Serous Epithelial Ovarian Cancer Research Articles

Exploring estrogen-related mechanisms in ovarian carcinogenesis: association between bone mineral density and ovarian cancer risk in a multivariable Mendelian randomization study.

Estrogen may play a role in epithelial ovarian cancer (EOC) carcinogenesis, with effects varying by EOC histotype. Measuring women's long-term exposure to estrogen is difficult, but bone mineral density (BMD) may be a reasonable proxy of longer-term exposure. We examined this relationship by assessing the association between genetic predisposition for higher BMD and risk of EOC by histotype. We used Mendelian randomization (MR) to assess associations between genetic markers for femoral neck and lumbar spine BMD and each EOC histotype. We used multivariable MR (MVMR) to adjust for probable pleiotropic traits, including body mass index, height, menarcheal age, menopausal age, smoking, alcohol intake, and vitamin D. Univariable analyses suggested greater BMD was associated with increased risk of endometrioid EOC (per standard deviation increase; lumbar spine OR = 1.21; 95% CI 0.93,1.57, femoral neck: OR = 1.25; 0.99,1.57), but sensitivity analyses indicated that pleiotropy was likely. Adjustment using MVMR reduced the magnitude of estimates slightly (lumbar spine: OR = 1.13; 95% CI 1.00,1.28, femoral neck: OR = 1.18; 1.03,1.36). Results for lumbar spine BMD and high-grade serous EOC were also suggestive of an association (univariable MR: OR = 1.16; 95% CI 1.03,1.30; MVMR: OR = 1.06; 0.99,1.14). Our study found associations between genetic predisposition to higher BMD, a proxy for long-term estrogen exposure, and risk of developing endometroid and high-grade serous EOC cancers. These findings add to existing evidence of the relationship between estrogen and increased risk of EOC for certain histotypes.

FIGO position statement on opportunistic salpingectomy as an ovarian cancer prevention strategy.

Epithelial ovarian cancer, with the highest mortality rate among gynecologic malignancies, often goes undetected until advanced stages due to non-specific symptoms. Traditional prevention strategies such as bilateral salpingo-oophorectomy (BSO) are limited to high-risk women and induce surgical menopause, often leading to significant health concerns. Recent findings suggest that many serous epithelial ovarian cancers originate in the fallopian tubes rather than the ovaries. This has led to the hypothesis that salpingectomy, with preservation of the ovaries, may reduce the risk of ovarian cancer while avoiding the adverse effects of early menopause. Studies show that bilateral salpingectomy (BS) significantly reduces ovarian cancer incidence even in average-risk women. Bilateral salpingectomy has been demonstrated to be safe with minimal added operative time, no adverse effects on ovarian function and is also cost effective. Opportunistic salpingectomy (OS), at the time of non-gynecologic surgeries, is a promising strategy for reducing ovarian cancer risk, especially among average-risk women who have completed childbearing. It offers a safe and cost-effective alternative to traditional methods. Emerging data supports incorporating OS into standard surgical practices for benign gynecologic conditions and considering it during unrelated abdominal/pelvic surgeries after adequate patient counseling and informed consent. Further training of non-gynecologic surgeons in OS is recommended to expand its preventive benefits.

Appraisal of the causal effect of Chlamydia trachomatis infection on epithelial ovarian cancer risk: a two-sample Mendelian randomisation study.

History of Chlamydia trachomatis infection has previously been associated with epithelial ovarian cancer (EOC) in observational studies. We conducted a two-sample univariable Mendelian randomisation (MR) study to examine whether genetically predicted seropositivity to the C. trachomatis major outer membrane protein (momp) D is causally associated with EOC. MR analyses employed genetic associations derived from UK Biobank as proxies for momp D seropositivity in 25 509 EOC cases and 40 941 controls that participated in the Ovarian Cancer Association Consortium. Findings were replicated using a GWAS meta-analyses of global biobanks including the UK Biobank, FinnGen and BioBank Japan. Genetically predicted momp D seropositivity was associated with overall and high-grade serous EOC risk in inverse-variance weighted (IVW) and MR-Egger univariable MR analysis (odds ratio (OR) 1.06; 95% confidence interval (CI) 1.02-1.10, and OR 1.08; 95%CI 1.01-1.16, respectively). Replication yielded similar results for overall EOC (OR 1.11; 95%CI 1.01-1.22). This MR study supports a causative link between C. trachomatis infection and overall and high-grade serous EOC.

