC and rEOC cases, indicates the immune signature of pEOC undergoes some changes in circulation that might facilitated the disease relapse. They also maintains some common immune signatures such as reduced expression of NKG2D, high level of MICA as well as IL-6, IL10 and TNF-α, which indicates irreversible immune suppression of ovarian cancer patients. It is also emphasized that a restoration of cytokines level, NKG2D and DNAM-1on tumor infiltrated immune cells may be targeted to develop specific therapeutic approaches for high-grade serous epithelial ovarian cancer.

Real world study on the effect of PARPi as maintenance therapy after first-line and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer.

e17574 Background: This study investigated the effect of PARPi as maintenance therapy after 1st-line and 2nd-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). Methods: 172 patients with rHGSOC at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital from Jan 2017 to Dec 2021were retrospectively analyzed. Patients who received PARPi as maintenance therapy after first-line chemotherapy were enrolled to the 1st-PARPi group (n=23), and subjects who did not receive PARPi maintenance therapy were enrolled to the 1st control group (n=105). Similarly, 2nd- PARPi group (had not use PARPi in first-line treatment n=30), 2nd-control group (n=89) were divided. To evaluate progression-free survival (PFS), the first progression to second progression (TTSP), the second progression to third progressio (TTTP), PFS between the second progression and the end of the second-line chemotherapy (PFSs), PFS between the third progression and the end of the third-line chemotherapy (PFSt) and to compare whether PARPi as maintenance therapy affects the platinum sensitivity of these patients. Results: PFSs in 1st-PARPi vs.1st-control group (median 5 vs. 11 m; p=0.0037). PFSt in 2nd-PARPi vs. 2nd-control group(median 4.5 vs. 9.0 m; p=0.0009). TTSP in 1st-PARPi vs. 1st-control group (median 11 vs. 16 m; p=0.0045). TTTP in 2nd-PARPi vs. 2nd-control group (median 10 vs. 15 m; p=0.0007). Among the 23 patients in 1st-PARPi group and 105 patients in 1st-control group, 9 and 99 patients were platinum sensitive while 14 and 6 patients were platinum resistant respectively (HR 14.46, 95% CI =4.07-51.53, P &lt; 0.0001). Among the 30 patients in 2nd-PARPi group and 89 patients in 2nd-control group, 10 and 71 patients were platinum sensitive while and 20 and 18 patients were platinum resistant respectively (HR 4.37 95% CI=1.98-9.64, P &lt; 0.0001). Age, stage, residual tumor after initial surgery treatment and the courses of platinum-based chemotherapy before PARPi,BRCA gene mutation were not the related factors affecting the platinum sensitivity of next line chemotherapy. There was no statistical difference in the effect of duration of PARPi on the platinum sensitivity of next line chemotherapy (duration of PARPi≥ 18 months vs. &lt;18 months in 1st-PARPi group, HR 0.60, 95% CI=0.18-2.04, P=0.41; duration of PARPi≥ 12 months vs. &lt;12 months in 2nd-PARPi group, HR 0.62, 95% CI=0.26-1.48, P=0.24, respectively). Conclusions: Patients with rHGSOC using PARPi affected the platinum sensitivity and were more likely to lead to platinum resistance no matter how long the during of PARPi were.This conclusion was consistent with the cross resistance between PARPi and platinum. Care should be taken when using PARPi after 1st-line and 2nd-line chemotherapy as maintenance therapy.

Correlation of cyclin E1 expression and clinical outcomes in a phase 1b dose-escalation study of azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum-resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC).

