Ovarian Cancer Cases Research Articles

Menopausal status, ultrasound and biomarker tests in combination for the diagnosis of ovarian cancer in symptomatic women.

Menopausal status, ultrasound and biomarker tests in combination for the diagnosis of ovarian cancer in symptomatic women.

Inhibiting DNA methylation improves antitumor immunity in ovarian cancer

Cancer cells resist the immune response in a process known as immune editing or immune evasion. Therapies that target the immune system have revolutionized cancer treatment; however, immunotherapies have been ineffective for the majority of ovarian cancer cases. In this issue of the JCI, Chen, Xie, et al. hypothesized that hypomethylating agent (HMA) treatment would induce antitumor immunity to sensitize patients with ovarian cancer to anti-PD-1 immunotherapy. The authors performed a phase II clinical trial to test the combination of guadecitabine, a second-generation HMA, along with pembrolizumab, an immune checkpoint inhibitor of PD-1. The trial included a group of 35 patients with platinum-resistant ovarian cancer. While the clinical benefit from the combined HMA plus immune checkpoint blockade regimen was lower than hoped, the correlate analyses gave important information about which patients with ovarian cancer may be more likely to respond to immune therapy.

Gynecologic Cancers Estimates in the I.R. Iran, 2012- 2040

Background: Gynecologic cancers (GCs) are among the leading causes of morbidity and mortality in females worldwide. Estimating the cancer burden is invaluable to set up priorities for research funding allocations, cancer control policies, and prevention strategies. The International Agency for Research on Cancer (IARC) has recently released the latest estimates on the prevalence, incidence, and mortality for 36 types of cancer and all cancer sites combined in 185 countries in 2020. We aimed to report GCs estimates in the I.R. Iran from 2012 to 2040 based on the GLOBOCAN 2020.
 Methods: We obtained data on the incidence, mortality, and prevalence of GCs in the Iranian female population from the GLOBOCAN 2020 database presented by the IARC, compared the burden with the previous reports presented in 2012 and 2018, and provided the estimates for 2040. In addition, we compared the burden to that of the WHO Eastern Mediterranean Region (EMRO) and the world.
 Results: The top 3 incident GCs were ovarian, uterine, and cervical cancer, respectively. In 2020, approximately 2,000 new cases of ovarian cancer (ASR: 4.4), 1,535 new patients with uterine cancer (ASR: 3.5), and 1,056 incident cervical cancer cases (ASR: 2.3) were diagnosed in the I.R. Iran. With 1,269 cancer deaths and an age-standardized mortality rate (ASMR) of 3.0, ovarian cancer is considered to be the leading cause of death from GCs, followed by cervical cancer (644 deaths; ASMR: 1.5) and uterine cancer (537 deaths; ASMR: 1.3). Among 157,930 prevalent female cases reported in the GLOBOCAN 2020 database, 13,663 cases were categorized as GC. With a 5-year prevalence of 5,539, ovarian cancer was the most prevalent type, while uterine cancer (with 4,904 prevalent cases) and cervical cancer (with 2,948 prevalent cases) were less prevalent types.
 Conclusion: There has been a slight increase in the incidence of GCs in recent years after stable rates for a couple of decades. Therefore, primary and secondary prevention measures such as lifestyle modifications and screening programs must be prioritized.

Genetic Testing for All: Overcoming Disparities in Ovarian Cancer Genetic Testing.

Nearly 3% of the population carries genetic variants that lead to conditions that include hereditary breast and ovarian cancer and Lynch syndrome. These pathogenic variants account for approximately 20% of ovarian cancer cases, and those with germline pathogenic variants have an odds ratio between 4 and 40 for developing ovarian cancer compared with noncarriers. Given the high prevalence of genetic variants, multiple organizations, including ASCO, recommend universal genetic counseling and testing for women diagnosed with epithelial ovarian cancer. Unfortunately, most individuals with a hereditary ovarian cancer syndrome are unaware of their underlying mutation, and racial and ethnic minority individuals as well as patients of low socioeconomic status experience disproportionate rates of underrecognition, leading to late and missed diagnoses. In this article, we review the current understanding of disparities in genetic testing for people with ovarian cancer, the role of population-based genetic testing, and innovative strategies to overcome the critical inequities present in current cancer genetic medicine. Underuse and disparities related to accessing recommended genetic services are complex and multifactorial, requiring improvements in processes related to provider identification, genetic counseling and testing referral, and patient uptake/adherence. Through the expansion of remote genetic counseling, offering online strategies for genetic testing, and reaching at-risk relatives through direct relative contact cascade testing and population-based genetic testing, there are a growing number of innovations in the field of genetic medicine, many of which emphasize health equity and offer promising alternatives to the current paradigm of genetic testing.

