Serous Epithelial Ovarian Carcinoma Research Articles

Role of magnetic resonance imaging to differentiate between borderline and malignant serous epithelial ovarian tumors.

We aimed to differentiate serous borderline ovarian tumors (SBOT) from serous epithelial ovarian carcinomas (SEOC) using morphological and functional MRI findings, to improve the patient management. We retrospectively investigated 24 ovarian lesions diagnosed with SBOT and 64 ovarian lesions diagnosed with SEOC. Additional to the demographic and morphological findings T2W signal intensity ratio, mean apparent diffusion coefficient (ADCmean) and total apparent diffusion coefficient (ADCtotal) values were analyzed and compared between two groups. Bilaterality, pelvic free fluid presence, serum CA-125 level (U/mL), presence of pelvic peritoneal implant were in favor of SEOC. Lower maximum size of solid component and solid size to maximum size ratio, dominantly cystic and solid-cystic appearance, exophytic growth pattern, presence of papiller projection and papillary architecture and internal branching pattern, higher T2W signal intensity ratio, ADCmean and ADCtotal values were in favor of SBOT. Our study revealed that morphological and functional imaging findings were valuable in differentiating BSOT from SEOC.

Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas.

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight 'anomalous' cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first 'anomalous' non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Pelvic inflammatory disease and risk of epithelial ovarian cancer: a national population-based case-control study in Sweden

Epithelial ovarian cancer is an insidious disease, and women are often diagnosed when the disease is beyond curative treatment. Accordingly, identifying modifiable risk factors is of paramount importance. Inflammation predisposes an individual to cancer in various organs, but whether pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer has not been fully determined. This study aimed to investigate a possible association between clinically verified pelvic inflammatory disease and the risk of epithelial ovarian cancer. In this national population-based case-control study, all women in Sweden diagnosed with epithelial ovarian cancer between 1999 and 2020 and 10 controls for each were identified, matched for age and residential district. Using several Swedish nationwide registers, data on previous pelvic inflammatory disease and potential confounding factors (age, parity, educational level, and previous gynecologic surgery) were retrieved. Adjusted odds ratios and 95% confidence intervals were estimated using conditional logistic regression. Histotype-specific analyses were performed for the subgroup of women diagnosed with epithelial ovarian cancer between 2015 and 2020. Moreover, hormonal contraceptives and menopausal hormone therapy were adjusted in addition to the aforementioned confounders. This study included 15,072 women with epithelial ovarian cancer and 141,322 controls. Most women (9102 [60.4%]) had serous carcinoma. In a subgroup of cases diagnosed between 2015 and 2020, high-grade serous carcinoma (2319 [60.0%]) was identified. A total of 168 cases (1.1%) and 1270 controls (0.9%) were diagnosed with pelvic inflammatory disease. Previous pelvic inflammatory disease was associated with an increased risk of epithelial ovarian cancer (adjusted odds ratio, 1.39; 95% confidence interval, 1.17-1.66) and serous carcinoma (adjusted odds ratio, 1.46; 95% confidence interval, 1.18-1.80) for the entire study population. For the subgroup of women diagnosed in 2015-2020, pelvic inflammatory disease was associated with high-grade serous carcinoma (adjusted odds ratio, 1.43; 95% confidence interval, 1.01-2.04). The odds ratios of the other histotypes were as follows: endometrioid (adjusted odds ratio, 0.13; 95% confidence interval, 0.02-1.06), mucinous (adjusted odds ratio, 1.55; 95% confidence interval, 0.56-4.29), and clear cell carcinoma (adjusted odds ratio, 2.30; 95% confidence interval, 0.90-5.86). A dose-response relationship was observed between the number of pelvic inflammatory disease episodes and the risk of epithelial ovarian cancer (Ptrend<.001). A history of pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer and a dose-response relationship is evident. Histotype-specific analyses show an association with increased risk of serous epithelial ovarian cancer and high-grade serous carcinoma and potentially also with clear cell carcinoma, but there is no significant association with other histotypes. Infection and inflammation of the upper reproductive tract might have serious long-term consequences, including epithelial ovarian cancer.

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.

The Role of Perioperative C-Reactive Protein in Predicting the Prognosis of Epithelial Ovarian Carcinoma.