Aggressiveness evaluation of borderline serous ovarian tumors by analysis of Psammoma bodies present in cancer tissues using micro-FTIR spectroscopy

Borderline ovarian tumor is a type of tumor with generally low malignant potential. However, these tumors pose diagnostic challenges with benign and malignant epithelial ovarian tumors because the clinical symptoms are similar and investigation procedures for specific diagnosis are still debated. In addition, a small number of borderlines transform into high-grade serous ovarian carcinoma with a poor prognosis. Therefore, tools improving a better characterization of high-risk subtypes of borderline tumors to enable understanding of possible unfavorable evolution are essential for patients’ management. Psammoma bodies (PBs) are microcalcifications found both in serous epithelial ovarian cancer and serous borderline tumors with possible correlation with disease progressionIn this work, the chemical composition of PBs found in the tissues of borderline, high-grade and low-grade ovarian tumors was evaluated using micro-FTIR spectroscopy. Applying principal component analysis to spectral data, it was observed that among the borderline tumors analyzed (1-bl,2-bland3-bl), the PBs of3-blshowed a different chemical content from that of the PBs of the high-grade and low-grade tumors, while the PBs of1-bland2-blappeared to have similar chemical content to the PBs of high- and low-grade tumors. The discriminating wavenumbers were found to be those related to carbonate CO32− (1454, 1413 cm−1and 872 cm−1) and phosphate PO43−(1018 cm−1and 960 cm−1) present in microcalcifications. A higher ratio between peak intensities at 1413 cm−1and 1018 cm−1(I1413/I1018) was observed in the PBs of3-blcompared with those of high- and low-grade ovarian carcinoma patients, which correlates with higher CO32− content. On the other hand, the PBs of1-bland2-blshowed a CO32−level close to that of the PBs of high- and low-grade patients. Several studies on microcalcifications in breast carcinoma have reported that increased carbonate content is related to decreased tumor aggressiveness. Therefore, case bl-3 appeared to be the less aggressive. The results obtained from FTIR analysis were in agreement with histopathological tumor classification and molecular analysis for BRAFV600E. The FTIR technique could become a reliable tool for identifying borderline low- and high-risk tumors.

The up-regulation of PAK2 indicates unfavorable prognosis in patients with serous epithelial ovarian cancer and contributes to paclitaxel resistance in ovarian cancer cells

BackgroundThe main challenge in treating ovarian cancer is chemotherapy resistance. Previous studies have shown that PAK2 is highly expressed in various cancers. This research investigates whether increased PAK2 expression contributes to chemo-resistance and poor prognosis in ovarian cancer.MethodsInitially, bioinformatics analysis was used to assess the importance of PAK2 mRNA up-regulation in ovarian cancer. This was then validated using tissue microarray to confirm PAK2 protein expression and localization in clinical samples. Univariate and multivariate logistic regression analyses were carried out to identify potential risk factors for chemo-resistance in serous epithelial ovarian cancer (EOC), while multivariate Cox regression and Kaplan-Meier analysis were conducted to ascertain prognostic factors for overall survival (OS) and disease-free survival (DFS) in patients with serous EOC. In vitro experiments were conducted to verify if inhibiting PAK2 expression could increase A2780/Taxol cells’ sensitivity to paclitaxel, as shown by evaluating cell proliferation, apoptosis, transwell, and clone formation. Additionally, the interaction between PAK2, lnc-SNHG1, and miR-216b-5p was verified using RIP and luciferase reporter assays. Rescue experiments were undertaken to examine the influence of the lnc-SNHG1/miR-216b-5p/PAK2 axis on the development of paclitaxel resistance in A2780/Taxol cells.ResultsThe bioinformatics analysis indicated a notable increase in PAK2 expression in ovarian malignant tumors compared to adjacent tissues, particularly in patients with stage III-IV disease compared to those with stage I-II disease (P = 0.0056). Elevated levels of PAK2 were linked to reduced OS in ovarian cancer patients, although no significant association was observed with DFS. Immunohistochemistry findings further supported these results, showing positive PAK2 protein expression in chemo-resistant serous EOC tissues, predominantly localized in the cytoplasm, which correlated with poorer OS and DFS outcomes. In vitro experiments demonstrated that the downregulation of PAK2 in A2780/Taxol cells led to a reduction in colony formation, an increase in apoptosis, and a diminished capacity for cell invasion. Subsequent analysis confirmed that lnc-SNHG1 functions as a competitive endogenous RNA (ceRNA) by interacting with miR-216b-5p and regulating PAK2 expression. Rescue experiments demonstrated that lnc-SNHG1 induces resistance to paclitaxel in A2780/Taxol cells by modulating the miR-216b-5p/PAK2 axis.ConclusionsPAK2 shows promise as a predictor of chemotherapy resistance and poor outcomes in ovarian cancer, indicating its potential use as a treatment target to overcome this resistance.