Jinekolojik Onkoloji Pratiğimizde Risk Azaltıcı Cerrahi Yönetimi Gerektiren Genetik Değişiklikler

Kanser, fonksiyonu hücre büyümesi ve DNA’nın bütünlüğünü koruma olan genlerdeki mutasyonlar sonucu gelişir. Mutasyonlar, germ hücrelerinde(germline)(GLM) ve diğer hücrelerde (somatik)(SM) olabilir. Kanserlerin %5-10’undan germline mutasyonlar sorumludur. Erken dönemde GLM’ların tespit edilmesi; risk altındaki bireylerin belirlenmesi, takibinin yapılması ve risk azaltıcı koruyucu stratejilerin geliştirilmesi açısından önemlidir. Ayrıca son zamanlarda tümör dokusunda SM’ların tespiti, hedefe yönelik ve adjuvan tedaviyi düzenlemede rehber olmaktadır. Over ve meme kanserlerinin yaklaşık %10-30’u ailesel kümelenme göstermekle birlikte vakaların sadece %5-10’u kalıtsaldır. Özellikle, kalıtsal over kanserlerinin yaklaşık %65-85’ini DNA onarım kusurlarına neden olan BRCA1/2 genlerinde GLM’lar sonucu oluşmaktadır. BRCA1/2 genlerinde patojenik mutasyonu olan bireyler için risk azaltıcı mastektomi (RRM) meme kanseri riskini %90-95 oranında azaltırken, salpingo-ooferektomi (RRSO) ile meme ( %50), over ve fallop tüpü kanseri insidansı da ( %70-96) azalmaktadır. Ayrıca RRSO, kansere özgü genel mortaliteyi azaltmakla ve over kanserini önlemede en etkili seçenek olarak kabul edilmektedir. BRCA1/2 dışında homolog rekombinasyon yolu DNA tamirinde rol oynayan RAD51C, RAD51D ve BRIP1 genlerdeki patojenik mutasyonlar over kanserinde rol oynamaktadır. RAD51C, RAD51D ve BRIP1, genlerinin patojenik mutasyon taşıyıcılarında rehberler, RRSO’i önermektedir. Lynch sendromu (LS), kolorektal ve endometriyal kanser gelişme riskinde artış ile karakterize otozomal dominant bir hastalıktır. LS’da endometrium ve over kanseri risk artışı en fazla olan MLH1, MSH2 ve MSH6 genlerinde patojenik mutasyon taşıyıcılarında fertilitesini tamamladıktan sonra risk azaltıcı cerrahi olarak histerektomi ve RRSO önerilmektedir. Bu derlemede amacımız, jinekolojik onkoloji pratiğimizde son zamanlarda kullanımı gittikçe artan risk azaltıcı profilaktik cerrahi uygulamaları gerektiren genetik hastalıkları son rehberler eşliğinde özetlemektir.

Clinical and Histopathological Features of Ovarian Cancer in Iraq, Baghdad Between 2014-2020

Ovarian cancer is a heterogeneous disease with disparities in clinical performance and consequences. It is a cluster of numerous subtypes with diverse biological topographies that cause alterations in response to treatments, relapse rates, and endurance. This task was designed to investigate the epidemiology of the diagnosed cases of ovarian cancer from 2014 to 2020 in Baghdad. A total of 51 cases of different ovarian cancer samples were collected from Al-Elwea Maternity Hospital and Medical City Teaching Hospital, Baghdad. Clinical information including patients' age, tumor size and location, pathological grade and stage were also collected. Results revealed high incidence of OC in patients at age of ˂55 years for the rate 59%. The most common type was epithelial serous ovarian cancer by 52.9% overall, with high frequency at right ovary by 63.3%. The dominant tumor size was 5cm in malignant cases. While the most frequent tumor stage was stage IC with rate of 29.6%, and Grade 3 was the foremost one by 40.7%. Conclusion: The most common type of cancer is epithelial serous ovarian cancer that occur in patients younger than 55years and presented at early stage of disease (IC) with high tumor grade (poor differentiation) at the time of diagnosis

Nonepithelial ovarian cancer – the current clinical practice in the Nordic countries. Survey from the surgical subcommittee of the Nordic society of gynecological oncology (NSGO)