Increasing epidemiological evidence supported that chronic inflammatory factors might be involved in the carcinogenesis and progression of various cancers. The present study tried to investigate the prognostic value of perioperative C-reactive protein (CRP) in prognosis of patients with epithelial ovarian carcinoma (EOC) from a tertiary university teaching hospital. The cutoff value of CRP was calculated according to receiver operating characteristic (ROC) curve. Variables were compared using Chi-square test. Progress-free survival (PFS) and overall survival (OS) time were assessed by Kaplan-Meier (KM) survival analysis and Log rank test based on serum CRP level. Univariate and multivariate Cox regression analyses were applied for assessing the relationship between clinicopathological parameters and survival. Higher perioperative CRP levels (preoperative ≥5.15 mg/L and postoperative ≥72.45 mg/L) were significantly associated with serous tumor, high-grade, advanced stage, elevated preoperative CA125, suboptimal surgery, chemotherapy resistance, recurrence and death in EOC (P < 0.01). KM analysis suggested patients with elevated preoperative, postoperative and perioperative CRP had shorter survival (P < 0.01). Elevated perioperative CRP was an independent risk factor for PFS (HR 1.510, 95% CI 1.124-2.028; P = 0.006) and OS (HR 1.580, 95% CI 1.109-2.251; P = 0.011). Similar results were obtained for elevated preoperative CRP. Subgroup analysis further suggested that elevated perioperative CRP was also an independent risk factor for prognosis in advanced stage and serous EOC. Elevated perioperative CRP was an independent risk factor for poorer prognosis of EOC, particularly in advanced stage and serous patients.

Racial Disparities in Survival Outcomes of Patients With Serous Epithelial Ovarian Cancer: A Retrospective Cohort Analysis.

To identify racial disparities in five-year survival rates in women affected by serous epithelial ovarian carcinoma in the United States (US). This retrospective cohort study analyzed data from the 2010 to 2016 Surveillance, Epidemiology, and End Results (SEER) program database. Women with a primary malignancy of serous epithelial ovarian carcinoma, using International Classification of Diseases for Oncology (ICD-O) Topography Coding and ICD-O-3 Histology Coding, were included in this study. Race and ethnicity were combined into the following groups: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic Other (NHO), and Hispanics. Cancer-specific survival was measured at five years post-diagnosis. A comparison of baseline characteristics was assessed using Chi-squared tests. Unadjusted and adjusted Cox regression models were used to calculate hazard ratios (HR) and corresponding 95% confidence intervals (CI). From 2010 to 2016, there were 9,630 women with a primary diagnosis of serous ovarian carcinoma identified in the SEER database. A higher proportion of Asian/PI women (90.7%) were diagnosed with high-grade malignancy (poorly differentiated/undifferentiated) compared to NHW women (85.4%). NHB women (9.7%) were less likely to undergo surgery when compared to NHW women (6.7%). Hispanic women had the highest proportion of uninsured women (5.9%), while NHW and NHAPI had the lowest (2.2% each). A higher proportion of NHB (74.2%) and Asian/PI (71.3%) women presented with the distant disease compared to NHW women (70.2%). After adjustment for age, insurance, marital status, stage, metastases, and surgical resection, NHB women had the highest hazard of death within five years compared to NHW women (adjusted (adj) HR 1.22, 95% CI 1.09-1.36, p<0.001). Hispanic women also had lower five-year survival probabilities compared to NHW women (adj HR 1.21, 95% CI 1.12-1.30, p<0.001). Patients undergoing surgery had significantly increased survival probability compared to those who did not (p<0.001). As expected, women with Grade III and Grade IV disease both had significantly lower five-year survival probabilities compared to Grade I (p<0.001). This study reveals that there is an association between race and overall survival in patients with serous ovarian carcinoma, with NHB and Hispanic women having the highest hazards of death compared to NHW women. This adds to the existing body of literature as survival outcomes in Hispanic patients relative to NHW patients are not well documented. Because of the potential interplay between overall survival and several factors including race, future studies should aim to investigate other socioeconomic factors that may be impacting survival.

Immune Profile of Blood, Tissue and Peritoneal Fluid: A Comparative Study in High Grade Serous Epithelial Ovarian Cancer Patients at Interval Debulking Surgery.