5513 Background: Azenosertib (ZN-c3) is a novel, selective, and orally bioavailable WEE1 inhibitor demonstrating single-agent antitumor activity. Azenosertib may inhibit CT-induced DNA damage repair and provide benefit in pts with platinum R/R EOC. Cyclin E1 amplification/overexpression is present in ≥35% of metastatic ovarian cancer. High expression/amplification of Cyclin E1 is a poor prognostic marker and predictive of lack of response to platinum-based CT. Ovarian models overexpressing Cyclin E1 have exquisite sensitivity to azenosertib in vitro and in vivo; forced Cyclin E1 overexpression sensitizes cell lines with low endogenous Cyclin E1 to azenosertib. Methods: This open-label, multicenter study (NCT04516447) assessed azenosertib + paclitaxel (PAC), carboplatin (Carbo), gemcitabine (GEM), or pegylated liposomal doxorubicin (PLD) in pts with metastatic high-grade serous EOC after ≤2 lines of CT including platinum CT. Primary endpoint is safety and identification of RP2D of each combination. Secondary endpoints include clinical activity. Azenosertib was given continuously or intermittently QD in 21 or 28D cycles until PD or unacceptable toxicity. Results: 103 pts were enrolled; at data cut-off, 94 were efficacy evaluable. 26.6% had a partial response (PR) and median progression free survival (PFS) = 9.03 mo (95%CI: 5.52-11.01). Azenosertib + PAC demonstrated the highest ORR [9/18 (50%)], followed by Carbo [9/27 (33.3%)]; ORR for azenosertib + PLD or + GEM was 14.3% (5/35, 2/14 respectively). 80 pts had available Cyclin E1 expression data by IHC; higher Cyclin E1 (H-score &gt;50) correlated with higher ORR and longer PFS (ORR = 31.3% vs 7.7%; PFS = 10.35 vs 3.25 mo, HR=0.3; Table). Frequent Grade ≥3 TEAEs (%) were neutropenia (44.4), thrombocytopenia (30.3), anemia (12.1), leukopenia (11.1), fatigue (10.1), diarrhea (6.1), nausea (5.1), and vomiting (5.1). Conclusions: Azenosertib + CT is well tolerated and has encouraging clinical activity, with durable responses in pts with platinum R/R EOC. Pts with Cyclin E1 overexpressing tumors, a subgroup with suboptimal benefits from CT, demonstrated significant improvements in ORR and PFS vs pts with tumors having low expression. These data support a planned trial of azenosertib + CT vs CT alone in Cyclin E1 overexpressing platinum R/R EOC. Clinical trial information: NCT04516447 . [Table: see text]

BRCA 1 and 2 somatic mutation in high grade serous epithelial ovarian cancer in Indonesian women that was operated on Dr. Soetomo General Hospital, Surabaya in 2019-2021

Link of Video Abstract: https://youtu.be/9kem7M9SNWIBackground: Ovarian cancer remains as major problem worldwide. BRCA1 and BRCA2 play a unique role in deoxyribonucleic acid (DNA) damage repair, especially in homologous recombination repair. There are no data on the prevalence of BRCA1 and BRCA2 somatic mutations in the Indonesian population. This study aimed to determine the incidence of BRCA1 and BRCA2 somatic mutations among a cohort of patients with high-grade serous epithelial ovarian cancer, and assess its correlation with clinical characteristics of the cohort. Methods: This was an analytical observational study of 26 patients admitted to our hospital from 2019 to 2021. Pathological specimens were obtained from the patients and examined for BRCA1 and BRCA2 somatic mutations. Data on clinical characteristics were collected from medical records. Statistical analysis was performed to determine the relationship between BRCA mutation status and clinical characteristics, including age, stage, menopausal status, parity, family history of malignancy, and patient outcomes. Results: Twenty-six patients with high-grade serous epithelial ovarian cancer were included in the study. Six patients (27% of 22 patients) had BRCA1 and BRCA2 somatic mutations, four did not pass the quality control test, and the remaining tested negative for these mutations. Most patients were over 50 years of age (73%). Additionally, 84% of patients were diagnosed at stage III, and only one patient had a family history of malignancy. At the end of the study, most patients (65%) had died. Statistical analysis showed no significant differences between the clinical characteristics of the groups. Conclusion: The incidence of BRCA1 and BRCA2 somatic mutations among patients with high-grade serous epithelial ovarian cancer at our hospital during 2019–2021 was 27%. There were no significant differences in the clinical characteristics of those with and without mutations, hence NGS screening following diagnosis establishment may be beneficial in further management plans.