Background Nonepithelial ovarian cancer (NEOC) represents a wide variety of rare tumors. They are often diagnosed at an early stage and have a good prognosis compared to epithelial ovarian cancer. In the Nordic countries, the total annual number of patients diagnosed with ovarian cancer, Fallopian tube cancer or primary peritoneal carcinoma (hereafter ovarian cancer) was 2281 in 2014–2018, of which 3–10% were NEOC. International guidelines for diagnosis, treatment and follow-up have been developed. We present the results of a survey, aiming at clarifying current clinical practice in the Nordic countries. Material and Methods Between 09.2020 and 02.2021 a 33-question electronic survey was distributed to 22 hospitals in Finland, Sweden, Norway, Iceland and Denmark via the Nordic Society of Gynecological Oncology (NSGO) National Representatives. Data were collected in a secure web-based software platform. The questionnaire focused on demographics, diagnosis, treatment and follow-up programs. Results Twenty-one (95,4%) centers completed the survey. A total of 155 annual new NEOC cases treated in the Nordic countries were reported, corresponding to approximately 7% of all ovarian cancer cases. Most centers measured some or all of the recommended biomarkers routinely. Vaginal ultrasound and computed tomography (CT) were the preferred imaging modalities. The majority of centers conducted multidisciplinary team (MDT) meetings. The primary reported treatment was surgery. In 65% of centers, lymph node dissection was only performed in cases with suspicious lymph nodes. Surveillance was usually offered > four years. Discussion Despite, the presence of clinical European guidelines, variation in the current clinical practice amongst participating centers adhering to national guidelines was observed. Prospective clinical national research programs are sparse, and an enhanced cooperation in the Nordic countries toward development of a Nordic guideline and database is highly warranted and a prerequisite for future research, preferably in cooperation with the larger international groups.

Correlation between Early Diagnosis of Ovarian Neoplasm and Long-Term Prognosis

Ovarian cancer is the seventh most commonly diagnosed cancer in women, with the highest mortality rate among female genital cancers. Due to the nonspecific symptoms and the lack of effective screening strategies, ovarian cancer is often diagnosed in an advanced stage of the disease, with a 5-year survival rate of 25%. The efforts of specialists are aimed at identifying screening methods, with the lowest possible rates of false positive or false negative results in order to diagnose the disease at an early stage, when the 5-year survival rate is 92%. In this study we analyzed the incidence of ovarian cancer in the last five years in the Bucharest University Emergency Hospital, being registered 153 cases of ovarian cancer. The aim of this paper is to analyze the correlation between the early diagnosis of ovarian cancer and the long-term prognosis.

The Utilization of Bevacizumab in Patients with Advanced Ovarian Cancer: A Systematic Review of the Mechanisms and Effects.

Most ovarian cancer cases are diagnosed at an advanced stage (III or IV), in which a primary debulking surgery combined with adjuvant systemic chemotherapy is the standard management. Since targeted therapy is less toxic to human cells than systemic chemotherapy, it has drawn much attention and become more popular. Angiogenesis is a critical process during the proliferation of ovarian cancer cells. Currently, many studies have put emphases on anti-angiogenetic medication, such as bevacizumab, the first and most investigated angiogenesis inhibitor that can exert anti-neoplastic effects. Bevacizumab is a recombinant humanized monoclonal antibody that has been approved for first-line maintenance treatment of advanced ovarian cancer. This review is a summary of current literature about the molecular mechanisms of actions, safety, and effects of bevacizumab for use in advanced epithelial ovarian cancer. Some common side effects of bevacizumab will be also discussed. As an inhibitor of angiogenesis, bevacizumab binds to circulating vascular endothelial growth factor (VEGF) and thereby inhibits the binding of VEGF to its receptors on the surface of endothelial cells. Neutralization of VEGF prevents neovascularization and leads to apoptosis of tumor endothelial cells and a decrease in interstitial fluid pressure within the tumors, which allows greater capacity for chemotherapeutic drugs to reach specific targeted sites. Grossly, bevacizumab has demonstrated some significant therapeutic benefits in many randomized trials in combination with the standard chemotherapy for advanced epithelial ovarian cancer. Based on the available evidence, a higher dosage and a longer duration of bevacizumab appear to achieve better therapeutic effects and progression-free survival. On the other hand, patients with more severe diseases or at a higher risk of progression seem to benefit more from bevacizumab use. However, many unknown aspects of bevacizumab, including detailed mechanisms of actions, effectiveness, and safety for the treatment of ovarian cancer, warrant further investigation.

The Great Majority of Homologous Recombination Repair-Deficient Tumors Are Accounted for by Established Causes.