High-grade serous epithelial ovarian carcinoma (HGSOC) is an immunogenic tumor with a unique tumor microenvironment (TME) that extends to the peritoneal cavity. The immunosuppressive nature of TME imposes the major challenge to develop effective treatment options for HGSOC. Interaction of immune cells in TME is an important factor. Hence, a better understanding of immune profile of TME may be required for exploring alternative treatment options. Immune profiling of peritoneal fluid (PF), tumor specimens, and blood were carried out using flowcytometry, ELISA, and Procartaplex immunoassay. The frequency of CD56BrightNK cells and expression of functional receptors were reduced in PF. Increased activating NKp46+CD56DimNK cells may indicate differential antitumor response in PF. Functional receptors on NK, NKT-like and T cells were reduced more drastically in tumor specimens. Soluble ligands MIC-B and PVR were reduced, whereas B7-H6 was increased in PF. Dissemination of tumor cells contributes to soluble ligands in PF. A differential cytokine profile was found in serum and PF as IL-2, IL-8, IL-15, IL-27, IFN-γ, and GM-CSF were elevated specifically in PF. In conclusion, the differential immune profile and correlation of soluble parameters and NK cell receptors with chemo response score may add knowledge to understand anti-tumor immune response to develop effective treatment modality.

Complex molecular profile of DNA repair genes in epithelial ovarian carcinoma patients with different sensitivity to platinum-based therapy.

Epithelial ovarian carcinoma (EOC) is known for high mortality due to diagnosis at advanced stages and frequent therapy resistance. Previous findings suggested that the DNA repair system is involved in the therapeutic response of cancer patients and DNA repair genes are promising targets for novel therapies. This study aimed to address complex inter-relations among gene expression levels, methylation profiles, and somatic mutations in DNA repair genes and EOC prognosis and therapy resistance status. We found significant associations of DUT expression with the presence of peritoneal metastases in EOC patients. The high-grade serous EOC subtype was enriched with TP53 mutations compared to other subtypes. Furthermore, somatic mutations in XPC and PRKDC were significantly associated with worse overall survival of EOC patients, and higher FAAP20 expression in platinum-resistant than platinum-sensitive patients was observed. We found higher methylation of RAD50 in platinum-resistant than in platinum-sensitive patients. Somatic mutations in BRCA1 and RAD9A were significantly associated with higher RBBP8 methylation in platinum-sensitive compared to platinum-resistant EOC patients. In conclusion, we discovered associations of several candidate genes from the DNA repair pathway with the prognosis and platinum resistance status of EOC patients, which deserve further validation as potential predictive biomarkers.

Abstract CT148: A phase 1b dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy (CT) in subjects with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer

Abstract Background: ZN-c3 is a novel, selective, and orally bioavailable WEE1 inhibitor that has demonstrated significant antitumor activity in in-vitro and in-vivo models. Combining ZN-c3 with CT may inhibit repair of CT-induced DNA damage and provide therapeutic benefit in patients with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer. Methods: This Phase 1b, open-label, multicenter study is assessing ZN-c3 plus pegylated liposomal doxorubicin (PLD), carboplatin, paclitaxel, or gemcitabine in adult women with high-grade serous epithelial ovarian, peritoneal, or fallopian tube carcinoma who have received 1-2 prior regimens/lines of therapy in the metastatic setting and are refractory or resistant to platinum-based therapy. The primary objective is to investigate the safety and tolerability of ZN-c3 in combination with chemotherapy including identification of the MTD/RP2D. Secondary endpoints include estimates of clinical activity of ZN-c3 in combination with chemotherapy. Treatment is given in repeated 21- or 28-day cycles with once-daily ZN-c3 until disease progression or unacceptable toxicity. Results: As of the cutoff date of Oct 28, 2021, based on interim data, a total of 25 subjects (all dose levels, all chemotherapy cohorts) had measurable disease at baseline and at least 1 post-baseline radiological assessment. Of those, 6/25 (24%) had a partial response (1 confirmed and 5 unconfirmed), 14/25 (56%) had stable disease (6 ongoing), and 5/25 (20%) had radiological progressive disease (80% disease control rate defined as complete response, partial response, and stable disease). In the ZN-c3 plus carboplatin cohort (cutoff date Jan 5, 2022), 4/10 (40%) had a partial response (2 confirmed and 2 unconfirmed), 4/10 (40%) had stable disease, and 2/10 (20%) had radiological progressive disease (80% disease control rate). As of the cutoff date of Oct 28, 2021, 41 subjects were evaluable for safety (i.e., received at least 1 dose of ZN-c3). Adverse events (≥20% all Grade in any treatment group) were (all Grade/≥ Grade 3) [n(%)]: nausea 22 (53.7%)/3 (7.3%), neutropenia 21 (51.2%)/14 (34.1%), thrombocytopenia 14 (34.1%)/7 (17.1%), anemia 10 (24.4%)/4 (9.8%), diarrhea 10 (24.4%)/1 (2.4%), fatigue 10 (24.4%)/1 (2.4%), vomiting 10 (24.4%)/4 (9.8%), leukopenia 8 (19.5%)/3 (7.3%), abdominal pain 7 (17.1%)/3 (7.3%), hypoalbuminemia 6 (14.6%)/1 (2.4%), alanine aminotransferase increased 5 (12.2%)/3 (7.3%), and hypomagnesemia 5 (12.2%)/1 (2.4%). The study is ongoing including combination dose-finding (NCT04516447). Conclusions: ZN-c3, combined with CT, appears to be well-tolerated and is demonstrating clinical activity in patients with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer. Citation Format: Anes Pasic, Gary Richardson, Zivko Vranjes, Tarek Meniawy, Jennifer Rodriquez, Lukas Makris, Soamnauth Misir, Philippe Pultar, Dimitris Voliotis, Siqing Fu. A phase 1b dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy (CT) in subjects with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT148.

Clinical implications of tumor-based next-generation sequencing in ovarian cancer.

5545 Background: Epithelial ovarian cancer is genetically heterogeneous, both among and within histologic subtypes. Advances in next-generation sequencing have made it feasible to ascertain the somatic genetic signature of each patient, however, critical analysis of population-level sequencing results is required to maximize the potential of this technology. Here, we aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in a large cohort of patients with high-grade epithelial ovarian cancer. Methods: Our study population comprised patients with high-grade serous (n = 972), clear cell (n = 33), endometrioid (n = 28), mucinous (n = 4), and mixed (n = 34) or unspecified (n = 21) epithelial ovarian carcinoma diagnosed between April 2013 and September 2021. tbNGS results were identified within the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected for patients who had undergone tbNGS. Progression-free survival (PFS) and overall survival (OS) were calculated from date of first treatment to date of first recurrence and date of death, respectively. Data were analyzed using descriptive statistics, univariate and multivariate Cox regression models, and clustering analyses. Results: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results identified. Nearly all (96.1%) revealed one or more genetic aberrations. Most patients (74.6%) had an actionable mutation, defined as relaying eligibility for a targeted treatment or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations; and CCNE1 amplification. Ten different targeted institutional and commercial panels were employed, covering a range of 35 to 600+ gene loci. The median time from diagnosis to testing was 14.5 months, likely corresponding to time of recurrence. Though no standalone alterations were significantly related to survival, multivariate and clustering analyses identified several genetic patterns which corresponded to patient outcomes. Mutation of BRAF, PIK3R1, NOTCH3, MET, and/or ATR was correlated with shorter PFS (HR 1.84, p = 0.001); mutation of ATM, RB1, CDKN2A, FGFR1, and/or FGFR2 was associated with improved PFS (HR 0.64, p = 0.04), as was mutation of NBN and/or ATRX (HR 0.54, p &lt; 0.05). MYC, NOTCH3, and/or CREBBP mutations were significantly correlated with worse OS (HR 1.95, p = 0.02). In our population, 40 patients (9.78%) were enrolled in genotypically-relevant clinical trials. Conclusions: tbNGS is prevalent at our institution, and often yields actionable information. We identified several mutational patterns that correlate to patient survival. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools.

Prognostic Significance of HE4 Tissue Expression in Serous Epithelial Ovarian Carcinoma.