Consensus on the management of platinum-sensitive high-grade serous epithelial ovarian cancer in Lebanon

Ovarian cancer is the most lethal gynecologic cancer. The high grade serous epithelial (HGSE) subtype is the most aggressive and it often presents at advanced stages, while screening programs have not proven beneficial. Management of the advanced stages (FIGO III and IV), which constitute the majority of diagnoses, usually consists of platinum-based chemotherapy and cytoreductive surgery (primary or interval) followed by maintenance therapy. Currently, the standard-of-care for advanced newly diagnosed HGSE ovarian cancer, as per international medical societies, starts with upfront cytoreductive surgery, followed by platinum-based chemotherapy (mostly carboplatin and paclitaxel) and/or anti-angiogenic agent bevacizumab, then maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor with/without/or bevacizumab (continued). PARP inhibitor use depends on the patient’s genetic signature, mainly the breast cancer gene (BRCA) mutation and the homologous recombination deficiency (HRD) status. Therefore, genetic testing is recommended at diagnosis to inform treatment and prognosis.In line with the evolving standard-of-care for ovarian cancer, a panel of experts in treating advanced ovarian cancer convened to lay down practical recommendations on the management of advanced ovarian cancer in Lebanon; since the currently applicable guidelines by the Lebanese Ministry of Public Health for cancer treatment have not been updated yet to reflect the treatment paradigm shift brought upon by the development and approval of PARP inhibitors. The current work reviews the leading clinical trials on PARP inhibitors (as maintenance for newly diagnosed advanced and platinum-sensitive relapsed ovarian cancer), presents international recommendations, and proposes treatment algorithms for optimal local practice.

Abstract 3189: Pre-clinical evaluation of novel folate receptor 1 directed CAR T cells for high grade serous ovarian cancer

Abstract Purpose: Treatment of ovarian cancer remains challenging. A high unmet clinical need for targeted, efficient, and persisting drugs still is a major issue for clinicians and patients diagnosed with ovarian cancer, particularly platinum-resistant and-refractory, recurrent disease. Genetically modified T cells expressing chimeric antigen receptors (CARs) have shown efficient, as well as persisting anti-tumor functionality in hematological malignancies. However, solid cancers have not yet been as efficiently treated with CAR T cells, potentially due to the lack of appropriate targets. Therefore, we thoroughly characterized FOLR1 as CAR T cell target for ovarian cancer, designed novel CAR T cells, and assessed these drug candidates preclinically in vitro and in vivo. Experimental Design: We performed ultra-high content imaging on high-grade serous epithelial ovarian cancer as well as healthy tissue samples to profile the expression of the tumor-associated antigen FOLR1. Subsequently, we designed a series of CAR T cell candidates based on different monoclonal antibodies targeting FOLR1, in order to leverage on clinical experience with these binders, particularly safety aspects. The CAR designs differed in the VL-VH orientation and the spacer domain of the CAR construct. The preclinical assessment of various FOLR1-directed CAR T cell constructs was evaluated against various ovarian cancer cell lines in vitro and in vivo. Results: In this study we show high and consistent expression of the tumor-associated antigen FOLR1 on primary ovarian cancer samples, namely high-grade serous ovarian cancer. Moreover, FOLR1 expression is low, restricted, and polarized in healthy tissues. We generated diverse FOLR1-specific CAR T cells and characterized their efficacy and specificity in vitro as well as in an ovarian cancer xenograft model. CAR T cells rapidly and efficiently eradicate xenograft tumors. This anti-tumor response is accompanied by CAR T cell expansion, FOLR1-dependent cytokine secretion, and infiltration of CAR T cells into the tumor. Conclusions: These findings demonstrate the feasibility of a preclinical CAR T cell approach targeting FOLR1 as treatment option for ovarian cancer and potentially other FOLR1-expressing tumors. Citation Format: Christoph Herbel, Julie Daigre, Manuel Martinez-Osuna, Maria Bethke, Larissa Steiner, Janina Brauner, Jens Kopatz, Paurush Praveen, Dominik Eckardt, Andreas Bosio. Pre-clinical evaluation of novel folate receptor 1 directed CAR T cells for high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3189.