Background: Gene-agnostic genomic biomarkers were recently developed to identify homologous recombination deficiency (HRD) tumors that are likely to respond to treatment with PARP inhibitors. Two machine-learning algorithms that predict HRD status, CHORD, and HRDetect, utilize various HRD-associated features extracted from whole-genome sequencing (WGS) data and show high sensitivity in detecting patients with BRCA1/2 bi-allelic inactivation in all cancer types. When using only DNA mutation data for the detection of potential causes of HRD, both HRDetect and CHORD find that 30–40% of cases that have been classified as HRD are due to unknown causes. Here, we examined the impact of tumor-specific thresholds and measurement of promoter methylation of BRCA1 and RAD51C on unexplained proportions of HRD cases across various tumor types. Methods: We gathered published CHORD and HRDetect probability scores for 828 samples from breast, ovarian, and pancreatic cancer from previous studies, as well as evidence of their biallelic inactivation (by either DNA alterations or promoter methylation) in HR-related genes. ROC curve analysis evaluated the performance of each classifier in specific cancer. Tenfold nested cross-validation was used to find the optimal threshold values of HRDetect and CHORD for classifying HR-deficient samples within each cancer type. Results: With the universal threshold, HRDetect has higher sensitivity in the detection of biallelic inactivation in BRCA1/2 than CHORD and resulted in a higher proportion of unexplained cases. When promoter methylation was excluded, in ovarian carcinoma, the proportion of unexplained cases increased from 26.8 to 48.8% for HRDetect and from 14.7 to 41.2% for CHORD. A similar increase was observed in breast cancer. Applying cancer-type-specific thresholds led to similar sensitivity and specificity for both methods. The cancer-type-specific thresholds for HRDetect reduced the number of unexplained cases from 21 to 12.3% without reducing the 96% sensitivity to known events. For CHORD, unexplained cases were reduced from 10 to 9% while sensitivity increased from 85.3 to 93.9%. Conclusion: These results suggest that WGS-based HRD classifiers should be adjusted for tumor types. When applied, only ∼10% of breast, ovarian, and pancreas cancer cases are not explained by known events in our dataset.

Abstract 30: A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database

Abstract Introduction: Genetic risk variants are critical to risk prediction for invasive epithelial ovarian cancer (EOC), yet an estimated 50-55% of EOC heritability remains missing. Novel approaches to risk variant discovery are needed to detect variants that have not been uncovered by linkage analysis or genome-wide association studies (GWAS). We approach risk variant discovery using Shared Genomic Segment analysis (SGS), a novel statistical genetics method that enables risk variant discovery in extended high-risk pedigrees. Methods: The Utah Population Database (UPDB) is a population-based resource of over ten million individuals connected to the state of Utah, five million of whom are linked to a minimum of three generations of genealogy data. By linking this genealogy data with cancer data from the Utah Cancer Registry, we identified pedigrees with an excess risk of EOC. We generated germline genotyping data from cases (diagnosed 1983-2018) in a subset of these high-risk pedigrees, focusing on pedigrees well-suited for SGS (i.e., at least 3 cases separated by a total of at least 12 meioses). SGS identifies all runs of consecutive alleles that are shared identical-by-state by cases in a pedigree and determines which of these genomic segments are longer than would be expected by chance. These long segments are likely to be identical-by-descent, inherited from a common founder, and may harbor risk variants. Results: We successfully linked UPDB genealogy data to information from the Utah Cancer Registry to identify approximately 2,000 extended high-risk pedigrees with ≥5 ovarian cancer cases, an average of 7-10 meioses between pairs cases, and a statistically significant excess risk of ovarian cancer (α=0.05). We obtained biospecimens for 141 cases in 36 of the most promising pedigrees (i.e., high familial standardized incidence ratio, p-value<0.005, not attributable to known risk variants in BRCA1 or BRCA2 as observed in first-, second- or third-degree relatives of EOC cases). We genotyped 96 out of the 141 cases in these pedigrees (68%). SGS analyses to identify genomic regions that may harbor risk variants are currently underway. Conclusions: Using pedigrees identified in the UPBD, SGS has identified risk loci and novel risk variants for a number of diseases, including breast and hematologic cancers. We have identified a set of EOC high-risk pedigrees for SGS analysis and will leverage SGS to identify genomic regions that may harbor EOC risk variants. Citation Format: Mollie E. Barnard, Robert Sargent, G. Bryce Christensen, Bonita A. Mahaffey, James Albro, Elke A. Jarboe, Terence Rhodes, Nicola J. Camp, Jennifer A. Doherty. A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database [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 30.

Abstract 3223: Prospective study for the assessment of exosomes in ascitic fluid as prognostic markers in patients with advanced ovarian cancer