Pathological PCI as a prognostic marker of survival after neoadjuvant chemotherapy in patients undergoing interval cytoreduction with or without HIPEC in FIGO stage IIIC high grade serous ovarian cancer.

To determine the best possible value of pathological PCI (pPCI) as a prognostic marker for survival in high-grade serous epithelial ovarian cancer patients in patients treated with neoadjuvant chemotherapy and interval cytoreductive surgery. All patients with FIGO stage IIIC high-grade serous ovarian carcinoma were included. Receiver operating curves (ROC) were used to determine the best possible score for pPCI in predicting survival. Survival curves were calculated using the Kaplan-Meier test, and factors affecting survival were compared using the log-rank test. From January 2018 to January 2024, 171 patients who underwent interval cytoreductive surgery were included. Complete cytoreduction was achieved in 88% of the patients. ROC curves determined a (pPCI) cut-off value of 8 as the best possible score for predicting survival with a sensitivity of 82% and specificity of 67% (Youden's Index = 0.60). pPCI with a cut-off value of 8 showed improved OS (p = 0.002) and DFS, (p = 0.001) in both univariate and multivariate analyses. Following interval cytoreductive surgery, despite optimal complete cytoreductive surgery, a pathological PCI of 8 is a poor prognostic indicator of survival and may serve as a surrogate clinical marker for guiding clinicians in adjuvant treatment, especially in resource-driven settings in the real world.

Impact of the Treatment-Free Interval on Health-Related Quality of Life in Patients with Early-Stage Serous Epithelial Ovarian Cancer

Background: Although the incidence of ovarian cancer is less than that of other female cancers, the morbidity and mortality associated with the disease course is high. Because treatment involves radical surgery and intense courses of chemotherapy, health-related quality of life (HRQOL) is often compromised. Most patients recur post-first-line therapy and undergo multiple rounds of chemotherapy. Thus, HRQOL is further disrupted. Objective: The aim of this study is to assess impact of the treatment-free interval on health-related quality of life in patients with early-stage serous epithelial ovarian cancer. Methods: The cross-sectional observational study was conducted in the Department of Gynecological Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. A total 38 women with histopathologically confirmed serous epithelial ovarian cancer were included in the study. Participants were divided into two groups according to their mutation status; patients with BRCA mutation were Exposed Group and those without BRCA mutation as Unexposed Group. The questionnaire was pretested, corrected and finalized. Data were collected by face-to-face interview and analyzed by appropriate computer based programmed software Statistical Package for the Social Sciences (SPSS), version 24. Results: In this study, maximum study subjects 26 (68.4%) were in >45 years age group and 12 (31.6%) were in ≤45 years age group. Mean age of the study subjects was 52.43±4.22 years and majority of the patients 29 (76.3%) were literate and 9 (23.7%) were illiterate. About 25 (65.8%) respondents had family history of breast / ovarian cancer and 11 (28.9%) had no family history of breast / ovarian cancer. Majority 20 (52.6%) respondents underwent Primary Debulking Surgery as primary treatment modality, whereas 18 (47.4%) did not receive Primary Debulking Surgery and majority respondents 21 (55.3%) received neoadjuvant chemotherapy and interval debulking surgery, whereas 19 (44.7%) ..........

The effect of tinzaparin on biomarkers in FIGO stages III-IV ovarian cancer patients undergoing neoadjuvant chemotherapy - the TABANETOC trial: study protocol for a randomized clinical multicenter trial.