Neerja BhatlaBackground Human Epididymis protein 4 (HE4) is expressed in ovarian cancer. Preoperative serum testing is still not widely available. This pilot study aimed to investigate the magnitude of expression of HE4 in tissue sections of serous epithelial ovarian carcinoma, its correlation with clinical outcome, and the feasibility of HE4 immunohistochemistry as a prognostic marker. Materials and Method In this ambispective study, immunohistochemistry (IHC) was used to evaluate tissue sections of ovarian serous epithelial carcinoma at primary cytoreductive surgery. On HE4 immunohistochemistry (IHC), the magnitude of HE4 expression was assessed categorically as high or low HE4 expression and semiquantitatively by the H-score, and correlated with clinical outcome in terms of survival status, progression-free survival, and overall survival. Results Of 32 cases, most ( n = 31, 96.8%) were positive for HE4 IHC. The mean age was 49 ± 8.2 years; 29 (90.6%) patients were in FIGO stage IIIC; 25 (78.9%) had ≥1cm residual disease after surgery; 31 (96.8%) received adjuvant chemotherapy, either 3-weekly ( n = 25, 81.2%) or dose-dense weekly ( n = 6, 18.8%) regimen. The majority ( n = 31, 96.8%) had a high-grade tumor, of whom 19 (59.4%) had high HE4 expression and 13(40.6%) patients had H-score in the range of 5 to 8. The mean H-score was 6.97 ± 3.61 (range 0 to 12). The overall survival of the study population at 64 months was 36.65% (95% CI: 8.59-66.34), with median overall survival of 59 months. A new scoring system was developed combining categorical HE4 expression and serum CA-125 levels; the combination of HE4 expression with postoperative CA-125 levels was found to be the best prognostic marker for overall survival ( p = 0.05). A composite score of 2 identified patients with poor progression-free survival (HR 4.64, p = 0.039) and overall survival (HR 5.45, p = 0.05). Conclusion The new composite scoring system using HE4 IHC with postoperative serum CA-125 levels offers an extremely useful option for prognosticating patients with serous epithelial ovarian carcinoma than serum CA-125 alone. This is useful where preoperative records are not available to the treating clinician.

562TiP A phase Ib dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian, peritoneal, or fallopian tube cancer

Ovarian, peritoneal, and fallopian tube cancer are deadly diseases with similar pathological and clinical features. Despite initial therapy with cytoreductive surgery and platinum-based therapy, many patients experience disease relapse either during (refractory) or within 6 months after (resistant) first-line platinum-based therapy. In these patients, various chemotherapies offer clinical activity but none is universally preferred. WEE1 tyrosine kinase is a critical component of G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of cyclin-dependent kinase 1 (CDK1). Inhibition of WEE1 leads to premature mitotic entry, DNA damage and apoptosis induction, and cell death. ZN-c3 is a novel, selective, and orally bioavailable WEE1 inhibitor that has demonstrated significant antitumor activity in nonclinical in vitro and in vivo models. A first-in-human study identified the maximum tolerated dose (MTD) of ZN-c3 when given as monotherapy. Combining ZN-c3 with chemotherapy may inhibit repair of chemotherapy-induced DNA damage and provide therapeutic benefit in this population. This phase 1b, open-label, multicenter study is evaluating the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of ZN-c3 in combination with pegylated liposomal doxorubicin, carboplatin, paclitaxel, or gemcitabine. The primary objectives are to determine MTDs and recommended phase 2 doses for each combination by a modified Bayesian continual reassessment method. Subjects are adult women with high-grade serous epithelial ovarian, peritoneal, or fallopian tube carcinoma who have received 1 or 2 prior chemotherapy regimens including platinum-based therapy and are refractory or resistant to platinum-based therapy. Study drug therapy is given in repeated 21- or 28-day cycles until disease progression or unacceptable toxicity. ZN-c3 is taken orally once daily. Chemotherapy is administered per protocol. Pharmacodynamic effects of therapy in tumor tissue and hair follicle samples will be explored. Subject recruitment is ongoing. NCT04516447 Zentalis Pharmaceuticals.