Abstract Background: Exosomes have been involved in tumor progression and the development of therapeutic resistances in several malignancies. These extracellular vesicles (EVs) promote angiogenesis, premetastatic niches formation and the communication between the tumor and its environment. Ovarian cancer (OC) is a highly lethal tumor that typically spreads within the abdominal cavity rather than through the blood vessels. Based on this behavior, we aimed to study the presence of exosomes in ascitic fluid of OC patients and explore their potential as predictors of tumor volume and chemoresistance. Methods: We designed an observational prospective study in advanced OC patients who underwent a diagnostic laparoscopy or cytoreductive surgery at our institution. Abdominal washings of a cohort of non-cancer patients were collected as controls. All cases provided written consent. Clinical data and tumor genomic alterations (NGS, FoundationOne CDx) were recorded. EVs pellets were collected by ultracentrifugation and profiled by NTA and western blot (WB) (EVs markers: CD9, TSG101 and ALIX; non EVs related markers: ALB and APOB). PAX8, a protein characteristically expressed in OC cells, was used as a marker of tumor EVs. EVs proteins were quantified by BCA assay; mass spectrometry profiling is ongoing. Results: 45 peritoneal fluids from 40 OC patients (median age [range] 62 [44-79] years) and 29 peritoneal washings from controls have been collected. Our cohort comprise various histological subtypes (high-grade serous, n=32 [80%]; low-grade serous, n=2 [5%]; endometrioid, n=3 [8%)]; clear cells, n=2 [5%] and mucinous, n=1 [2%]) and tumor stages (TI-II, n=5 [12%]; TIII; n=24 [60%]; TIV, n=11 [28%]). Samples were collected either from primary, n=18 (40%); interval, n=15 (33%); or relapse surgery, n=12 (27%). Pathogenic BRCA events were detected in 25% of patients. Mean concentration of exosomes (MCE) was 6.5x106 vs. 3.2x106 particles/ml (p/ml) in cases vs. controls (p<0.0005). No differences in MCE were observed regarding stages I-II vs. stages III-IV (7.1x106 vs. 6.5x106 p/ml; p=0.84), BRCA status (mutant=6.9x106 vs. wild type=6.8x106 p/ml, p=0.46) or platinum response (resistant=7.7x106 vs. sensitive=9.5x106 p/ml, p=0.14). WB analysis showed an enrichment in EVs markers from cancer patients vs. controls (>3-fold). Protein mean concentration in EVs of cancer patients vs. controls was 0.85µg/µl and 0.51µg/µl respectively (p=0.04). Proteomic characterization through mass spectrometry is ongoing and will be presented at the time of the meeting. Conclusions: Our data, although preliminary, show a higher concentration of EVs and EVs proteins in OC cases vs controls with no difference between stages or genomic backgrounds. These results lead to the notion that exosomes could be involved in OC evolution and spread regardless of tumor volume or the molecular subtype. Citation Format: Miguel Quiralte, Arantzazu Barquin, Elena Sevillano, Paloma Navarro, Monica Yagüe, Maria Barba, Juan F. Rodriguez-Moreno, Alejandra Balarezo, Héctor Peinado, Elena Izquierdo, Jesús García-Donas, Sergio Ruiz-Llorente. Prospective study for the assessment of exosomes in ascitic fluid as prognostic markers in patients with advanced ovarian 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 3223.

Abstract 3228: Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival

Abstract Background: While excess adiposity is positively associated with ovarian cancer risk, the relationship with patient prognosis remains to be fully elucidated, especially with regard to changes over time during survivorship. Methods: We assembled a retrospective cohort of tumor registry confirmed ovarian, fallopian tube, and primary peritoneal cancer cases and evaluated peri- and post-diagnosis (±30 days and up to 5 years after, respectively) body mass index (BMI) from electronic medical records (EMR) from the Vanderbilt University Medical Center. Associations with overall survival (OS) were quantified by Hazards Ratios (HRs) and corresponding 95% confidence intervals (CIs) from Cox proportional hazards regression; multivariable adjustment included age, stage, grade, histologic subtype, treatment, race, and year of diagnosis. Results: We evaluated 13,676 peri- and post-diagnosis BMI observations for 616 predominantly Caucasian (87.0%) cases; the majority had serous histology (62.5%), advanced stage (58.1% Stage III or IV), high grade (52.4% poorly or undifferentiated) disease. Compared to peri-diagnosis (median =29.0), BMI was lowest 6 months post-diagnosis (median=27.4) and then gradually increased over time among survivors. In multivariable adjusted models, each 5-unit increase in mean peri-diagnosis BMI corresponded with a nonsignificant increase (HR: 1.07, 95% CI: 0.97-1.18) while higher mean post-diagnosis BMI corresponded to a significantly decreased risk of death (HR: 0.92, 95% CI: 0.84-1.00). Adjusted models that incorporated all peri- and post-diagnosis BMI observations evaluated indicated that each 5-unit increase in BMI was associated with a 15% reduced risk of death (HR: 0.85, 95% CI: 0.77-0.94). Conclusions: Whereas lower adiposity may be beneficial in terms of risk, higher adiposity appears to benefit ovarian cancer survival. Factors including cancer cachexia, weight loss among ill patients, and weight gain among survivors may contribute to this seemingly protective association. Additional research to disentangle the influence of BMI on ovarian cancer outcomes and inform adiposity guidance for ovarian cancer survivors is needed. Citation Format: Alicia Beeghly-Fadiel, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, Marta A. Crispens. Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival [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 3228.