Tinzaparin, a low-molecular weight heparin (LMWH), has shown anti-neoplastic properties in animal models and in in vitro studies of human cancer cell lines. The reduction of CA-125 levels during neoadjuvant chemotherapy (NACT) in patients with epithelial ovarian cancer (EOC) co-varies with the prognosis; the larger the decrease in CA-125, the better the prognosis. This study aims to evaluate the potential anti-neoplastic effects of tinzaparin by investigating changes in serum CA-125 levels in advanced EOC patients who receive NACT. This is an open randomized multicenter pilot trial. Forty patients with EOC selected to receive NACT will be randomized 1:1 to receive daily addition of tinzaparin or no tinzaparin. The processing and treatment of the patients will otherwise follow the recommendations in the Swedish National Guidelines for Ovarian Cancer. Before every cycle of chemotherapy, preoperatively, and 3 weeks after the last cycle of chemotherapy, a panel of biomarkers, including CA-125, will be measured. Inclusion criteria are women aged 18 years or older, World Health Organization performance status 0-1, histologically confirmed high-grade serous, endometrioid or clear cell EOC, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV. In addition, a CA-125 level of ≥ 250 kIE/L at diagnosis. Exclusion criteria are contraindications to LMWH, ongoing or recent treatment with unfractionated heparin, LMWH, warfarin or non-vitamin K antagonist oral anticoagulants. This study will make an important contribution to the knowledge of the anti-neoplastic effects of tinzaparin in EOC patients and may thus guide the planning of a future study on the impact of tinzaparin on survival in EOC.

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.

Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004-12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.

Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization study

Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations with survival and response to treatment in ovarian cancer study of The Cancer Genome Atlas (TCGA) were estimated controlling for chemotherapy and clinical factors. Insomnia was associated with higher risk of endometrioid EOC (OR=1.60, 95% CI 1.05-2.45) and lower risk of high-grade serous EOC (HGSOC) and clear cell EOC (OR=0.79 and 0.48, 95% CI 0.63-1.00 and 0.27-0.86, respectively). In survival analysis, insomnia was associated with shorter survival of invasive EOC (OR=1.45, 95% CI 1.13-1.87) and HGSOC (OR=1.4, 95% CI 1.04-1.89), which was attenuated after adjustment for body mass index and reproductive age. Insomnia was associated with reduced survival in TCGA HGSOC cases who received standard chemotherapy (OR=2.48, 95% CI 1.13-5.42), but was attenuated after adjustment for clinical factors. This study supports the impact of insomnia on EOC risk and survival, suggesting treatments targeting insomnia could be pivotal for prevention and improving patient survival. National Institutes of Health, National Cancer Institute. Full funding details are provided in acknowledgments.

A phase II study evaluating the effect of IMNN-001 on second-look laparoscopy (SLL) when administered in combination with bevacizumab (BEV) and neoadjuvant chemotherapy (NACT) in patients newly diagnosed with advanced epithelial ovarian cancer (EOC).

TPS5633 Background: IMNN-001, an interleukin-12 (IL-12) DNA plasmid formulated with a DNA carrier, polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, has been shown to exhibit a favorable benefit/risk ratio when administered intraperitoneally (IP), in combination with intravenous platinum-taxane chemotherapy, up to doses of 100 mg/m2 in women with advanced EOC in earlier Phase I &amp; II studies. The 201-21-202 study (NCT05739981) is a multi-center, randomized, open-label phase I/II study which hypothesizes the addition of IMNN-001 to neoadjuvant &amp; adjuvant carboplatin-paclitaxel and bevacizumab (chemo + BEV) reduces the risk of histologically documented minimal residual disease (MRD) as determined by SLL by 50%. Methods: Patients with newly diagnosed stage III and IV high grade serous EOC who are candidates for NACT will be enrolled into the trial. Initial safety lead-in will evaluate at least 6 patients randomized to the experimental arm. Upon confirmation of safety by the DSMB, a target of ~50 patients will be randomized 1:1 to receive either chemo + BEV with or without IMNN-001. Patients receive at least 4 cycles of NACT followed by interval cytoreductive surgery (ICS), and 3 additional adjuvant cycles of study treatments will be administered. BEV will be included with each cycle except cycle 1, the last cycle of NACT immediately preceding ICS, and the first cycle of adjuvant chemotherapy. In the experimental arm, IMNN-001 will be administered on C1D15 and continue weekly though the last cycle of adjuvant therapy. Following adjuvant therapy, all patients will undergo SLL with peritoneal washing and multiple biopsies. Pathologic detection of residual tumor in any biopsies or peritoneal cytology constitutes presence of MRD. All patients will receive maintenance therapy with Olaparib + BEV, IMNN-001 + BEV, or BEV alone based on their homologous recombination deficiency status and treatment randomization. Translational:All subjects will undergo biospecimen collection and organoid preparation prior to treatment, at the time of ICS and SLL for comprehensive longitudinal genomic, circulating tumor DNA, immune, and microbiome profiling. Subjects in the experimental arm will also undergo peritoneal lavage and collection of fluid and cells for assessment of the peritoneal tumor environment. Endpoints: The primary endpoint is the rate of MRD at SLL. Secondary endpoints include progression-free survival, overall survival, objective response rate, chemotherapy response score, surgical response, and serologic response. All patients will be evaluated for safety. Status: The study is actively enrolling and is in the safety lead-in portion. We plan to enlist approximately 4 sites in USA. Clinical trial information: NCT05739981 .