Racial disparities in women with serous epithelial ovarian cancer: a Surveillance, Epidemiology, and End Results (SEER) survival analysis

<h3>Objectives:</h3> Serous epithelial ovarian carcinoma (SOC) is the most lethal form of gynecological malignancy in the United States (US), with high-grade SOC accounting for up to 80% of cancer-specific deaths. Existing literature has identified socioeconomic barriers in gynecologic malignancies. However, patterns of racial disparity have not been fully examined. This study aims to identify racial and ethnic disparities in five-year survival rates in women affected by SOC in the US. <h3>Methods:</h3> This retrospective cohort study analyzed data from the 2010-2016 Surveillance, Epidemiology, and End Results (SEER) program database. Women with a primary malignancy of serous epithelial ovarian carcinoma, using ICD-O Topography Coding and ICD-O-3 Histology coding, were included in this study. Race and ethnicity were combined into the following groups: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic Other (NHO), and Hispanics. Cancer-specific survival was measured at five years post-diagnosis. Comparison of baseline characteristics were assessed using Chi-square tests (Table 1). Unadjusted and adjusted Cox regression models were used to calculate hazard ratios (HR) and corresponding 95% confidence intervals (CI). <h3>Results:</h3> From 2010-2016, there were 9,630 women with a primary diagnosis of SOC. A higher proportion of Asian/Pacific Islander women (90.7%) were diagnosed with high grade malignancy (poorly differentiated/undifferentiated) compared to NHW women (85.4%). NHB women (9.7%) were less likely to undergo surgery when compared to NHW women (6.7%). Hispanic women had the highest proportion of uninsured women (5.9%), when compared to other racial groups. A higher proportion of NHB (74.2%) and Asian/PI (71.3%) women presented with distant disease compared to NHW women (70.2%). After adjustment for age, insurance, marital status, stage, metastases, and surgical resection, NHB women had the highest hazard of death within five years compared to NHW women (adjusted (adj) HR 1.22 95% CI 1.09-1.36, p<0.001). Additionally, Hispanic had lower five-year survival probabilities compared to NHW women (adj HR 1.21 95% CI 1.12-1.30, p<0.001). Patients undergoing surgery had significantly increased survival probability compared to those who did not (p<0.001). As expected, women with Grade III and Grade IV disease both had significantly lower five-year survival probabilities compared to Grade I (p<0.001). <h3>Conclusions:</h3> This study reveals that there are racial and ethnic disparities in five-year survival in patients with serous ovarian carcinoma, with NHB and Hispanic women having the highest hazards of death compared to NHW women. The racially and ethnically disparate outcomes of ovarian cancer are likely due to an interplay between several factors including unmeasured social determinants of health, and therefore future studies should aim to investigate other socioeconomic factors that may be impacting survival.

Racial disparities in women with triple-negative breast cancer: a 2010-2016 SEER-based survival analysis

Objectives: Serous epithelial ovarian carcinoma (SOC) is the most lethal form of gynecological malignancy in the United States (US), with high-grade SOC accounting for up to 80% of cancer-specific deaths. Existing literature has identified socioeconomic barriers in gynecologic malignancies. However, patterns of racial disparity have not been fully examined. This study aims to identify racial and ethnic disparities in five-year survival rates in women affected by SOC in the US. Methods: This retrospective cohort study analyzed data from the 2010-2016 Surveillance, Epidemiology, and End Results (SEER) program database. Women with a primary malignancy of serous epithelial ovarian carcinoma, using ICD-O Topography Coding and ICD-O-3 Histology coding, were included in this study. Race and ethnicity were combined into the following groups: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic Other (NHO), and Hispanics. Cancer-specific survival was measured at five years post-diagnosis. Comparison of baseline characteristics were assessed using Chi-square tests (Table 1). Unadjusted and adjusted Cox regression models were used to calculate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Download : Download high-res image (227KB) Download : Download full-size image Results: From 2010-2016, there were 9,630 women with a primary diagnosis of SOC. A higher proportion of Asian/Pacific Islander women (90.7%) were diagnosed with high grade malignancy (poorly differentiated/undifferentiated) compared to NHW women (85.4%). NHB women (9.7%) were less likely to undergo surgery when compared to NHW women (6.7%). Hispanic women had the highest proportion of uninsured women (5.9%), when compared to other racial groups. A higher proportion of NHB (74.2%) and Asian/PI (71.3%) women presented with distant disease compared to NHW women (70.2%). After adjustment for age, insurance, marital status, stage, metastases, and surgical resection, NHB women had the highest hazard of death within five years compared to NHW women (adjusted (adj) HR 1.22 95% CI 1.09-1.36, p Conclusions: This study reveals that there are racial and ethnic disparities in five-year survival in patients with serous ovarian carcinoma, with NHB and Hispanic women having the highest hazards of death compared to NHW women. The racially and ethnically disparate outcomes of ovarian cancer are likely due to an interplay between several factors including unmeasured social determinants of health, and therefore future studies should aim to investigate other socioeconomic factors that may be impacting survival.