Abstract 736: Exploring the impact of infertility and its treatments on risk of ovarian cancer

Abstract Background: Infertility is related to both nulligravidity and endometriosis, which are both well-established risk factors for ovarian cancer. Infertility is also characterized by various underlying causes and can be treated with different types of fertility drugs. However, most studies to date have been unable to properly address these important issues when examining the infertility-ovarian cancer association due to small numbers of patients and a lack of detailed infertility and risk factor information. Methods: We pooled self-reported data from 8,324 invasive, epithelial ovarian cancer cases and 13,325 control women in eight population-based case-control studies participating in the Ovarian Cancer Association Consortium (OCAC) to study the infertility-ovarian cancer relationship. Women classified as having a history of infertility were those who had spoken to a doctor about infertility problems or those who had regular sexual intercourse without birth control for a prolonged period (usually one year) without getting pregnant. Cause of infertility as well as use of fertility drugs was examined among those who experienced infertility issues. These associations with risk of ovarian cancer were evaluated using logistic regression models and quantified using odds ratios (ORs) and 95% confidence intervals (CIs). Gravidity and endometriosis were considered in the analyses as well as potential confounding factors. Results: Overall, infertility was not associated with risk of ovarian cancer (OR=1.02, 95% CI 0.95-1.09). However, women who reported their infertility was due to problems with ovulation or menstruation showed a decreased risk (OR=0.72, 95% CI 0.52-1.01 and OR=0.62, 95% CI 0.43-0.91, respectively) whereas women who reported their infertility was due to endometriosis were at an increased risk (OR=1.54, 95% CI 1.19-1.98). Among women who reported infertility issues, use of fertility drugs was not associated with an increased risk of ovarian cancer regardless of their gravidity status (OR=0.89, 95% CI 0.76-1.05). Conclusions: The relationship between infertility and risk of ovarian cancer is complex. Although infertility does not appear to be an independent risk factor for ovarian cancer, specific causes of infertility may be differentially associated with ovarian cancer risk, which may shed light on the disease’s underlying etiology. In addition, for women experiencing infertility issues, use of fertility drugs did not show an increased risk of ovarian cancer, which may have important clinical implications. Citation Format: Alice W. Lee, Minh T. Phung, Allan Jensen, Anna H. Wu, Daniel W. Cramer, Francesmary Modugno, Holly Harris, Jennifer A. Doherty, Joellen Schildkraut, Kathryn L. Terry, Kirsten B. Moysich, Malcolm C. Pike, Marc T. Goodman, Penelope M. Webb, Susanne K. Kjaer, Celeste L. Pearce. Exploring the impact of infertility and its treatments on risk of ovarian 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 736.

Abstract 5147: The prion-like protein doppel as a seurm biomarker for epithelial ovarian cancer

Abstract Ovarian cancer has a dire prognosis with an overall 5-year survival rate of ~40%, whereas stage III and IV has a survival rate of only 3-19%. Failure to detect early contributes highly to the poor survival rate of ovarian cancer. Thus, early detection of EOCs is likely to translate into mortality benefit. Two tests used clinically to detect ovarian cancer are serum cancer antigen-125 (CA-125) and transvaginal ultrasound. Both have limitations of specificity and sensitivity. CA-125 along with other biomarkers that are in clinical trials express both in the ovaries and serum of healthy females. Thus, the specific detection among cancer-free controls versus ovarian cancer cases remains highly variable. We hypothesize to assess the Doppel (PRND gene) as a serum biomarker in the detection of epithelial ovarian cancers (EOC) at the early stages. Doppel, a prion-like protein first identified in 1996, is known to express in testis and appears to regulate male fertility. Previously, we and others reported that Doppel is a highly specific tumor endothelium marker. In this study, to validate the potential of Doppel as an EOC serum biomarker, using ELISA, we detected Doppel concentration in the sera of 76 sera samples from patients with stage and histopathology information, and in 18 normal human sera (NHS). Doppel level was significantly higher in sera of EOC patients than NHS (0.720 vs 6.653 ng/ml, p<0.0001); 72 out of 76 patients were positive for Doppel expression (cut off value was calculated as Mean+3×SEM = 1.296 ng/mL) while only 3 out of 18 cases were positive for NHS. Receiver operating characteristic (ROC) analysis showed that Doppel can differentiate EOC patients from normal individuals with AUC of 0.957, sensitivity of 90.8%, and specificity of 90%. Doppel was markedly higher in all stages of EOC than NHS (Stage I, 6.261 ng/mL; Stage II, 8.045 ng/ml; Stage III, 7.040 ng/mL; and Stage IV, 5.726 ng/ml vs NHS 0.720 ng/ml; p<0.001). Interestingly, serum Doppel level was higher among EOC of serous adenocarcinoma (7.020 ng/mL; n = 39), mucinous (10.780 ng/mL; n = 8), and endometroid (7.295 ng/mL; n = 7) than clear cell (3.114 ng/mL; n = 7) or other types (4.855 ng/mL; n = 15). Together, our study showed the potential of Doppel as a serological biomarker for EOC detection. Citation Format: Xiaojun Zhang, Bowon Kang, Mazharul Karim, Jianying Zhang, Jae Yun Song, In-San Kim, Taslim A. Al-Hilal. The prion-like protein doppel as a seurm biomarker for epithelial ovarian 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 5147.