CytoSaLPs score: a promising new tool for the detection and screening of extrauterine high grade serous carcinoma

BackgroundA recent theory supports that high-grade serous epithelial ovarian cancer derives from the fimbrial end of the fallopian tube and during the last decade, a few studies have examined the fallopian tube cytology. Our study aims to determine the cytomorphological characteristics of both benign and non-benign salpingeal samples, in order to establish fallopian cytology as a valuable diagnostic test for women with high risk for development of ovarian/fallopian/peritoneal cancer.MethodsOur study included patients undergoing salpingoophorectomy or total hysterectomy and salpingoophorectomy for any gynecological pathology. Using a soft brush, fallopian tube smears from the fimbrial end were collected ex vivo. The Cytologists of our Institution described the morphological characteristics of the fallopian cells by adopting a proposed Table, which had a calibration system ranging from 3 to 29. This Table is referred to as the CytoSaLPs Score. Our study compared the two diagnostic cytological methods, the one of the conventional cytology and the other using the CytoSaLPs Score, having as gold standard the tubal’s pathological findings.ResultsA total of 230 tubal specimens from 144 patients were included in this study. The Score’s mean for the benign and non-benign arm was 12.8 and 18.7 respectively. The cut-off point for both arms was 16.5. The CytoSaLPs Score tool showed significantly higher specificity (87.50% vs. 75.96, p-value < 0.001) and positive predictive value PPV (40.91% vs. 26.47%, p-value < 0.001) compared to conventional cytology. Regarding the accuracy, the Score’s superiority is highlighted (86.96% vs. 76.52%, p-value < 0.001).ConclutionsThe evaluation of tubal cytology using the CytoSaLPs Score could be used as a reliable diagnostic method. Further evaluation with larger studies is warranted.

Predicting chemoresponsiveness in epithelial ovarian cancer patients using circulating small extracellular vesicle-derived plasma gelsolin

BackgroundResistance to chemotherapy continues to be a challenge when treating epithelial ovarian cancer (EOC), contributing to low patient survival rates. While CA125, the conventional EOC biomarker, has been useful in monitoring patients’ response to therapy, there are no biomarkers used to predict treatment response prior to chemotherapy. Previous work in vitro showed that plasma gelsolin (pGSN) is highly expressed in chemoresistant EOC cell lines, where it is secreted in small extracellular vesicles (sEVs). Whether sEVs from tumour cells are secreted into the circulation of EOC patients and could be used to predict patient chemoresponsiveness is yet to be determined. This study aims to identify if sEV-pGSN in the circulation could be a predictive biomarker for chemoresistance in EOC.MethodsSandwich ELISA was used to measure pGSN concentrations from plasma samples of 96 EOC patients (primarily high grade serous EOC). sEVs were isolated using ExoQuick ULTRA and characterized using western blot, nanoparticle tracking analysis, and electron microscopy after which pGSN was measured from the sEVs. Patients were stratified as platinum sensitive or resistant groups based on first progression free interval (PFI) of 6 or 12 months.ResultsTotal circulating pGSN was significantly decreased and sEV-pGSN increased in patients with a PFI ≤ 12 months (chemoresistant) compared to those with a PFI > 12 months (chemosensitive). The ratio of total pGSN to sEV-pGSN further differentiated these groups and was a strong predictive marker for chemoresistance (sensitivity: 73.91%, specificity: 72.46%). Predetermined CA125 was not different between chemosensitive and chemoresistant groups and was not predictive of chemoresponsiveness prior to treatment. When CA125 was combined with the ratio of total pGSN/sEV-pGSN, it was a significant predictor of chemoresponsiveness, but the test performance was not as robust as the total pGSN/sEV-pGSN alone.ConclusionsTotal pGSN/sEV-pGSN was the best predictor of chemoresponsiveness prior to treatment, outperforming the individual biomarkers (CA125, total pGSN, and sEV-pGSN). This multianalyte predictor of chemoresponsiveness could help to inform physicians’ treatment and follow up plan at the time of EOC diagnosis, thus improving patients’ outcomes.