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].

Differentiation of Serous and Non-serous Epithelial Ovarian Cancer by Radiological Imaging

Background: Ovarian cancer has a high incidence and fatality rate, with the most prevalent type is epithelial origin. The serous subtype of epithelial cancer predominates. For therapy selection, it is important to differentiate this subtype by histopathological examination as a gold standard method. Since some patients are not eligible for a biopsy, radiological modalities such as Magnetic Resonance Imaging (MRI) are superior in discriminating tissue compared to computed tomography (CT) or ultrasound. The use of the T1 weighted imaging (T1WI) and T2WI sequences can best differentiate between a cystic and a solid lesion. The goal of this study was to use radiological examination to assist in the identification of ovarian cancer.Methods: This cross-sectional study used secondary data from histopathology and MRI results from patients with ovarian cancer. Data was gathered utilizing electronic medical records in Dr. Sardjito Hospital between January 2017 and May 2022. The following MRI characteristics are evaluated including ascites, papillary projection, solid nodule, signal intensity of solid and cystic components, size, configuration, enhancement of contrast, and bilateral of the lesion.Results: Thirty-eight subjects made up the study’s sample, and 63% of them had serous subtypes. Bilateral lesion suggested a three times greater likelihood that it was serous ovarian cancer (p 0.02; binary logistic regression). Age 50 years old and strong enhancement on contrast was also relevant for separating the serous subtype from other subtypes (enhancement p 0.02; age p 0.044). Conclusions: A bilateral lesion with a significantly enhanced pattern can be seen on the MRI of a serous subtype of epithelial ovarian cancer. The elderly are also more likely to develop this cancer.

Abstract 6739: Efficacy and toxicity of microbial mimetic mesoporous silica nanoparticles in a mouse model of ovarian cancer

Abstract Ovarian cancer is predominately left undetected and untreated until the later stages of the disease where it becomes incredibly difficult to treat. Preclinical studies demonstrate that immunotherapy can be highly effective. Our lab has been working on an immunotherapy approach to treat women with ovarian cancer that utilizes mesoporous silica nanoparticles(MSN). MSN that present pathogen-associated molecular patterns (PAMPS) are able to significantly reduce tumor burden in mouse models of serous epithelial ovarian cancer when administered by intraperitoneal injection. These microbial mimetic particles are decorated with polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA). When in the presence of antigen presenting cells, they bind to Toll-like receptors (TLR) present on the cell surface and within the endosome. To better understand mechanisms underlying their efficacy, we injected fluorescent MSN-PEI-CpG-MPLA (100 or 500 nm) or unmodified MSN into mice with advanced ovarian cancer. The particles, regardless of the presence of TLR-agonists, were rapidly internalized by myeloid cells, with trafficking almost exclusively to immune clusters located in tumor-burdened adipose tissues when administered by intraperitoneal injection. Conversely, intravenous injection of MSN-PEI-CpG-MPLA led to predominate accumulation in liver, with no particles found in tertiary lymphoid clusters 24 hours post injection. Furthermore, unlike intraperitoneal injection, intravenous injection of MSN-PEI-CpG-MPLA was without therapeutic effect. Currently we are studying MSN safety and the impact of administration route and dose on efficacy and cytotoxicity. In summary, MSN, with and without TLR agonists, are trafficked by myeloid cells to tumor-burdened fat-associated lymphoid clusters when administered by intraperitoneal injection. Intraperitoneal injection of TLR-agonist modified MSN effectively reduces tumor burden in mice with ovarian cancer. Citation Format: Lorel Y. Medina, Rita E. Serda, Benjamin Marwedel, Melanie S. Jun, Josh Adogola. Efficacy and toxicity of microbial mimetic mesoporous silica nanoparticles in a mouse model 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 6739.

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.

Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study.

To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. ClinicalTrials.gov Identifier: NCT03759600.