Abstract 2306: BLU-222, an investigational, potent, and selective CDK2 inhibitor, demonstrated robust antitumor activity in CCNE1-amplified ovarian cancer models

Abstract Background: Cyclin-dependent kinases (CDK) are a class of enzymes that, along with their regulatory cyclin binding partners, drive cell cycle progression. Cell cycle dysregulation is a hallmark of cancer and targeting its genetic drivers can confer therapeutic benefits. Cyclin E1 (CCNE1) gene alterations are common in patients with ovarian cancer and can be found in ~20% of high-grade serous ovarian cancer cases, which tend to be platinum therapy resistant and therefore represent a high medical need. Cyclin E1 is the canonical binding partner of CDK2, which becomes constitutively active when CCNE1 is amplified and overexpressed. Selectively inhibiting CDK2 is an attractive therapeutic option for CCNE1-amplified tumors and may limit off-target CDK-driven toxicities. Here we report preclinical validation studies leading to the development of an orally available CDK2 inhibitor, BLU-222, for the treatment of ovarian cancer harboring a CCNE1 amplification. Methods: BLU-222 selectivity was measured by enzyme assays, cellular target engagement assays (NanoBRET), and proliferation assays in a panel of ovarian cancer cell lines. In vitro cellular potency was assessed by phospho-Rb levels. In vivo antitumor activity of BLU-222 as a single agent or in combination with carboplatin was measured in an OVCAR-3 cell line-derived xenograft (CDX) tumor model harboring a CCNE1 amplification. Results: BLU-222 demonstrated selectivity, both biochemically and in cells, with low nanomolar potency for CDK2 vs other CDK family members (CDK1, -4, -6, -7, and -9). In a panel of ovarian cancer cell lines, those with CCNE1 amplifications were highly sensitive to BLU-222. Consistent with the in vitro profiling, BLU-222 exhibited significant antitumor activity in the OVCAR-3 CDX model. While administration of single-agent carboplatin led to stasis in vivo, the combination of BLU-222 + carboplatin induced durable tumor regression even after treatment cessation. Conclusions: These data provide a strong rationale for advancing BLU-222 towards clinical development in patients with CCNE1-amplified ovarian cancer. Citation Format: Victoria Brown, Phil Ramsden, Nealia House, Richard Vargas, Jian Guo, Ruduan Wang, Riadh Lobbardi, Maxine Chen, Douglas Wilson, Joseph Kim, Neil Bifulco, Michelle Maynard, Emanuele Perola, Dean Zhang, Steve Wenglowsky, Yoon Jong Choi. BLU-222, an investigational, potent, and selective CDK2 inhibitor, demonstrated robust antitumor activity in CCNE1-amplified ovarian cancer models [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 2306.

Predictive features of borderline ovarian tumor recurrence in patients with childbearing potential undergoing conservative treatment.

Borderline ovarian tumors (BOT) represent 10-12% of ovarian cancer cases with a higher prevalence in young patients. Although reproductive outcomes are satisfactory after conservative treatment, several authors reported a higher relapse rate in patients undergoing fertility-sparing surgery compared with radical treatment. The aim of the present study was to identify predictive factors of BOT recurrence in patients with childbearing potential undergoing conservative treatment with unilateral salpingo-oophorectomy. From January 2010 to December 2020 all patients with childbearing potential undergoing conservative treatment for early-stage BOT were included in the analysis. Expert sonographers performed the ultrasounds and classified the ovarian lesion according to International Ovarian Tumor Analysis criteria. A total of 230 patients with BOT that underwent surgical treatment during the study period were analyzed. Of these, 82 patients met the inclusion criteria. Relapse was experienced in 11 cases (13.4%), one (1.2%) peritoneal surface and 10 (12.2%) recurrences on the contralateral ovary. Ovarian tumor size >50 mm (P=0.032; OR 7.317; 95% CI 0.89-60.29), multilocular cysts >10 loculi (P=0.016; OR 7.543; 95% CI 1.64-34.78), cysts with >4 papillae (P=0.025; OR 6.190; 95% CI 1.40-27.36) were statistically correlated with recurrent BOT. Overall, the present study showed that lesions with maximum diameter >50 mm (P=0.014), multilocular cysts >10 loculi (P=0.012) and cysts with >4 papillae (P=0.003) were independent predictive factors of BOT recurrence (P<0.001; correlation coefficient R=0.481) in patients with the potential to bear children undergoing conservative treatment.