Mitochondria in epithelial ovarian carcinoma exhibit abnormal phenotypes and blunted associations with biobehavioral factors

Malignant tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and mitochondria in malignant tumors remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign tissue and in high-grade epithelial ovarian carcinoma (EOC) in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n = 1435) showed that gene expression of specific mitochondrial proteins in EOC is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in tissue from 51 patients with benign ovarian masses and 128 patients with high-grade EOC revealed that compared to benign tissue, EOCs exhibit 3.3–8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P < 0.001) but similar mitochondrial DNA (mtDNA) levels (− 3.1%), documenting abnormal mitochondrial phenotypes in EOC. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r = − 0.43 to 0.47). In contrast, serous EOCs showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in EOC and warrant further research on the link between biobehavioral factors and mitochondria in cancer.

Potential Role of KRAS and BRAF in Epithelial Ovarian Cancer

KRAS and BRAF are key proto-oncogenes of MAPK/ERK pathway and are essential for cell growth and proliferation. Mutations of these oncogenes are known to have role in pathogenesis of epithelial ovarian carcinoma (EOC). However, limited studies have evaluated the role of KRAS and BRAF protein expression. Hence, this study aimed to explore their role in EOC patients, specifically to correlate KRAS and BRAF protein expression with the histological subtypes and other histopathological prognostic factors. Immunohistochemistry was performed using paraffin-embedded tumor tissue blocks of 55 untreated and histologically confirmed EOC patients and 20 benign ovarian tumors to study KRAS and BRAF protein expression. Data were analyzed using SPSS software. Cytoplasmic expression of both KRAS and BRAF was observed in EOC and benign tumors. KRAS protein expression was significantly higher in serous EOC patients than the mucinous EOC patients (P = 0.016). KRAS expression was also significantly positively correlated with the presence of lymphatic permeation (P = 0.030), while a trend toward significance was found with vascular permeation (P = 0.052). Furthermore, BRAF protein expression was significantly higher in EOC patients than in benign ovarian tumors (P = 0.027). Its expression was significantly higher in patients with moderately/poorly differentiated tumors than well-differentiated tumors (P = 0.008), and in patients having serous EOC than in mucinous EOC (P = 0.001). A trend of higher BRAF expression was also observed in patients with lymphnode metastasis (P = 0.079). KRAS and BRAF proteins have a potential role in EOCs. However, further studies in larger group of patients and follow-up for a longer period are required to identify their role in prognosis.

Ultrasound, macroscopic and histological features of serous epithelial ovarian carcinomas

We present a video showing two cases of serous epithelial ovarian carcinomas. The first video shows clinical, ultrasound, macroscopic, and histological features of a patient with high grade serous ovarian...

In Situ Localization of Human Cytomegalovirus DNA and Translated Proteins of BRCA1 and BRCA2 Genes in Histological Specimens from Patients with Serous Epithelial Ovarian Carcinoma in Baghdad Province