Risk factors among patients with ovarian cancer attending oncology hematology center in Basrah city

Worldwide, approximately 225,500 ovarian cancers are diagnosed annually . The leading cause of gynecological cancer death (140,200 worldwide annually) is the ovarian cancer, which accounts for more deaths than all the other gynecological cancers combined. The ovarian cancer is the fourteenth commonest cancer among population in Basrah city in Iraq. Methods This is a case control study carried out in the Basrah oncology –hematology center and primary health care centers in Basrah city . The study include 103 cases of ovarian cancer and 206 control. Result we found that more than half of case of ovarian cancer aged 50 years and above. History of insulin treatment is a risk factor for ovarian cancer (OR more than one) with significant statistical association. Hysterectomy and tubal ligation are protective against ovarian cancer . Conclusion There are many risk factors of ovarian cancer some of these are modifiable while the others are not modifiable. Hysterectomy and tubal ligation considered as protective factors.

Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis.

e17597 Background: Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), there are other genes for which the cancer risk is less certain and management recommendations remain controversial, including partner and localizer of BRCA 2 (PALB2). We sought to evaluate the association between PALB2 germline pathogenic mutations and ovarian cancer in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42021281325). We searched key electronic databases to identify studies evaluating multigene panel testing in patients with ovarian cancer. Eligible trials were subjected to meta-analysis. Results: Thirty-seven studies met inclusion criteria. We found 55,137 cases of ovarian cancer with information available on germline PALB2 pathogenic variant status. Reported histological subtypes included serous adenocarcinoma (74.8%), endometroid (6.5%), clear cell (2.1%), mucinous (3.1%), and other (13.5%). Most ovarian cancers were stages III (73.5%) and IV (22.3%), followed by II (6.0%), and I (4.1%). Among ovarian cancer cases with PALB2 sequencing data available, 0.4% demonstrated a germline pathogenic variant in the PALB2 gene and the pooled odds ratio (OR) for having a PALB2 mutation was 2.31 (95% CI 0.89- 5.98). Among 94 patients with a germline PALB2 pathogenic variant, the pooled odds ratio (OR) for developing ovarian cancer was 2.85 (95% CI 1.58-5.15) relative to 33,855 patients without PALB2 mutations. Conclusions: Our meta-analysis demonstrates that the pooled OR for developing ovarian cancer with an underlying PALB2 germline pathogenic variant was 2.85 (95% CI 1.58-5.15). While this risk is lower than many of the well-established hereditary ovarian cancer genes, it does exceed the baseline population risk of 1-2%. Whether this meets the threshold to consider risk-reducing salpingo-oophorectomy is up for debate. Large population-based studies and evaluation of the combination of PALB2 mutations and cancer family history are needed to improve management recommendations for patients harboring pathogenic mutations in this gene.

Detection of early-stage ovarian cancer using a liquid biopsy test based on extracellular vesicle proteins.

e17558 Background: We have recently conducted a study to evaluate the predictive value of proteins associated with extracellular vesicles (EVs) isolated using an alternating current electrokinetic (ACE) system, for the detection of early stage (I &amp; II) ovarian cancer cases. Ovarian cancer patients, typically, have few symptoms in stages I &amp; II; the disease is often undetected until it is advanced. Currently, only 15% of cases are detected at early stages when clinical treatment outcomes are improved. Methods: We tested the feasibility of detecting the presence of early stage (I-II) ovarian cancer using protein biomarkers carried by EVs in patient blood. Using an ACE microelectrode array, EVs were purified from ovarian cancer patient plasma (N = 70; Stage I = 51, Stage II = 19) and female non-cancer donors (N = 290) and tested for the presence of cancer biomarker proteins with multiple bead-based multiplex immunoassay kits. An adaptive boosted trees machine learning algorithm with 100x cross-validation was developed to identify the most important features for differentiation between cases and controls. Results: The machine learning algorithm identified relevant biomarkers for the detection of ovarian cancer with a receiver-operator characteristic area under the curve (AUC) of 0.952 (95% CI: 0.918 – 0.985). Overall sensitivity was 72.9% at 99% specificity, rising to 84.3% at 95% specificity. When further stratified, Stage I sensitivity was 70.6% and stage II sensitivity was 78.9% at the 99% specificity level, as expected. We also separated the cases into endometroid carcinoma (N = 24) and serous carcinoma (N = 36). At the 99% specificity level, the sensitivity was 87.5% and 63.9%, respectively. Conclusions: These results suggest that it is possible to detect early-stage ovarian cancer by analyzing the EV-bound proteins isolated with the ACE technology. EVs may carry the earliest signals of cancer development and a blood-based EV-protein biomarker test can yield high sensitivity and specificity. Stable biomarker detection with small input volumes may be possible. These results require further investigation in larger datasets to validate the current observations with the potential application for general, routine screening, as well as for populations at elevated disease risk.