HCMV has been detected in various types of tumors. Besides its well-describedoncomodulation, recentlyan oncogenic properties of HMCV per se as well asits direct transforming role in infected cells have beendescribed.HCMV in serous ovarian adenocarcinoma and its relation to BRCA1and BRCA2 was scarcelystudied.The study was designed to examine cellular dysregulation mediated by the concordant protein expressionsof BRCA1 and BRCA2 tumor suppressor genes with HCMV in tissues from ovarian cancers.Eighty ovarian tissues were examined for HCMV-DNA and BRCA1 & BRCA2 genes expression. Thosesamples belonged to (40) patients diagnosed with ovarian cancer and (40) from apparently normal ovariantissues. The detection of HCMV-DNA was done by chromogenic in situ hybridization (CISH) whereas thetranslated proteins of the expressed BRCA1 & BRCA2 genes by immunohistochemistry (IHC).Positive signals of HCMV-DNA -CISH reactions in malignant serous epithelial ovarian tumors, was detectedin 45% (18 out of 40)tissues and followed by the apparently healthy ovarian control tissues (12.5%,5 outof 40 tissues). The difference of the HCMV in ovarian cancers and control was highly significant. Thetranslated proteins of the expressed BRCA1 & BRCA2 genes was detected by IHC in 60% (24 out of 40tissues) of malignant serous epithelial ovarian tumors while no signal was reported in the control tissues.The difference between the percentages of BRCA1 as well as BRCA2proteins detection in ovarian cancer &control group was statistically significant (<0.05).The significant detection of either HCMV o rBRCA1 & BRCA2 genes expression in the studied ovariancancer tissues could support a role for that virus along with these genes in ovarian carcinogenesis.

Abstract GMM-032: UNRAVELLING THE STEROID METABOLOME IN EPITHELIAL OVARIAN CANCER

Abstract INTRODUCTION: Ovarian tissue possesses the capacity for steroidogenesis from as early as seven weeks gestation. Perturbations in the steroidogenic pathways have been implicated in the development and progression of epithelial ovarian carcinoma in adulthood but the evidence has been limited. Analysis of RNA-seq data from ovarian tissue now allows the genes involved in these pathways to be studied comprehensively helping direct future investigations and highlighting possible mechanisms of the disease. METHODS: RNA-seq data from 293 serous epithelial ovarian carcinomas from The Cancer Genome Atlas were extracted and the genes involved in steroidogenesis were systematically interrogated for high and low expression. Pathway analysis was employed to confirm significant findings. Comparison was made with novel RNA-seq data from first trimester fetal ovary and healthy adult ovary. RESULTS: Genes involved in the synthesis of androgens (HSD17B1, SRD5A1, AKR1C3, AR and STS) were all significantly upregulated in the high grade serous ovarian carcinoma group when compared to normal healthy ovary (p&amp;lt;0.05). Expression of several steroidogenic genes in malignancy appeared to mimic increased fetal expression with relative quiescence noted in the healthy ovary group. CONCLUSIONS: Transcriptome analysis shows upregulated gene expression of the androgen synthesis pathway is associated with epithelial ovarian cancer. This is supported by immunohistochemistry findings in recent studies. Investigation of the androgen pathway does remain a valid opportunity for mechanistic insight into this disease and potentially diagnostic and therapeutic exploitation. Ovarian steroidogenic gene expression in the first trimester appears to correlate with neoplastic growth in serous ovarian cancer but the significance of this is uncertain. Citation Format: David N. Jeevan, Wiebke Arlt, Paul A. Foster and Sudha Sundar. UNRAVELLING THE STEROID METABOLOME IN EPITHELIAL OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-032.

Expression of zinc finger transcription factors (ZNF143 and ZNF281) in serous borderline ovarian tumors and low-grade ovarian cancers

Low-grade ovarian cancers represent up to 8% of all epithelial ovarian carcinomas (EOCs). Recent studies demonstrated that epithelial-mesenchymal transition (EMT) is crucial for the progression of EOCs. EMT plays a key role in cancer invasion, metastasis formation and chemotherapy resistance. An array of novel EMT transcription factors from the zinc finger protein family have been described recently, among them zinc finger protein 143 (ZNF143) and zinc finger protein 281 (ZNF281). The study included tissue specimens from 42 patients. Based on histopathological examination of surgical specimens, eight lesions were classified as serous borderline ovarian tumors (sBOTs) and 34 as low-grade EOCs. The proportions of the ovarian tumors that tested positively for ZNF143 and ZNF281 were 90 and 57%, respectively. No statistically significant differences were found in the expressions of ZNF143 and ZNF281 transcription factors in SBOTs and low-grade EOCs. Considering the expression patterns for ZNF143 and ZNF281 identified in this study, both sBOTs and low-grade EOCs might undergo a dynamic epithelial-mesenchymal interconversion. The lack of statistically significant differences in the expressions of the zinc finger proteins in sBOTs and low-grade serous EOCs might constitute an evidence for common origin of these two tumor types.